CN1899280A - Use of chlorogenic acid in preparing medicine for improving bone marrow cell efficiency - Google Patents
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Abstract
The present invention discloses the use of chlorogenic acid in preparing medicine for raising the function of bone marrow cell alone or together with other medicine component. The present invention discloses also the use of chlorogenic acid in preparing medicine for raising the function of leukocyte alone or together with other medicine component.
Description
Technical field
The present invention relates to the new purposes of chlorogenic acid, is chlorogenic acid has leukocyte increasing and increase bone marrow cell efficiency medicine in preparation purposes specifically.
Background technology
Chlorogenic acid extensively is present in various medicinal plants such as the Flos Lonicerae etc., and is at present clear to its chemical constitution research, and existing people carries out medicinal research to it, has reported that chlorogenic acid can be applied to treat diseases such as tumor.However, we further find again that by pharmacological evaluation it also has many other new medical functions, and these new medical functions were also never reported in existing document.
Summary of the invention
An object of the present invention is to provide chlorogenic acid and have the purposes that increases the bone marrow cell efficiency medicine in preparation.
Another purpose of the present invention provides chlorogenic acid has leukocyte increasing effect medicine in preparation purposes.
Through experiment, but find the chlorogenic acid leukocyte increasing; Can stimulate Os Canitis myelocyte hypertrophy, comprise increase effect, and chlorogenic acid causes the mouse spleen hematopoietic stem cell injuries to the 60Co-gamma-rays protective effect is significantly arranged bone marrow stem cell.
The hematopoiesis of body is the process of an active cell proliferation, differentiation, maturation and release.It is to keep the constant of its quantity by the self renewal of pluripotency hematopoietic stem cell, and by the pluripotency hematopoietic stem cell to respectively being committed progenitor, further breed, break up, be discharged into peripheral blood circulation again.Medicine can influence hematopoiesis by the multiple links such as proliferation and differentiation that influence hematopoietic stem cell, CFU-GM.Therefore, the effect that we inquire into medicine that is established as of hemopoietic progenitor cell In vitro culture technology provides means and method.
The SAM mice is to develop a kind of quick aging model white mice of growing of training by Japanese scholar bamboo professor Tian Junnan, and it is characterized in that increases the aging all features of Lock-in with the monthly age, and these features comprise outward manifestation and pathology, biochemistry, immune aspects.Wherein SAM P8 subbreed mice is again with learning memory disorder and is reduced to the Ageing Model of principal character with immunologic function, its hemopoietic function also low state increase to occur with the monthly age, thus we to select the SAM P8 mice at 9 monthly ages for use be experimental model and serve as that the influence of chlorogenic acid to its hemopoietic function inquired in contrast with the SAM R1 with the monthly age.The proliferation and differentiation ability of result of study demonstration SAM P8 mice CFU-S, CFU-GM, CFU-E and BFU-E and peripheral blood WBC number are starkly lower than the SAMR1 mice with the monthly age.And the CFU-S number that chlorogenic acid can make SAM P8 mice reduce obviously increases, but the propagation of chlorogenic acid hemopoietic stem cell is described, chlorogenic acid can obviously promote SAM P8 mouse bone marrow cells grain monosystem CFU-GM simultaneously, in early days, late period CFU-E proliferation and differentiation, and its peripheral blood WBC number is raise, the prompting chlorogenic acid can influence the whole process of mice hemopoietic.Therefore we have reason to infer that chlorogenic acid may regulate hemopoietic regulator control system in the body.The measurement result explanation chlorogenic acid of mice serum colony-stimulating vigor can produce the proliferation and differentiation that colony stimulating factor strengthens its CFU-GM by promoting the mice body.Histological result of study has confirmed further that then chlorogenic acid really can strengthen the hemopoietic function of SAM P8 mice.
Thus, chlorogenic acid can be treated the anemia that a variety of causes causes, as but be not limited only to hemorrhagic anemia, hemolytic anemia, the defective blood formation anemia comprises macrocytic anemia, aplastic anemia and hypersplenism, leukopenia state, granulocytopenia, agranulocytosis that a variety of causes is caused have therapeutical effect, the macronucleus system that a variety of causes is caused change as but be not limited only to idiopathic thrombocytopenic purpura therapeutical effect arranged; To the myelofibrosis that a variety of causes causes, marrow infection has certain therapeutical effect.
Based on above-mentioned discovery, chlorogenic acid can be separately or with other medicines with known effect adopt various pharmaceutical technologies be prepared into various pharmaceutical dosage forms as but be not limited only to peroral dosage form, intravenously administrable dosage form and exterior-applied formulation.
In addition, " other have the medicine of known effect " of the present invention is meant medicine of having reported in the prior art with leukocyte increasing effect and the medicine that increases bone marrow cell efficiency.
Below by experiment the above-mentioned effect that chlorogenic acid had is confirmed.It should be understood that experimental example of the present invention is to be used to illustrate the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.
Experimental example 1 chlorogenic acid is to the influence of peripheral hemogram
With cyclophosphamide dog is made leukopenic canine model.
