Use of a flavonoid compound

Abstract

The present application belongs to the technical field of new use of natural compounds, and particularly relates to a use of a flavonoid compound. The use of a flavonoid compound (naringenin) in preparation of a preparation for maintaining body stability after radiation, such as maintaining body weight, improving hematopoietic system reconstruction efficiency, reducing hair loss or discoloration, and the like. Through examples, it is known that the product prepared by using naringenin as a main raw material or an active ingredient and orally administered to mice three days before irradiation and two weeks after irradiation has an obvious positive protection effect on the health recovery of mice after high-dose radiation transplantation, especially in improving the survival rate of mice after radiation, reducing the body weight loss of mice after radiation transplantation, and reducing the hair loss and discoloration of mice.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of new uses of natural compounds, and particularly relates to a use of a flavonoid compound. BACKGROUND

[0002] Citrus is the world's largest fruit tree, with rich cultivation types and high economic value. Citrus whole plant (fruit, root, stem, leaf and flower) is rich in various secondary metabolites, including coumarin, flavonoids, volatile substances, etc. Among them, a variety of bioactive substances have been applied to the development of health food and drugs. Naringenin (5,7,4'-trihydroxy flavone) is a flavonoid widely present in fruits such as Citrus maxima (Burm) Merr., which has important effects such as anti-inflammatory, antioxidant, anticancer, spasmolysis and sedation. Naringenin has a wide source, low preparation difficulty, stable extraction and purification system, and low toxic and side effects. At present, it has been applied in clinic to a certain extent.

[0003] The circulatory system is one of the eight major systems of advanced mammals, and has important significance in maintaining the life function and relative stability of the body. The effective and stable hematopoiesis is one of the material bases for maintaining the circulatory system. The hematopoietic system is composed of hematopoietic organs and hematopoietic cells, and is the entire system for manufacturing blood in the body. The endogenous stem cell regulation mechanism disorder or strong exogenous factors (such as large doses of radiation, intake of chemotherapy drugs, etc.) can seriously affect the function of hematopoietic stem cells, and then affect the entire hematopoietic system, leading to the occurrence of blood diseases. For example, when the body receives 6-10 Gy of whole body irradiation for a short time, it can cause serious hematopoietic damage, and hematopoietic stem cell transplantation is needed to reconstruct the hematopoietic function of the body. The hematopoietic system reconstruction efficiency will greatly determine the survival rate and health status of hematopoietic defect patients. The low hematopoietic system reconstruction efficiency affects the transportation function of the circulatory system, and then affects the material exchange, information exchange and energy metabolism of cells in various systems, tissues or organs of the body; on the other hand, the hematopoietic system function defect seriously affects the efficiency of the body's immune response, and patients are prone to pathogenic infection, and severe cases can endanger life. Therefore, exploring the treatment or auxiliary method for improving hematopoietic reconstruction efficiency has a direct impact on the treatment of nuclear radiation damage and the field of blood disease treatment to improve the survival rate and quality of life of patients.

[0004] At present, there is no literature showing that the flavonoid compounds (such as naringenin) of citrus have a protective effect on the hematopoietic system of the body in radiation, or have an effect of improving the hematopoietic reconstruction efficiency of the body after hematopoietic stem cell transplantation after radiation. SUMMARY

[0005] In view of the above, the present application aims to provide a flavonoid compound in the preparation of some preparations for protecting the body during radiotherapy. In particular, the use of naringin in the preparation of a medicament for the health protection effect during the recovery period after myeloablative radiotherapy and bone marrow transplantation. To achieve the above-mentioned use, specifically by naringin to stabilize the long-term survival rate of mice after radiotherapy and bone marrow transplantation, maintain the relative stability of body weight, and inhibit the aging of hair in mice after radiotherapy and bone marrow transplantation, ultimately achieve the purpose of promoting the health recovery of mice after radiotherapy and bone marrow transplantation.

