CN103976987A - Composition for treating atherosclerosis - Google Patents
Composition for treating atherosclerosis Download PDFInfo
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- CN103976987A CN103976987A CN201410242854.0A CN201410242854A CN103976987A CN 103976987 A CN103976987 A CN 103976987A CN 201410242854 A CN201410242854 A CN 201410242854A CN 103976987 A CN103976987 A CN 103976987A
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- citral
- geranialdehyde
- smooth muscle
- composition
- density lipoprotein
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Abstract
The invention discloses a composition for treating atherosclerosis. The composition is characterized by comprising geranialdehyde used as an effective component, wherein the geranialdehyde is from lemon myrtle, litsea cubeba, cubeb litsea tree, lemon grass and lemon tea tree, wherein the concentration of the geranialdehyde is 1-51g/ml. The pharmaceutical composition containing the geranialdehyde has an unequal inhibition effect on hyperplasia of human aortic smooth muscle cells stimulated by lipopolysaccharide. Compared with the geranialdehyde and other flavonoid compounds, the composition has the best activity, can inhibit hyperplasia of human aortic smooth muscle cells caused by oxidized low-density lipoprotein, does not have toxicity on cells, and can inhibit inflammatory response.
Description
Technical field
The present invention relates to the compositions of a kind of prevention and treatment arteriosclerosis.
Background technology
Cardiovascular disease is the syndrome of heart and blood vessel, and cardiovascular disease can be divided into coronary heart disease, cerebrovascular disease, peripheral arterial occlusive disease, rheumatic heart disease, congenital heart disease, deep venous thrombosis and pulmonary embolism.If generation coronary atherosclerosis, may cause angina pectoris, myocardial infarction or sudden death, if brain or Carotid Sclerosis will cause even uremia of renal hypertension, Peripheral arteries sclerosis causes aneurysm or Arteriosclerosis obliterans.Therefore, arteriosclerotic and cardiovascular disease is inseparable.
Because the cause of disease of arteriosclerosis is hyperlipidemia or blood coagulation phenomenon, for example lipopolysaccharide body activating cell element TNF-á,
and then stimulate smooth muscle cell proliferation and increase the generation of adhesion factor.In addition, the TLR4 regional interaction on lipopolysaccharide cognition and endotheliocyte or macrophage, with postactivated
with the path of the protease of p44/p42 mitosis activation promoter, so the inflammatory response that lipopolysaccharide body brings out will cause arteriosclerosis.
Arteriosclerosis belongs to a kind of inflammatory response, impaired vascular endothelial cell can cause barrier and the permeability changes of blood vessel endothelium, make low density lipoprotein, LDL enter in a large number in endotheliocyte, and produce oxidized low-density lipoprotein, stimulating endothelial cell or smooth muscle produce chemical taxis material, it attracts monocyte to enter space under endotheliocyte, changes into macrophage, oxidized low-density lipoprotein is engulfed and is formed foam cell.The accumulation of a large amount of foam cells increases cytokines, somatomedin and prostaglandin, cytokines can stimulate the smooth muscle cell proliferation of media and travel to endodermis, schizogamy, produce collagen fiber and form speckle, sticky glutinous, the gathering of attraction platelet etc., form thrombosis, block blood flow, present clinically the emergency cases such as unstable angina, acute myocardial infarction, apoplexy.
The medicine for the treatment of arteriosclerosis is often blood lipid-lowering medicine or anti-thrombi medicine at present.
