CN101347424A - Use of luteolin in preparing anticomplement medicament - Google Patents
Use of luteolin in preparing anticomplement medicament Download PDFInfo
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- CN101347424A CN101347424A CNA2007100441004A CN200710044100A CN101347424A CN 101347424 A CN101347424 A CN 101347424A CN A2007100441004 A CNA2007100441004 A CN A2007100441004A CN 200710044100 A CN200710044100 A CN 200710044100A CN 101347424 A CN101347424 A CN 101347424A
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Abstract
The invention belongs to the field of traditional Chinese medicine, and relates to a new application of luteolin for preparing an anti-complement medicine. In the invention, the luteolin is separated and extracted from a traditional Chinese medicine formula used for preventing and treating severe acute respiratory syndrome (SARS); the traditional Chinese medicine formula consists of heartleaf houttuynia herb, wild chrysanthemum, herba artemisiae capillaries, fortune eupatorium herb and tsaoko with the weight ratio of 15: 6: 15: 10: 3; and experiments prove the anticomplement activity of the classical pathway and alternative pathway. The compound luteolin contained in the anticomplement medicine can be taken as an active ingredient for preparing a novel anticomplement medicine.
Description
Technical field
The invention belongs to the field of Chinese medicines, relate to a kind of antialexic medicine, be specifically related to the new purposes of luteolin in the preparation anticomplement medicament.
Background technology
Under normal physiological condition, the function of complement mainly is to attack external cause of disease and remove immune complex, and keeps the balance of body.Yet the improper activation of complement system can cause human immune system's overreaction, causes the damage and the inflammatory reaction of human body self normal structure.Studies show that the disease relevant with the complement excessive activation has rejection after rheumatoid arthritis, alzheimer disease, systemic lupus erythematosus (sle) (SLE), the organ transplantation, multiple organ dysfunction syndrome syndrome, adult respiratory distress syndrome (ARDS) etc.It is reported, serious symptom severe acute respiratory syndrome (SARS) and the bird flu that causes by H5N1 type viral infection, can find immune overreaction symptom clinically, as ARDS, septic shock and Reyes syndrome etc. have research to think that above-mentioned reaction symptom and cellular immunization, humoral immunization excessive activation are relevant.Existingly studies confirm that the excessive activation of SARS and complement system is relevant, though do not prove at present the excessive activation that can cause complement system behind the highly pathogenic H5N1 type avian influenza people as yet on evidence, yet the existing influenza infection activating complement alternative pathway that studies show that plays an important role in the generation of viral respiratory system disease.In view of the important function of complement excessive activation in causing human many critical illness, therefore be badly in need of seeking the novel complement inhibitor of high-efficiency low-toxicity.
Luteolin (luteolin) is a kind of representative natural flavone, belongs to faintly acid kaempferol compounds, and chemistry is called 3 ', 4 ', 5, and (3 ', 4 ', 5,7-Tetralydroxyflavone), chemical formula is C to the 7-kaempferol
15H
10O
6, molecular weight is 286.Because of at first from the leaf of the herbaceous plant reseda (R.odorata L.) of Resedaceae (Resedaceae) Reseda (Reseda), stem, branch institute isolate and gain the name.Luteolin is distributed more widely in plant kingdom, is distributed in Labiatae (Labiatae) and Compositae (Compositae) plant more.Have cough-relieving clinically, eliminate the phlegm, antiinflammatory, antibiotic, antiviral and effects such as blood fat reducing and cholesterol, also have stronger antioxidant activity, can be used for the bad change of oil-control food.Pharmacological evaluation shows, luteolin can suppress rats'liver sternzellen (hepatic stellatecell external, HSC) propagation, thereby and, have the effect of prevention or treatment hepatic fibrosis and the hepatocyte injury due to the antagonism carbon tetrachloride in animal body by removing free radical inhibition collagen gene expression.Luteolin has better therapeutic effect to the inductive Pulmonary Fibrosis in Rats model of bleomycin, expresses relevant with transforming growth factor (TGF-β 1) mRNA in its inhibition lung tissue.Luteolin can also the coronary artery dilating blood flow and is reduced the arteria coronaria vascular resistance, and myocardial oxygen consumption is not had obvious influence.The luteolin that studies confirm that in recent years all has remarkable inhibitory action to multiple solid tumor, ehrlich ascites carcinoma and leukaemia, has many target spots antitumor action, both can directly act on the metabolism of tumor cell interference cell, cell growth inhibiting is induced or the enhanced sensitivity apoptosis; Also can pass through the enhancing human body immunity function, the performance antitumor action is a kind of very promising potential antitumor drug.Significant be that the anti-inflammatory activity of luteolin is very remarkable.The clinical research that hundreds of bronochitic participates in shows that luteolin can both effectively be alleviated as cough, expectoration, asthma etc. the chronic bronchitis shape, and do not see liver is arranged, heart or Toxicity of Kidney report.Other has research to think that luteolin is the antianaphylactic main component of Chinese medicine Folium Perillae antiinflammatory, show and suppress TNF α generation in the body, suppress ear swelling and allergy edema, its mechanism of action is by suppressing 5-lipoxygenase (5-LO) and 12-lipoxygenase (12-LO), and the inhibition leukotriene B4, C4, D4, the generation of E4; Can significantly reduce the autonomous pruritus behavior of the mice that drying property dermatitis causes, reduce the PGE2 content in the affected skin, its mechanism of action may be by realizing anti-allergic effects such as mast cell degranulation and histamine release.
