CN101007015A - Application of flavonoids of celery seed and coumarins in preparation of drug for preventing and treating gout - Google Patents
Application of flavonoids of celery seed and coumarins in preparation of drug for preventing and treating gout Download PDFInfo
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Abstract
The invention disclosed the application of celery seed coumarins and flavanoid in preparing arthrifuge, anti-inflammatory agent or health food, which belongs to the natural occurring drugs and medical technology domain. The coumarins and flavanoid is the extract from acetic ether. The preparing method includes the following steps: selecting 10kg celery dry seed, adding 15-20 times of 75-95%(V/V) as the seed or extracting with 4-5 times of 75-95%(V/V) alcohol at higher temperature, heating for 1-1.5h every time; vacuum condensing the extracts until nearly all the alcohol is away; adding 1-2 times of water, extracting with 1/3 volume of the diluted solution sherwood oil (60-90DEG C) for 2-3 times; reclaiming the sherwood oil; extracting the water layer with 1/3 volume of acetic ether for 4 times; reclaiming the acetic ether to get the extracts. The invention has very simple preparing technologies; the product in the invention has obvious anti-inflammatory function; it can also decrease the amount of serum uric acid of rats.
Description
Technical field
The present invention relates to celery seed flavonoid and coumarin kind compound and prevent and treat the purposes of gout medicine in preparation, specifically, relate to the flavonoid of extraction separation from the seed of Herba Apii graveolentis Apium graveolens L. and coumarin kind compound and prevent and treat application in gout medicine, anti-inflammatory drug or the health food, belong to Natural Medicine Chemistry and medical technical field in preparation.
Background technology
Celery seed is the seed of samphire Herba Apii graveolentis Apium graveolens L., and the treatment arthralgia is existing century-old history in Australia, is regarded as traditional folk prescription among the people, takes the celery seed extracts and alleviate arthralgia.The cloudy step of modern nutriology is contained the nutritional labeling useful to articular cartilage in the seed oil of Herba Apii graveolentis certainly, is proved yet there is no strong evidence.The chemical constituent that the foreign scholar has reported is mainly umbelliferone, apiolin [Grag, S.K.; Gupta, S.R.; Sharma, N.D.Apiumoside, a new furanocoumarin glucoside from the seeds of Apiumgraveolens.Phytochemistry 1979b, 18,1764-1765], isoimpinellin, apiin, bergapton, Herba Apii graveolentis coumarin glycoside [Grag, S.K.; Gupta, S.R.; Sharma, N.D.Minor Phenolics of Apiumgraveolens seeds.Phytochemistry 1979a, 18,352.], Herba Apii graveolentis coumarin, seselin [Grag, S.K.; Gupta, S.R.; Sharma, N.D.Apiumetin-A New Furanocoumarin from the seeds of Apiumgraveolens.Phytochemistry 1978,17,2135-2136.].The pharmacologically active aspect, the existing report of xanthine oxidase inhibitory activity [Chun-Mao Lin about apigenin and luteolin, Chien-Shu Chen, Chien-Tsu Chen, Yu-Chih Liang.Molecular modeling of flavonoids that inhibits xanthine oxidase.Biochemical and Biophysical Research Communications, 2002,294:167-172], suppress the active report except that apigenin and luteolin have xanthine oxidase, other chemical compounds are not seen the report of preventing and treating gout and antiinflammatory action research both at home and abroad so far.
Summary of the invention
The technical problem to be solved in the present invention provides celery seed flavonoid and coumarin kind compound are prevented and treated the gout medicine in preparation purposes.
For achieving the above object, the present invention is by the following technical solutions:
Celery seed Coumarins and flavone compound are used for preparing the purposes of preventing and treating gout medicine, anti-inflammatory drug or health food, described celery seed Coumarins and flavone compound are the celery seed acetic acid ethyl ester extract, flavonoid content is 55-65% in the extract, and the content of Coumarins is 5-10%.
Described celery seed acetic acid ethyl ester extract prepares by the following method: Herba Apii graveolentis dry seed 10kg, with 15～20 times of amount 75～95% (V/V) ethanol percolate extraction or with 4～5 times of amount 75～95% (V/V) ethanol heating extraction 3～4 times, heated 1～1.5 hour at every turn; Extracting solution is evaporated to nearly no ethanol, gets concentrated solution; Add 1～2 times of water gaging dilution suspendible in concentrated solution after, the petroleum ether (60～90 ℃) with diluent 1/3rd volumes extracts 2～3 times, tells petroleum ether and reclaims petroleum ether, gets petroleum ether extract; Water layer reuse 1/3rd volume ethyl acetate extractions 4 times are told ethyl acetate and are reclaimed ethyl acetate and get the celery seed acetic acid ethyl ester extract.Obtain 12 flavone compounds and 6 Coumarins compounds from further separation of this extract and evaluation.
6 coumarin kind compounds are: SOC-1: umbelliferone [Chatterjee A., Sen R.and Ganguly D..Aegelinol, A minor Lactonic Constituent of Aegle Marmelos.Phytochemistry, 1978,17:328], SOC-2: xanthotoxol, [Elgamal M.H., N.H.Elewa, Elkhrisy E.A..
