CN115887554A - Application of compound phellodendron bark liquid liniment in preparing medicine for treating myeloproliferative tumor - Google Patents
Application of compound phellodendron bark liquid liniment in preparing medicine for treating myeloproliferative tumor Download PDFInfo
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- CN115887554A CN115887554A CN202211586316.4A CN202211586316A CN115887554A CN 115887554 A CN115887554 A CN 115887554A CN 202211586316 A CN202211586316 A CN 202211586316A CN 115887554 A CN115887554 A CN 115887554A
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Abstract
The invention relates to application of a compound phellodendron amurense liquid coating agent in preparing a medicine for treating myeloproliferative tumors. The invention discovers that the compound phellodendron bark liquid liniment has good curative effect in myeloproliferative tumors for the first time, and carries out experimental verification in the myeloproliferative tumors, and animal experimental results show that the application of the relapse phellodendron bark liquid liniment has remarkable treatment effect on abnormal increase of cells of various lines of myeloproliferative model mice, can remarkably reduce abnormal increase of cells caused by the myeloproliferative tumors, relieve splenomegaly, regulate the hematopoietic function of a blood system, and can inhibit the progress of primary thrombocytosis to myelofibrosis.
Description
Technical Field
The invention relates to application of a compound phellodendron amurense liquid coating agent in preparing a medicine for treating myeloproliferative tumors, belonging to the technical field of application of traditional Chinese medicines.
Background
Myeloproliferative neoplasms (MPNs) are a group of hematological diseases in which malignant proliferation of hematopoietic stem/progenitor cells leads to hyperproliferation of blood cells. Myeloproliferative tumors fall into two broad categories: the first is philadelphia chromosome positive myeloproliferative tumors, i.e. chronic myelogenous leukemia; another group are the classical philadelphia chromosome-negative myeloproliferative tumors, including polycythemia vera, primary thrombocythemia, and primary myelofibrosis. Among them, polycythemia vera and essential thrombocythemia also turn into myelofibrosis in the advanced stage. Myeloproliferative tumor patients have pathological symptoms such as extramedullary hematopoiesis, splenomegaly, thrombus, myelofibrosis and the like due to intramedullary hematopoiesis abnormality. The theory of traditional Chinese medicine is that MPN is named as 'marrow stasis virus disease' through deep analysis of disease position, disease nature and pathogenesis of MPN, and the disease is considered to belong to the categories of 'blood stasis', 'accumulation', 'dizziness', 'marrow depletion', 'blood impediment' and 'mass' in traditional Chinese medicine. As the disease progresses, it eventually turns into bone marrow failure or acute leukemia.
Because of the extramedullary infiltration such as malignant tumor cell metastasis and invasion, the treatment means of the disease such as radiotherapy, chemotherapy and the like have poor effect, and even if a patient carries out bone marrow cell transplantation, the disease relapse is caused because the extramedullary infiltrated tumor cells are not completely eliminated. At present, the incidence rate of leukemia in China is about 2.76/10 ten thousand, the incidence rate of tumor diseases in various regions in China ranks sixth, and the incidence rate of malignant tumors of children and adults under 35 years old is the first, so that the life health of people in China is seriously harmed. At present, myeloproliferative tumors are clinically used for mainly reducing the number of overhigh blood cells to relieve symptoms such as splenomegaly and prevent thrombosis, and although the treatment means can prolong the life cycle of patients, the treatment means cannot effectively cure diseases and improve the life quality of the patients.
Mutations in the JAK2, MPL and CALR genes have been shown to be the major causative genes for MPN, with JAK2 V617F Mutations account for 95%, 59%, and 53% of polycythemia vera, primary thrombocythemia, and primary myelofibrosis, respectively, and are the most common mutations. MPL and CALR mutations occur mainly in essential thrombocythemia and myelofibrosis. Recent studies have shown that inflammation may play an important role in the development of MPN. The overproduction of inflammatory cytokines is a common feature of many hematologic malignancies, suggesting that these cytokines play a role in the development of hematologic malignancies. Inflammatory signals have a major impact on the bone marrow microenvironment and hematopoietic stem cell homeostasis, healthy bone marrow cell output, etc., and inflammation can trigger fibrosis and angiogenesis, contributing to the generation of MPN. Therefore, it can be used as a new therapeutic strategy for MPN by interfering in inflammatory state to repair the damaged hematopoietic microenvironment and hematopoietic stem cell function.
The Chinese medicine prescription compound phellodendron liquid liniment is a classic prescription consisting of forsythia, phellodendron, honeysuckle, dandelion and centipede, is suitable for yang syndrome of ulcer, wound infection and the like, and is recorded in 2015 edition of Chinese pharmacopoeia. At present, the clinical compound phellodendron bark liquid liniment is usually used as an external medicine for treating diseases such as skin ulcer, infection and the like, and has better curative effect.
Although the compound phellodendron amurense liquid liniment has been widely applied clinically, the application of the compound phellodendron amurense liquid liniment to myeloproliferative tumor related diseases is never reported in the prior application.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides the application of a compound phellodendron amurense liquid coating agent in preparing a medicine for treating myeloproliferative tumors.
The technical scheme of the invention is as follows:
application of compound cortex Phellodendri liquid liniment in preparing medicine for treating myeloproliferative tumor is provided.
Preferably, according to the invention, the myeloproliferative neoplasm is a classical philadelphia chromosome-negative myeloproliferative neoplasm.
Further preferably, the myeloproliferative neoplasm is polycythemia vera, essential thrombocythemia and myelofibrosis.