With chlorogenic acid to dog drug treatment 7 days, the leukocyte WBC of positive drug (mannatide) group and each dosage group of chlorogenic acid all raises, and wherein rate of increase and the model group of leukocyte WBC has significant difference (P＜0.05) in administration the 13rd day and the 14 days big or middle dosage groups.See Table 1, chlorogenic acid is to the influence of canine leucocyte.Table 2, chlorogenic acid is to the hematoblastic influence of dog.
Table 1 chlorogenic acid is to the influence of canine leucocyte
| Group | Dosage | Number of animals | The medicine proleukocyte | Modeling is leukocyte after 6 days | * 100 after treatment back leukocyte rate of change=(after the treatment back-modeling)/modeling | |||
| (mg/kg) | (only) | (x10 9/l) | (x10 9/L) | Treat after 7 days | Treat after 11 days | Treat after 13 days | Treat after 14 days | |
| Chlorogenic acid is little in the big chlorogenic acid of normal control group model matched group positive group chlorogenic acid | 1 20 10 5 | 6 6 6 6 6 6 | 9.23±2.37 11.17±0.81 13.90±5.20 13.02±1.46 13.70±3.57 13.28±0.60 | 12.83±3.18 5.22±1.30** 3.37±0.72** 3.48±0.79** 4.02±1.48** 5.45±0.71** | 1.19±41.48 22.86±41.47 36.42±53.17 39.14±74.89 15.83±43.39 | 35.62±21.86 115.02±57.89 77.38±45.15 72.48±70.10 48.00±18.05 | 38.40±35.78 251.90±126.95 △△ 167.43±127.48 △ 159.45±130.12 △ 59.42±31.66 | 43.92±54.88 233.02±150.57 △ 213.17±176.05 △ 233.05±151.76 △ 68.95±41.55 |
Compare * * P＜0.001 with the normal control group
Compare with model control group
△P＜0.05
△ △P＜0.01
Table 2 chlorogenic acid is to the hematoblastic influence of dog
| Group | Dosage | Number of animals | PLT before the medicine | Modeling is PLT after 6 days | * 100 after treatment back PLT rate of change=(after the treatment back-modeling)/modeling | |||
| (mg/kg) | (only) | (x10 9/l) | (x10 9/L) | Treat after 7 days | Treat after 11 days | Treat after 13 days | Treat after 14 days | |
| Chlorogenic acid is little in the big chlorogenic acid of normal control group model matched group positive group chlorogenic acid | 1 20 10 5 | 6 6 6 6 6 6 | 266.83±99.26 298.83±47.17 281.33±45.16 258.67±24.59 186.83±55.86 330.33±19.33 | 288.83±87.25 284.33±82.12 233.50±37.22 225.00±16.75 188.17±57.42 297.83±26.23 | -88.88±9.04 -91.00±2.74 -90.28±8.13 -87.20±6.98 -76.67±5.84 | -32.11±33.11 -27.27±23.63 -3.24±8.32 -20.16±39.56 6.05±11.92 | -3.15±32.45 8.70±32.99 20.42±35.04 -13.88±1877 27.09±12.15 | 7.69±22.86 7.81±26.35 43.73±33.42 21.62±39.46 28.71±19.51 |
Compare with model control group
△P＜0.05
The influence of 2 pairs of pathological model animal bone marrow of experimental example
The results are shown in Table 3,4,5.
Normal marrow cell inspection before table 3 experiment (%, X ± SD)
| Index | Normal control (n=6) | Model contrast (n=6) | Positive control (n=6) | High dose (n=6) | Middle dosage (n=6) | Low dosage (n=6) |
| The neutral stab form granulocyte neutrophilic segmented granulocyte of hemogonia myeloblast progranulocyte myelocyte neutrophilic metamyelocyte is had a liking for sour myelocyte and had a liking for sour metamylocyte and have a liking for sour stab form granulocyte and have a liking for sour leaflet granulocyte and have a liking for the alkali myelocyte and have a liking for the alkali metamylocyte and have a liking for the alkali stab form granulocyte and have a liking for early megalocyte polychromatic megaloblast megalocyte grain in evening system of alkali leaflet granulocyte pronormoblast early erythroblast rubricyte metarubricyte: (M: E) the inmature megakaryocytic maturation of the full sheet megacaryocyte sum of the inmature monocyte monocyte of the inmature lymphocyte lymphocyte of lymphoblast monoblast Megakaryoblast has blood platelet to form ripely to form bare nucleus cell desmacyte endothelial cell phagocyte thick liquid cell without blood platelet and organize giant cell to fail to understand the cell degradation cell in red system | 0 0 0 5.67±0.60 3.58±0.74 50.50±0.45 3.25±0.52 0 0 0 0 0 0 0 0 0 0 0 25.25±0.52 0 0 0 2.47±0.08 0 0 11.83±1.04 0 0 0 109.8±16.8 0 0 21.8±1.7 3.2±1.7 0 0 0 0 0 0 0 0 | 0 0 0 5.25±0.52 4.00±0.63 50.50±1.79 3.50±0.71 0 0 0 0 0 0 0 0 0 0 0 25.00±0.71 0 0 0 2.48±0.08 0 0 11.75±1.13 0 0 0 112.8±1.83 0 0 19.8±0.7 5.2±0.7 0 0 0 0 0 0 0 0 | 0 0 0 5.25±0.76 3.50±0.83 50.50±1.05 3.33±0.68 0 0 0 0 0 0 0 0 0 0 0 24.80±1.78 0 0 0 2.42±0.08 0 0. 11.83±0.93 0 0 0 110.1±21.2 0 0 21.0±1.8 4.0±1.8 0 0 0 0 0 0 0 0 | 0 0 0 5.25±0.61 3.25±0.52 49.90±0.92 4.00±0.71 0 0 0 0 0 0 0 0 0 0 0 25.17±0.52 0 0 0 2.45±0.05 0 0 12.42±0.74 0 0 0 100.0±27.2 0 0 21.3±2.4 3.7±2.4 0 0 0 0 0 0 0 0 | 0 0 0 5.08±0.49 3.00±0.45 50.20±0.82 3.75±0.94 0 0 0 0 0 0 0 0 0 0 0 25.58±0.86 0 0 0 2.33±0.19 0 0 12.41±0.74 0 0 0 104.2±27.9 0 0 21.0±2.5 4.0±2.5 0 0 0 0 0 0 0 0 | 0 0 0 5.58±1.15 2.75±1.13 50.10±0.82 3.33±0.82 0 0 0 0 0 0 0 0 0 0 0 25.08±0.80 0 0 0 2.45±0.10 0 0 12.42±0.80 0 0 0 105.5±20.6 0 0 21.5±2.3 3.5±2.3 0 0 0 0 0 0 0 0 |
