CN101711758A - Application of apigenin in preparing medicament for preventing and treating diseases caused by ischemic injuries of humans - Google Patents
Application of apigenin in preparing medicament for preventing and treating diseases caused by ischemic injuries of humans Download PDFInfo
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- CN101711758A CN101711758A CN200910084958A CN200910084958A CN101711758A CN 101711758 A CN101711758 A CN 101711758A CN 200910084958 A CN200910084958 A CN 200910084958A CN 200910084958 A CN200910084958 A CN 200910084958A CN 101711758 A CN101711758 A CN 101711758A
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Abstract
The invention relates to application of apigenin in preparing a medicament for preventing and treating diseases caused by ischemic injuries of humans, wherein the diseases comprise acute myocardial infarctions, cerebral infarctions, intestinal ischemia, avascular necrosis of limbs and necrocytosis and function damages caused by ischemia of organs of livers, kidneys, and the like.
Description
One, technical field
The present invention relates to of the application of natural drug apigenin as the preventive or the therapeutic agent of ischemia injury disease.
Two, background technology
When the organ or tissue of body narrow or inaccessible when not having sufficient side Zhi Xunhuan or side Zhi Xunhuan in time not to set up because of lumen of artery, cytopathy and necrosis can take place owing to anoxia, nutrient substance input pause and metabolite gathering etc. change in ischemic tissue, the ischemic necrosis of this local organization is called infarction again.Take care, during vitals generation infarction such as brain, will obviously influence the heart, brain function, serious threat people's life not only also will obviously reduce survival patient's work capacity and quality of life.
Cell stress with the damage situation under, death can take place, its type comprises apoptosis and necrosis.People think always for a long time, and apoptosis belongs to programmed cell death, are the active death process that is subjected to the several genes network regulation, and are downright bad then be the passive death process that can not regulate and control.Yet progress in recent years shows, the necrosis of cell also can be to mediate by the activation of multiple signal transduction path, regulated and control by gene, epigenetic and medicine, and play an important role at fetal development and maintaining in the homeostatic process of adult tissue as apoptotic process, therefore also be classified as programmed cell death
[1-4]Discover that the RIP1 kinases is played an important role in the cell in the process of the procedural necrocytosis of mediation
[5], adopt the kinase whose activity of micromolecular inhibitor blocking-up RIP1 can effectively suppress the generation of procedural necrosis
[6]Because proteic stability of RIP1 and kinase activity need the molecular chaperone function of heat shock protein 90 (Hsp90), therefore the molecular chaperone function that suppresses Hsp90 can cause the degraded of RIP1 kinases, thereby blocks the generation of procedural necrosis by reducing the proteic expression of RIP1
[7,8]The RIP1 kinases micromolecular inhibitor Necrostatins that has been found that can be by the kinase activity of blocking-up RIP1; and then the protection of the approach by the non-dependence of radical damage cell avoids the necrosis that ischemia causes, and all shows tangible cytoprotection in the cerebral ischemic model of laboratory animal and myocardial infarction and ischemia model
[9,10]Not only can reduce cell death quantity owing to suppress the generation of the procedural necrocytosis of ischemia mediation, more can alleviate the follow-up inflammatory reaction that produces by the necrocytosis mediation, thereby will provide new therapeutic strategy for the treatment ischemic diseases by the generation of targeting inhibition RIP1 albumen (suppress its kinase activity or reduce its protein expression) blocking-up programmed cell necrosis.