[0006] Bone marrow transplantation after radiation is a long-term, coordinated process involving multiple organs, and its effects may be manifested in the long term and in multiple tissues / organs. During the process of high-dose radiation damage, the hematopoietic system may not be the only system damaged, and epithelial tissues (skin, intestinal tract, etc.) and endothelium (blood vessels, etc.) may also be damaged to varying degrees, resulting in phenomena such as weight loss, vitality decline, and hair loss and discoloration. Generally, radiation damage can be divided into four stages: initial stage, pseudo-recovery stage, extreme stage, and recovery stage. In clinical cases, some radiation-induced damage may persist for a long time.

[0007] The research team of the applicant belongs to the Southwest Fruit Nutrition Research Institute and Southwest University, and has many years of experience in the extraction, separation, purification, and biological activity research of fruit active ingredients, and has a systematic research and discussion on fruit nutrition and human health.

[0008] The present application researches and finds that the colonization, proliferation and differentiation of hematopoietic stem cells after transplantation affect the survival of recipient mice, and the physiological condition of recipient mice can significantly regulate the hematopoietic reconstitution process, and natural small molecule compounds (such as naringin) have the development potential as natural anti-radiation compounds.

[0009] The present application aims to provide a flavonoid compound for preparing a preparation for improving the hematopoietic reconstitution efficiency of the body after hematopoietic stem cell transplantation after radiation, and the flavonoid compound is naringin.

[0010] Further, the preparation is in the form of a medicament.

[0011] Further, the medicament is in the form of an oral dosage form or an injection dosage form, the oral dosage form is in the form of a tablet, a powder, a granule, a tea, a soft capsule, an oral liquid, a pill, a paste, a liquor; and the injection dosage form is in the form of an injection liquid.

[0012] Specifically, the preparation of the medicament is an oral preparation or an injection preparation prepared by adding a pharmaceutically conventional or acceptable excipient to naringin as an active ingredient.

[0013] In some embodiments, the naringenin is administered or injected in an amount of 190-210 mg / Kg, preferably 200 mg / Kg, when assisting hematopoietic reconstruction after hematopoietic stem cell transplantation after radiation of the body.

[0014] The present application aims to provide the use of a flavonoid compound in the preparation of a preparation for improving the survival rate of the body after radiation, wherein the flavonoid compound is naringenin.

[0015] Further, the preparation is in the form of a medicine.

[0016] Further, the medicine is in the form of an oral dosage form or an injection dosage form, wherein the oral dosage form is in the form of a tablet, a powder, a granule, a tea, a capsule, a soft capsule, a liquid for oral administration, a pill, a paste, or a liquor; and the injection dosage form is in the form of an injection liquid.

[0017] Specifically, the medicine preparation is prepared by using naringenin as an active ingredient and adding pharmaceutically conventional or acceptable excipients to prepare an oral preparation or an injection preparation.

[0018] In some embodiments, the naringenin is administered or injected in an amount of 190-210 mg / Kg, preferably 200 mg / Kg, when assisting hematopoietic reconstruction after hematopoietic stem cell transplantation after radiation of the body.

[0019] The present application aims to provide the use of a flavonoid compound in the preparation of a preparation for maintaining the body weight of the body after radiation, wherein the flavonoid compound is naringenin.

[0020] Further, the preparation is in the form of a medicine.

[0021] Further, the medicine is in the form of an oral dosage form or an injection dosage form, wherein the oral dosage form is in the form of a tablet, a powder, a granule, a tea, a capsule, a soft capsule, a liquid for oral administration, a pill, a paste, or a liquor; and the injection dosage form is in the form of an injection liquid.

[0022] Specifically, the medicine preparation is prepared by using naringenin as an active ingredient and adding pharmaceutically conventional or acceptable excipients to prepare an oral preparation or an injection preparation.

[0023] In some embodiments, the naringenin is administered or injected in an amount of 190-210 mg / Kg, preferably 200 mg / Kg, when assisting hematopoietic reconstruction after hematopoietic stem cell transplantation after radiation of the body.