Normal marrow resembled microscopically observation, each Os Canitis myelocyte active proliferation, no abnormality seen before each organized the dog administration.
Neutrophilic granulocyte is shaft-like to be main, accounts for full sheet sum 45～50%, secondly is middle children, late children, divides leaf cell.Accidental eosinophilic granulocyte is not seen original, promyelocyte.Children and metamyelocyte in not seeing.The erythrocyte system: based on normoblast, accounting for full sheet counting about 25～30%, be polychromatophilic erythroblast secondly, do not see under the full sheet mirror former red, early the children is red, morning is huge, in huge, late megalocyte.Lymphsystem:, do not see original and inmature lymphocyte based on mature lymphocyte (accounting for 9～12%).The monokaryon system: each is organized each dog and is not seen that original, inmature, mononuclear cell are arranged.Megalokaryocyte: have platelet-shaped to become the master with maturation, ripe no platelet forms takes second place, and does not see inmature megalokaryocyte.Other cell: do not see plasma cell, do not see netted, endothelium, engulf, parasite, organize giant cell, not clear-cells and special cells.More equal no difference of science of statistics (P＞0.05) between each group of the ratio of granulocyte system and erythrocyte system.
Table 4 modeling medullary cell inspection in 6 days (%, X ± SD)
| Index | Normal control (n=6) | Model contrast (n=6) | Positive control (n=6) | High dose (n=6) | Middle dosage (n=6) | Low dosage (n=6) |
| The neutral stab form granulocyte neutrophilic segmented granulocyte of hemogonia myeloblast progranulocyte myelocyte neutrophilic metamyelocyte is had a liking for sour myelocyte and is had a liking for sour metamylocyte and have a liking for sour stab form granulocyte and have a liking for sour leaflet granulocyte and have a liking for the alkali myelocyte and have a liking for the alkali metamylocyte and have a liking for the alkali stab form granulocyte and have a liking for early megalocyte polychromatic megaloblast megalocyte grain in evening system of alkali leaflet granulocyte pronormoblast early erythroblast rubricyte metarubricyte: (the M: E) lymphoblast of red system | 0 0 0 5.20±0.91 4.00±0.71 49.80±0.75 3.42±0.74 0 0 0 0 0 0 0 0 0 0 0 25.30±0.61 0 0 0 2.40±0.09 0 | 0 0 0 0 0 3.83±0.82 28.83±2.58 0 0 0 0 0 0 0 0 0 0 0 3.58±1.66 0 0 0 0 0 | 0 0 0 0 0 8.67±1.31 29.08±4.64 0 0 0 0 0 0 0 0 0 0 0 5.17±1.63 0 0 0 0 0 | 0 0 0 0 0 4.42±1.74 28.50±1.41 0 0 0 0 0 0 0 0 0 0 0 5.58±1.24 0 0 0 0 0 | 0 0 0 0 0 4.75±1.64 29.3±1.54 0 0 0 0 0 0 0 0 0 0 0 5.17±1.63 0 0 0 0 0 | 0 0 0 0 0 4.42±1.74 28.50±1.41 0 0 0 0 0 0 0 0 0 0 0 5.58±1.24 0 0 0 0 0 |
| The inmature megakaryocytic maturation of the inmature monocyte monocyte of inmature lymphocyte lymphocyte monoblast full sheet megacaryocyte sum Megakaryoblast has blood platelet to form ripe no blood platelet formation bare nucleus cell desmacyte endothelial cell phagocyte thick liquid cell to organize giant cell to fail to understand the cell degradation cell | 0 12.17±0.82 0 0 0 106.0±13.2 0 0 20.8±1.5 4.2±1.5 0 0 0 0 0 0 0 0 | 0 63.50±2.88 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 | 0 61.9±3.9 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 | 0 64.8±10.5 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 | 0 61.9±3.9 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 | 0 64.8±10.5 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 |
The 7th day 36 Os Canitis marrow hypertrophy of modeling are low, non-hematopoietic cell lymphocytosis, and grain is a cell, erythroid cells, the megalokaryocyte sum reduces, and does not see that maturation has platelet to form and ripe no platelet forms.
