CN104546820A - Application of stilbene dimer in preventing and curing hematopoietic stem cell radioactive damage - Google Patents
Application of stilbene dimer in preventing and curing hematopoietic stem cell radioactive damage Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- Pharmacology & Pharmacy (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses an application of Vam3(Amurensis H) as shown in a formula (I) in the preparation of a medicine for preventing and/or treating hematopoietic stem cell radioactive damage disease.
Description
Technical field
The present invention relates to the novel medical use of the stilbene dimer Vam3 (Amurensis H) shown in formula I, it is specially the application of Vam3 in preparation control hematopoietic stem cell radiation injury disease medicament.
Background technology
Along with the continuous expansion in Application of Nuclear Technology field, the especially appearance of nuclear power station, RADIATION PROCESSING technique etc., Nuclear Accidents present increase trend, cause serious environmental radiation contact scar, casualties and economic loss.Equally, due to the popularization and application of household electrical appliance, particularly for the harm that the electromagnetic radiation such as daily mobile phone, TV, computer, microwave oven bring to human body, as insomnia, impatient, fatiguability, serious have that aplastic anemia is poor, leukemia etc., also all the physical and mental health of people in serious harm, also there is no special control medication at present, need equally to cause our great attention.
Hematopoietic stem cell is that in hemopoietic tissue, a class has self renewal, and can be divided into the CFU-GM of all kinds of maturation in peripheral blood system.The marrow hemopoietic stem cells (Hematopoietic stem cell, HSC) of the overwhelming majority is present in myeloid tissue, is free on a small quantity in peripheral blood circulation system.The radiation of daily life small can strengthen immune function of human body, but the ionizing radiation of heavy dose can cause serious biological effect to body, and comprise the change of sexual cell hereditary material, hemopoietic system dysfunction, the incidence rate of cancer increases.Large quantifier elimination shows in recent years, and radiation can cause the change of marrow hemopoietic stem cells DNA structure and function, abnormal gene expression, the increase etc. of apoptosis and active oxygen (reactiveoxygen species, ROS) level.Under normal circumstances, marrow hemopoietic stem cells and sustenticular cell thereof are mainly positioned in the hypoxia microenvironment of bone marrow, and this makes marrow hemopoietic stem cells from being oxidized the damage caused, can maintain the normal self renewal of marrow hemopoietic stem cells and differentiation function.When reactive oxygen species level raises, the marrow hemopoietic stem cells that directed differentiation produces erythron clone and granulocyte/erythrocyte/monocyte/macrophage colony forming unit (FCU-GEMN) then directed differentiation produces more medullary system clone instead of erythron is cloned, and then affects self renewal and the directed differentiation of marrow hemopoietic stem cells.In addition, ROS also can have an impact to marrow hemopoietic stem cells cell cycle, as high-caliber ROS can reduce the G being in relative static conditions
0the ratio of phase marrow hemopoietic stem cells, causes marrow hemopoietic stem cells defect resting stage, marrow hemopoietic stem cells is consumed.Developing rapidly in recent years along with tumor radiotherapy and nuclear industry, have object to find toxicity low, the radioprotective new drug that curative effect is high becomes current study hotspot.Amino compound, protease inhibitor, natural drug, hormone, vitamin, metallic element and some biological preparation etc. play a part very large to radiation protection, but these medicines generally can only relief of symptoms, cannot reach the object of curing completely, and some medicine has certain negative interaction, life-time service inevitably causes the infringement of biological organs.
Vam3 (Amurensis H), that inventor's separation first from Vitis amurensis Rupr. ethanol extraction obtains, now can chemosynthesis, structural formula is as shown in formula I, preparation method is shown in " purposes of Vitis amurensis Rupr. extract for treating inflammation disease " (application number 03134647.2, publication number CN1600304).Vam3 prevents and/or treats hematopoietic stem cell radiation injury and has no report.
Summary of the invention
The object of the present invention is to provide and prepared such as formula the compound Vam3 (AmurensisH) described in I the effect prevented and/or treated in hematopoietic stem cell radiation injury disease medicament.
BMNC (Bone marrow mononuclear cells, BMMNCs), containing multiple non-stem cell constituents and cofactor, has important effect for the self renewal maintaining hematopoietic stem cell.In addition, the hematopoietic support cells also containing some in these cells, as hemopoietic stromal progenitor cells, mature substrate cell etc., they may produce cytokine profiles, have support and promote proliferation of hematopoietic progenitors and differentiation function.Therefore, the vigor of BMNC directly affects the normal function of medulla hematopoietic system.The patient being subject to ionizing radiation usually shows as lower BMNC vigor.At the compounds of this invention in radioactive exposure mice BMMNCs effect of vigor, Vam3 promotes that mice BMMNCs cell viability adds 30% (P<0.005), show that the compounds of this invention has the effect strengthening BMMNCs cell viability, can be used for preventing and/or treating hematopoietic stem cell radiation injury disease.
