CN109731002B - Application of sapogenin R in preparation of hematopoietic stem cell mobilizing agent - Google Patents
Application of sapogenin R in preparation of hematopoietic stem cell mobilizing agent Download PDFInfo
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- CN109731002B CN109731002B CN201910216518.1A CN201910216518A CN109731002B CN 109731002 B CN109731002 B CN 109731002B CN 201910216518 A CN201910216518 A CN 201910216518A CN 109731002 B CN109731002 B CN 109731002B
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Abstract
The invention discloses a hematopoietic stem cell mobilizer, which comprises: and (5) baijiu grass saponin R. It may further comprise dexamethasone, HS6101 and the like. The selective expression of CD34 on the surface of early hematopoietic stem/progenitor cells is a main marker for the isolation and purification of hematopoietic stem cells. If the number of hematopoietic stem cells in peripheral blood increases, the number of leukocytes also increases. Therefore, the number of leukocytes in peripheral blood can be used as an index reflecting the content of hematopoietic stem cells in peripheral blood. Experiments show that the injection of the dioscin R or the dexamethasone can obviously increase the content of white blood cells in peripheral blood, and the combined medicine has a synergistic effect. A brand-new hematopoietic cell mobilizer is discovered, has low toxic and side effects and good mobilization effect, and also has obvious synergistic effect with other medicines.
Description
Technical Field
The invention relates to a hematopoietic stem cell mobilizer and application thereof, belonging to the technical field of biological engineering.
Background
Hematopoietic stem cells are adult stem cells in the blood system, which have not yet developed to maturity, are the origin of hematopoietic cells and immune cells, can differentiate into erythrocytes, leukocytes and platelets, and can also systemically differentiate into cells of various tissue organs, having the potential for self-renewal, multidirectional differentiation and homing (i.e., directed migration to hematopoietic tissue organs). Hematopoietic stem cells are pluripotent stem cells, also known as "universal cells," which are the primary progenitors of the human body.
Hematopoietic stem cell transplantation refers to the transplantation of allogeneic or autologous hematopoietic stem cells into a recipient, which are responsible for corresponding functions, including the reconstitution of the erythroid, leukocyte, megakaryocyte and immune functions. Since multipotent hematopoietic stem cells are present in tissues such as bone marrow, peripheral blood, umbilical cord, and the like, hematopoietic stem cells are also included in the broad term "bone marrow transplantation", and the international bone marrow transplantation registry, european bone marrow transplantation team, and asia-pacific bone marrow transplantation team are all named after bone marrow transplantation.
In normal conditions, the number of stem cells in peripheral blood is low, and mobilization of hematopoietic stem cells in donor bone marrow to peripheral blood is critical for hematopoietic stem cell transplantation. Granulocyte colony stimulating factor is one of the most commonly used hematopoietic stem cell mobilizing agents, but has short duration of action and high cost, and in addition, about 1/3 patients cannot mobilize enough hematopoietic stem cells. Therefore, other effective methods for mobilizing hematopoietic stem cells are needed to meet the needs of clinical application.
The invention aims to provide a hematopoietic stem cell mobilizer and application thereof.
Disclosure of Invention
The invention aims to provide a hematopoietic stem cell mobilizing agent and an application effect thereof.
Dexamethasone is a glucocorticoid drug, often used to promote mobilization of hematopoietic stem cells. Research shows that dexamethasone 10mg is given to intravenous injection 3h before peripheral blood hematopoietic stem cells are collected, and the hematopoietic stem cells in bone marrow can be promoted to be released into peripheral blood. In addition, dexamethasone and other medicines have combined action to promote the mobilization of hematopoietic stem cells, and the combined medicines comprise thalidomide, granulocyte colony stimulating factor, cyclophosphamide, bortezomib and the like. Dexamethasone and glycosylated granulocyte colony stimulating factor are combined for application, so that the time of adverse reaction can be shortened.
HS6101(6101) is a small molecular lipopeptide which is independently developed by Zhejiang Hezhengyao pharmaceutical Co., Ltd, and has hematopoietic stimulating activity similar to cytokines such as rhG-CSF.
In the prior art, 2 new triterpenoid saponins are separated and identified from an ethanol extract of the whole herb of the brevicaulis diffusa, which are respectively named as brevicoside R (conyzasaponin R, 1) and brevicoside S (conyzasaponin S, 2), in a prior application of the applicant, the application of the 2 new triterpenoid saponins in immune cells is successively discovered, the applicant further researches and discovers that the brevicoside R has a mobilization effect and is combined with other medicines for application, so that the application has a better synergistic effect, the degree and the occurrence time of adverse reactions can be greatly reduced, and the molecular structural formula is as follows:
the applicant used the aspalathus arborescens saponin R for the first time for hematopoietic cell mobilization and found that its combined use with other drugs had a significant synergistic effect.