Table 5 treatment medullary cell inspection in 14 days (%, X ± SD)
| Index | Normal control (n=6) | Model contrast (n=6) | Positive control (n=6) | High dose (n=6) | Middle dosage (n=6) | Low dosage (n=6) |
| The neutral stab form granulocyte neutrophilic segmented granulocyte of hemogonia myeloblast progranulocyte myelocyte neutrophilic metamyelocyte is had a liking for sour myelocyte and is had a liking for sour metamylocyte and have a liking for sour stab form granulocyte and have a liking for sour leaflet granulocyte and have a liking for the alkali myelocyte and have a liking for the alkali metamylocyte and have a liking for the alkali stab form granulocyte and have a liking for alkali leaflet granulocyte pronormoblast | 0 0 0 5.25±0.76 3.75±0.52 50.50±0.45 3.25±0.61 0 0 0 0 0 0 0 0 0 | 0 0 0 3.16±0.52 2.41±1.91 35.40±22.8 14.17±1.67 0 0 0 0 0 0 0 0 0 | 0 0 0 5.25±0.42 3.91±0.86 50.40±0.49 3.17±0.75 0 0 0 0 0 0 0 0 0 | 0 0 0 5.25±0.42 3.67±0.75 50.40±0.80 3.33±0.60 0 0 0 0 0 0 0 0 0 | 0 0 0 6.00±0.63 3.50±0.71 51.50±1.41 2.83±0.61 0 0 0 0 0 0 0 0 0 | 0 0 0 3.42±2.65 2.25±1.78 36.50±2.21 11.40±0.82 0 0 0 0 0 0 0 0 0 |
| Early erythroblast rubricyte metarubricyte is megalocyte polychromatic megaloblast megalocyte grain in evening system early: (M: E) the inmature megakaryocytic maturation of the full sheet megacaryocyte sum of the inmature monocyte monocyte of the inmature lymphocyte lymphocyte of lymphoblast monoblast Megakaryoblast has blood platelet to form ripely to form bare nucleus cell desmacyte endothelial cell phagocyte thick liquid cell without blood platelet and organize giant cell to fail to understand the cell degradation cell in red system | 0 0 25.30±0.52 0 0 0 2.43±0.05 0 0 11.92±0.80 0 0 0 78.7±11.6 0 0 20.0±2.1 5.0±2.1 0 0 0 0 0 0 0 0 | 0 0 21.58±6.48 0 0 0 1.57±1.21 0 0 22.42±16.7 0 0 0 41.5±37.0 0 0 12.7±10.0 4.0±3.8 0 0 0 0 0 0 0 0 | 0 0 21.50±9.56 0 0 0 2.45±0.05 0 0 12.0±0.71 0 0 0 99.5±10.3 0 0 21.0±0.9 4.0±0.9 0 0 0 0 0 0 0 0 | 0 0 25.30±0.60 0 0 0 2.43±0.60 0 0 12.00±0.74 0 0 0 87.1±20.5 0 0 20.2±1.5 4.8±1.5 0 0 0 0 0 0 0 0 | 0 0 25.10±0.93 0 0 0 2.50±0.14 0 0 1.22±1.26 0 0 0 68.0±7.9 0 0 20.3±1.8 4.7±1.8 0 0 0 0 0 0 0 0 | 0 0 21.50±6.34 0 0 0 1.57±1.22 0 0 24.9±19.6 0 0 0 24.3±25.7 0 0 11.3±8.9 5.3±8.9 0 0 0 0 0 0 0 0 |
Treated the 14th day, and removed 2 dogs of model group, 2 Os Canitis marrows of small dose group hypertrophy is low, non-hematopoietic cell lymphocytosis, and grain is a cell, and the erythrocyte system reduces, and myelosis fails to recover, and all the other each Os Canitis myelocyte active proliferations have recovered normal.
The influence of 3 pairs of normal marrow cells of experimental example
The results are shown in Table 6,7,8.