Radiation-induced ROS can react with DNA, causes DNA oxidized, double-strand break; React with membrane lipid, cause cell membrane and nucleus damage.ROS comprises the free radical of such as superoxides and hydroxyl, also has non-free radical, as H
2o
2.The biological behaviour relevant to ROS comprises a large amount of radical pair cell functions and vigor is harmful, and ROS and NO combines the generation etc. causing nitrite.Be subject to the patient of ionizing radiation, in BMMNCs, ROS level raises.High-caliber ROS suppresses the performance of BMMNCs normal function, and then affects the long-term self renewal of marrow hemopoietic stem cells and directed differentiation.At the compounds of this invention in the impact of radioactive exposure mice BMMNCs intracellular ROS level, Vam3 promotes mice BMMNCs cell ROS level decline 19% (P<0.005), show that the compounds of this invention has the effect suppressing BMMNCs cell ROS level to increase, can be used for preventing and/or treating hematopoietic stem cell radiation injury disease.
Bone marrow is the sexy high tissue of radiation-sensitive.After radiation damage, the quantity of the hematopoietic cell of survival and multiplication capacity decide state and the prognosis of the rear hemopoietic function of wound.BMMNCs clonality directly affects the number of bone marrow HSC and self renewal and differentiation capability, and then decides the normal hemopoietic function of bone marrow HSC.At the compounds of this invention in the impact of radioactive exposure mice BMMNCs Cell clonality, Vam3 promotes that mice BMMNCs Cell clonality increases enhancing 75% (P<0.05), show that the compounds of this invention has the clonality promoting BMMNCs cell, can be used for preventing and/or treating hematopoietic stem cell radiation injury disease.
Above-mentioned experiment proves, as shown in formula I, compound can for the preparation of the product preventing and/or treating hematopoietic stem cell radiation injury disease.Described product comprises medicine, health food.
Accompanying drawing illustrates:
Fig. 1, Vam3 are on the impact of radioactive exposure mice BMMNCs vigor.With ctr(normal group) compare, P<0.001; With IR(radiation group) compare, P<0.001.n=9。
Fig. 2, Vam3 are on the impact of ROS level in radioactive exposure mice BMMNCs.With ctr(normal group) compare, P<0.001; With IR(radiation group) compare, P=0.0188.n=6。
Fig. 3, Vam3 affect radioactive exposure mice BMMNCs clonality.With ctr(normal group) compare, P=0.015; With IR(radiation group) compare, P=0.0156.n=6。
Detailed description of the invention
1, administration and illuminating method: mouse stomach administration, dosage is 25mg/kg, 1 hour mice 4Gy gamma-rays total irradiation after administration, close rate 0.80Gy/min.
2, the separation of mice BMMNCs cell aseptic separating mouse bilateral femur and tibia, removes surface attachment muscle, is gone out by medullary cell with 2.5ml disposable sterilized injector in Hank's liquid.The cell suspension gone out is added in 50ml EP pipe, bottom cell suspension, slowly add Ficoll according to cell suspension and Ficoll2:1 ratio lumbar puncture needle, during separation, centrifuge raising speed and reduction of speed are all adjusted to minimum.Centrifugally completely get middle batt layer and be added in another 50ml EP pipe, Hank's liquid centrifuge washing cell twice, finally adds 10% hyclone with RPMI-1640() cell concentration is adjusted to 1 × 10 by culture medium
6cell/ml uses.
3, mice BMMNCs cell viability test experience is divided into matched group, irradiation control group, irradiation dosing group.By 1 × 10
6cell/ml concentrations of cells suspension be inoculated in 96 orifice plates, every hole 200 μ l.Multi-functional microplate reader detects cell viability.
4, in mice BMMNCs, the experiment of ROS horizontal detection is divided into matched group, irradiation control group, irradiation dosing group.By 1 × 10
6cell/ml concentrations of cells suspension 1ml adds in the aseptic EP pipe of 2ml, and each pipe adds DCFH-DA according to the ratio of cell suspension and active oxygen detector probe (DCFH-DA) 1000:1,37 DEG C of CO
2centrifugal after hatching 30min in incubator, three times are washed to wash away probe by serum-free RPMI-1640 culture medium after supernatant discarded, finally clean `RPMI-1640 culture medium with depletion of blood to be hanged by cell, be seeded in 96 hole blackboards, multi-functional microplate reader detects cell fluorescence value.Absorbing light 488nm, utilizing emitted light 522nm.
5, mice BMMNCs clonality test experience is divided into matched group, irradiation control group, irradiation dosing group.Adjustment cell concentration is 10 times of inoculum density, 0Gy inoculating cell concentration 1 × 10
4cell/ml, 4Gy inoculating cell concentration 1 × 10
5cell/ml.Add 0.2ml cell in 2ml M3534 culture medium, agitator fully mixes, and leaves standstill 2 ~ 5min, treats bubble collapse.Connect 16# tack syringe needle with 2.5ml syringe, draw 0.5ml cell suspension, add 24 orifice plates, jog culture plate, culture medium is uniformly distributed.Culture plate is inserted 37 DEG C, 5%CO
2cultivate in incubator, within the 5th day, low power observes Colony forming situation, and cell number>=30 are positive colonies.