Take a broad view of report both domestic and external, there is no the anticomplementary drug effect of luteolin and suppress medicine with the complement of its preparation.
Summary of the invention
The purpose of this invention is to provide the new pharmaceutical usage of luteolin, be specifically related to the purposes of luteolin in preparation complement inhibition medicine.
Luteolin of the present invention has chemical constitution as follows:
The present invention obtains the luteolin monomeric compound from Chinese medicine compound (State Administration of Traditional Chinese Medicine's recommendation) separation and Extraction that is used for preventing and treating serious symptom severe acute respiratory syndrome (SARS).
Described Chinese medicine compound is made up of Herba Houttuyniae, Flos Chrysanthemi Indici, Herba Artemisiae Scopariae, Herba Eupatorii, Fructus Tsaoko, and its ratio is 15: 6: 15: 10: 3.
Purpose of the present invention is achieved through the following technical solutions:
1. extract and the separation and purification luteolin:
Herba Houttuyniae, Flos Chrysanthemi Indici, Herba Artemisiae Scopariae, Herba Eupatorii, Fructus Tsaoko Chinese medicine of the five flavours are 15: 6: 15 by its proportion of composing: 10: 3 compatibilities amount to 19.8Kg.Extract with 95% ethanol merceration, filtration, decompression recycling ethanol gets ethanol extraction to there not being the alcohol flavor.Ethanol extraction adds the water suspendible, respectively with isopyknic petroleum ether, ethyl acetate, n-butanol extraction, obtains petroleum ether part, ethyl acetate extract and n-butanol portion.Ethyl acetate extract is through silica gel column chromatography, with petroleum ether-acetone gradient elution.Wherein petroleum ether-acetone (8: 2) eluting stream part is carried out repeatedly silica gel column chromatography (petroleum ether-acetone 7: 3), again through Sephadex LH-20 (chloroform-methanol 1: 1) purification, gets luteolin.
2. luteolin is used for anticomplement test.Confirm that through in vitro tests luteolin activates the cell haemolysis that is caused to classical and alternative pathway inhibition is all arranged.
1) anticomplementary activates classical pathway cell hemolytic test
1: 80 diluent of guinea pig serum is as complement, the antigenic activation classical pathway of complement causes sheep red blood cell haemolysis, reference literature method (Kabat, E.A., Mayer, M.M..Complement and complement fixation in experimental immunology.Charles C.Thomas Publisher, Ilinois U.S.A.1964.pp.133-240.) records luteolin and can suppress cell haemolysis.CH
50＝54μg/mL，n＝3。
2) anticomplementary activates 1: 10 diluent of alternative pathway cell hemolytic test human serum as complement, the activating complement alternative pathway causes rabbit erythrocyte haemolysis, reference literature method (Klerx, J.P., Beukelman, C.J., Van, D.H., Willers, J.M..Microassayfor colorimetric estimation of complement activity in guinea pig, human and mouse serum.Journal of Immunological Methods.1983.63 215-220) records luteolin and can suppress cell haemolysis.AP
50＝48μg/mL，n＝3。
Described luteolin confirms to have strong anticomplementary activity through experiment in vitro.Can be used for preparing complement and suppress medicine.