Blood lipid-lowering medicine is divided into 4 large classes: cholic acid binding resin, fiber acid derivative, nicotinic acid derivant and Shi Dating class medicine.(1) cholic acid binding resin stops the cholic acid in intestines and stomach to be absorbed, and to increase liver compensatory, utilizes cholesterol to manufacture cholic acid, reduces the content of cholesterol in hepatocyte, but the side effect such as gastrointestinal upset (diarrhoea, constipation) may occur.(2) fiber acid derivative reduces triglyceride concentration in blood, may cause the side effect such as stomachache, diarrhoea, nauseating, vomiting and the rising of liver function index.(3) nicotinic acid derivant can reduce the concentration of low density lipoprotein, LDL, triglyceride, cholesterol, and can increase the concentration of high density lipoprotein, but there are the side effect such as gastrointestinal upset, metabolic arthritis, gout, erythema, liver function exponent increase, if long-term taking may increase the probability of cholelithiasis.(4) Shi Dating class medicine as effect the strongest and modal anticholesteremic agent, it suppresses the rate limit enzyme of cholesterol biosynthesis in hepatocyte, and then the cholesterol level in minimizing blood, side effect for liver function index rises, headache, nauseating, tired etc.
And anti-thrombi medicine is divided into 3 classes: anticoagulant, antiplatelet drug and thrombolytic agent.Anticoagulant is divided into again 4 groups: vitamin K antagon, heparin and derivant thereof, direct thrombin inhibitor and other class anticoagulation medicines.(1) vitamin K antagon comprises Warfarin (Warfarin, once be raticide), dicoumarol etc., the similar vitamin K of its chemical constitution, mechanism of action is the active reaction of antagonism vitamin K-dependent clotting factor II, VII, IX, X, but can produce the side effect such as hematuria, gastrointestinal tract and intracerebral hemorrhage.(2) heparin is alternately comprised of GLUCOSAMINE, L-iduronic acid and D-glucuronic acid, it is first combined with anticoagulation factor III, and then the deactivation effect of acceleration thrombin, and reach blood coagulation resisting function, it also can be combined with multiple prothrombin a, Xa, XIa, XIIa, make it to lose activity, yet may produce the side effect such as hemorrhage, anaphylaxis and aleucia.(3) direct thrombin inhibitor comprises hirudin and bivalirudin etc., wherein hirudin is from Hirudo glandula and has the albumen of 65 amino acids, it plays the part of pivotal player in anastalsis and inhibition thrombosis, although hirudin is the strongest natural thrombin inhibitor, it is difficult to refine in Hirudo and must prepares with restructuring biotechnology.(4) example of other class anticoagulation medicines comprises Leimaquban, and it is thromboxane receptor inhibitor.
Antiplatelet drug is divided into again 5 groups: COX inhibitor, adenosine diphosphate (ADP) acceptor inhibitor, phosphodiesterase inhibitor, adenylic acid reuptake inhibithors and blood coagulation fat inhibitor.
Aspirin in COX inhibitor (low dosage) can suppress platelet aggregation and pre-preventing thrombosis generates, because the secretion of stomach Protective substances can be reduced in aspirin, so can produce the side effect such as gastrointestinal upset, gastrorrhagia.Plavix in adenosine diphosphate (ADP) acceptor inhibitor (Clopidogrel) can produce the risk of gastrorrhagia.The metabolism of cilostazol interior phosphodiesterase activity capable of inhibiting cell (selective to phosphodiesterase iii especially) in phosphodiesterase inhibitor and obstruction cAMP, impel the cAMP concentration in platelet and blood vessel to increase, and have anti-platelet aggregation and vasorelaxation action, but have headache, diarrhoea, feel sick, the side effect such as erythema, blood dyscrasia.Persantin in adenylic acid reuptake inhibithors (Dipyridamole) can suppress the caused platelet aggregation effects such as platelet activation factor, collagen, adenosine diphosphate (ADP), its side effect be dizzy, feel dizzy, faintness, flushing, headache, feel sick, vomiting, skin dermexanthesis, stomach colic or weak etc.When persantin and heparin close And and use, can increase hemorrhage danger.Platelet agglutination and vasoconstriction that Terutroban blood coagulation fat capable of blocking in blood coagulation fat inhibitor causes, promote endothelial function and have anti-atherosclerotic arteriosclerosis effect, yet but having hemorrhagic risk.