[0024] The present application aims to provide the use of a flavonoid compound in the preparation of a preparation for reducing hair loss of the body after radiation, wherein the flavonoid compound is naringenin.

[0025] Further, the preparation is in the form of a medicine.

[0026] Further, the medicine is in the form of oral dosage or injection dosage, wherein the oral dosage is in the form of tablet, powder, granule, tea, soft capsule, oral liquid, pill, paste, liquor, and the injection dosage is in the form of injection liquid.

[0027] Specifically, the medicine preparation is prepared by using naringenin as the active ingredient and adding pharmaceutically conventional or acceptable excipients to prepare oral preparation or injection preparation.

[0028] In some embodiments, the content of naringenin for oral administration or injection is 190-210 mg / Kg, preferably 200 mg / Kg, when the hematopoietic stem cell transplantation is used to assist the hematopoietic reconstruction after the radiation of the body.

[0029] The application aims to provide the use of a flavonoid compound in the preparation of a preparation for reducing the damage of the hematopoietic system of the body in radiation, wherein the flavonoid compound is naringenin.

[0030] Further, the preparation is in the form of medicine.

[0031] Further, the medicine is in the form of oral dosage or injection dosage, wherein the oral dosage is in the form of tablet, powder, granule, tea, soft capsule, oral liquid, pill, paste, liquor, and the injection dosage is in the form of injection liquid.

[0032] Specifically, the medicine preparation is prepared by using naringenin as the active ingredient and adding pharmaceutically conventional or acceptable excipients to prepare oral preparation or injection preparation.

[0033] In some embodiments, the content of naringenin for oral administration or injection is 190-210 mg / Kg, preferably 200 mg / Kg, when the hematopoietic stem cell transplantation is used to assist the hematopoietic reconstruction after the radiation of the body.

[0034] The application aims to provide the use of a flavonoid compound in the preparation of a preparation for reducing the damage of the hematopoietic system of the body in radiation, wherein the flavonoid compound is naringenin.

[0035] Further, the preparation is in the form of medicine.

[0036] Further, the medicine is in the form of oral dosage or injection dosage, wherein the oral dosage is in the form of tablet, powder, granule, tea, soft capsule, oral liquid, pill, paste, liquor, and the injection dosage is in the form of injection liquid.

[0037] Specifically, the medicine preparation is prepared by using naringenin as the active ingredient and adding pharmaceutically conventional or acceptable excipients to prepare oral preparation or injection preparation.

[0038] In some specific embodiments, when assisting in hematopoietic reconstitution after irradiation-induced hematopoietic stem cell transplantation, the oral or injected content of naringenin is 190-210 mg / Kg, preferably 200 mg / Kg.

[0039] The present invention also aims to provide the use of a flavonoid compound in the preparation of an agent for reducing skin damage during radiation exposure, wherein the flavonoid compound is naringenin.

[0040] Furthermore, the formulation is in the form of a drug.

[0041] Furthermore, the drug is in oral or injectable form. The oral dosage form includes the following dosage forms: tablets, powders, granules, tea, soft capsules, oral liquids, pills, ointments, and tinctures. The injectable dosage form is an injection solution.

[0042] Specifically, the preparation of pharmaceutical formulations involves using naringenin as the active ingredient and adding pharmaceutically conventional or acceptable excipients to create oral or injectable formulations.

[0043] In some specific embodiments, when assisting in hematopoietic reconstitution after irradiation-induced hematopoietic stem cell transplantation, the oral or injected content of naringenin is 190-210 mg / Kg, preferably 200 mg / Kg.

[0044] The present invention also aims to provide the use of a flavonoid compound in the preparation of an agent for reducing intestinal damage during radiation exposure, wherein the flavonoid compound is naringenin.

[0045] Furthermore, the formulation is in the form of a drug.

[0046] Furthermore, the drug is in oral or injectable form. The oral dosage form includes the following dosage forms: tablets, powders, granules, tea, soft capsules, oral liquids, pills, ointments, and tinctures. The injectable dosage form is an injection solution.

