CN100364563C - Combination for restraining p38 subfanmily of protein kinase activated by mitogen and application - Google Patents
Combination for restraining p38 subfanmily of protein kinase activated by mitogen and application Download PDFInfo
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- CN100364563C CN100364563C CNB2004100772323A CN200410077232A CN100364563C CN 100364563 C CN100364563 C CN 100364563C CN B2004100772323 A CNB2004100772323 A CN B2004100772323A CN 200410077232 A CN200410077232 A CN 200410077232A CN 100364563 C CN100364563 C CN 100364563C
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Abstract
The present invention relates to a combination for restraining activity of subfanmily of mitogen activated protein kinase p38. The present invention can be used for preparing medicine for preventing and treating atherosclerosis. The present invention is composed of the following raw materials of 0 to 6 portions of milk vetch and 0 to 6 portions of angelica by weight, wherein the proportion of one group is not zero. A p38MAPK signal can be blocked to conduct a path by the composition of the present invention, and the phenomenon that mononuclear cells are induced to aggregate by OxLDLs is avoided. Thus, the processes of pathologic change of hyperlipemia or atheromatosis in an early stage of development are blocked, and the development of pathologic change of a later stage can be relieved.
Description
Technical field
The present invention relates to the Chinese medicine composition field, specifically is compositions and the application in preparation prevention and treatment atherosclerosis medicine thereof that suppresses p 38 subfanmily of protein kinase activated by mitogen (p38 MAPK) signal transduction pathway.
Background technology
(atherosclerosis, As) diseases related coronary heart disease and apoplexy remain one of the highest disease of present mortality rate to atherosclerosis.Further investigation to atherosclerosis mechanism is an international front subject in recent years always.It is generally acknowledged that the earliest period process that atherosclerotic lesions forms is to assemble at the subendothelium place after the mononuclear cell that derives from blood becomes macrophage, develops into the foam cell that contains lipid then.The oxidized low-density lipoprotein (oxLDL) that low density lipoprotein, LDL (LDL) forms through oxidative modification can be induced the variation of a plurality of cell functions, and this variation may participate in atheromatous formation.At this atherosclerotic commitment, oxLDL can cause propagation, the migration of vascular cell, and can hinder the regeneration of endotheliocyte, and itself is exactly the lymphocytic strong chemoattractant of a kind of mononuclear cell and T.OxLDL can promote adhesion molecule, cytokine, chemotactic factor, heat shock protein and the expression of coagulated protein altogether in nearly all arteries cell, and can suppress the generation of the vasodilator factor, nitric oxide and the prostacyclin in endotheliocyte source, also can induce multiple pro-inflammatory cytokine and somatomedin.
Cell signalling then is one to study focus greatly in the world at present.MAPK is important signal transduction person in the cell, has participated in the adjusting of multiple physiological and pathological process, has found and cloned ERK, JNK/SAPK, ERK5/BMK1T and four subtribes of p38 in mammalian cell.Cell born of the same parents external stimulus activates MAPK, makes its phosphorylation retrodisplacement go into other positions in the cell, effect respective objects and bring into play regulating action (1.Debree FM, brzozowski AM, Gellerfors P, et al.[J] .Protein ExprPurif, 1998,13 (3): 319-325.2. Jiang Yong .p38 MAPK signal transduction pathway. life sciences, 1999; 11 (3): 102-106.).Result of study shows: OxLDLs activates mononuclear cell mitogen activated protein kinase (the mitogen-activated protein kinase in the blood, MAPK) p38 subtribe, be p38MAPK, by this intracellular signal transduction pathway, induce mononuclear cell to gather to arterial wall (1.QingJing, et al.Lysophosphatidylcholine activates p38 and p42/44mitogen-activated protein kinases in monocytic THP-1 cells, but onlyp38 activation is involved in its stimulated chemotaxis.CirculationResearch, 2000 (7): 52-59.).
Summary of the invention
The object of the present invention is to provide the active compositions of a kind of inhibition p38MAPK, it can be by suppressing the THP-1 mononuclear cell p38MAPK phosphorylation and the activation of oxLDL mediation, blocking-up p38MAPK signal transduction pathway, thus reach prevention and treat atherosclerotic purpose.
The present invention also aims to provide the application of described compositions in preparation treatment and prevention hyperlipemia or atherosclerosis medicine.