The effect of thrombolytic agent is to activate plasmin, promotes fibrinolysis, is applicable to treat deep venous thrombosis, pulmonary infarction, acute myocardial infarction and acute arterial embolism, but can causes hemorrhage and anaphylaxis.
The treatment arteriosclerosis medicine of aforementioned two large classes all has different chemical constitutions and multiple side effect to produce, in order to develop new treatment arteriosclerosis medicine, and the phase can avoid side effect to produce, present inventor is in view of deficiency of the prior art, through concentrated test and research, and under the spirit of working with perseverance, visualize eventually the present application, can overcome the deficiencies in the prior art, be below the application's brief description.
Summary of the invention
The present invention finds that the hyperplasia of mankind's aortic smooth muscle cell that citral stimulates lipopolysaccharide body has the inhibition not waiting, citral is compared with other flavone compounds and is had optimum activity and can suppress the mankind's aortic smooth muscle cell hypertrophy being caused by oxidized low-density lipoprotein, and cell is not had to toxicity and can suppress inflammatory response.In addition, citral and gamma type peroxidating body multiplication agent activation receiver part (for example marketed drugs rosiglitazone) has hyperplasia, cyclin D1 and the cyclin D3 that synergism can suppress to be induced by oxidized low-density lipoprotein and expresses, is situated between plain in vain
and the expression of the white element-6 that is situated between.
Citral of the present invention is used for suppressing p44/42 mitogen activated protein kinase (MAPK) phosphorylation, thereby further suppresses to be situated between white element-6 (IL-6) and/or the white element that is situated between
expression.Aforementioned citral also can be used to activate gamma type peroxidating body multiplication agent activation receiver
, and further suppress IL-6 and/or
expression.Activation
separately can further suppress the expression of cyclin D1 (cyclin D1) and/and cyclin D3 (cyclin D3).
Therefore, the invention provides a kind of being used for the treatment of or the compositions of prevention of arterial atherosclerotic sclerosis, it is characterized in that containing citral.Said composition is for increasing this
the expression of messenger RNA (mRNA).
Accompanying drawing explanation
Fig. 1: citral suppresses the active result of mankind's aortic smooth muscle cell hypertrophy
Fig. 2: the hypertrophy rate impact of the smooth muscle cell that citral is processed oxidized low-density lipoprotein
The specific embodiment
The application's proposed invention can be illustrated by following embodiment, should fully understand, embodiments of the present invention and specific embodiment are the references proposing in order to allow those skilled in the art implement the present invention, not say that the present invention is restricted to these embodiments and embodiment.Within not exceeding purport scope of the present invention, can modify to embodiments of the present invention, change, will all belong to scope of the present invention.
Citral of the present invention (English: Citral) be " 3,7-dimethyl-2,6-octadiene aldehyde ", chemical formula C
10h
16o is the unsaturated chain aldehydes monoterpene that contains two two keys.
It has the two key cis-trans-isomers of following two kinds of 2-:
Citral a (Genarial): having another name called geranial, Mang geranial, is the E-isomer of 2 two keys, structural chemical formula (1).Weak yellow liquid, has strong Fructus Citri Limoniae abnormal smells from the patient, relative density 0.8898, and 228 ℃ of boiling points, are insoluble in water, can be miscible with ethanol, ether.
Citral b (Neral): having another name called neral, is the Z-isomer of 2 two keys, and structure is shown in chemical formula (2).Colourless pleasantly sweet liquid, relative density 1.4900,103 ℃ of boiling points (1599.8Pa).
Generally citral is above both mixture, for the faint yellow oily volatile liquid that has citrus scented, is insoluble in water.Dissolve in ethanol, ether, propylene glycol, glycerol, mineral wet goods organic solvent.Relative density 0.891 (25/25 ℃), boiling point 228-229 ℃.Be present in tangerine oil, Fructus Citri Limoniae oil, Indian oil of verbena, litsea cubeba oil, white lemon oil, Herba Verbenae wet goods plants essential oil.
