CN103027908A - Application of Aphanamixoid A to preparation of drug for treating atherosclerosis - Google Patents
Application of Aphanamixoid A to preparation of drug for treating atherosclerosis Download PDFInfo
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- CN103027908A CN103027908A CN2012104704762A CN201210470476A CN103027908A CN 103027908 A CN103027908 A CN 103027908A CN 2012104704762 A CN2012104704762 A CN 2012104704762A CN 201210470476 A CN201210470476 A CN 201210470476A CN 103027908 A CN103027908 A CN 103027908A
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- aphanamixoid
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Abstract
The invention relates to application of Aphanamixoid A to preparation of a drug for treating atherosclerosis. The Aphanamixoid A can realize the action of preventing atherosclerosis by regulating blood lipids and protecting endothelial cells. The anti-atherosclerosis drug prepared from the Aphanamixoid A has a good curative effect on the atherosclerosis, and can be used for preventing the atherosclerosis of human or animals. The use of the Aphanamixoid A in the invention in the preparation of the drug for treating atherosclerosis is firstly disclosed. The framework type is a brand-new framework type and has an unexpected strong effect of restraining the bacterial activity, and so the Aphanamixoid A is impossibly reveled by other compounds, and has outstanding substantial characteristics. Meanwhile, the Aphanamixoid A has significant progress in preventing and treating atherosclerosis.
Description
Technical field
The present invention relates to the application of Aphanamixoid A in preparation treatment atherosclerosis medicine.
Background technology
Cardiovascular and cerebrovascular disease is to be detrimental to health the present age and the most serious disease of life, be in, common complaint among the elderly and frequently-occurring disease, all be positioned at first of the severe disease at the M ﹠ M of many countries and regions.Atherosclerosis (atherosclerosis, AS) is the main pathological basis of cardiovascular and cerebrovascular disease, and its etiology and pathogenesis is illustrated not yet fully up to now, so do not have concisely at present effectively prophylactico-therapeutic measures and medicine.
The compd A phanamixoid A that the present invention relates to is one and delivered (Cai in 2012, J. Y. et al., 2012. Aphanamixoid A, a Potent Defensive Limonoid, with a New Carbon Skeleton from Aphanamixis polystachya. Organic Letters 14 (10), 2524 – 2527.) New skeleton compound, this chemical compound has brand-new framework types, present purposes only relates to insect antifeedant activity (Cai, J. Y. et al., 2012. Aphanamixoid A, a Potent Defensive Limonoid, with a New Carbon Skeleton from Aphanamixis polystachya. Organic Letters 14 (10), 2524 – 2527.), belong to open first for the purposes of the Aphanamixoid A that the present invention relates in the preparation Antiatherosclerosis medicine, because framework types belongs to brand-new framework types, and it is active unexpectedly strong for atherosclerotic inhibition, there is not the possibility that is provided any enlightenment by other chemical compounds, possess outstanding substantive distinguishing features, be used for simultaneously atherosclerosis and obviously have significant progress.
Summary of the invention
The present invention provides the application of Aphanamixoid A in the preparation Antiatherosclerosis medicine for the problems referred to above, and the antiatherogenic medicine with Aphanamixoid A preparation has preferably curative effect.
Technical scheme provided by the invention is: the effect of Aphanamixoid A in the preparation Antiatherosclerosis medicine.
The present invention can be used as the atherosclerosis of anti-human or animal.Medicine of the present invention can give by oral or intravenous injection.Those skilled in the art can easily determine dosage according to practical situation.
Described compd A phanamixoid A structure is shown in formula I:
The purposes of the Aphanamixoid A that the present invention relates in the preparation Antiatherosclerosis medicine belongs to open first, because framework types belongs to brand-new framework types, and it is active unexpectedly strong for atherosclerotic inhibition, there is not the possibility that is provided any enlightenment by other chemical compounds, possess outstanding substantive distinguishing features, be used for simultaneously atherosclerosis and obviously have significant progress.
The specific embodiment
The preparation method of compd A phanamixoid A involved in the present invention is referring to document (Cai, J. Y. et al., 2012. Aphanamixoid A, a Potent Defensive Limonoid, with a New Carbon Skeleton from Aphanamixis polystachya. Organic Letters 14 (10), 2524 – 2527.).
The present invention is further detailed explanation by the following examples, but protection scope of the present invention is not subjected to any restriction of specific embodiment, but limited by claim.