According to the optimization of the invention, the compound phellodendron amurense liquid coating agent comprises the following raw materials: phellodendron bark, forsythia fruit, honeysuckle flower, dandelion and centipede.
According to the preferable selection of the invention, the weight ratio of the active ingredient raw materials of the compound phellodendron bark liquid liniment is as follows: 35 to 45 weight portions of phellodendron, 70 to 90 weight portions of forsythia, 35 to 45 weight portions of honeysuckle, 35 to 45 weight portions of dandelion and 2.1 to 2.7 weight portions of centipede.
Further preferably, the weight ratio of the active ingredient raw materials of the compound phellodendron bark liquid coating agent is as follows: 40 parts of phellodendron, 80 parts of forsythia, 40 parts of honeysuckle, 40 parts of dandelion and 2.4 parts of centipede.
The preparation method of the compound phellodendron amurense liquid liniment comprises the following steps:
(1) Weighing cortex phellodendri, fructus forsythiae, honeysuckle, dandelion and centipede according to the weight ratio, and adding water for decocting and extracting for three times; 1 hour for the first time, 45 minutes for the second time, and 30 minutes for the third time;
(2) Mixing decoctions, filtering, and concentrating the filtrate to obtain fluid extract with relative density of 1.10-1.15;
(3) Adding ethanol to make ethanol content reach 70%, standing for 24 hr, filtering, and concentrating the filtrate under reduced pressure until no ethanol smell exists to obtain clear liquid;
(4) And (4) adding water to 1000 parts by weight of the clear liquid obtained in the step (3), uniformly stirring, standing, refrigerating for 24 hours, filtering, filling and sterilizing to obtain the tea drink.
Preferably, according to the invention, in step (2), the relative density is measured at 50 ℃.
According to the preferable application of the invention, the solution concentration of the compound phellodendron amurense liquid liniment stock solution is improved by 2-4 times, and the compound phellodendron amurense liquid liniment is used by adopting an intraperitoneal injection method.
Further preferably, the application is to improve the concentration of the compound phellodendron amurense liquid liniment stock solution by 3 times and use the solution by adopting an intraperitoneal injection method.
The invention has the technical characteristics that:
the main pharmacological actions of the compound phellodendron amurense liquid comprise antibiosis, and the compound phellodendron amurense liquid has inhibition effect on more than 270 clinical common pathogenic bacteria such as staphylococcus aureus, streptococcus, escherichia coli and the like; the inflammation is reduced, the expression of a plurality of inflammatory factor proteins can be reduced, and the symptoms such as redness, swelling, heat, pain and the like can be quickly relieved; promoting healing and regulating the release and expression of growth factors; enhancing immunity, obviously influencing the immunoregulation function of A-MSC, enhancing the phagocytic function of mononuclear macrophage and the like. Myeloproliferative tumors are diseases which are mainly caused by mutations of hematopoietic stem cells, cause abnormal activation of signal pathways mainly based on JAK/STAT signal pathways, and cause abnormal proliferation of one or more blood cells. Based on the above, the invention discovers that the compound phellodendron liquid coating agent can influence the generation and development of MPN through the intervention on an NF-kB signal channel, a TGF-beta signal channel and a JAK-STAT signal channel, and intervenes and treats myeloproliferative tumor diseases.
Has the advantages that:
1. the invention provides a new idea of applying a compound phellodendron amurense liquid liniment to the preparation of a medicament for treating myeloproliferative tumors, in particular to the application of a medicament for treating polycythemia vera and a medicament for treating essential thrombocythemia. The invention discovers that the compound phellodendron bark liquid liniment has good curative effect in myeloproliferative tumors for the first time, and experimental verification is carried out in the myeloproliferative tumors, and animal experimental results show that the application of the compound phellodendron bark liquid liniment has obvious curative effect on mouse models of the myeloproliferative tumors, can obviously reduce abnormal hyperplasia of hematopoietic stem progenitor cells and blood cells of various lines caused by the myeloproliferative tumors, relieve splenomegaly, reduce infiltration of tumor cells to other tissues, and inhibit the progress of primary thrombocytosis to myelofibrosis.
2. The compound phellodendron amurense liquid liniment is used clinically, has low price compared with the prior MPN treatment chemical medicine, is convenient to use, has no toxic or side effect, and is suitable for wide popularization and application.
Drawings
FIG. 1 shows the prediction of signal pathways for intervention of myeloproliferative tumor diseases by compound cortex Phellodendri liquid liniment through network pharmacology.
Wherein: a is GO analysis visual diagram, and B is KEGG enrichment analysis histogram.
FIG. 2 shows the effect of the liquid coating of phellodendron amurense on the red blood cell change of normal mice.
FIG. 3 shows the effect of the liquid coating of phellodendron amurense on the change of white blood cells in normal mice.
FIG. 4 shows the effect of the liquid coating of phellodendron amurense on the platelet change of normal mice.
FIG. 5 shows the effect of the liquid coating of phellodendron amurense on the change of body weight of normal mice.
FIG. 6 shows the effect of FUFANGHUANGCHUANG liquid liniment on the size of spleen of normal mouse.
FIG. 7 is a photograph showing the change in weight of spleen, kidney tissue and liver of normal mice when the Chinese medicinal liquid is applied to the mice.
FIG. 8 is a graph of the effect of a compound phellodendron bark liquid liniment on the change of red blood cells in EPO-induced polycythemia mice.
FIG. 9 shows the effect of the liquid coating of Phellodendri cortex on the change in blood volume ratio of EPO-induced polycythemia mice.
FIG. 10 shows the effect of FUFANGHUANGPhellodendri liquid liniment on the change of hemoglobin in EPO-induced erythrocytosis mice.