The chemical property of citral is more active, redox reaction easily occurs and generate geranic acid or transformation of geraniol/nerol.Under effect of sulfuric acid, can cyclisation generate cymene.Unstable in alkali, can resinification under highly basic effect.
Citral content in each plants essential oil is: NINGMENGXIANG peach wood (90-98%), Fructus Litseae Listsea citrata (90%), cubeb litsen tree Litsea cubeba (70-85%), lemon grass (Cymbopogon citratus) (65-85%), Fructus Citri Limoniae tea tree ethereal oil (70-80%), Ocimum Basilicum Ocimum gratissimum (66.5%), Linderaberazoin Lindera citriodora (～65%), Petitgrain quintessence oil (36%), Herba Verbenae (30-35%), history Tag eucalyptus globolus (26%), Herba Melissae officinalis (11%), blue or green lemon (6-9%), Fructus Citri Limoniae (2-5%).
Citral of the present invention can be any one in above-mentioned citral a or citral b, can be also both mixture.Citral of the present invention can be used above-mentioned plants essential oil, also can obtain by the method for chemosynthesis, preferably uses content in more than 50% blend of essential oils.
Citral of the present invention dissolves in ethanol, glycerol, ether, propylene glycol, mineral wet goods organic solvent.Preferably be dissolved in ethanol, glycerol.More preferably be dissolved in ethanol.
Experimental example 1
-activity of citral inhibition mankind aortic smooth muscle cell hypertrophy-
The activity (hereinafter to be referred as " suppressing active ") that whether suppresses mankind's aortic smooth muscle cell (being called for short " smooth muscle cell ") hypertrophy in order to analyze citral, with hypertrophy and the cell survival degree of WST-1 reagent mensuration smooth muscle cell.WST-1 reagent is a kind of tetrazolium salt, and it can be cut into formazan (formazan) by Mitochondria dehydrogenase in living cells.First, smooth muscle cell is implanted to the culture dish of 96 porose discs, after cultivation is full to seventy percent, then smooth muscle cell is replaced in the DMEM culture fluid containing 0.5% N of embryo's serum and carried out " synchronization " 24 hours.In the situation that having or nothing adds citral compound, with 30 ì g/ml oxidized low-density lipoproteins (being called for short ox-LDL), stimulate smooth muscle cell 24 hours.Finally, add WST-1 reagent to cell culture fluid, with the light absorption value under elisa assay instrument detection 450nm wavelength, measure the total amount of formazan (formazan).With the WST-1 reagent mensuration hypertrophy of smooth muscle cell and the experiment of cell survival degree, will, for the present invention, below incite somebody to action no longer repeatedly illustrative experiment flow process.
Fig. 1 shows that the citral from different plants essential oils or chemosynthesis all suppresses the activity of the smooth muscle cell proliferation that caused in 24 hours by oxidized low-density lipoprotein (30 ì g/ml).According to experimental result, show that citral has the inhibition showing active, and cell is not had to toxicity.Wherein,
A: matched group
B: oxidized low-density lipoprotein
C: oxidized low-density lipoprotein+citral (purchased from Sigma company)
D: oxidized low-density lipoprotein+citral (NINGMENGXIANG peach wood)
E: oxidized low-density lipoprotein+citral (Fructus Litseae)
F: oxidized low-density lipoprotein+citral (cubeb litsen tree)
G: oxidized low-density lipoprotein+citral (lemon grass (Cymbopogon citratus))
H: oxidized low-density lipoprotein+citral (Fructus Citri Limoniae Camellia sinensis)
In above experimental group, institute's citral concentration is 5 ì g/ml.