The specific embodiment
Embodiment 1 preparation luteolin
Herba Houttuyniae, Flos Chrysanthemi Indici, Herba Artemisiae Scopariae, Herba Eupatorii, Fructus Tsaoko Chinese medicine of the five flavours are 15: 6: 15 by its proportion of composing: 10: 3 compatibilities amount to 19.8Kg.Extract with 95% ethanol merceration, filtration, decompression recycling ethanol gets ethanol extraction 1Kg to there not being the alcohol flavor.Ethanol extraction adds the water suspendible, respectively with isopyknic petroleum ether, ethyl acetate, n-butanol extraction, obtains petroleum ether part (405g), ethyl acetate extract (200g) and n-butanol portion (100g).Ethyl acetate extract (190g) is through silica gel column chromatography, with petroleum ether-acetone gradient elution.Wherein petroleum ether-acetone (8: 2) eluting stream part is carried out repeatedly silica gel column chromatography (petroleum ether-acetone 7: 3), again through SephadexLH-20 (chloroform-methanol 1: 1) purification, gets luteolin.
Luteolin (Luteolin): yellow needle.ESI-MS(m/z)：287[M+H]
+.C
15H
10O
6.
1H-NMR(DMSO-d
6，400MHz)δ12.96(1H，br?s，5-OH)，10.80(1H，s，7-OH)，9.63，9.62(each?1H，s，3’，4’-OH)，7.37(2H，m，H-2’，6’)，6.82(1H，d，J＝8.0Hz，H-5’)，6.55(1H，s，H-3)，6.33(1H，d，J＝1.8Hz，H-8)，6.08(1H，d，J＝1.8Hz，H-6).
13C-NMR(DMSO-d
6，100MHz)δ181.0(C-4)，167.4(C-7)，163.5(C-5)，161.3(C-9)，157.4(C-3’)，151.3(C-2)，146.2(C-4’)，120.2(C-1’)，118.7(C-6’)，115.8(C-2’)，112.5(C-5’)，102.3(C-3)，101.9(C-10)，99.5(C-6)，94.2(C-8).
Embodiment 2 classical pathway complement inhibition tests
Get guinea pig serum, with VBS
2+(barbitol buffer solution, pH=7.4 contain 0.5mMMg to buffer
2+With 0.15mM Ca
2+) dilution is 1: 80, as the complement of classical pathway source.With the antibody of the anti-sheep red blood cell of rabbit with VBS
2+Buffer dilution be 1: 1000 as hemolysin; The sheep red blood cell (SRBC) that is stored in the Alsever liquid is configured to 2%SRBC.Precision weighing luteolin 1mg adds VBS
2+Buffer dissolving (the DMSO hydrotropy of adding 1%) is diluted to 8 concentration.The luteolin solution 200 μ L of variable concentrations and 1: 80 complement 200 μ L are behind 37 ℃ of preincubate 10min, add 100 μ L hemolysins (1: 1000) and 100 μ L2%SRBC successively, behind 37 ℃ of water-bath 30min, put into the low-temperature and high-speed centrifuge, centrifugal 10min under 5000rpm, 4 ℃ of conditions.Get every pipe supernatant 200 μ L respectively in 96 orifice plates, measure absorbance at 405nm.Experiment is provided with the luteolin matched group simultaneously, and (luteolin solution of 200 μ L respective concentration adds 400 μ L VBS
2+Buffer), the complement control group is (with 200 μ L VBS
2+Buffer replaces luteolin solution) and full haemolysis group (100 μ L 2%SRBC are dissolved in the 500 μ L tri-distilled waters).The luteolin group absorbance of each concentration deducted calculate the haemolysis suppression ratio behind the corresponding luteolin matched group absorbance.As X-axis, the haemolysis suppression ratio is mapped as Y-axis with the logarithm of luteolin concentration, and the fitting a straight line that obtains is calculated CH
50Value.As positive control drug, the result shows that luteolin can suppress classical pathway of complement and activate the cell haemolysis (table 1) that is caused with heparin sodium.