FIG. 11 is a graph showing the results of peripheral blood smears of EPO-induced polycythemia mice with the liquid coating of phellodendron amurense.
FIG. 12 is a graph showing the results of spleen size and weight of EPO-induced erythrocytosis mice treated with the FUFANGHUANGYELIU lotion.
FIG. 13 is a diagram showing the pathological results of EPO induced polycythemia mice with the liquid coating of phellodendron bark.
FIG. 14 is a graph of bone marrow erythroid flow pattern of mice with EPO-induced erythrocytosis caused by the compound cortex Phellodendri liquid liniment.
FIG. 15 is a flow chart of marrow system of EPO-induced erythrocytosis mice with the compound cortex Phellodendri liquid liniment.
FIG. 16 is a graph showing the results of pathological section of liver and kidney of a mouse with EPO-induced polycythemia by using the liquid coating of phellodendron amurense.
FIG. 17 is a graph showing the results of the weight, liver and kidney of the EPO-induced polycythemia mouse treated with the liquid coating of phellodendron amurense.
FIG. 18 is JAK2 V617F Knock-in mouse bone marrow transplantation model mouse blood item result chart.
FIG. 19 shows the effect of the liquid coating of Phellodendri cortex on the change of erythrocytes in polycythemia vera mice.
FIG. 20 shows the effect of the liquid coating of Phellodendri cortex on the hemoglobin change in polycythemia vera mice.
FIG. 21 shows the effect of the FUFANGHUANGCHUANG liquid liniment on the change of blood volume ratio in polycythemia vera mice.
FIG. 22 is a graph showing the results of the FUFANGHUANGCHUANG liquid liniment on the size and weight of spleen of polycythemia vera mouse.
FIG. 23 is a result chart of bone marrow erythrocyte flow of the compound cortex Phellodendri liquid liniment to polycythemia vera mice.
FIG. 24 is an MPL W515L Transfect transplanted mouse bone marrow transplantation model mouse blood item result chart.
FIG. 25 is a graph showing the result of changes in white blood cells of mice with primary thrombocythemia caused by the compound cortex Phellodendri liquid liniment.
FIG. 26 is a graph showing the results of changes in the myelogenous cells of mice with primary thrombocythemia caused by the compound cortex Phellodendri liquid liniment.
FIG. 27 is the result of the compound Huangbai liquid liniment on the change of thrombocytes in primary thrombocythemia mice.
FIG. 28 is the result chart of the compound Huangbai liquid liniment on peripheral blood smears of idiopathic thrombocythemia mice.
FIG. 29 is a graph showing the results of spleen size and weight of mice with essential thrombocythemia treated with the Chinese medicinal liquid of cortex Phellodendri.
FIG. 30 is the result of pathological section of the compound Huangbai liquid liniment on the sternum and spleen of mice with essential thrombocythemia.
FIG. 31 is the result of fibrosis of bone marrow network of mice with primary thrombocythemia caused by the compound cortex Phellodendri liquid liniment.
FIG. 32 is the result of slicing the pathological section of the liver and lung tissues of mice with essential thrombocythemia by using the liquid coating of phellodendron amurense.
FIG. 33 is a cytoflow chart of the compound Huangbai liquid liniment on bone marrow of mice with essential thrombocythemia.
FIG. 34 is a flow chart of the compound Huangbai liquid liniment on bone marrow megakaryocyte of mice with essential thrombocythemia.
FIG. 35 is a graph showing the result of colony formation of CFU-GEMM in mice with essential thrombocythemia by using the liquid coating of phellodendron amurense.
FIG. 36 is a graph showing the result of colony formation of CFU-GM in mice with essential thrombocythemia by using the liquid coating of Phellodendri cortex.
FIG. 37 is the result chart of the compound Huangbai liquid liniment on lung tissue, liver and kidney of mice with essential thrombocythemia
Fig. 38 is a graph showing survival of mice with essential thrombocythemia by using the compound cortex phellodendri liquid liniment.
Detailed Description
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 some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the results shown in the drawings without creative efforts.
The invention firstly predicts the signal path of the intervention of the myeloproliferative tumor disease of the compound phellodendron bark liquid liniment through network pharmacology, and the result is shown in figure 1. The invention discovers through figure 1 that the compound phellodendron liquid coating agent can interfere with NF-kB signal channel, JAK-STAT signal channel and TGF-beta channel, and further can influence the generation and development of MPN, and the following embodiment is specific verification data.
The weight ratio of active ingredient raw materials of the compound phellodendron bark liquid liniment in the following embodiments is as follows: 40 parts of phellodendron, 80 parts of fructus forsythiae, 40 parts of honeysuckle, 40 parts of dandelion and 2.4 parts of centipede.
The preparation method comprises the following steps:
(1) Weighing cortex phellodendri, fructus forsythiae, honeysuckle, dandelion and centipede according to the weight ratio, and adding water for decocting and extracting for three times; 1 hour for the first time, 45 minutes for the second time, and 30 minutes for the third time;
(2) Mixing decoctions, filtering, and concentrating the filtrate to obtain fluid extract with relative density of 1.10;
(3) Adding ethanol to make ethanol content reach 70%, standing for 24 hr, filtering, and concentrating the filtrate under reduced pressure until no ethanol smell exists to obtain clear liquid;
(4) And (4) adding water to 1000 parts by weight of the clear liquid obtained in the step (3), uniformly stirring, standing, refrigerating for 24 hours, filtering, filling and sterilizing to obtain the tea drink.