Embodiment 1: the preparation of compd A phanamixoid A tablet involved in the present invention:
Get 20 and digest compound Aphanamixoid A, add conventional adjuvant 180 grams of preparation tablet, mixing, conventional tablet machine are made 1000.
Embodiment 2: the preparation of compd A phanamixoid A capsule involved in the present invention:
Get 20 and digest compound Aphanamixoid A, add conventional adjuvant such as starch 180 grams of preparation capsule, mixing is encapsulatedly made 1000.
Further specify its pharmaceutically active below by pharmacodynamic experiment.
The present invention by cellular level research and set up the technology such as Atherosclerosis Model and disclosed Aphanamixoid A to atherosclerotic effect.
Per os of the present invention and intravenous injection give Aphanamixoid A, and atherosclerotic rat plaque area/Intimal area (%), inner film thickness (um)/media thickness (%) are significantly reduced; Make triglyceride in the blood, T-CHOL and low density lipoprotein, LDL content decrease, show that Aphanamixoid A can treat atherosclerosis.
Materials and methods
1. experiment material:
1.1 animal and feedstuff
Laboratory animal: healthy rat, male and female half and half, body weight (200.0 ± 20) g.
Feedstuff: normal feedstuff is provided by Jiangsu Province's Experimental Animal Center; High lipid food is comprised of 2% cholesterol, 10% Adeps Sus domestica and 88% normal feedstuff, is machined by Jiangsu Province's Experimental Animal Center.
1.2 medicine and reagent
Cholesterol Kit: bio-engineering research institute is built up in Nanjing;
The Triglyceride Reagent box: bio-engineering research institute is built up in Nanjing;
The high density lipoprotein test kit: bio-engineering research institute is built up in Nanjing;
The low density lipoprotein, LDL test kit: bio-engineering research institute is built up in Nanjing;
The Coomassie brilliant blue protein determination kit: bio-engineering research institute is built up in Nanjing;
MDA measures test kit: bio-engineering research institute is built up in Nanjing;
SOD measures test kit: bio-engineering research institute is built up in Nanjing;
1.3 equipment
The AEROSET of U.S. Abbott Laboratories automatic clinical chemistry analyzer;
JY601 electronic balance: Haikang, Shanghai Electronic Instruments Plant;
TN-100B type table pan torsion bal: upper marine flat instrument company;
OLYMPUS inversion type system microscope;
WF10X-18MM optical microscope: optical instrument factory, Chongqing;
TGL-16G centrifuge: Town in Shanghai booth science and technology instrument plant
1. experimental technique:
2.1 Endothelial cell culture and Aphanamixoid A effect research
2.1.1 set up the endotheliocyte model of Hyperlipidemic Serum damage
Get 6 of healthy Japan large ear rabbits, high lipid food (2% cholesterol of feeding every day, 10% Adeps Sus domestica, 88% normal feedstuff), heart extracting blood 5ml under the aseptic condition after 4 weeks, separation of serum, merge, 56 ℃ of water-bath 30min inactivation treatment, again with behind the 0.45 and 0.22 double-deck filtering with microporous membrane ,-30 freezing saving backup.
2.1.2 cell culture and going down to posterity
The human umbilical vein endothelial ECV304 that cultivates is incubated in the DMEM culture medium that contains 20% calf serum, 2mmol/L L-glutaminate, 100U/ml penicillin and 100g/L streptomycin with going down to posterity.With 0,25% trypsin solution and 0.02%EDTA(1:1) had digestive transfer culture.Be inoculated in the 100ml culture bottle, send into 5%CO
2Cultivate in the incubator.Use in order to experiment.
Aphanamixoid A dilutes with serum-free medium before use.
2.1.3 grouping
The cell of trophophase of taking the logarithm is used for experiment.24h changed serum-free medium before cell added the processing factor, made cell synchronization to G
1Phase, then divide at random 5 groups: matched group, Hyperlipidemic Serum group, Aphanamixoid A organize that 0.4 μ g/ml group, Aphanamixoid A are organized 2 μ g/ml group, Aphanamixoid A organizes 10 μ g/ml group.Matched group wherein: add serum-free DMEM culture medium; Hyperlipidemic Serum group: add and contain 5% Hyperlipidemic Serum DMEM culture medium.