List of references
1.Degterev?A?and?Yuan?J.Expansion?and?evolution?of?cell?death?programmes?Nat?RevMol?Cell?Biol.2008?May；9(5)：378-90
2.Kroemer?G，et?al.Classification?of?cell?death：recommendations?of?theNomenclature?Committee?on?Cell?Death?2009.Cell?Death?Differ.2009?Jan；16(1)：3-11
3.Golstein?P，Kroemer?G.Cell?death?by?necrosis：towards?a?molecular?definition.Trends?Biochem?Sci.2007Jan；32(1)：37-43
4.Galluzzi?L?and?Kroemer?G.Necroptosis：a?specialized?pathway?of?programmednecrosis.Cell.2008?Dec?26；135(7)：1161-3
5.Festjens?N，et?al.RIP1，a?kinase?on?the?crossroads?of?a?cell’s?decision?to?liveor?die.Cell?Death?Differ.2007；14：400-410
6.Degterev?A，et?al.Identification?of?RIP1?kinase?as?a?specific?cellular?targetof?necrostatins.Nat?Chem?Biol.2008?May；4(5)：313-21
7.Holler?N，et?al.Fas?triggers?an?alternative，caspase-8-independent?cell?deathpathway?using?the?kinase?RIP?as?effector?molecule.Nat?Immunol?2000；1(6)：489-495
8.Horita?H，et?al.Acute?myeloid?leukemia-targeted?toxin?activates?both?apoptoticand?necroptotic?death?mechani?sms.PLoS?ONE.2008；3(12)：e3909
9.cDegterev?A，et?al.Chemical?inhibitor?of?nonapoptotic?cell?death?with?therapeuticpotential?for?ischemic?brain?injury.Nat?Chem?Biol.2005Jul；1(2)：112-9
10.Christopher?CTS，et?al.Necrostatin：A?Potentially?Novel?Cardioprotective?Agent？Cardiovasc?Drugs?Ther(2007)21：227-233
Three, summary of the invention
The present invention relates to the new purposes of apigenin on preparation prevention and treatment ischemic diseases, its objective is that providing a kind of brings into play the caused biological organs damage of antagonism ischemia and alleviate its handicapped prevention and medicine by the blocking-up programmed cell is downright bad.
Apigenin (Apigenin, 4 ', 5,7-Trihydroxyflavone, 5,7-dihydroxy-2-(4-hydroxyphenyl)-4h-1-benzopyran-4-on, 4,5, the 7-trihydroxyflavone) is main bioactive ingredients in the Herba Apii graveolentis, extensively be present in multiple fruit, vegetable, beans and Folium Camelliae sinensis, goatweed HERBA VERONICAE DILATATAE, Polygonaceae Rhizoma Polygoni Cuspidati, Liliaceae hair leaf Rhizoma et radix veratri (Radix Rhizoma Veratri) and the pinaceae plant, belong to the Polyphenols flavone compound, have the various biological activity.Have now and studies show that it has the effects such as carcinogenic activity, antiviral, antiinflammatory, antioxidation and cell death inducing that suppress carcinogen, therefore be used to experimental treatments such as antitumor, though being arranged early stage, indivedual researchs notice that apigenin can alleviate the liver dysfunction phenomenon that nerve injury regulating liver-QI ischemic reperfusion that the perfusion of cerebral ischemia-again causes causes, but because of not knowing its mechanism of action, so can't clear and definite apigenin can be widely used in the blocking treatment of ischemic necrosis.
We find under study for action, under appropriate drug concentration, apigenin is in the cultured cell in vitro system, thereby can be by suppressing the phosphorylation [Fig. 1] that intracellular CK2 kinases reduces auxiliary chaperone cdc37 important in the Hsp90 complex, because the phosphorylation of cdc37 is vital for the molecular chaperone function that maintains Hsp90, the phosphorylation that reduces cdc37 can cause the molecular chaperone function of Hsp90 to be suppressed, the substrate protein molecule that mediates multiple Hsp90 is degraded, comprising necrosis has the RIP1 kinase protein of important mediation for programmed cell, compare with other natural drugs with Hsp90 inhibit feature, tripterine (Cel) can obviously reduce the expression of RIP1, but induce PARP albumen to shear simultaneously, apoptosis appears in cell, and the prompting cytotoxicity is stronger.Curcumin (Cur) then shows to have the effect that reduces the RIP1 protein expression, has only apigenin cell death inducing (Fig. 2) not when reducing RIP1 and expressing.Continue we in the experimental system of external programmed cell necrosis by death receptor mediation, detected the influence of apigenin and tripterine for the programmed cell necrosis of blocking-up death receptor mediation; the result shows that tripterine has stronger cytotoxicity really; the apigenin pretreatment then can obviously strengthen the toleration [Fig. 3] of L929 cell to the necrosis of tumor necrosis factor mediated cell; confirm that apigenin can be by the effect of powerful reduction RIP1 kinase protein level; realize the protective effect of the procedural necrosis of its pair cell, and its action effect and known necrocytosis protective agent Necrostatin-1 (Nec-1) suitable [Fig. 3].Protective effect cerebral ischemia in the rat body-reperfusion injury model of apigenin pair cell antagonism necrosis is also further confirmed [table 1].