Example 1: toxicity test of compound cortex Phellodendri liquid liniment on normal mice
1. Experimental animals:
clean-grade 8-week-old adult female mice C57/BL6, weighing 19-21 g, provided by Jinanpunyue laboratory animal Breeding Co., ltd, animal certification number: SYXK (Lu) 20200022.
2. Experimental grouping:
animals were acclimatized for 1 week and weighed before being randomly divided into two groups, control (Normal) and dosing (Nor + HBY), 8 animals per group.
3. The administration method comprises the following steps:
the mice of the administration group and the mice of the control group are subjected to intraperitoneal injection administration every afternoon, the administration group uses 3 times of concentrated compound phellodendron bark liquid liniment to administer according to the proportion of 0.3mL/20g of body weight, the administration is continuously carried out for 21 days, the administration time and the administration route of the control group are consistent with those of the administration group, and PBS buffer solution is used for replacing the drugs.
4. Observation indexes are as follows:
4.1 peripheral blood index Change test
All mice were monitored for changes in each index in peripheral blood of the mice before and after administration. The mice are subjected to tail cutting and blood sampling every week, placed into an EDTA anticoagulation tube, and various components in peripheral blood are detected by a blood item detector for analysis.
4.2 toxicity test
Mice were sacrificed 21 days after administration, and the weight of spleen, kidney, liver and lung tissues was recorded.
5. The experimental results are as follows:
5.1, peripheral blood detection experiment results: see fig. 2-4.
As can be seen from the results shown in FIGS. 2-4, the injection of the compound cortex Phellodendri liquid liniment to normal mice has no influence on the normal hematopoietic function of mice, and the number of leukocytes, erythrocytes and platelets in peripheral blood has no obvious difference.
5.2, toxicity detection experiment results: see fig. 5-7.
From the results in fig. 5, it can be seen that the normal mice have no effect on the body weight of the mice after being injected with the compound phellodendron amurense liquid liniment.
As can be seen from the results of FIGS. 6 to 7, the normal mice were not affected in the size and weight of the spleen of the mice after the intraperitoneal injection of the compound phellodendron bark liquid liniment, and the weight of the kidney and the weight of the liver of the mice were not significantly different from those of the control group.
6. Conclusion of the experiment
Compared with the control group of mice, the peripheral blood of the mice of the administration group has no obvious abnormality in red blood cells, white blood cells and platelets, and the hematopoietic function of normal mice is not influenced. In addition, the weight of the mouse and the weight of each organ have no obvious change after 21 days of administration, which shows that the compound phellodendron bark liquid liniment is safe for intraperitoneal injection and has no toxic or side effect.
Example 2: experiment of treatment effect of compound cortex phellodendri liquid liniment on EPO-induced erythrocytosis
1. Experimental animals:
clean-grade 8-week-old adult mice, C57/BL6, weighing 19-21 g, provided by denapone experimental animal breeding limited, animal certification number: SYXK (Lu) 20200022.
2. Experimental grouping:
after 1 week of acclimation, animals were weighed and then randomized into 3 groups, i.e., normal control group (Normal), model group (Model) and Model administration group (Mod + HBY), 8 animals per group.
3. EPO-induced polycythemia mouse model was used.
The EPO-induced polycythemia mouse model establishment method comprises the following steps: injecting recombinant human erythropoietin injection into the abdominal cavity of a mouse at 5000UI/kg once every 2 days for 21 days, establishing a polycythemia mouse model with the erythrocyte rising as the main component, and then continuously injecting the recombinant human erythropoietin injection once every 2 days to maintain the disease symptoms.
4. The administration method comprises the following steps:
after the model is successfully established, the medicine is administrated by intraperitoneal injection every afternoon for 23 days continuously. The model administration group uses triple concentrated compound cortex Phellodendri liquid liniment to administer medicine according to the proportion of 0.3ml/20g, the administration time and route of the normal control group and the model group are consistent with those of the administration group, and PBS buffer solution is used to replace the medicine.
5. Observation indexes are as follows:
5.1 peripheral blood index Change test
All mice were tested for changes in peripheral blood indices before, after and during the dosing process. The mice were bled by tail dissection every week, placed in EDTA anticoagulant tubes, and analyzed by blood component detection using a blood item detector.
5.2 mouse peripheral blood smear test
23 days after administration to the model group mice, the mice were bled, smeared, stained with May-Grunnwald for 5 minutes at room temperature, transferred to phosphate buffer for 1.5 minutes, stained with Wright-Giemsa for 15 minutes, washed twice with clear water, air dried, mounted, and photographed under a microscope for recording.
5.3 spleen Change test
At 23 days after the administration of the drug to the model group mice, the mice were sacrificed and the material was taken. Spleens from all mice were taken and their size and weight were recorded.
5.4 detection of pulmonary thrombosis
After 23 days of treatment for all mice, lung tissue was fixed in formalin, paraffin sectioned and HE stained.
5.5 detection of mouse bone marrow erythrocytes
All mice were treated for 23 days, and then the femurs and tibias of the mice were harvested, bone marrow was flushed out, single cell suspensions were prepared, flow antibody stained, and red blood cell expression was detected.
5.6 toxicity test
Mice weight changes were monitored weekly during the course of the experiment. All mice were treated 23 days later and kidney and liver were taken to record weight changes. Liver and kidney were fixed in formalin, paraffin sectioned and HE stained.
6. The experimental results are as follows:
6.1 peripheral blood index variation experiment results: see fig. 8-10.
From the results in fig. 8, it was found that the number of red blood cells in peripheral blood of mice in the model group was significantly reduced compared to that in the model group 9 days after the treatment with the compound phellodendron amurense liquid varnish. On day 23 of treatment, the red blood cells of the model-administered mice were restored to the normal control level.