Table 6 administration medullary cell inspection in 90 days (%, X ± SD)
| Index | Heavy dose of (n=2) | Middle dosage (n=2) | Low dose of (n=2) | Matched group (n=2) |
| Primitive blood cell myeloblast promyelocyte myelocyte | 0 0 0 5.25±0.35 | 0 0 0 5.00±0.71 | 0 0 0 4.00±0.71 | 0 0 0 5.75±0.35 |
| The neutral stab form granulocyte neutrophilic segmented granulocyte of neutrophilic metamyelocyte is had a liking for sour myelocyte and had a liking for sour metamylocyte and have a liking for sour stab form granulocyte and have a liking for sour leaflet granulocyte and have a liking for the alkali myelocyte and have a liking for the alkali metamylocyte and have a liking for the alkali stab form granulocyte and have a liking for early megalocyte polychromatic megaloblast megalocyte grain in evening system of alkali leaflet granulocyte pronormoblast early erythroblast rubricyte metarubricyte: (M: E) the inmature megakaryocytic maturation of the full sheet megacaryocyte sum of the inmature monocyte monocyte of the inmature lymphocyte lymphocyte of lymphoblast monoblast Megakaryoblast has blood platelet to form ripely to form bare nucleus cell desmacyte endothelial cell phagocyte thick liquid cell without blood platelet and organize giant cell to fail to understand the cell degradation cell in red system | 4.00±0.00 50.75±1.06 3.50±0.71 0 0 0 0 0 0 0 0 0 0 0 24.50±0.71 0 0 0 2.55±0.07 0 0 12.00±1.41 0 0 0 78.00±8.49 0 0 21.50±0.71 3.00±0.00 0 0 0 0 0 0 0 0 | 3.75±0.35 50.50±0.71 4.00±1.41 0 0 0 0 0 0 0 0 0 0 0 25.75±1.06 0 0 0 2.40±0.14 0 0 11.00±0.00 0 0 0 80.00±9.90 0 0 23.00±2.83 3.50±0.71 0 0 0 0 0 0 0 0 | 4.75±0.35 49.75±1.77 4.50±1.41 0 0 0 0 0 0 0 0 0 0 0 25.75±0.35 0 0 0 2.40±0.00 0 0 11.25±0.35 0 0 0 78.50±4.95 0 0 21.50±2.12 3.50±2.12 0 0 0 0 0 0 0 0 | 3.50±0.71 50.50±0.71 4.00±0.00 0 0 0 0 0 0 0 0 0 0 0 25.50±0.71 0 0 0 2.45±0.07 0 0 10.75±1.06 0 0 0 72.50±16.26 0 0 20.50±2.12 4.50±2.12 0 0 0 0 0 0 0 0 |
90 days 8 dogs of administration, microscopically is observed, each Os Canitis myelocyte active proliferation and extremely active.
Table 7 administration medullary cell inspection in 180 days (%, X ± SD)
| Index | Heavy dose of (n=2) | Middle dosage (n=2) | Low dose of (n=2) | Matched group (n=2) |
| Primitive blood cell myeloblast promyelocyte myelocyte | 0 0 0 5.25±0.35 | 0 0 0 5.25±1.06 | 0 0 0 4.50±0.71 | 0 0 0 6.25±0.35 |
| The neutral stab form granulocyte neutrophilic segmented granulocyte of neutrophilic metamyelocyte is had a liking for sour myelocyte and had a liking for sour metamylocyte and have a liking for sour stab form granulocyte and have a liking for sour leaflet granulocyte and have a liking for the alkali myelocyte and have a liking for the alkali metamylocyte and have a liking for the alkali stab form granulocyte and have a liking for early megalocyte polychromatic megaloblast megalocyte grain in evening system of alkali leaflet granulocyte pronormoblast early erythroblast rubricyte metarubricyte: (M: E) the inmature megakaryocytic maturation of the full sheet megacaryocyte sum of the inmature monocyte monocyte of the inmature lymphocyte lymphocyte of lymphoblast monoblast Megakaryoblast has blood platelet to form ripely to form bare nucleus cell desmacyte endothelial cell phagocyte thick liquid cell without blood platelet and organize giant cell in red system | 4.50±0.71 49.75±1.06 3.25±1.06 0 0 0 0 0 0 0 0 0 0 0 25.75±0.35 0 0 0 2.40±0.00 0 0 11.50±0.71 0 0 0 80.00±24.04 0 0 21.50±2.12 3.50±2.12 0 0 0 0 0 0 | 4.00±0.00 50.50±0.71 3.00±0.71 0 0 0 0 0 0 0 0 0 0 0 25.75±0.35 0 0 0 2.35±0.07 0 0 11.50±0.71 0 0 0 90.50±14.85 0 0 20.00±2.83 5.00±2.83 0 0 0 0 0 0 | 4.75±1.06 49.50±0.71 4.00±0.71 0 0 0 0 0 0 0 0 0 0 0 25.25±0.35 0 0 0 2.45±0.07 0 0 12.00±0.00 0 0 0 104.00±15.56 0 0 21.50±0.71 3.50±0.71 0 0 0 0 0 0 | 3.25±1.06 48.75±0.35 4.00±0.71 0 0 0 0 0 0 0 0 0 0 0 25.00±0.00 0 0 0 2.45±0.07 0 0 12.75±1.06 0 0 0 105.00±72.12 0 0 22.50±3.54 2.50±3.54 0 0 0 0 0 0 |
| Not clear cell degradation cell | 0 0 | 0 0 | 0 0 | 0 0 |
180 days 8 dogs of administration, microscopically is observed, each Os Canitis myelocyte active proliferation and extremely active.