The technical problem to be solved by the invention can be realized by the following technical scheme.
A hematopoietic stem cell mobilizer comprising: and (5) baijiu grass saponin R.
Preferably, the composition can further comprise dexamethasone, HS 6101.
The research method of the invention comprises the following steps:
materials: SPF grade C57BL/6 mice 90, 8-12 weeks old, half male and half female, with body mass 18-24g, were purchased from Shanghai laboratory animals center, Chinese academy of sciences. HS6101 is available from Zhejiang Haizheng pharmaceutical Co. Ficoll-Hypague, dexamethasone, methylcellulose were purchased from Sigma; Ficoll-Paque Plus lymphocyte isolates were purchased from GE, USA; bovine serum albumin, fetal bovine serum, glutamine, penicillin, streptomycin were purchased from Gibco; IMDM medium was purchased from HyClone.
The grouping administration method comprises the following steps:
90C 57BL/6 mice were randomly assigned to 6 groups: a control group, an HS6101 group, a dexamethasone group, a dioscin R + dexamethasone group, a dioscin R + HS6101 group, and 15 in each group. The preparation method comprises the steps of carrying out subcutaneous injection on HS 61018 mg/kg, dexamethasone 0.2mg/kg and dioscin R1 mg/kg in sequence, and injecting physiological saline with the same volume as that of a control group. Peripheral blood and bone marrow blood were collected at 0, 4, 12h post injection, 5 per time point.
The selective expression of CD34 on the surface of early hematopoietic stem cells is a main marker for the isolation and purification of hematopoietic stem cells. Flow cytometry detection shows that after the dioscin R is mobilized, CD34+ cells of mouse bone marrow and peripheral blood are obviously higher than those of a control group, which indicates that the dioscin R can promote the mobilization of hematopoietic stem cells, and compared with the single use of HS6101 or dexamethasone, the dioscin R and the combined application thereof can obviously increase the content of CD34+ cells in circulating peripheral blood and improve the mobilization capability of the hematopoietic stem cells.
If the number of hematopoietic stem cells in peripheral blood increases, the number of leukocytes also increases. The peripheral blood leukocyte count indirectly reflects the peripheral blood hematopoietic stem cell content. Experiments show that the injection of the agrimonia pilosa saponin R can obviously increase the content of white blood cells in peripheral blood, and the combined medication has a synergistic effect. HS6101 and dexamethasone can stimulate the hematopoietic function of bone marrow, so that the neutrophil in the bone marrow is released into peripheral blood. The content of peripheral blood leukocytes of mice injected with the saporin R is increased more obviously, so that the saporin R can indirectly promote the mobilization of hematopoietic stem cells.
The difference between the number of formed mouse colonies injected with dexamethasone or HS6101 and the control group is not large, the number of formed mouse colonies injected with the baijiu grass saponin R is obviously increased, and the number of formed colonies injected in combination with the formed mouse colonies is higher in the single injection group, which shows that the baijiu grass saponin R can promote the mobilization of hematopoietic stem cells, and the baijiu grass saponin R has synergistic effect with other medicines.
The present invention studies the mobilization effect by observing the above two factors.
The invention has the advantages that:
a brand-new hematopoietic cell mobilizing agent is discovered, has low toxic and side effects and good mobilizing effect, and also has obvious synergistic effect with other medicines.
Detailed Description
The following examples of the present invention are described in detail, and are only for the purpose of illustrating the present invention and are not to be construed as limiting the present invention.
Specific examples of the present invention are described below.
Example 1
A hematopoietic stem cell mobilizer comprising: and (5) baijiu grass saponin R.
It may further comprise dexamethasone, HS 6101.
The study method of this example:
materials: SPF grade C57BL/6 mice 90, 8-12 weeks old, half male and half female, with body mass 18-24g, were purchased from Shanghai laboratory animals center, Chinese academy of sciences. HS6101 is available from Zhejiang Haizheng pharmaceutical Co. Ficoll-Hypague, dexamethasone, methylcellulose were purchased from Sigma; Ficoll-Paque Plus lymphocyte isolates were purchased from GE, USA; bovine serum albumin, fetal bovine serum, glutamine, penicillin, streptomycin were purchased from Gibco; IMDM medium was purchased from HyClone.