2.1.4 mtt assay detects cell survival rate
Well-grown EVC304 cell is prepared into 5 * 10
7Individual L
-1Cell suspension, be inoculated in 96 orifice plates by every hole 0.1ml, 37 ℃, 5%CO
2Incubation 24h, serum-free synchronization process and divide into groups the same.After each organized cytosis 24h, every hole added 20ul MTT(5.0gL
-1), hatch 4h for 37 ℃, abandoning supernatant, every hole adds dimethyl sulfoxide 100ul, fully cell survival rate (%)=processed group A
570/ control group A
570* 100%
2.1.5 MDA and SOD assay
Cell divides into groups and processes the same.Abandoning supernatant behind the effect 24h, every hole adds 0.5ml cell pyrolysis liquid (150mmol/L NaCl after washing 3 times with PBS, 150mmol/L Tris-HCl, 1mmol/L EDTA, 1%TritonX-100), after the abundant cracking of cell, measure cell MDA content with reference to MDA and SOD detection kit description.
2.2 Aphanamixoid A is on the impact of high fat animal
2.2.1 animal is fed 1w with normal feedstuff, as the laundering period.Be divided at random 6 groups: normal group, model group, Aphanamixoid A low dose group (dosage group among 400 μ g/kg), the Aphanamixoid A (2000 μ g/kg), Aphanamixoid A high dose group (10000 μ g/kg) and Max EPA matched group.Normal group with normal feedstuff 100g is only fed
-1D
-1Model group and other administration groups are fed with high lipid food 20g100g
-1D
-1, administration group per os every day or injection give the Aphanamixoid A medicine of corresponding dosage, successive administration 20d.
2.2.2 the mensuration of index
2.2.2.1 the mensuration of blood fat
20d after administration can't help water 12h with the animal fasting, heart blood sampling, 3000 rpmmin
-1Centrifugal 10 min get upper serum 0.5 ml, measure.Utilize the AEROSET of U.S. Abbott Laboratories automatic clinical chemistry analyzer, respectively with oxidation enzymatic assays TG, TC content, direct measuring method is measured the content of HDLC, LDLC.
2.2.2.2 the pathological changes classification of Aortic Plaque
Behind the sacrifice of animal, win immediately aorta (from heart to the iliac artery crotch), the fatty tissue on it is rejected, in the dorsal surface longitudinal incision, fix with 10% formalin, Sudan IV dyes, and speckle is taken on a red color, and paves, and takes pictures.Image analyzer is measured plaque area and the tunica intima gross area, and calculates speckle/tunica intima Area Ratio.
Carry out classification by following provisions:
0 grade: without pathological changes
1 grade: pathological changes accounts for 1%-25%;
2 grades: pathological changes accounts for 26%-50%;
3 grades: pathological changes accounts for 51%-75%;
4 grades: pathological changes accounts for 76%-100%.
2.2.2.3 the mensuration of serum MDA and SOD
The animal hearts blood sampling, 3000 rpmmin
-1Centrifugal 10min gets supernatant, and with 5 times of normal saline dilutions, mixing is to be measured.Adopt MDA kit measurement MDA content and SOD active.
Experimental result
(1) Aphanamixoid A is on the impact of the endotheliocyte cell survival rate of Hyperlipidemic Serum damage
Hyperlipidemic Serum can significantly reduce the cell survival rate (P＜0.01) of endotheliocyte, Aphanamixoid A 0.004mg/ml, Aphanamixoid A 0.02mg/ml, three concentration of Aphanamixoid A 0.1mg/ml can suppress reduction (P＜0.05 of the cell survival rate that Hyperlipidemic Serum causes in various degree, P＜0.01, P＜0.01).
Table 1 Aphanamixoid A is on the impact (x ± s, n=6) of the endotheliocyte cell survival rate of Hyperlipidemic Serum damage
Compare * P＜0.05 with normal group, * * P＜0.01; Compare with model group
▲P＜0.05,
▲ ▲P＜0.01
(2) Aphanamixoid A is on the endotheliocyte MDA of Hyperlipidemic Serum damage and the impact of SOD content
Can significantly the raise content (P＜0.01) of MDA in the endotheliocyte of Hyperlipidemic Serum, the SOD changes of contents is not obvious.Aphanamixoid A can suppress the rising of the MDA content that Hyperlipidemic Serum causes in various degree, improves the SOD in serum enzymatic activity.
Table 2 Aphanamixoid A is on the endotheliocyte MDA of Hyperlipidemic Serum damage and the impact (x ± s, n=4) of SOD
Compare * P＜0.05 with normal group, * * P＜0.01; Compare with model group
▲P＜0.05,
▲ ▲P＜0.01
(3) Aphanamixoid A is on the impact of Induced by High Fat Diet in Rats blood fat
Compare with normal group, the content of model group triglyceride (TG), cholesterol (TC), low density lipoprotein, LDL LDLC all significantly raises (P＜0.01), and high density lipoprotein (HDLC) has no significant effect; Compare with model group, the content of Aphanamixoid A group and Max EPA matched group TC, LDLC all significantly reduces (P＜0.01), and HDLC is had no significant effect.
