CN103381176A - Application of Houttuynoid C in drug for treating atherosclerosis - Google Patents
Application of Houttuynoid C in drug for treating atherosclerosis Download PDFInfo
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- CN103381176A CN103381176A CN2013102537685A CN201310253768A CN103381176A CN 103381176 A CN103381176 A CN 103381176A CN 2013102537685 A CN2013102537685 A CN 2013102537685A CN 201310253768 A CN201310253768 A CN 201310253768A CN 103381176 A CN103381176 A CN 103381176A
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- houttuynoid
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Abstract
The invention relates to an application of Houttuynoid C in preparation of a drug for treating atherosclerosis. Houttuynoid C plays a role in resisting atherosclerosis by regulating blood lipid and protecting endothelial cells. The anti-atherosclerosis drug prepared by Houttuynoid C has relatively good curative effect on atherosclerosis, and can be used for resisting atherosclerosis of human or animals. The application of Houttuynoid C in preparing anti-atherosclerosis drug is disclosed for the first time. Because a skeleton type of Houttuynoid C belongs to a brand new skeleton type, Houttuynoid C has an unexpectedly high inhibition activity on atherosclerosis, the possibility that other compounds give any enlightenment does not exist, and Houttuynoid C has prominent substantial characteristics and simultaneously obviously has significant progress in resisting atherosclerosis.
Description
Technical field
The present invention relates to the application of Houttuynoid C 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 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, therefore there is no concisely at present prophylactico-therapeutic measures and medicine effectively.
the compound H outtuynoid C that the present invention relates to is one and delivered (Chen in 2012, S. D. et al., 2012. Houttuynoid A-E, Anti-Herpes Simplex Virus Active Flavonoids with Novel Skeletons from Houttuynia cordata. Organic Letters 14 (7), 1772 – 1775.) New skeleton compound, this compound has brand-new framework types, present purposes only relates to the active (Chen of active anti-herpes simplex virus, S. D. et al., 2012. Houttuynoid A-E, Anti-Herpes Simplex Virus Active Flavonoids with Novel Skeletons from Houttuynia cordata. Organic Letters 14 (7), 1772 – 1775.), belong to open first for the purposes of the Houttuynoid C 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 compounds, possesses 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 Houttuynoid C in the preparation Antiatherosclerosis medicine for the problems referred to above, and the antiatherogenic medicine with Houttuynoid C preparation has curative effect preferably.
Technical scheme provided by the invention is: the effect of Houttuynoid C 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 compound H outtuynoid C-structure is as shown in formula I:
Formula I
The specific embodiment
The preparation method of compound H outtuynoid C involved in the present invention is referring to document (Chen, S. D. et al., 2012. Houttuynoid A-E, Anti-Herpes Simplex Virus Active Flavonoids with Novel Skeletons from Houttuynia cordata. Organic Letters 14 (7), 1772 – 1775.).
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 compound H outtuynoid C tablet involved in the present invention:
Get 20 and digest compound Houttuynoid C, add conventional adjuvant 180 grams that prepare tablet, mixing, conventional tablet machine are made 1000.
Embodiment 2: the preparation of compound H outtuynoid C capsule involved in the present invention:
Get 20 and digest compound Houttuynoid C, add the conventional adjuvant such as starch 180 grams that prepare capsule, mixing is encapsulatedly made 1000.
Further illustrate 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 Houttuynoid C to atherosclerotic effect.
Per os of the present invention and intravenous injection give Houttuynoid C, and atherosclerotic rat plaque area/Intimal area (%), inner film thickness (um)/media thickness (%) are significantly reduced; Triglyceride in blood, T-CHOL and low density lipoprotein, LDL content are descended, show that Houttuynoid C 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 Houttuynoid C 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 aseptic condition after 4 weeks, separation of serum, merge, 56 ℃ of water-bath 30min inactivation treatment, then with after 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 incubator.Use in order to experiment.
Houttuynoid C dilutes with serum-free medium before use.