As can be seen from the results of fig. 9 to 10, the hemoglobin content and blood volume ratio of the mice were significantly reduced at day 9 after the administration, as compared to the model group.
6.2, peripheral blood smear experiment result: see fig. 11.
From the results of fig. 11, it is clear that the number of reticulocytes in the peripheral blood of the mice in the model group was significantly reduced as compared with the mouse in the model group.
6.3, results of mouse spleen change experiment: see fig. 12.
As can be seen from the results in fig. 12, both the spleen size and the spleen weight of the mice in the model-administered group were significantly reduced compared to those in the model group, and the levels of the mice in the normal control group were restored.
6.4, lung thrombus detection experiment result: see fig. 13.
As can be seen from the results in FIG. 13, pulmonary embolism in the mice in the model group was significantly reduced compared to that in the model group, indicating that pulmonary blood clot aggregation caused by EPO-induced polycythemia was improved after administration.
6.5, bone marrow flow detection experiment result: see fig. 14-15.
As can be seen from the flow analysis results of mouse bone marrow erythrocytes (TER 119 positive) in fig. 14 to 15, the bone marrow erythrocyte ratio in mice of the model administration group was significantly decreased and the abnormal proliferation and differentiation of erythrocytes in EPO-induced polycythemia mice were significantly improved, as compared with the mice of the model group.
6.6, toxicity detection experiment result: see fig. 16-17.
From the results shown in fig. 16-17, it can be seen that, compared with the normal control group, the compound cortex phellodendri liquid liniment has no obvious changes in the body weight, kidney and liver of the mouse after being administered to the abdominal cavity, and no pathological damage is seen in the liver and kidney of the mouse, which indicates that the compound cortex phellodendri liquid liniment has no toxicity after being administered to the abdominal cavity.
7. Conclusion of the experiment
The number of peripheral red blood cells, hemoglobin content, blood volume ratio and spleen change of the mice are common detection indexes for detecting the polycythemia vera in the myeloproliferative tumors. Compared with a normal control group, the number of erythrocytes, the content of hemoglobin and the blood volume ratio in the model group are all obviously increased, which indicates that the EPO-induced polycythemia mouse model is successfully established and can simulate the polycythemia vera in the human myeloproliferative tumor.
After the compound phellodendron bark liquid liniment is used for abdominal administration treatment, compared with a model group, the number of erythrocytes, the content of hemoglobin and the blood volume ratio of the model group are all obviously reduced, the number of reticulocytes in peripheral blood is obviously reduced, splenomegaly is obviously improved, and pulmonary thrombus is also obviously reduced, which shows that the compound phellodendron bark liquid liniment has obvious curative effect on EPO-induced erythrocytosis. The weight, kidney and liver of the mice in the model administration group are not abnormal, and further the compound phellodendron bark liquid liniment is effective and safe.
Example 3: compound cortex Phellodendri liquid liniment for treating JAK2 in myeloproliferative tumors V617F Experiment on therapeutic Effect of induced polycythemia vera
1. Laboratory animal
JAK2V617F FL/+ Mice and Vav-cre mice are supplied by Jackson Laboratory, animal numbers: B6N.129S6 (SJL) -Jak2tm1.2Ble/AmlyJ and B6.Cg-Commd10Tg (Vav 1-icre) A2Kio/J. Female mice C57/BL6, weighing 19-21 g, provided by Jinanpunyue laboratory animal Breeding Co., ltd, and animal certification number: SYXK (Lu) 20200022.
2. Experiment grouping
The experiment was divided into three groups: JAK2 wild type group (JAK 2) FL/+ )、JAK2 V617F Knock-in groups, i.e. model groups (JAK 2) V617F ) And JAK2 V617F Knock-in mouse plusDrug group (JAK 2) V617F +HBY)。
3、JAK2 V617F Establishment of induced polycythemia vera model
JAK2V617F FL/+ The mice were mated with Vav-cre mice to obtain JAK2V617F FL/+ (ii) a Vav-Cre mouse, i.e. JAK2 V617F Knock-in genomics; removal of JAK2 V617F The bone marrow of the knock-in mice was transplanted into irradiated wild mice. And detecting the change of the red blood cells of the mouse after 2 weeks, and establishing a polycythemia vera model mouse. JAK2 FL/+ Group mice used JAK2V617F FL/+ The donor mice were bone marrow transplanted.
4. Method of administration
The drug administration is started at 2 weeks after transplantation, and the drug administration group is administered by intraperitoneal injection with 3 times of concentrated compound phellodendron bark liquid liniment according to the proportion of 0.3ml/20g body weight every afternoon for 42 days continuously. The administration time and route of the model group are consistent with those of the administration group, and PBS buffer is used for replacing the drug.
5. Observation index
5.1 model building and evaluation
At 2 weeks after transplantation, peripheral blood of mice was taken to detect blood item changes.
5.2 peripheral blood item test
The mice were subjected to fundus venous plexus blood sampling every week, placed in an EDTA anticoagulation tube, and analyzed by detecting components in the blood with a blood item detector.
5.3 spleen Change test
After the mice were continuously administered for 42 days, the mice were sacrificed and the material was taken. The spleen of the mouse was removed and its size and weight were recorded.
5.4 mouse bone marrow cell flow assay
After the mice were continuously administered for 42 days, the mice were sacrificed, and bone marrow was washed out of femurs and tibias of one side of the mice to prepare a single cell suspension; flow antibody staining, detecting cell proportion change.
6. Results of the experiment
6.1, establishing an evaluation result graph by a model: see fig. 18.