[0047] Specifically, the preparation of pharmaceutical formulations involves using naringenin as the active ingredient and adding pharmaceutically conventional or acceptable excipients to create oral or injectable formulations.

[0048] In some specific embodiments, when assisting in hematopoietic reconstitution after irradiation-induced hematopoietic stem cell transplantation, the oral or injected content of naringenin is 190-210 mg / Kg, preferably 200 mg / Kg.

[0049] The beneficial effects of this invention are as follows:

[0050] It is known from the embodiments of the present application that the product prepared by using naringenin as the main raw material or active ingredient and administered to the mice by gavage three days before irradiation and two weeks after irradiation has obvious positive protection effect on the health recovery of the mice after large-dose radiation transplantation, especially in improving the survival rate of the mice after radiation, reducing the weight loss of the mice after radiation transplantation, and reducing the hair loss and discoloration of the mice. BRIEF DESCRIPTION OF DRAWINGS

[0051] Figure 1 It is a diagram for experimental design.

[0052] Figure 2 It is the influence of the candidate active substance on the survival rate of the mice after transplantation.

[0053] Figure 3 It is the influence of the candidate active substance on the weight of the mice after transplantation.

[0054] Figure 4 It is the influence of the candidate active substance on the hair of the mice 60 days after transplantation.

[0055] Figure 5 It is the influence of the candidate active substance on the hair of the mice 90 days after transplantation DETAILED DESCRIPTION

[0056] The embodiments are used to better illustrate the present application, but are not the content of the present application, and are limited to the embodiments. Therefore, the skilled in the art can make non-essential improvements and adjustments to the embodiments according to the above content, which still belongs to the protection scope of the present application.

[0057] In the embodiments of the present application, naringenin (mass fraction 99%), nobiletin (mass fraction 98%) and red orange peel poly-methoxyflavone crude extract (PMFs) are self-extracted by the laboratory of the applicant; carboxymethylcellulose sodium (food grade, Zhejiang Yinao Biological Technology Co., Ltd.).

[0058] In the embodiments of the present application, the recipient mice are healthy male C57BL / 6J mice (CD45.2), 7-10 weeks old, weighing 25-30g, provided by Chengdu Yaoke Biological Technology Co., Ltd., animal license number SCXY (Chuan) 2020-034, animal quality certificate number 202108512.

[0059] In the embodiments of the present application, the donor mice are male CD45.1 mice independently bred in the laboratory of Professor Hou Yu, Department of Hematology, Southwest Hospital, 7-10 weeks old, weighing 25-30g.

[0060] In the embodiment of the present application, the mouse feeding and grouping method is as follows: feeding in a barrier system of SPF level, keeping the temperature of the barrier system at (22±1) ℃ and the humidity at (60±5)%, using light and dark 12 h interval lighting control, weighing the body weight after adaptive feeding for 1 week, and randomly grouping into a control group, a PMFs group, a nobiletin group (NOB group) and a naringenin group (NAR group).

[0061] The embodiment of the present application aims to screen natural citrus products having a positive auxiliary effect on the hematopoietic reconstruction process of mice. In the early stage of the formation of the application, biological activity screening is performed on naringenin and polymethoxylated flavones, which are characteristic compounds of Liangpingyou (Citrus maxima (Burm) Merr.cv.liangpingyou) and Dahongpao red orange (Citrus reticulata L.cv.dahongpao), the main characteristic citrus species in Chongqing.

[0062] The embodiment of the present application aims to screen monomers or mixtures that may have a positive auxiliary effect on the hematopoietic reconstruction process of mice. By taking the survival rate of mice after transplantation, body weight and long-term hair condition after transplantation as evaluation criteria, the auxiliary effects of polymethoxylated flavone crude extract of Dahongpao red orange, nobiletin, which is one of the main components of the crude extract, and naringenin, a flavanone, on the hematopoietic reconstruction process are compared.