Embodiment 1Vam3 affects radioactive exposure mice BMMNCs cell viability
Mouse stomach administration, dosage is 25mg/kg, and after administration, 1 hour mice is with the total irradiation of 4Gy gamma-rays, close rate 0.80Gy/min.Aseptic separating mouse BMMNCs cell, adds 10% hyclone with RPMI-1640() cell concentration is adjusted to 1 × 10 by culture medium
6cell/ml, is inoculated in 96 orifice plates, every hole 200 μ l.
The object of this experiment is to investigate Vam3 to the impact of radioactive exposure mice BMMNCs vigor, the results are shown in Figure 1.
Result: Irradiated Mice compares with without radioactive exposure mice, BMMNCs vigor declines 27.4%, and after the radioactive exposure of gastric infusion mice, BMMNCs vigor is not compared with giving the mice of Vam3 radioactive exposure group, and cell viability improves 30%.
Embodiment 2Vam3 is on ROS level impact in radioactive exposure mice BMMNCs
By 1 × 10
6the mice BMMNCs cell suspension 1ml of cell/ml concentration mixes with active oxygen detector probe (DCFH-DA), after hatching centrifuge washing, hanged by cell by serum-free RPMI-1640 culture medium, be seeded in 96 hole blackboards, multi-functional microplate reader detects cell fluorescence value.
The object of this experiment is to investigate Vam3 to the impact of ROS level in radioactive exposure mice BMMNCs, the results are shown in Figure 2.
Note: with ctr(normal group) compare, P<0.001; With IR(radiation group) compare, P=0.0188.n=6。
Result: after radioactive exposure, mice is compared with without radioactive exposure mice, BMMNCs unicellular interior ROS value rising 75%, after the radioactive exposure of gastric infusion mice, the unicellular interior ROS level of BMMNCs declines about 20%.
Embodiment 3Vam3 affects radioactive exposure mice BMMNCs clonality
Adjustment cell concentration is 10 times of inoculum density, 0Gy inoculating cell concentration 1 × 10
4cell/ml, 4Gy inoculating cell concentration 1 × 10
5cell/ml.Add 0.2ml cell to 2ml M3534, fully mix, be inoculated in 24 orifice plates, put into incubator and cultivate, within the 5th day, low power observes Colony forming situation.
The object of this experiment is that investigating Vam3 affects radioactive exposure mice BMMNCs clonality.
Result: after radioactive exposure, mice is compared with without radioactive exposure mice, BMMNCs clonality significantly declines, after the radioactive exposure of gastric infusion mice BMMNCs clonality with do not give increase by 75% compared with Vam3 radioactive exposure group mice.
Claims (2)
1. as shown in formula I, compound prevents and/or treats hematopoietic stem cell radioactivity in preparation
Application in damage disease product
2. application according to claim 1, is characterized in that, described product comprise medicine, health food.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310466926.5A CN104546820A (en) | 2013-10-09 | 2013-10-09 | Application of stilbene dimer in preventing and curing hematopoietic stem cell radioactive damage |
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| CN201310466926.5A CN104546820A (en) | 2013-10-09 | 2013-10-09 | Application of stilbene dimer in preventing and curing hematopoietic stem cell radioactive damage |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113304139A (en) * | 2021-06-30 | 2021-08-27 | 贵州医科大学 | Application of Viniferifuran in preparation of xanthine oxidase inhibition drugs |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1600304A (en) * | 2003-09-23 | 2005-03-30 | 中国医学科学院药物研究所 | Application of extractive of ussurian grape on curing inflammatory disease |
| CN101057840A (en) * | 2006-04-21 | 2007-10-24 | 中国医学科学院药物研究所 | Application of Vam3 in preparing medicine for treating chronic obstructive disease of lung |
-
2013
- 2013-10-09 CN CN201310466926.5A patent/CN104546820A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1600304A (en) * | 2003-09-23 | 2005-03-30 | 中国医学科学院药物研究所 | Application of extractive of ussurian grape on curing inflammatory disease |
| CN101057840A (en) * | 2006-04-21 | 2007-10-24 | 中国医学科学院药物研究所 | Application of Vam3 in preparing medicine for treating chronic obstructive disease of lung |
Non-Patent Citations (3)
| Title |
|---|
| GEORGE A. KRAUS等: "A new synthetic strategy for the synthesis of bioactive stilbene dimers. A direct synthesis of amurensin H", 《TETRAHEDRON LETTERS》 * |
| 张俊伶等: "山葡萄根提取物Vam3对辐射致小鼠骨髓单个核细胞损伤作用研究", 《中国药理通讯》 * |
| 张俊伶等: "山葡萄根提取物Vam3对辐射致小鼠骨髓单个核细胞损伤保护作用研究", 《第七届中国核学会"三核"论坛中国放射医学教育五十年暨育五十年暨中国毒理学会放射毒理委员会第八次全国会议论文集》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113304139A (en) * | 2021-06-30 | 2021-08-27 | 贵州医科大学 | Application of Viniferifuran in preparation of xanthine oxidase inhibition drugs |
| CN113304139B (en) * | 2021-06-30 | 2022-04-29 | 贵州医科大学 | Application of Viniferifuran in preparation of xanthine oxidase inhibition drugs |
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Application publication date: 20150429 |