From the results in FIG. 18, it is clear that the protein binds to JAK2 FL/+ TransplantationMurine phase comparison, JAK2 V617F The knock-in transplanted mice showed significant increases in red cell number, hemoglobin and blood volume, indicating successful model establishment.
6.2, peripheral blood item detection experiment result chart: see FIGS. 19-21
From the results in FIG. 19, it was found that 42 days after the administration of the compound phellodendron amurense decoction, the phellodendron amurense decoction was mixed with JAK2 V617F Group comparison, JAK2 V617F The number of erythrocytes in peripheral blood of + HBY group mice was significantly reduced.
From the results in FIG. 20, it was found that 42 days after the administration of the complex phellodendron bark liquid varnish, the complex phellodendron bark liquid varnish was mixed with JAK2 V617F Group comparison, JAK2 V617F The amount of hemoglobin in peripheral blood of mice in the + HBY group was significantly reduced.
From the results in FIG. 21, it was found that 42 days after the administration of the complex phellodendron bark liquid varnish, the complex phellodendron bark liquid varnish was mixed with JAK2 V617F Group comparison, JAK2 V617F The peripheral blood volume was significantly reduced in the + HBY group mice.
6.3 spleen Change Experimental results chart:
from the results in FIG. 22, it was found that 42 days after the administration of the complex phellodendron bark liquid varnish, the complex phellodendron bark liquid varnish was mixed with JAK2 V617F Group comparison, JAK2 V617F Spleen weight and size were significantly reduced in + HBY group mice.
6.4 mouse bone marrow cell flow assay result graph
The results in FIG. 23 show that the compound cortex Phellodendri liquid liniment is administered 42 days later with JAK2 V617F Group comparison, JAK2 V617F The + HBY group mice significantly reduced the proportion of red blood cells in the bone marrow of the MPN mice.
7. Conclusion of the experiment
With JAK2 V617F Compared with mice, the compound phellodendron bark liquid liniment remarkably relieves JAK2 after intraperitoneal injection V617F The resulting increase of peripheral red blood cells, the improvement of abnormal splenomegaly of MPN mice and the obvious inhibition of JAK2 V617F The number and the proportion of the induced red blood cells in the bone marrow of the MPN mice indicate that the compound phellodendron bark liquid coating is applied to JAK2 V617F The induced polycythemia vera has obvious treatment effect.
Example 4: application of compound cortex Phellodendri liquid in treating MPL in myeloproliferative tumor W515L Induced primaryTest of therapeutic Effect of thrombocythemia
1. Experimental animals:
clean-grade 8-week-old adult female BALB/c mice, weighing 19-21 g, provided by Jinan Pengye laboratory animal Breeding Co., ltd, and animal certification number: SYXK (Lu) 20200022.
2. Grouping experiments:
after 1 week acclimatization of the animals, the animals were weighed and then randomly divided into 3 groups, i.e., normal control group (MPL) WT ) Model group (MPL) W515L ) And model administration group (MPL) W515L + HBY), 8 per group.
3. Establishing a primary thrombocytosis model:
extracting hematopoietic stem progenitor cells from mouse bone marrow (c-kit positive), culturing in incubator for 10 hr, and culturing with MSCV-IRES-GFP-MPL WT Virus-transfected progenitor cells were cultured at 37 ℃ at 2500rpm for 90 min. MSCV-IRES-GFP-MPL for model group and model administration group W515 L transfected progenitor cells at 37 ℃ at 2500rpm for 90 min. After 24 hours of culture, the cells were transplanted into lethally irradiated mice. Blood term changes are monitored, and a primary thrombocythemia model is established after 14 days.
4. Method of administration
Beginning on 14 th day of model building, carrying out intraperitoneal injection administration on a model administration group with a three-time concentrated compound phellodendron bark liquid liniment every day at a ratio of 0.3ml/20g of body weight for 35 days continuously. The administration time and route of the control group and the model group are consistent with those of the administration group, and PBS buffer is used for replacing the drug.
5. Observation index
5.1 model building and evaluation
At 2 weeks after transplantation, peripheral blood of mice was taken to detect blood item changes.
5.2 peripheral blood item test
All mice were tested for changes in peripheral blood indices during the course of the experiment. The mice are subjected to fundus venous plexus blood sampling every week, placed into an EDTA anticoagulation tube, and the blood components are detected by a blood item detector for analysis.
5.3 peripheral blood smear test
After 35 days of administration to the model group mice, the mice were bled, smeared, stained with May-Grunnwald for 5 minutes at room temperature, transferred to phosphate buffer for 1.5 minutes, stained with Wright-Giemsa for 15 minutes, washed twice with clear water, air dried, mounted, and photographed under a microscope for recording.
5.4 spleen Change experiment (size, weight and pathological section staining)
The mice were sacrificed and the material was taken 35 days after the administration of the mice in the model group. Spleens from all mice were taken, recorded for size and weight, fixed in formalin, paraffin sectioned, and HE stained.
5.5 pathological section of mouse bone marrow
After 35 days of all mice treatment, the mouse sternum was taken, fixed in formalin, paraffin sectioned, HE stained and mesh fibrosis stained.
5.6 pathological section of lung, liver and kidney of mouse
After 35 days of all mice treatment, mice lung tissue, liver, kidneys were fixed in formalin, paraffin sections, HE staining.
5.7 mouse bone marrow cell flow assay
After all mice were treated for 35 days, the mice were sacrificed and the femurs and tibias of the mice were taken out to wash out bone marrow to prepare single cell suspensions; flow antibody staining, detecting the change of cell proportion.