The active compositions of inhibition p 38 subfanmily of protein kinase activated by mitogen of the present invention is characterized in that being made by following materials of weight proportions: Radix Astragali 0-6 part, and Radix Angelicae Sinensis 0-6 part, wherein a set of dispense is than non-vanishing.
The optimal components ratio of raw material: Radix Astragali 1-6 part, Radix Angelicae Sinensis 1-6 part.
The best proportioning of raw material: 5 parts of the Radixs Astragali, 1 part of Radix Angelicae Sinensis.
Described compositions can prepare the medicine of treatment and prevention hyperlipemia disease.
Described compositions can prepare the medicine of treatment and prevention coronary heart disease.
Described compositions can prepare the medicine of treatment and prevention of stroke disease.
Described compositions can prepare the medicine of treatment and the atherosis disease of prevention renal artery.
The medicine of preparation is injection or oral formulations, and described oral formulations is one or more in following: hard capsule, soft capsule, tablet, granule, powder, pill, teabag, medicated wine, oral liquid.Can adopt existing method in common preparation.
The present invention compared with prior art has following advantage: compositions of the present invention can be blocked the p38MAPK signal transduction pathway, avoid OxLDLs to induce the mononuclear cell clustering phenomena, thereby block its process at the early stage of development of hyperlipemia or atherosclerotic lesion; Can alleviate the development of later stage pathological changes again.
The specific embodiment
Embodiment 1
Get Radix Angelicae Sinensis 10g, Radix Astragali 50g decocts and the concentrated oral liquid made from clear water.
Embodiment 2
Get Radix Angelicae Sinensis 10g, Radix Astragali 60g pulverizes and makes granule.
Embodiment 3
Get Radix Angelicae Sinensis 60g, Radix Astragali 10g is pressed into tablet after the pulverizing.
Embodiment 4
Get Radix Angelicae Sinensis 10g, Radix Astragali 10g is packaged into teabag.
Embodiment 5
Radix Angelicae Sinensis 10g decocts and the concentrated oral liquid made from clear water.
Embodiment 6
Radix Astragali 50g decocts and the concentrated oral liquid made from clear water.
Clinical trial result:
Reagent: KBr (chemical reagent two factories in potassium bromide Guangzhou produce, lot number 2001051502); EDTA-Na (disodiumedetate), protein determination kit (Lowry method) and DMEM culture medium are Shanghai Shenergy Biocolor BioScience ﹠ Technology Company and produce; P38MAPK measures test kit;
1. instrument
Superspeed refrigerated centrifuge (OptimaTM XL-cook Ultracentrifuge, BeckMAN rotary head model: 70Ti (60,000 ten thousand change 4.5 hours)); CO
2Incubator (BNA-3210 type C02 incubator, Japanese ESPEC), inverted microscope (Japanese COIC); Bio-Rad GS-800 alignment light gravimetry instrument (Calibrated Densitometer), GS-800 microplate reader (Japanese BioRad); High speed refrigerated centrifuge (German Sigma);
2. animal
6 of new zealand rabbits, regular grade, male and female half and half, weight average 2kg is provided by Traditional Chinese Medicine University Of Guangzhou's Experimental Animal Center, the quality certification number: Guangdong probatio inspectionem pecuoarem word 2003A001 number.
Every rabbit feeds the feedstuff with 1 gram cholesterol every day, and 1 intravenous injection bovine serum albumin (250mg/kg) makes tremulous pulse generation immunologic injury simultaneously, 5 week the back form the pathological changes of similar people As (atherosclerosis).
3. medicine feed
The medicinal liquid of embodiment 1 preparation gives new zealand rabbit respectively and divides secondary to irritate stomach every day, successive administration 3 days, fasting behind the 3rd day filling stomach, inferior perfusion in morning 1 time, 1h heart aseptic condition blood sampling down after the perfusion, separation of serum.Not deactivation group drug serum with the double-deck filtering with microporous membrane degerming of 0.45 μ m and 0.2 μ m after ,-40 ℃ of preservations are standby; Deactivation group drug serum is with behind 56 ℃, 30min deactivation, and is standby with-40 ℃ of preservations after 0.45 μ m and the double-deck filtering with microporous membrane degerming of 0.2 μ m again.
4. the separation and the oxidative modification of low density lipoprotein, LDL (LDL)
With reference to the comparative study that LDL oxidation is modified and malonaldehyde is modified. Acta Biochimica et Biophysica Sinica, 1992,24 (6): 569, disposable density gradient ultracentrifugation method preparation is adopted in the LDL preparation, utilizes protein determination kit (Lowry method) to measure LDL content.