The grouping administration method comprises the following steps:
90C 57BL/6 mice were randomly assigned to 6 groups: a control group, an HS6101 group, a dexamethasone group, a dioscin R + dexamethasone group, a dioscin R + HS6101 group, and 15 in each group. The preparation method comprises the steps of carrying out subcutaneous injection on HS 61018 mg/kg, dexamethasone 0.2mg/kg and dioscin R1 mg/kg in sequence, and injecting physiological saline with the same volume as that of a control group. Peripheral blood and bone marrow blood were collected at 0, 4, 12h post injection, 5 per time point.
Example 2
Peripheral blood hematopoietic stem cell collection mouse orbital venous plexus blood collection, Ficoll-Hypague density gradient centrifugation, and washing the obtained peripheral blood mononuclear cells with PBS for 2 times to prepare suspension.
Collecting bone marrow hematopoietic stem cells, immediately performing cervical dislocation to kill mice after peripheral blood collection, then sterilizing in 75% ethanol for 1min, flushing bone marrow cells by IMDM, blowing to obtain cell suspension, filtering out aggregates by a filter with a pore size of 70 μm, and separating mononuclear cells by Ficoll-Paque Plus lymphocyte separation liquid. The suspension was centrifuged at 1000 Xg for 8min at 4 ℃ to prepare a mononuclear cell suspension. At 1 × 10
9L
-1The cell concentration of (2) is inoculated in IMDM culture medium (containing green and streptomycin) containing 15% by volume of fetal bovine serum, the IMDM culture medium is placed in a CO2 culture box with the volume fraction of 5% at the temperature of 37 ℃, and suspension cells are collected after 48 hours of culture.
Detection of peripheral blood and bone marrow hematopoietic stem cell phenotype CD34 200. mu.L of cell suspension was drawn and divided into 2 groups, one group was added with FITC-labeled rat anti-mouse CD34 antibody, the other group was added with FITC-labeled rat IgG2a as a control, incubated at room temperature in the dark for 30min, and the percentage of CD34+ cells was detected by flow cytometry.
Peripheral blood leukocyte count was performed using a cell counting plate.
Detection of colony formation of peripheral blood and bone marrow hematopoietic Stem cells cell suspensions at 1X 10
8L
-1The cell concentration of (2) was inoculated in a semi-solid medium containing 0.1g/mL of deionized bovine serum albumin, fetal bovine serum, 1.2% of methylcellulose, 3% of glutamine, and IMDM medium. The granulocyte-macrophage colony-forming units (CFU) were counted after 2 weeks of incubation at 37 ℃ with a volume fraction of 5% CO 2.
The observation indexes ① mouse peripheral blood and bone marrow hematopoietic stem cell phenotype CD34+ cell content, ② peripheral blood leukocyte content, ③ peripheral blood and bone marrow hematopoietic stem cell colony forming unit.
The results are as follows:
TABLE 1 peripheral blood hematopoietic stem cell phenotype CD34+ cell content of different treatment groups ((C))
n＝5，％)
| Item | 0h | 4h | 12h |
| Control group | 0.31±0.02 | 0.37±0.01 | 0.33±0.04 |
| HS6101 group | 0.33±0.03 | 1.33±0.21 | 1.12±0.13 |
| Dexamethasone group | 0.31±0.04 | 1.25±0.08 | 1.10±0.03 |
| Baijiu grass saponin R group | 0.34±0.02 | 1.95±0.11 | 1.72±0.13 |
| Saponin R + dexamethasone | 0.30±0.01 | 2.31±0.08 | 2.01±0.19 |
| Saponin R + HS6101 | 0.31±0.06 | 2.42±0.21 | 1.98±0.17 |
TABLE 2 bone marrow hematopoietic stem cell phenotype CD34+ cell content of different treatment groups ((C))
n＝5，％)
| Item | 0h | 4h | 12h |
| Control group | 5.18±0.05 | 5.21±0.03 | 5.53±0.05 |
| HS6101 group | 5.21±0.02 | 8.31±0.19 | 7.68±0.16 |
| Dexamethasone group | 5.19±0.06 | 7.12±0.03 | 6.45±0.06 |
| Baijiu grass saponin R group | 5.43±0.01 | 8.35±0.02 | 7.53±0.11 |
| Saponin R + dexamethasone | 5.75±0.02 | 9.35±0.04 | 8.32±0.09 |
| Saponin R + HS6101 | 5.18±0.03 | 9.82±0.14 | 7.98±0.07 |
TABLE 3 mouse peripheral blood leukocyte content: (
n＝5，1×10
9L
-1)
TABLE 4 peripheral blood hematopoietic stem cell colony forming units: (
n is 5, 10
6)
| Item | 0h | 4h | 12h |
| Control group | 5.53±1.87 | 5.21±0.78 | 5.82±1.66 |
| HS6101 group | 5.18±1.12 | 10.17±0.36 | 9.94±1.32 |
| Dexamethasone group | 5.06±0.55 | 7.65±1.34 | 6.25±1.01 |