Table 8 administration medullary cell inspection in 270 days (%, X ± SD)
| Index | Heavy dose of (n=4) | Middle dosage (n=4) | Low dose of (n=4) | Matched group (n=4) |
| The neutral stab form granulocyte neutrophilic segmented granulocyte of hemogonia myeloblast progranulocyte myelocyte neutrophilic metamyelocyte is had a liking for sour myelocyte and had a liking for sour metamylocyte and have a liking for sour stab form granulocyte and have a liking for sour leaflet granulocyte and have a liking for the alkali myelocyte and have a liking for the alkali metamylocyte and have a liking for the alkali stab form granulocyte and have a liking for early megalocyte polychromatic megaloblast megalocyte grain in evening system of alkali leaflet granulocyte pronormoblast early erythroblast rubricyte metarubricyte: (M: E) the inmature megakaryocytic maturation of the full sheet megacaryocyte sum of the inmature monocyte monocyte of the inmature lymphocyte lymphocyte of lymphoblast monoblast Megakaryoblast has blood platelet to form ripely to form bare nucleus cell desmacyte endothelial cell phagocyte without blood platelet in red system | 0 0 0 4.75±0.96 4.00±0.71 50.13±0.63 3.00±0.41 0 0 0 0 0 0 0 0 0 0 0 25.5±0.58 0 0 0 2.40±0.10 0 0 12.50±0.41 0 0 0 69.75±11.18 0 0 19.50±1.29 5.50±1.29 0 0 0 0 | 0 0 0 5.25±0.56 4.13±0.41 49.50±0.50 3.75±0.56 0 0 0 0 0 0 0 0 0 0 0 25.75±0.25 0 0 0 2.38±0.04 0 0 11.63±0.41 0 0 0 66.25±9.98 0 0 20.25±1.92 4.25±2.17 0 0 0 0 | 0 0 0 4.38±0.41 3.88±0.96 57.88±12.81 3.63±1.14 0 0 0 0 0 0 0 0 0 0 0 25.25±0.43 0 0 0 2.43±0.04 0 0 12.38±0.65 0 0 0 76.50±9.60 0 0 20.50±1.12 4.25±1.30 0 0 0 0 | 0 0 0 4.88±0.85 4.00±0.82 50.13±0.25 3.75±0.29 0 0 0 0 0 0 0 0 0 0 0 25.50±0.71 0 0 0 2.43±0.10 0 0 11.75±0.65 0 0 0 64.75±7.14 0 0 19.0±1.83 5.50±2.08 0 0 0 0 |
| Plasma cell organizes giant cell to fail to understand the cell degradation cell | 0 0 0 0 | 0 0 0 0 | 0 0 0 0 | 0 0 0 0 |
270 days 16 dogs of administration, microscopically is observed, each Os Canitis myelocyte active proliferation and extremely active.
Experimental example 4 chlorogenic acids are right
60The Co-gamma-rays causes the protective effect of mouse spleen hematopoietic stem cell injuries
1., experimental technique
Get healthy C
5760 of mices are divided into 5 groups at random according to the sex body weight.By grouping administration respectively, negative each Mus intraperitoneal injection of saline 0.4ml/20g body weight of group, positive group (granulocyte colony-stimulating factor) each Mus lumbar injection gives 0.4ml/20g body weight (2ug/kg), and its excess-three group is organized each Mus lumbar injection 0.4ml/20g body weight (dosage 20,10 and 5mg/kg) with 0.1%, 0.05% and 0.025% chlorogenic acid medicinal liquid respectively to each.More than 5 groups of each Mus be administered once equal every day, continuous 7 days, claimed the surviving animals body weight on 7th, after the last administration 1 hour.Cervical vertebra dislocation in the 9th day was put to death after each organized mice whole body once irradiating, take out spleen, remove the fat of adhesion, place fixedly 3min of Bouins liquid then, observe and carry out endogenous spleen tuberosity counting (CFU-S), BMNC counting (BMNC) with magnifier.Compare significant difference between group.
2, experimental result
Table 9 chlorogenic acid is right
60The Co-gamma-rays causes the protective effect of mouse spleen hematopoietic stem cell injuries
| Group | Dosage (mg/kg) | Number of animals (only) | CFU-S (10 -1/spleen) | BMNC (10 4/fermr) |
| Chlorogenic acid is little in the big chlorogenic acid of model control group positive group chlorogenic acid | 0.025 20 10 5 | 12 12 12 12 12 | 23.6±1.7 78.2±12.2*** 82.8±5.3*** 72.4±12.6** 53.10±8.2* | 21±3.51 88.6±12.9*** 89.8±13.7*** 69.2±6.8** 51.2±11.2* |
Compare * * * P＜0.001 * * P＜0.01 * P＜0.05 with model control group
4, conclusion
The result of table 9 shows that chlorogenic acid 20,10 and 5mg/kg inject to mouse peritoneal, and is once a day, continuous 7 days, right
60The Co-gamma-rays causes the mouse spleen hematopoietic stem cell injuries stronger protective effect.