Experimental example 2
-the hypertrophy rate impact of the smooth muscle cell that citral is processed oxidized low-density lipoprotein-
As shown in Figure 2, after 30 ì g/ml oxidized low-density lipoproteins stimulate, approximately 50% smooth muscle cell proliferation.With respect to an experimental group of only processing with oxidized low-density lipoprotein, the hyperplasia rate of processing through 1,2.5 and 5 ì g/ml citrals is showing and is reducing, and is dose-dependent effect.
Claims (4)
1. a compositions that is used for the treatment of arteriosclerosis, it is characterized in that containing citral is effective ingredient.
2. compositions as claimed in claim 1, is characterized in that, described citral is from NINGMENGXIANG peach wood, Fructus Litseae, cubeb litsen tree, lemon grass (Cymbopogon citratus), Fructus Citri Limoniae Camellia sinensis.
3. compositions as claimed in claim 1 or 2, is characterized in that, the concentration of described citral is 1～5 ì g/ml.
4. compositions as claimed in claim 1 or 2, is characterized in that, also contains the medically acceptable supporting agent of other effective dose.
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| CN201410242854.0A CN103976987A (en) | 2014-06-04 | 2014-06-04 | Composition for treating atherosclerosis |
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| CN201410242854.0A CN103976987A (en) | 2014-06-04 | 2014-06-04 | Composition for treating atherosclerosis |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105726576A (en) * | 2016-02-04 | 2016-07-06 | 刘玉财 | Tablet used for treating angina in slow-release stage and preparation method thereof |
| CN108135955A (en) * | 2015-10-16 | 2018-06-08 | 株式会社钟化 | muscle-building agent |
| WO2019017677A3 (en) * | 2017-07-18 | 2019-03-07 | 연세대학교 산학협력단 | Composition comprising citral as effective ingredient for exhibiting effect of muscle strengthening, muscle enhancement, muscle differentiation, muscle regeneration, or sarcopenia suppression |
| JP2021521248A (en) * | 2018-04-16 | 2021-08-26 | ラ ホヤ インスティテュート フォア アラージー アンド イムノロジー | Modulation of immune response by targeting olfactory receptor activity |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101969968A (en) * | 2008-03-13 | 2011-02-09 | 松下电器产业株式会社 | Aromatic antihypertensive agent, and method for lowering blood pressure in mammals |
-
2014
- 2014-06-04 CN CN201410242854.0A patent/CN103976987A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101969968A (en) * | 2008-03-13 | 2011-02-09 | 松下电器产业株式会社 | Aromatic antihypertensive agent, and method for lowering blood pressure in mammals |
Non-Patent Citations (1)
| Title |
|---|
| 胡祖光等: "柠檬醛对大鼠及人血小板聚集作用的影响", 《中药药理与临床》 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108135955A (en) * | 2015-10-16 | 2018-06-08 | 株式会社钟化 | muscle-building agent |
| EP3363449A4 (en) * | 2015-10-16 | 2019-06-26 | Kaneka Corporation | Muscle-enhancing agent |
| US10729737B2 (en) | 2015-10-16 | 2020-08-04 | Kaneka Corporation | Muscle-enhancing agent |
| CN105726576A (en) * | 2016-02-04 | 2016-07-06 | 刘玉财 | Tablet used for treating angina in slow-release stage and preparation method thereof |
| WO2019017677A3 (en) * | 2017-07-18 | 2019-03-07 | 연세대학교 산학협력단 | Composition comprising citral as effective ingredient for exhibiting effect of muscle strengthening, muscle enhancement, muscle differentiation, muscle regeneration, or sarcopenia suppression |
| JP2021521248A (en) * | 2018-04-16 | 2021-08-26 | ラ ホヤ インスティテュート フォア アラージー アンド イムノロジー | Modulation of immune response by targeting olfactory receptor activity |
| EP3781173A4 (en) * | 2018-04-16 | 2022-04-27 | La Jolla Institute for Allergy and Immunology | Modulating immune response via targeting of olfactory receptor activity |
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