5.8 CFU-GEMM and CFU-GM colony formation experiments
After 35 days of all mice treatment, bone marrow was taken from the mice and the line negative cells were purified. Respectively culturing in directional differentiation culture medium Methocuult TM GFM3534 and MethoCult TM GFM3234+50ng/ml rmSCF +10ng/ml rmIL-3+10ng/ml rmIL-6+3U/ml rhEPO, at 37 ℃,5% CO 2 Colony formation was observed in a medium with humidity > 95% for 7-9 days.
5.9 toxicity monitoring
After the treatment of the drug on the mice is finished, the kidney, the liver and the lung are taken to record the weight change.
5.10 statistics of survival rates of mice
For successfully modelled mice, the mice were randomly divided into two groups, namely a model group A and a drug administration group B, 9 mice in the model group A and 8 mice in the drug administration group B. Group B was administered with 0.3ml/20g of compound cortex Phellodendri liquid liniment by intraperitoneal injection every afternoon, and group A was replaced with PBS buffer solution of the same dosage. The mice were recorded for time to death and survival curves were plotted.
6. The experimental results are as follows:
6.1, establishing a model evaluation result graph: see fig. 24.
As can be seen from the results in fig. 24, the model group mice showed a significant increase in the number of leukocytes and the number of platelets, compared to the normal group, indicating successful model establishment.
6.2, peripheral blood item detection experiment results: see fig. 25-27.
As is clear from the results in FIG. 25, the number of leukocytes in peripheral blood of mice in the model group was significantly reduced 35 days after the administration of the liquid coating agent of Compound Phellodendri cortex.
As can be seen from the results in fig. 26, 35 days after the administration of the liquid liniment of compound phellodendron amurense, the numbers of lymphocytes, monocytes and granulocytes in the peripheral blood of the mice in the model group were significantly reduced as compared to the model group.
From the results in FIG. 27, it was found that 35 days after the administration of the liquid paint of Compound Phellodendri cortex, the peripheral blood platelets in mice in the model group were decreased as compared with those in the model group.
6.3, peripheral blood smear experiment result: see fig. 28.
From the results in fig. 28, it is understood that granulocytes were significantly reduced in peripheral blood of mice in the model group after 35 days of administration of the liquid coating of compound phellodendron amurense as compared with the model group.
6.4, spleen change experiment results: see fig. 29-30.
From the results in FIG. 29, it was found that 35 days after the administration of the liquid paint of Compound Phellodendri cortex, the weight and size of the spleen of the mice in the model group were significantly reduced and the level of the spleen was restored to the level of the mice in the control group.
As shown in FIG. 30, the staining results of the pathological sections showed that the infiltration of leukocytes in the spleen of mice in the model group was significantly reduced 35 days after the administration of the liquid liniment of Phellodendri cortex.
6.5, pathological section result of mouse bone marrow: see fig. 30-31.
The results in fig. 30 show that the compound phellodendron bark liquid liniment significantly reduces the infiltration of granulocytes in the bone marrow of mice 35 days after administration compared to the model group.
The results in fig. 31 show that, compared with the model group, the compound cortex phellodendri liquid liniment significantly eases the level of reticular fibrosis of the mouse bone marrow after administration for 35 days.
6.6, pathological section results of lung, liver and kidney of a mouse: see fig. 32.
The results in fig. 32 show that after the compound cortex phellodendri liquid liniment is administered, the infiltration of granulocytes in lung tissues and liver is significantly reduced after 35 days of the compound cortex phellodendri liquid liniment, compared with the model group.
6.7, mouse bone marrow cell flow results: see fig. 33-34.
The results in fig. 33 show that the ratio of myeloid cells in the MPN mice bone marrow was significantly reduced 35 days after administration of the compound phellodendron amurense liquid liniment, compared to the model group.
The results in fig. 34 show that the ratio of megakaryocytes in the bone marrow of MPN mice was significantly reduced 35 days after administration of the compound phellodendron amurense liquid liniment, compared to the model group.
In summary, 35 days after administration of the compound cortex Phellodendri liquid liniment can significantly improve MPL W515L Induced MPN symptoms.
6.8 cloning results: see fig. 35-36.
As shown in the results of fig. 35, the bone marrow-derived granulocyte-erythrocyte-macrophage-megakaryocyte colony number and size of the mice in the model administration group were significantly reduced compared to those in the model group.
As shown by the results in fig. 36, the number and size of bone marrow-derived granulocyte-macrophage colonies were significantly reduced in the mice of the model administration group as compared with those of the model group.
6.9 toxicity monitoring results: see fig. 37.
From the results of fig. 37, it can be seen that the weight of the small liver, the weight of the kidney and the weight of the lung did not change significantly after 35 days of the administration of the compound phellodendron amurense liquid liniment, compared with the control group.
6.10 statistical results of mouse survival: see fig. 38.
As can be seen from the results in fig. 38, the average lifespan of the mice was prolonged after the administration of the compound phellodendron amurense liquid liniment, compared to the model group, and the difference was significant.
7. Conclusion of the experiment
Mouse peripheral blood cell abnormal proliferation, spleen enlargement, extramedullary hematopoiesis and the like are common detection methods for myeloproliferative tumors. The results of this example show that, compared with the control group, the number of platelets and leukocytes in peripheral blood of mice in the model group was significantly increased, the proportion of GFP positive cells in peripheral blood was significantly increased, spleen was enlarged, and leukocyte infiltration in spleen, bone marrow, liver and kidney was significant, indicating MPL W515L The establishment of the induced myeloproliferative tumor model is successful.