The influence of experimental example 5 chlorogenic acid mice hemopoietic functions
1 experimental technique
Quick aging model white mice (being called for short SAM).Wherein be divided into the R system of normal aging and the P system of quick aging again according to aging speed and condition of illness feature.Adopt 9 monthly age SAMR1 and SAMP8 two strains.
After the disconnected ridge of animal is put to death in the preparation of medullary cell (BMC), alcohol disinfecting, the aseptic side femur that strips washes medullary cavity for several times with RPMI-1640 liquid repeatedly by No. 6 syringe needles, again the medullary cell liquid of going out is prepared into single cell suspension by No. 4 syringe needles.
The mensuration of mouse bone marrow cells hematopoietic stem cell (CFU-S) is lived and is killed mice, sterile preparation BMC suspension, be made into every milliliter of 5 * 104 cells behind the counting nucleated cell, give mouse tail vein infusion 0.2ml cell suspension after 8.0 Gy60Go irradiation, the receptor Mus is killed in work in the 9th day, get spleen with the liquid-solid 24h of deciding of Bouin after count table tuberculum faciale number.
The mensuration general's quantitative (1 * 105) of bone marrow grain monosystem CFU-GM (CFU-GM) bone marrow cell suspension adds horse serum and the RPMI-1640 culture fluid is incubated 10～20min in 37 ℃ of water-baths, mixing behind the adding 30g/L agar, change in the agar culture dish that contains 0.2ml rat lung strip spare stimulation fluid, in 37 ℃, cultivated in the incubator of 0.05%CO2 saturated humidity 5～7 days, and put the colony (CFU-GM) that counting contains more than 50 cells under the low power lens and count.
Bone marrow is early stage, late period CFU-E (BFU-E, CFUE) it is 10% bone marrow cell suspension (5 * 104ml) that mensuration is made into final concentration with cultivating system, the 200g/L horse serum, the 100g/L bSA, 1 * 10-5mol/L 3-mercaptoethanol, 10% quick-fried formula colony promoting activity (BPA), after 0.8% methylcellulose and every milliliter of 1U EPO etc. fully mix, add 10 μ l to the cellular plastic culture plate, put in the incubator and cultivated 3 days, with behind the benzidine staining under inverted microscope 8 above stained positive cell colonies of counting to count red be colony forming unit (CFU-E), cultivate to count that to contain 50 above benzidine staining positive cell colonies be burst forming unit erythroid (BFU-E) in 8 days.
The mensuration mouse tail vein blood sampling of mice peripheral hemogram, Coulter blood-counter system counting.
Bone marrow of mice is observed broken end and is lived and kill mice and get complete left side femur, and it is liquid-solid fixed to go into Hellyps, specimens paraffin embedding slices, HE dyeing, tissues observed variation under the light microscopic.
2 experimental results
The influence of chlorogenic acid mouse bone marrow cells hematopoietic stem cell
SAM P8 mice is divided into 3 groups at random: 1 group is SAM P8 matched group, and 2,3 groups is chlorogenic acid 10,20m g/kg/ days * 8 days, and intravenous injection.Other gets with monthly age SAMR1 and SAMP8 matched group, gives normal saline every day.Respectively organizing mice prepares the BMC suspension extremely in work in 9 days, presses the preceding method infusion and gives the receptor Mus.Fixedly observed result of spleen is got in work in 9 days extremely, and the result shows that SAM P8 mice CFU-S several 223 ± 107 is starkly lower than the SAMR1 mice CFU-S 550 ± 189 (n=12, P＜0.01) with the monthly age.And SAM P8 mice CFU-S counts showed increased after giving chlorogenic acid, and its CFU-S number is respectively 483 ± 125 and 527 ± 183 results suggest chlorogenic acids has certain stimulation to the proliferation and differentiation of SAMP8 mouse bone marrow cells hematopoietic stem cell.
Chlorogenic acid is to the influence of mouse bone marrow cells hemopoietic progenitor cell propagation
Animal grouping, administration are put to death mice sterile preparation BMC suspension in the 9th day disconnected ridge of administration and are experimentized by preceding method with preceding identical.The result shows that the multiplication capacity of SAM P8 mouse bone marrow cells hemopoietic progenitor cell is starkly lower than the SAMR1 mice, has notable difference between the two.Chlorogenic acid then can make the grain monosystem hemopoietic progenitor cell of SAM P8 mice, and the multiplication capacity that reaches the CFU-E in late period in early days all obviously increases.
Chlorogenic acid is to the influence of mice peripheral hemogram
The result shows that in the SAM P8 mice peripheral hemogram, its WBC number is starkly lower than the mice with monthly age SAMR1.Chlorogenic acid 10,20mg/kg then can obviously make its WBC number increase.