2.1.3 grouping
The cell of trophophase of taking the logarithm is used for experiment.Before cell adds the processing factor, 24h changes serum-free medium, makes cell synchronization to G
1Phase, then divide at random 5 groups: matched group, Hyperlipidemic Serum group, Houttuynoid C group 0.4 μ g/ml group, Houttuynoid C group 2 μ g/ml groups, Houttuynoid C group 10 μ g/ml groups.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 20 ul 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 after effect 24h, after washing 3 times with PBS, every hole adds 0.5ml cell pyrolysis liquid (150 mmol/L NaCl, 150 mmol/L Tris-HCl, 1 mmol/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 the impact of Houttuynoid C on 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, Houttuynoid C low dose group (dosage group in 400 μ g/kg), Houttuynoid C (2000 μ g/kg), Houttuynoid C 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 Houttuynoid C 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
After 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) impact of Houttuynoid C on the endotheliocyte cell survival rate of Hyperlipidemic Serum damage
Hyperlipidemic Serum can significantly reduce the cell survival rate (P＜0.01) of endotheliocyte, Houttuynoid C 0.004mg/ml, Houttuynoid C 0.02mg/ml, three concentration of Houttuynoid C 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).
The impact (x ± s, n=6) of table 1 Houttuynoid C on 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) Houttuynoid C 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 endotheliocyte of Hyperlipidemic Serum, the SOD changes of contents is not obvious.Houttuynoid C can suppress the rising of the MDA content that Hyperlipidemic Serum causes in various degree, improves the SOD in serum enzymatic activity.
Table 2 Houttuynoid C 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) impact of Houttuynoid C on the 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 Houttuynoid C group and Max EPA matched group TC, LDLC all significantly reduces (P＜0.01), and HDLC is had no significant effect.
The impact (x ± s, n=4) of table 3 Houttuynoid C on the 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) impact of Houttuynoid C on the pathological changes classification of high fat atherogenicity rat aorta speckle
Compare with model group, in Houttuynoid C, dosage group plaque area/Intimal area (%), inner film thickness (um), inner film thickness/media thickness (%) all significantly reduce (P＜0.05), and Houttuynoid C 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).
The impact (x ± s, n=4) of table 4 Houttuynoid C on 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) impact of Houttuynoid C on high fat atherogenicity rat blood serum MDA, SOD
Compare with normal group, in model group serum, the content of MDA significantly raises (P＜0.01), and SOD is active significantly to descend; Compare with model group, in the middle and high dosage group of AA serum, the content of MDA all significantly reduces (P＜0.05, P＜0.05), the content of SOD significantly raise (P＜0.05).
The impact (x ± s, n=4) of table 5 Houttuynoid C on MDA, SOD in high fat atherogenicity rat blood serum
Compare * * P＜0.01 with normal group; Compare with model group
▲P＜0.05,
▲ ▲P＜0.01
Conclusion: Houttuynoid C can significantly suppress atherosclerosis, can be used for preparing Antiatherosclerosis medicine.
Claims (1)
1.Houttuynoid the application of C in treatment atherosclerosis medicine, described compound H outtuynoid C-structure as
Formula IShown in:
Formula I.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1124957A (en) * | 1993-03-31 | 1996-06-19 | G·D·瑟尔公司 | 1-amidinophenyl-pyrrolidones piperidinones azetinones as platelet aggregation inhibitors |
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2013
- 2013-06-24 CN CN201310253768.5A patent/CN103381176B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1124957A (en) * | 1993-03-31 | 1996-06-19 | G·D·瑟尔公司 | 1-amidinophenyl-pyrrolidones piperidinones azetinones as platelet aggregation inhibitors |
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Effective date of registration: 20221229 Address after: Room 801, No. 1719-8, Huishan Avenue, Huishan District, Wuxi City, Jiangsu Province, 214000 Patentee after: Huangtu Pharmaceutical (Wuxi) Co.,Ltd. Address before: 401120 office building of Chongqing advertising industrial park, No.18, shifucheng Avenue, Yubei District, Chongqing Patentee before: CHONGQING SUMARTE TECHNOLOGY DEVELOPMENT CO.,LTD. |
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