After the abdominal cavity administration of the compound phellodendron bark liquid liniment, MPL can be obviously improved W515L Induced abnormal proliferation of MPN small peripheral blood cells, significantly reduced spleen size and weight and extramedullary hematopoiesis. Meanwhile, after the compound phellodendron bark liquid liniment is administrated, the malignant hyperplasia of cells of each line in bone marrow is reduced, and MPL is reduced W515L Induced clonal formation of MPN mouse stem progenitor cells, alleviation of MPL W515L Degree of bone marrow fibrosis in induced MPN mice. These results indicate that intraperitoneal administration of the compound cortex Phellodendri liquid liniment to MPL W515L The induced myeloproliferative tumor has good treatment effect and can inhibit MPL W515L Induced progression of myelofibrosis. Toxicity test experiments show that after the compound cortex phellodendri liquid liniment is administrated, no pathological damage is caused to the liver, the kidney and the lung of a mouse, and the compound cortex phellodendri liquid liniment is effective and safe to use.
In conclusion, the compound phellodendron bark liquid is used for MPL W515L The induced myeloproliferative tumor has obvious treatment effect and safe medication.
Claims (10)
1. Application of compound cortex Phellodendri liquid liniment in preparing medicine for treating myeloproliferative tumor is provided.
2. The use of claim 1, wherein the myeloproliferative neoplasm is philadelphia chromosome negative myeloproliferative neoplasm.
3. The use of claim 1, wherein the myeloproliferative tumor is polycythemia vera, essential thrombocythemia, or myelofibrosis.
4. The use of claim 1, wherein the compound cortex Phellodendri liquid liniment comprises the following raw materials: phellodendron bark, forsythia, honeysuckle, dandelion and centipede; the golden cypress and the weeping forsythia are monarch drugs, the honeysuckle is ministerial drugs, the dandelion is adjuvant drugs, and the centipede is conductant drugs.
5. The application of claim 4, wherein the compound phellodendron amurense liquid liniment comprises the following active ingredient raw materials in parts by weight: 35 to 45 weight parts of phellodendron, 70 to 90 weight parts of forsythia, 35 to 45 weight parts of honeysuckle, 35 to 45 weight parts of dandelion and 2.1 to 2.7 weight parts of centipede.
6. The application of claim 5, wherein the compound phellodendron amurense liquid coating agent comprises the following active ingredient raw materials in parts by weight: 40 parts of phellodendron, 80 parts of fructus forsythiae, 40 parts of honeysuckle, 40 parts of dandelion and 2.4 parts of centipede.
7. The preparation method of the compound phellodendron amurense liquid liniment according to claim 6, which is characterized by comprising the following steps:
(1) Weighing phellodendron, forsythia, honeysuckle, dandelion and centipede according to the weight ratio, and adding water for decoction and extraction for three times; 1 hour for the first time, 45 minutes for the second time, and 30 minutes for the third time;
(2) Merging the decoctions, filtering, and concentrating the filtrate to obtain clear paste with the relative density of 1.10-1.15;
(3) Adding ethanol to make ethanol content reach 70%, standing for 24 hr, filtering, and concentrating the filtrate under reduced pressure until no ethanol smell exists to obtain clear liquid;
(4) And (4) adding water to 1000 parts by weight of the clear liquid obtained in the step (3), uniformly stirring, standing, refrigerating for 24 hours, filtering, filling and sterilizing to obtain the tea drink.
8. The method according to claim 7, wherein in the step (2), the relative density is measured at 50 ℃.
9. The application of claim 1, wherein the application method comprises concentrating the original solution of the compound cortex Phellodendri liquid liniment by 2-4 times, and then using by intraperitoneal injection.
10. The use of claim 9, wherein the use is to increase the concentration of the original solution of the compound phellodendron amurense liquid liniment by 3 times, and the use is performed by using an intraperitoneal injection method.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1169863A (en) * | 1996-07-01 | 1998-01-14 | 谢景龙 | Chinese medicine preparation for sore, ulcer and infection caused by external wound and preparation method |
| CN104398642A (en) * | 2014-11-20 | 2015-03-11 | 山东汉方制药有限公司 | Preparation and quality detection method of compound prescription cortex phellodendri chinensis fluid |
| CN113350411A (en) * | 2021-07-14 | 2021-09-07 | 山东汉方制药有限公司 | Preparation process and application of compound phellodendron bark liquid liniment |
| CN113694109A (en) * | 2021-08-17 | 2021-11-26 | 山东汉方制药有限公司 | Compound cortex phellodendri medicinal preparation, preparation method and application |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1169863A (en) * | 1996-07-01 | 1998-01-14 | 谢景龙 | Chinese medicine preparation for sore, ulcer and infection caused by external wound and preparation method |
| CN104398642A (en) * | 2014-11-20 | 2015-03-11 | 山东汉方制药有限公司 | Preparation and quality detection method of compound prescription cortex phellodendri chinensis fluid |
| CN113350411A (en) * | 2021-07-14 | 2021-09-07 | 山东汉方制药有限公司 | Preparation process and application of compound phellodendron bark liquid liniment |
| CN113694109A (en) * | 2021-08-17 | 2021-11-26 | 山东汉方制药有限公司 | Compound cortex phellodendri medicinal preparation, preparation method and application |
Non-Patent Citations (2)
| Title |
|---|
| 张华梅;高静韬;赵轼轩;孟昭婷;王慧君;李筱梅;竺晓凡;茹永新;: "红细胞生成素诱导小鼠骨髓纤维化模型的实验研究", 中国实验血液学杂志, no. 04 * |
| 曲文闻;马俊丽;宋敏敏;周庆兵;胡晓梅;邓成珊;: "活血化瘀解毒法在骨髓增殖性疾病中的应用", 河南中医, no. 01 * |
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