[0063] Example 1

[0064] The recipient mice were given 200 mg / Kg of PMFs crude extract, nobiletin and naringenin three days in advance, and the control group was given the same volume of sterilized 0.8% carboxymethylcellulose sodium / normal saline. On the third day, the mice received 60 Co γ-ray total body irradiation (TBI=10 Gy), and within two hours after irradiation, the mice received CD 45.1 donor mouse bone marrow cell transplantation (1×10 7 The mice were fed in an SPF environment. After irradiation, 0.5% enrofloxacin-2% sucrose aqueous solution was used as the daily drinking water of the mice in the first week, and was replaced every three days. The mice were continuously given the medicine by gavage for 2 weeks, and were taken out on the 30th day (see Figure 1 ). During this period, the survival rate of the mice was observed, and the body weight information was recorded. The remaining mice were continuously observed for 90 days, and the survival rate, body weight and hair color of the mice were observed.

[0065] (1) The effect of supplementing PMFs, nobiletin and naringenin on the survival rate of mice after radiation transplantation, and the results are shown in Figure 2 .

[0066] A small number of mice died within one week after irradiation and bone marrow transplantation, and no mice died from the second to the fourth week. The final survival rate was 75%.

[0067] The survival rate of mice given nobiletin was 25% after one month.

[0068] No mice died in the groups given PMFs and naringin, and the survival rate was 100% after one month.

[0069] Conclusion: Most mice can survive after bone marrow transplantation, but nobiletin may have an adverse effect on survival after transplantation and is not suitable as a candidate for anti-radiation drugs. PMFs and naringin have no deaths, suggesting that PMFs and NAR may have a positive effect on the survival rate of mice after radiation and transplantation, and have the potential to be used as candidate substances for anti-radiation drugs.

[0070] Long-term survival rate observation of mice treated with PMFs and NAR found that all mice given PMFs died 90 days after transplantation; some mice in the control group died, and the final survival rate was 57%; no mice given NAR died, and the survival rate was 100%.

[0071] Conclusion: Naringin has the most positive effect on the recovery of mice after radiation and transplantation.

[0072] (2) The effects of PMFs crude extract, nobiletin, and naringin on the body weight of mice after radiation and transplantation are shown in Table 2. Figure 3 The body weight of mice given PMFs crude extract, nobiletin, and naringin before irradiation did not change significantly.

[0073] The body weight of mice in each group decreased significantly one week after radiation and transplantation. The maximum weight loss in the control group was about 20% of the initial body weight; the body weight of mice given PMFs, NAR, and NOB decreased relatively less (about 10%).

[0074] The body weight of mice entered the recovery period 2-4 weeks after irradiation. The body weight of mice in the control group recovered slowly, and the final body weight decreased by 10% of the original body weight; PMFs and NAR were better than the control group.

[0075] Summary: PMFs and naringin can maintain the relative stability of the body weight of mice after irradiation. PMFs crude extract and naringin may have a positive effect on the health status of mice during the recovery period after radiation and transplantation, and have the potential to be used as candidate substances for anti-radiation drugs.

[0076]

[0077] ​(3) The influence of PMFs, nobiletin and naringenin on the hair of the mice after radiation and transplantation was supplemented, and the hair growth condition, color and other apparent indexes of the mice after radiation and transplantation were observed at 60 days after radiation, and the results are shown in Table 3. Figure 4

[0078] The hair of the mice in the control group was obviously shed, the body hair was sparse, and the hair color of the distal end of the trunk changed from black to white;

[0079] The hair growth condition of the PMFs mice was good after radiation and transplantation for 60 days, more than 50% of the body hair was light gray-white in color, and the hair color was light gray-white;

[0080] The hair growth condition of the naringenin mice was good after radiation and transplantation for 60 days, the hair was lustrous, there was no obvious change in the hair color of the body part, and the black phenotype inherent to the C57BL / 6J mouse strain was presented.