Embodiment 3 alternative pathway complement inhibition tests
Get the volunteer of NAM serum, (barbitol buffer solution, pH=7.4 contain 5mM Mg with the VBS-Mg-EGTA buffer
2+With 8mM EGTA) dilution is 1: 10, as the complement of alternative pathway source.The rabbit erythrocyte that is stored in 3.8% liquor sodii citratis is configured to 2% rabbit erythrocyte with the VBS-Mg-EGTA buffer.Precision weighing luteolin 1mg adds VBS-Mg-EGTA buffer (the DMSO hydrotropy of adding 1%), is diluted to 8 concentration.The luteolin solution 150 μ L of variable concentrations and 1: 10 complement 150 μ L add 200 μ L, 2% rabbit erythrocyte behind 37 ℃ of preincubate 10min, put into the low-temperature and high-speed centrifuge behind 37 ℃ of water-bath 30min, centrifugal 10min under 5000rpm, 4 ℃ of conditions.Get every pipe supernatant 200 μ L respectively in 96 orifice plates, measure absorbance at 405nm.Experiment is provided with luteolin matched group (luteolin solution of 150 μ L respective concentration adds 350 μ L VBS-Mg-EGTA buffer), complement control group (replacing luteolin solution with 150 μ L VBS-Mg-EGTA buffer) and full haemolysis group (200 μ L, 2% rabbit erythrocyte is dissolved in the 300 μ L tri-distilled waters) simultaneously.The luteolin group absorbance of each concentration deducted calculate the haemolysis suppression ratio behind the corresponding luteolin matched group absorbance.As X-axis, the haemolysis suppression ratio is mapped as Y-axis with the logarithm of luteolin concentration, and the fitting a straight line that obtains is calculated AP
50Value.As positive control drug, the result shows that luteolin can suppress alternative pathway of complement and activate the cell haemolysis (table 1) that is caused with heparin sodium.
Table 1 luteolin is to the inhibitory action of complement
CH
50And AP
50Value is expressed as: meansigma methods ± SD (n=3).
Claims (2)
1. luteolin is in the purposes of preparation in the anticomplement medicament.
2. by the described purposes of claim 1, wherein said luteolin has following chemical constitution:
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| CNA2007100441004A CN101347424A (en) | 2007-07-20 | 2007-07-20 | Use of luteolin in preparing anticomplement medicament |
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| CNA2007100441004A CN101347424A (en) | 2007-07-20 | 2007-07-20 | Use of luteolin in preparing anticomplement medicament |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102552791A (en) * | 2012-01-14 | 2012-07-11 | 石家庄学院 | Active ingredient extracted from Amomum tsao-ko and application thereof in preparing blood sugar reducing medicine and food |
| CN102697768A (en) * | 2012-06-07 | 2012-10-03 | 中国人民解放军第二军医大学 | Application of luteolin flavonoid compounds in preparation of anti-tumor medicaments |
| CN108129437A (en) * | 2018-01-26 | 2018-06-08 | 扬州工业职业技术学院 | A kind of chromocor compound and preparation method and application |
| CN108125995A (en) * | 2018-01-26 | 2018-06-08 | 扬州工业职业技术学院 | A kind of ginko leaves flavone extract and its application |
| CN108239059A (en) * | 2018-01-29 | 2018-07-03 | 扬州工业职业技术学院 | It is a kind of using Simulation moving bed from ginkgo biloba p.e separating flavone class compound method |
| CN115282142A (en) * | 2022-07-14 | 2022-11-04 | 北京大学第三医院（北京大学第三临床医学院） | Application of luteolin in preparation of medicine for treating gastric precancerous diseases |
-
2007
- 2007-07-20 CN CNA2007100441004A patent/CN101347424A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102552791A (en) * | 2012-01-14 | 2012-07-11 | 石家庄学院 | Active ingredient extracted from Amomum tsao-ko and application thereof in preparing blood sugar reducing medicine and food |
| CN102552791B (en) * | 2012-01-14 | 2014-06-11 | 石家庄学院 | Active ingredient extracted from Amomum tsao-ko and application thereof in preparing blood sugar reducing medicine and food |
| CN102697768A (en) * | 2012-06-07 | 2012-10-03 | 中国人民解放军第二军医大学 | Application of luteolin flavonoid compounds in preparation of anti-tumor medicaments |
| CN108129437A (en) * | 2018-01-26 | 2018-06-08 | 扬州工业职业技术学院 | A kind of chromocor compound and preparation method and application |
| CN108125995A (en) * | 2018-01-26 | 2018-06-08 | 扬州工业职业技术学院 | A kind of ginko leaves flavone extract and its application |
| CN108125995B (en) * | 2018-01-26 | 2021-04-16 | 扬州工业职业技术学院 | Ginkgo leaf flavone extract and application thereof |
| CN108239059A (en) * | 2018-01-29 | 2018-07-03 | 扬州工业职业技术学院 | It is a kind of using Simulation moving bed from ginkgo biloba p.e separating flavone class compound method |
| CN115282142A (en) * | 2022-07-14 | 2022-11-04 | 北京大学第三医院（北京大学第三临床医学院） | Application of luteolin in preparation of medicine for treating gastric precancerous diseases |
| CN115282142B (en) * | 2022-07-14 | 2023-05-16 | 北京大学第三医院（北京大学第三临床医学院） | Application of luteolin in preparation of medicines for treating gastric precancerous diseases |
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Open date: 20090121 |