Chlorogenic acid is to the influence of mice serum CSA
With each group mice heart blood sampling respectively, static centrifugal preparation serum replaces lung conditional stimulus liquid (CSF-GM) with serum, observes its influence to CFU-GM propagation, represents CSA with the productive rate of CFU-GM.The result proves that the productive rate 79.6 ± 7.9 of CFU-GM of SAMR1 mice serum is apparently higher than SAM P8 mice CFU-GM 57.3 ± 7.4 (n=12, P＜0.01).And give behind the chlorogenic acid 10, the CFU-GM of 20mg/kg SAM P8 mice obviously increases (CFU-GM is respectively 74.2 ± 7.2 and 81.5 ± 8.2) and SAM P8 group and compares that there were significant differences, the prompting chlorogenic acid can obviously strengthen the intravital CSA of SAM P8 mice, promotes the proliferation and differentiation of SAM P8 mouse bone marrow cells hemopoietic progenitor cell.
Chlorogenic acid is to the influence of bone marrow of mice
The result of Histological research shows that SAM R1 mouse bone marrow cells intracavity hemopoietic progenitor cell is abundant, respectively be that cell all can be seen, and form is good, molecular marker for increased proliferation, and blood sinus is more.And obviously reduce with monthly age SAMP8 mouse bone marrow cells intracavity hematopoietic cell, hypertrophy is inactive, and based on middle metamyelocyte, even the part lacks hematopoietic cell, the fibrous connective tissue hypertrophy, blood sinus is less.The SAM P8 mice that gives behind the chlorogenic acid is compared hematopoietic cell showed increased in its medullary cavity with medication SAM P8 mice not, active proliferation, blood sinus is more, but than SAM R1 mouse bone marrow cells hematopoietic cell and blood sinus for few.This results suggest chlorogenic acid can obviously improve SAM P8 mouse bone marrow cells hemopoietic function.
Claims (10)
1, the chlorogenic acid list is used or is had the purposes that increases the bone marrow cell efficiency medicine in preparation with other drug.
2, purposes according to claim 1, wherein said medicine have the bone marrow stem cell of increasing effect.
3, purposes according to claim 1, myelofibrosis and marrow infection that wherein said curable substance a variety of causes causes.
4, purposes according to claim 1, the thrombocytopenia that wherein said curable substance a variety of causes causes.
5, purposes according to claim 1, wherein said medicine has significant protective effect to the spleen hematopoietic stem cell injuries.
6, according to claim 1,5 described purposes, wherein said medicine can strengthen hemopoietic function.
7, according to claim 1,5 described purposes, anemia and hypersplenism that wherein said curable substance a variety of causes causes.
8, according to claim 1,5 described purposes, wherein said curable substance hemorrhagic anemia, hemolytic anemia, macrocytic anemia and aplastic anemia.
9, the chlorogenic acid list with or with the purposes of other drug at preparation leukocyte increasing effect medicine.
10, purposes according to claim 9, the leukopenia that this curable substance a variety of causes wherein causes, granulocytopenia, agranulocytosis.
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| CNA2005100880248A CN1899280A (en) | 2005-07-22 | 2005-07-22 | Use of chlorogenic acid in preparing medicine for improving bone marrow cell efficiency |
| CN200680024175XA CN101212963B (en) | 2005-07-22 | 2006-07-21 | The use of chlorogenic acid in the manufacture of medicaments for increasing the effect of bone marrow cells |
| CN2009102461340A CN101703497B (en) | 2005-07-22 | 2006-07-21 | Application of Chlorogenic acid in preparing drug having protection and restoration functions on spleen hematopoietic stem cell injuries |
| PCT/CN2006/001795 WO2007009393A1 (en) | 2005-07-22 | 2006-07-21 | The use of chlorogenic acid in the manufacture of medicaments for increasing the effect of bone marrow cells |
| CN2009102466274A CN101695485B (en) | 2005-07-22 | 2006-07-21 | Use of chlorogenic acid in preparing medicament for treating thrombocytopenia and anemia |
| CN2009102466306A CN101695486B (en) | 2005-07-22 | 2006-07-21 | Use of chlorogenic acid in preparing medicament for treating marrow fibrillation |
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| CN115058389B (en) * | 2022-07-01 | 2023-07-25 | 济南大学 | Chlorogenic acid-calcium nano slow release agent and application thereof in promoting stem cell osteogenic differentiation |
| CN116712568B (en) * | 2023-08-04 | 2023-10-03 | 山东第一医科大学附属省立医院(山东省立医院) | Risedronate sodium inclusion compound, preparation and application |
| CN117205225B (en) * | 2023-09-12 | 2024-05-31 | 湖南普瑞玛药物研究中心有限公司 | Application of geniposide in preparation of medicament for treating myeloproliferative neoplasm |
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| CN1225262C (en) * | 2002-12-11 | 2005-11-02 | 万广灿 | Chinese medicine capsule for treating hemopathy and its prepn |
| CN1568960A (en) * | 2004-05-08 | 2005-01-26 | 四川九章生物化工科技发展有限公司 | High purity chlorogenic acid prescription |
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| US10723998B2 (en) | 2015-01-26 | 2020-07-28 | Northeast Normal University | Application of ethyl p-methoxycinnamate and derivatives thereof in maintaining self-renewal and pluripotency of stem cells |
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