Four, description of drawings
Fig. 1. apigenin (Api) is handled prostate cancer cell line LNCaP and PC-3 cell by the time of selecting, cracking behind the collecting cell, adopt the capable co-immunoprecipitation of anti-Cdc37 antibody (IP) experiment, precipitated product carries out the protein blot detection with anti-phosphorylation serine, Cdc37, Hsp90 and androgen (AR) antibody respectively through SDS-PAGE and after changeing film, is reference with full cell pyrolysis liquid (WCL).But the result shows apigenin time-dependent ground and reduces the phosphorylation of Cdc37, and Cdc37 and Hsp90 and substrate A R and Cdk4 combine the molecular chaperone function of inhibition Hsp90.
Fig. 2. after apigenin is handled prostate cancer cell line LNCaP and PC-3 cell, the collecting cell cracking, the protein blot method detects the change of each protein expression.But the result induces with showing the apigenin time dependence and comprises multiple Hsp90 substrate protein degraded such as RIP-1, Src, XIAP, Cdk4, Survivin.
Fig. 3. the protein blot method compares natural drug tripterine (Cel), curcumin (Cur) and apigenin (Api) to L929 cell RIP1 protein stability and apoptotic influence, the result shows that tripterine can obviously reduce the proteic expression of RIP1, but cause the shearing of PARP albumen simultaneously, cell death inducing.All less than influence, only apigenin can effectively reduce the proteic level of RIP1 to curcumin to RIP1 and PARP albumen, does not shear the protein induced apoptosis of PARP simultaneously.
Fig. 4. adopt the viable count method to detect tumor necrosis factor TNF-alpha and induce the L929 necrocytosis; compare Nec-1, apigenin and tripterine pretreatment influence simultaneously to the necrosis of TNF-α inducing cell; the result shows that tripterine self cytotoxicity is stronger; and apigenin has the good cell protective effect, and its effect is suitable with known necrocytosis protective agent Nec-1.
Five, the specific embodiment
Only the invention will be further described for the following example, and the present invention is not limited.
Embodiment one apigenin is to the protective effect of the L929 programmed cell necrosis of death receptor mediation
The trophophase L929 cell of taking the logarithm, 1x10
5/ ml is inoculated in the 6 porocyte culture plates.(1) normal control group is established in experiment; (2) simple tumor necrosis factor (TNF-α) processed group; (3) TNF-α and known inhibitor of cellular necrosis Nec-1 coprocessing group; (4) simple apigenin processed group; (5) add TNF-α processed group after the apigenin pretreatment; (6) simple tripterine (Cel) processed group; (7) add TNF-α processed group after the tripterine pretreatment.Next day (5) (7) group added apigenin and tripterine pretreatment respectively after 6 hours, remove medicine, cell is after the PBS flushing, change fresh culture, except that (1) group, each group adds 100ng/ml tumor necrosis factor (TNF-α) respectively, peptic cell after 24 hours, the blue dyeing of Placenta Hominis, the living cell counting number, and calculate the cells survival percentage rate.The result as shown in Figure 4, the apigenin pretreatment shows the downright bad protective effect of good cell, can obviously reduce the alpha mediated cell death of TNF-after the pretreatment, its protective effect and Nec-1 are suitable.