1. LDL preparation: get healthy human blood, 4 ℃ leave standstill centrifugalize serum behind the 2h, adjust density to 1.30g/mL with potassium bromide, put supercentrifuge, and 4 ℃ of 50 centrifugal 5h of 000RPM collects LDL.The 48h that dialyses in PBS, 4 ℃ of preservations are standby behind the heat sterilization.
2. OxLDL preparation: adding final concentration in LDL (1mg/mL) is the CuSO of 5 μ mol/L
4, 37 ℃ of incubation 24h make its oxidized modification, with PBS dialysis 24h, record thiobarbital acid reaction (TBARS) value for 63.0-78.5nmol/mg again, illustrate that LDL is by Cu
++Oxidation.
5. mononuclear cell (monocyte, separation MC)
Get As model Sanguis Leporis seu oryctolagi, with the EDTA-Na anticoagulant, utilize Percoll cell separation liquid to separate to obtain MC, the plastics plate absorption MC to handle through gelatin and self blood plasma collects the MC that adsorbs, and adding DMEM makes cell suspension, and cell density is 1 * 10
6/ mL.Non-specific ester enzyme dyeing detects cell purity＞95%, trypan blue exclusion test showed cell activity＞96%.
6. the packet transaction of cell and p38MAPK are active detects
Rabbit MC adopts the 10cm culture dish to cultivate, and contains 10mL1 * 10
6/ mL cell uses the DMEM culture fluid that contains 25% serum and 5 μ g/mL pertussis toxin, PTs.The different disposal cell adopt that embodiment 1 makes for containing the serum of relative medicine, matched group and OxLDL group are no medicine serum.Cell is at 37 ℃, 5%CO
2After cultivating 24h under the condition, except that matched group, each group adds the rapid mixing of OxLDL, effect 10min, each is handled cell and all abandons supernatant, prepares product of cell lysis by p38MAPK determination of activity kit method, adopts the Western blotting to carry out the active detection of p38MAPK.Adopt the spectrodensitometry instrument to gather the X-ray film image, with the optical density of the Quantity One-4.4.1 analysis software trace speckle of Bio-Rad.The result shows: the active obviously downward modulation of astragalus, angelica pastille serum group p38MAPK, the same substantially with the active matched group of no p38MAPK, though and Radix Astragali pastille serum group, Radix Angelicae Sinensis pastille serum group can be reduced the p38MAPK activity, not obvious.So the oral liquid that embodiment 1 makes can obviously suppress the p38MAPK activity.
Coronary heart disease and apoplexy are as the present the highest cardiovascular and cerebrovascular disease of mortality rate, and its cause of disease is all closely related with the heart, the cerebral atherosclerosis of human body.Cardiovascular and cerebrovascular disease due to the As, its sickness rate and case fatality rate majority state in the world are the trend that rises year by year.As pathophysiological mechanism and Preventing Countermeasures thereof are the research focuses of angiocardiology always.Verified, when lipids contents is too high in the blood of human body, low density lipoprotein, LDL in the blood fat just can soak into the subendothelial layer of blood vessel gradually, mononuclear cell adheres to vascular endothelial cell and the endothelium of moving into, to be converted into foam cell be atherosclerosis (atherosclerosis, As) the early stage crucial pathological change of Xing Chenging to the picked-up lipid.
MAPK is important signal transduction person in the cell, has participated in the adjusting of multiple physiological and pathological process, has found and cloned ERK, JNK/SAPK, ERK5/BMK1T and four subtribes of p38 in mammalian cell.Cell born of the same parents external stimulus activates MAPK, makes its phosphorylation retrodisplacement go into other positions in the cell, effect respective objects and bring into play regulating action.P38 has participated in signal transmission in the various kinds of cell, plays an important role in to the inflammation and the reaction that stress wait at the mediation eukaryotic cell.Studies show that: when the low density lipoprotein, LDL in the blood fat gathers in a large number and oxidative modification takes place in blood vessel endothelium lower floor, OxLDL activates p38MAPK in the blood, by this intracellular signal transduction pathway, induce mononuclear cell to gather to arterial wall, and generation cytotoxicity, cause the foam cell necrosis in the atheromatous plaque, and can make vascular smooth muscle cell secrete substrate minimizings such as collagen, cause atherosclerotic plaque fragility to increase, and be easy to fragmentation, thereby in blood vessel, form thrombosis, cause coronary heart disease and apoplexy patient's state of an illness outbreak.