[0081] (4) The influence of naringenin on the hair of the mice after radiation and transplantation was supplemented, and the hair growth condition, color and other apparent indexes of the mice after radiation and transplantation were observed at 90 days after radiation, and the results are shown in Table 4. Figure 5

[0082] The hair color of the mice in the control group changed from black to gray-white, and the gray-white area was more than 90%; the hair on the abdomen was all white;

[0083] The hair growth condition of the naringenin mice was good after radiation and transplantation for 90 days, more than 50% of the hair on the back maintained the black phenotype inherent to the C57BL / 6J mouse strain, and the degree of gray-white of the hair on the abdomen was lower than that of the control group;

[0084] In summary, naringenin can maintain the health condition of the hair of the mice for a long time.

[0085] The results of the embodiments of the present application show that the continuous supplementation of naringenin (200 mg / kg·d -1 ), the weight loss of the mice after transplantation is less than that of the control group, and the weight change is more stable than that of the control group; in addition, it is verified by two experiments that the naringenin gavage treatment can maintain a high survival rate of the mice after transplantation; long-term observation shows that naringenin also has a significant alleviating effect on hair shedding and discoloration of the mice after radiation. That is, naringenin has a certain positive auxiliary effect on the hematopoietic reconstruction process of the mice after bone marrow transplantation.

[0086] The results of the embodiments of the present application show that the survival rate of the naringenin treated mice is maintained at a high level (P < 0.05) after transplantation, Figure 2 which indicates that naringenin has a relatively stable effect on maintaining the health state of the hematopoietic reconstruction model mice, and has the potential as a natural anti-radiation drug.

[0087] ​​The results of the embodiments of the present application show that the naringin treatment group is better than the control group in the indexes of body weight, activity, hair growth degree, length, color and the like of mice in the long term after irradiation Figure 3 , Figure 4 , Figure 5 ), and no obvious aging phenotype appears. The change of hair may be jointly regulated by immune cells, endogenous hormones or nervous system, and is a physiological process regulated by multiple systems. Continuous intake of naringin can affect the differentiation process of hematopoietic stem cells after homing, and can also be regulated by multiple systems and multiple targets to maintain the health of mice for a long time, and is a natural anti-irradiation compound with great potential.

[0088] The results of the embodiments of the present application show that naringin can be used as a natural anti-irradiation compound for oral administration to assist the hematopoietic reconstruction process after irradiation myeloablation and stem cell transplantation, improve the hematopoietic reconstruction efficiency, and maintain the relative health of the mouse body.

[0089] The results of the embodiments of the present application show that the supplement of naringin (200 mg / Kg) can maintain the relative stability of body weight and the high survival rate of mice in the hematopoietic reconstruction process, the peripheral blood indexes of the naringin treatment group are closer to those of the non-irradiation-transplantation group than those of the control group, and naringin can reduce the hair loss and discoloration of mice in the long term after irradiation.

[0090] The results of the embodiments of the present application show that no death or poisoning occurs in the naringin treatment group during the experiment, and naringin as a natural compound can be used as an auxiliary agent for the functional reconstruction of the hematopoietic system.

[0091] Finally, it should be pointed out that the above embodiments are only used to illustrate the technical solutions of the present application but not limit the present application. Although the present application has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present application can be modified or replaced by equivalents without departing from the purpose and scope of the present application, and all of them should be covered in the scope of the claims of the present application.

Claims

1. The application of a flavonoid compound in the preparation of an agent for reducing hair loss after radiation exposure, characterized in that, The flavonoid compound is naringenin.

2. The application according to claim 1, characterized in that, The formulation is in the form of a drug.

3. The application according to claim 2, characterized in that, The drug is in oral or injectable form. The oral dosage form includes the following dosage forms: tablets, powders, granules, tea, soft capsules, oral liquids, pills, ointments, and tinctures. The injectable dosage form is an injection solution.

4. Use of a flavonoid compound in the preparation of an agent for reducing hair discoloration after radiation exposure, said flavonoid compound being naringenin.

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