Embodiment two apigenins are to the protective effect of SD (Sprague-Dawley) rat cerebral ischemia reperfusion injury
Healthy male SD rat, body weight 300-350 gram is divided into 4 groups at random: sham operated rats, model group (ligation cause cerebral ischemia after 2 hours perfusion 24 hours again), nimodipine positive controls and apigenin treatment group.First three sky of art, nimodipine group and apigenin treatment treated animal are respectively at lumbar injection 1mg/kg/day nimodipine or 20mg/kg/day apigenin.Adopt the method for Longa to prepare SD cerebral ischemic reperfusion in rats model after three days, each group press the 3mg/kg nimodipine or 3mg/kg apigenin dosage is distinguished intravenous administration once at ischemia after 1 hour, ischemia perfusion 24 hours again after 2 hours.Each treated animal sacrificed by decapitation is got cerebral tissue and is prepared crown brain sheet, and 2,3, the dyeing of 5-triphenyl tetrazolium chloride (TTC) method is observed and is measured the infarct volume.
Table 1. tripterine is to the influence of rat cerebral ischemia reperfusion injury cerebral infarct volume
Compare * P＜0.05 with model group; * P＜0.01; Compare #P＜0.05 with the nimodipine group
As can be seen from Table 1, compare with model group, known positive drug nimodipine can effectively reduce the volume by ischemic reperfusion damage causing cerebral infarction, and apigenin has significant protective effect equally, and effect is better than nimodipine.
Claims (9)
1. the application of apigenin in the medicine of preparation prevention and treatment ischemic injuries of humans disease.
2. application as claimed in claim 1 is characterized in that: described disease is the caused cerebral infarction of local cerebral ischemia.
3. application as claimed in claim 1 is characterized in that: described disease is the caused angina pectoris of regional myocardial ischemia, myocardial infarction.
4. application as claimed in claim 1 is characterized in that: described disease is the caused renal infarction of ischemia.
5. application as claimed in claim 1 is characterized in that: described disease is the caused hepatic injury of ischemia.
6. application as claimed in claim 1 is characterized in that: described disease is the caused skeletal muscle necrosis of extremity ischemia.
7. application as claimed in claim 1 is characterized in that: described disease is the caused injury of lung of ischemia of lung.
8. application as claimed in claim 1 is characterized in that: described disease is the caused intestinal mucosal injury of intestinal ischemia.
9. medicine as claimed in claim 1 is characterized in that being aided with pharmaceutically acceptable carrier or adjuvant and makes dry powder doses, tablet, capsule (containing soft, hard capsule), soft gelatin capsule, drop pill, liposome, granule, oral liquid, injection and exterior-applied formulation etc.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104523736A (en) * | 2015-01-06 | 2015-04-22 | 李子林 | Pharmaceutical composition for myocardial infarction prevention and treatment and application thereof |
| CN107823197A (en) * | 2017-11-01 | 2018-03-23 | 中国医学科学院阜外医院 | Application of the apiolin in hemorrhagic cerebrovascular disease and ICVD medicine caused by prevention and treatment hypertension is prepared |
| CN109568584A (en) * | 2018-12-06 | 2019-04-05 | 上海交通大学医学院 | BRAF inhibitor is used to prepare the newtype drug and its screening technique for the treatment of procedure necrosis disease |
| CN111557326A (en) * | 2020-05-20 | 2020-08-21 | 南昌大学 | Butter crisp biscuit and preparation method thereof |
-
2009
- 2009-06-05 CN CN200910084958A patent/CN101711758A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104523736A (en) * | 2015-01-06 | 2015-04-22 | 李子林 | Pharmaceutical composition for myocardial infarction prevention and treatment and application thereof |
| CN104523736B (en) * | 2015-01-06 | 2018-03-16 | 李子林 | A kind of pharmaceutical composition for preventing and treating myocardial infarction and its application |
| CN107823197A (en) * | 2017-11-01 | 2018-03-23 | 中国医学科学院阜外医院 | Application of the apiolin in hemorrhagic cerebrovascular disease and ICVD medicine caused by prevention and treatment hypertension is prepared |
| CN109568584A (en) * | 2018-12-06 | 2019-04-05 | 上海交通大学医学院 | BRAF inhibitor is used to prepare the newtype drug and its screening technique for the treatment of procedure necrosis disease |
| CN111557326A (en) * | 2020-05-20 | 2020-08-21 | 南昌大学 | Butter crisp biscuit and preparation method thereof |
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Open date: 20100526 |