| Baijiu grass saponin R group | 5.15±0.61 | 18.32±1.92 | 16.76±0.61 |
| Saponin R + dexamethasone | 5.07±1.58 | 21.71±1.27 | 20.67±1.03 |
| Saponin R + HS6101 | 5.28±1.74 | 22.97±0.62 | 20.32±0.64 |
TABLE 5 bone marrow hematopoietic stem cell colony Forming Unit: (
n is 5, 10
6)
| Item | 0h | 4h | 12h |
| Control group | 68.33±2.66 | 65.21±7.40 | 69.87±5.56 |
| HS6101 group | 65.18±3.02 | 87.55±4.77 | 76.22±7.42 |
| Dexamethasone group | 65.06±3.55 | 66.83±7.05 | 66.28±8.11 |
| Baijiu grass saponin R group | 60.15±6.67 | 110.12±4.01 | 100.76±3.62 |
| Saponin R + dexamethasone | 67.07±6.69 | 147.22±6.09 | 123.67±6.53 |
| Saponin R + HS6101 | 63.28±7.04 | 128.97±4.66 | 122.32±3.34 |
The selective expression of CD34 on the surface of early hematopoietic stem cells is a main marker for the isolation and purification of hematopoietic stem cells. Flow cytometry detection shows that after the dioscin R is mobilized, CD34+ cells of mouse bone marrow and peripheral blood are obviously higher than those of a control group, which indicates that the dioscin R can promote the mobilization of hematopoietic stem cells, and compared with the single use of HS6101 or dexamethasone, the dioscin R and the combined application thereof can obviously increase the content of CD34+ cells in circulating peripheral blood and improve the mobilization capability of the hematopoietic stem cells.
If the number of hematopoietic stem cells in peripheral blood increases, the number of leukocytes also increases. The peripheral blood leukocyte count indirectly reflects the peripheral blood hematopoietic stem cell content. Experiments show that the injection of the agrimonia pilosa saponin R can obviously increase the content of white blood cells in peripheral blood, and the combined medication has a synergistic effect. HS6101 and dexamethasone can stimulate the hematopoietic function of bone marrow, so that the neutrophil in the bone marrow is released into peripheral blood. The content of peripheral blood leukocytes of mice injected with the saporin R is increased more obviously, so that the saporin R can indirectly promote the mobilization of hematopoietic stem cells.
The mouse colony forming number of dexamethasone or HS6101 injection has no obvious difference with the control group, the mouse colony forming number of the C.brevicaulis R injection is obviously increased, and the single injection group with higher colony number formed by combined injection indicates that the C.brevicaulis R can promote the mobilization of hematopoietic stem cells, and the C.brevicaulis R has synergistic effect with other drugs.
Therefore, the invention discovers a brand-new hematopoietic cell mobilizer which has low toxic and side effects, good mobilizing effect and obvious synergistic effect with other medicines.
It is to be understood that the foregoing is only a preferred embodiment of the invention and that modifications, variations and changes may be made in the invention without departing from the spirit or scope of the invention as defined in the appended claims.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
While embodiments of the invention have been shown and described, it will be understood by those of ordinary skill in the art that: various changes, modifications, substitutions and alterations can be made to the embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the claims and their equivalents.
Claims (6)
1. Application of sapogenin R in preparing a hematopoietic stem cell mobilizer, wherein the hematopoietic stem cell mobilizer is used for bone marrow transplantation.
2. The use according to claim 1, wherein the brevicoside R and dexamethasone are used in combination to prepare a hematopoietic stem cell mobilizer.
3. The use according to claim 1, wherein brevicoside R and HS6101 are used in combination to prepare a hematopoietic stem cell mobilizer.
4. The use according to any one of claims 1 to 3 in an injectable form.
5. The use of any one of claims 1 to 3, wherein the hematopoietic stem cell mobilizer increases the expression of CD 34.
6. The use according to any one of claims 1 to 3, wherein the hematopoietic stem cell mobilizing agent increases the number of leukocytes.
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