Table 3 Aphanamixoid A is on the impact (x ± s, n=4) of Induced by High Fat Diet in Rats blood fat
Compare * P＜0.05 with normal group, * * P＜0.01; Compare with model group
▲P＜0.05,
▲ ▲P＜0.01
(4) Aphanamixoid A is on the impact of the pathological changes classification of high fat atherogenicity rat aorta speckle
Compare with model group, dosage group plaque area/Intimal area (%), inner film thickness (um), inner film thickness/media thickness (%) all significantly reduce (P＜0.05) among the Aphanamixoid A, and Aphanamixoid A high dose combination Max EPA matched group plaque area/Intimal area (%), inner film thickness (um), inner film thickness/media thickness (%) all significantly reduce (P＜0.01).
Table 4 Aphanamixoid A is on the impact (x ± s, n=4) of high fat atherogenicity rat aorta plaque area/Intimal area (%), inner film thickness/media thickness (%)
Compare * P＜0.05 with normal group, * * P＜0.01; Compare with model group
▲P＜0.05,
▲ ▲P＜0.01
(5) Aphanamixoid A is on the impact of high fat atherogenicity rat blood serum MDA, SOD
Compare with normal group, the content of MDA significantly raises (P＜0.01) in the model group serum, and SOD is active significantly to descend; Compare with model group, the content of MDA all significantly reduces (P＜0.05, P＜0.05) in the middle and high dosage group of the Aphanamixoid A serum, the content of SOD significantly raise (P＜0.05).
Table 5 Aphanamixoid A is on the impact (x ± s, n=4) of MDA, SOD in the high fat atherogenicity rat blood serum
Compare * * P＜0.01 with normal group; Compare with model group
▲P＜0.05,
▲ ▲P＜0.01
Conclusion: Aphanamixoid A can significantly suppress atherosclerosis, can be used for preparing Antiatherosclerosis medicine.
Claims (1)
1.Aphanamixoid the application of A in preparation treatment atherosclerosis medicine, described compd A phanamixoid A structure is shown in formula I:
Formula I.
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|---|---|---|---|
| CN2012104704762A CN103027908A (en) | 2012-11-19 | 2012-11-19 | Application of Aphanamixoid A to preparation of drug for treating atherosclerosis |
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| CN2012104704762A CN103027908A (en) | 2012-11-19 | 2012-11-19 | Application of Aphanamixoid A to preparation of drug for treating atherosclerosis |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011018763A1 (en) * | 2009-08-12 | 2011-02-17 | Horphag Research Ip (Pyc) Ltd. | Combination of proantocycidins such as pycnogenol or grape seeds and centella asiatica for the treatment of cardiovascular disorders such as atherosclerosis |
| CN102018699A (en) * | 2010-12-14 | 2011-04-20 | 中山大学 | Application of Xyloketal B in preparing antiatherosclerotic medicaments |
| CN102861037A (en) * | 2012-10-26 | 2013-01-09 | 吴俊华 | Application of Gypensapogenin B in medicine for treating atherosclerosis |
-
2012
- 2012-11-19 CN CN2012104704762A patent/CN103027908A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011018763A1 (en) * | 2009-08-12 | 2011-02-17 | Horphag Research Ip (Pyc) Ltd. | Combination of proantocycidins such as pycnogenol or grape seeds and centella asiatica for the treatment of cardiovascular disorders such as atherosclerosis |
| CN102018699A (en) * | 2010-12-14 | 2011-04-20 | 中山大学 | Application of Xyloketal B in preparing antiatherosclerotic medicaments |
| CN102861037A (en) * | 2012-10-26 | 2013-01-09 | 吴俊华 | Application of Gypensapogenin B in medicine for treating atherosclerosis |
Non-Patent Citations (1)
| Title |
|---|
| JIE-YUN CAI等: "Aphanamixoid A, a Potent Defensive Limonoid, with a New Carbon Skeleton from Aphanamixis polystachya", 《ORGANIC LETTERS》, vol. 14, no. 10, 27 April 2012 (2012-04-27), pages 2524 - 2527 * |
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Application publication date: 20130410 |