Observe the influence of compositions of the present invention to the effect of OxLDLs activated mononuclear cell p38MAPK signal transduction pathway, result of study shows that OxLDL can make the active rise of P38MAPK, and this is consistent with reported in literature; The single Radix Astragali, Radix Angelicae Sinensis are to the obviously influence of the active nothing of P38MAPK, and the present composition is obviously reduced the activity of P38MAPK.This presentation of results, the mechanism of action of present composition control As and relevant disease thereof mainly is by downward modulation p38MAPK activity, avoided OxLDLs to induce mononuclear cell to gather blood vessel endothelium, thereby blocked its process, can alleviate the development of later stage pathological changes again at the early stage of development of As pathological changes.
Claims (8)
1. one kind is suppressed the active compositions of p 38 subfanmily of protein kinase activated by mitogen, it is characterized in that being made by following materials of weight proportions: 5 parts of the Radixs Astragali, 1 part of Radix Angelicae Sinensis.
2. the application of the described compositions of claim 1 in the medicine of preparation treatment and prevention hyperlipemia disease.
3. the application of the described compositions of claim 1 in the medicine of preparation treatment and the atherosis disease of prevention of arterial.
4. the application of the described compositions of claim 1 in the medicine of preparation treatment and prevention coronary heart disease.
5. the application of the described compositions of claim 1 in the medicine of preparation treatment and prevention of stroke disease.
6. the application of the described compositions of claim 1 in the medicine of preparation treatment and prevention renal arteriosclerosis disease.
7. according to described application one of in the claim 2 to 6, it is characterized in that the medicine for preparing is injection or oral formulations.
8. application according to claim 7 is characterized in that the oral formulations for preparing is hard capsule, soft capsule, tablet, granule, powder, pill, teabag, medicated wine or oral liquid.
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| CNB2004100772323A CN100364563C (en) | 2004-12-10 | 2004-12-10 | Combination for restraining p38 subfanmily of protein kinase activated by mitogen and application |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110882378A (en) * | 2018-09-10 | 2020-03-17 | 上海清流生物医药科技有限公司 | Application of protein in preparing medicament for preventing and treating atherosclerosis and complications |
| CN109481494A (en) * | 2018-12-25 | 2019-03-19 | 辽宁中医药大学 | A kind of compound traditional Chinese medicine composite and animal experiment method preventing and treating coronary microcirculation dysfunction |
| CN113171388A (en) * | 2021-04-30 | 2021-07-27 | 广州中医药大学(广州中医药研究院) | Application of total saponins of astragalus or volatile oil of angelica in preparation of reagent for treating diseases related to abnormal protein expression |
| CN113893291A (en) * | 2021-11-09 | 2022-01-07 | 任秀江 | Traditional Chinese medicine extract for treating hyperhomocysteinemia and preventing myocardial infarction and cerebral infarction |
| CN115837042A (en) * | 2022-11-18 | 2023-03-24 | 重庆市中医院 | Application of angelica sinensis blood-enriching decoction in preparation of medicine for enhancing curative effect of immune checkpoint inhibitor |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1124857A (en) * | 1994-06-27 | 1996-06-19 | 日本金钱机械株式会社 | Apparatus for printing symbols printed on a document |
| CN1593475A (en) * | 2003-09-08 | 2005-03-16 | 北京大学第一医院 | Novel use for mixture of astragalus root and angelica |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1124857A (en) * | 1994-06-27 | 1996-06-19 | 日本金钱机械株式会社 | Apparatus for printing symbols printed on a document |
| CN1593475A (en) * | 2003-09-08 | 2005-03-16 | 北京大学第一医院 | Novel use for mixture of astragalus root and angelica |
Non-Patent Citations (4)
| Title |
|---|
| P38号信通路在人脐静脉内皮细胞表达选择素中的作用. 李艳波等.细胞与分子免疫学杂志，第19卷第3期. 2003 * |
| 中医药防动脉粥样硬 化研究进展. 宋剑南.中国中医基础医学杂志，第9卷第11期. 2003 * |
| 国外动脉粥样硬化研究进展. 林苹等.大连医科大学 学报，第23卷第2期. 2001 * |
| 脂多糖多同型半胱胺酸对济静脉内此细胞单核细胞趋化蛋白1MRNA表达的影响. 王淑英等.郑州大学学报（医学版），第38卷第5期. 2003 * |
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