13C NMRChemical shifts and carbon-proton coupling constants of some furocoumarins andfurochromones.Phytochemistry, 1979,18,139-143], SOC-3: bergapton [Elgamal M.H., Elewa N.H., Elkhrisy E.A..Helmut Duddeck.Phytochemistry, 1979,18:139-143], SOC-4:5,8-dimethoxy-6,7-furocoumarin [Chen.I.S., et al.Coumarins andanti-platelet aggregation constituents from Zanthoxylum schionifolium.Phytochemistry, 1995,39:1091], SOC-5:6-methoxyl group-umbelliferone [Melafferty F.W.and Douglas B.S..The wiley/NBS Registry of Mass Spectral Data.Volume1.], SOC-6: isoimpinellin [Tao Chaoyang, Chen Wansheng, Zhang Weidong. Zanthoxylum Dimorphophyllum Hemsl. Var Spinifolium Rhed. Et Wils Coumarins chemical constituent Acta Pharmaceutica Sinica, 2003, (28) 4,344-346].
12 flavone compounds are: SOC-7: chrysoeriol [Doo Y.C., Jeong Y.L., Kim M.R..Chrysoeriol potently inhibits the induction of nitric oxide synthase by blocking AP-1activation.Journal of Biomedical Science, 2005,12:949-959], SOC-8:5,7,3 ', 4 '-tetrahydroxy-3-methoxy flavone [Li Xiaodong, Wu Lijun, Zang Xiaoyan. northeast Cortex Sorbariae Arboreae The Chemical Constituents [J]. Chinese medicine is assorted, 2002,27 (11): 841-843.]; SOC-9: chrysoeriol 7-O-β-D-glucoside [Jia Zhongjian, Fei Houman, Li Yu; Zhu Ziqing. Saussurea medusa chemical analysis research (I). SCI; 1986,9 (7): 789-792], SOC-10 Quercetin [Xiang Guangya; Yang Yu; Ruan Jinlan. Radix Hyperici Monogyni (Herba Hyperici Monogyni) chemical constitution study [J]. Tongji Medical Univ's journal, 2001,30 (5): 481-483.] SOC-11: kaempferol [Zhang Chao, Fang Yanxiong. the separation and the evaluation of Chinese medicine Herba Melastomatis Dodecandri flavones ingredient. Chinese Pharmaceutical Journal, 2003,38 (4): 256-258], SOC-12: luteolin [Xie Mingyong, Yu Yingli, Wang Yuanxing etc. Cyclocarya paliurus Iljinskaja chromocor compound structure and content [J]. University Of Nanchang's journal (natural sciences version), 2003,27 (1): 49-52], SOC-13: apigenin [Cheng Yu bit of a bridle, Zhang Dongming, Yu Shishan, fourth is happy. wear the Rhizoma et radix smilacis santis The Chemical Constituents. and CHINA JOURNAL OF CHINESE MATERIA MEDICA, 2003,28 (3): 233-235], SOC-14: luteolin 3 '-O-β-D-glucoside [Mahmoud A.M., Nawwar S.H.andIrmgard M.Leaf phenolics of Punica granaturn.Phytochemistry, 1994,37 (4): 1175-1177], SOC-15: apigenin 7-O-β-D-glucoside [Bachir B., Albert J., Mourad K.and FrancoisT.Flavonoid glycosides from Erica Cinerea.Phytochemistry, 1992,31 (7): 2483-2486], SOC-16: luteolin 7-O-β-D-pyranglucoside [Zhang Chao, Fang Yanxiong, the separation and the evaluation of Chinese medicine Herba Melastomatis Dodecandri flavones ingredient. Chinese Pharmaceutical Journal, 2003,38 (4): 256-258], SOC-17:5,4 '-dihydroxy-6,7-methylene-dioxy isoflavone [Dhar KL, Kalla AK.A new isoflavone from Irisgermamca[J] .Phytochemistry, 1973,12 (4): 734-735], SOC-18: luteolin 7-O-[β-D-apiose (1 → 2)]-β-D-glucoside [Ochi T., Takaishi Y., Shibata H., Higuti T., Kataoka M.Chemical constituents of Capsicum annuum L var.angulosum, and antiHelicobacter pylori activity.Natural Medicines, 2005,59 (2): 76-84].
The present invention extracts, separates and has identified 6 coumarin kind compounds and 12 flavone compounds from celery seed Apium graveolens L..Coumarin kind compound in the discovery celery seed and flavone compound can be used for preparation and prevent and treat gout medicine, anti-inflammatory drug or health food medicine.
Chrysoeriol is used for preparing the purposes of preventing and treating gout medicine, anti-inflammatory drug or health food.
The compositions that contains chrysoeriol is used for preparing the purposes of preventing and treating gout medicine, anti-inflammatory drug or health food.
The chemical constitution of 6 coumarin compounds is as follows:
SOC-1 umbelliferone (Umbelliferone) SOC-2 xanthotoxol (Xanthotoxin)
SOC-3 bergapton SOC-4 5,8-dimethoxy-6,7-furocoumarin
(Bergapten) (5，8-Dimethoxy-furo[6，7]-2H-1-benzopyran-2-one)
SOC-5 6-methoxyl group-umbelliferone SOC-6 isoimpinellin
(Scopolean) (Isopimpinellin)
The chemical constitution of 12 flavone compounds is as follows:
SOC-7 chrysoeriol SOC-8 5,7,3 ', 4 '-tetrahydroxy-3-methoxy flavone
(Chrysoeriol) (5，7，3’，4’-tetrahydroxy-3-methoxy flavonol)
SOC-9 chrysoeriol 7-O-β-D-glucoside SOC-10 Quercetin (Quercetin)
(Chrysoeriol-7-O-β-D-glucoside)
SOC-11 kaempferol (Kaempferol) SOC-12 luteolin (Luteolin)
SOC-13 apigenin (Apigenin) SOC-14 luteolin 3 '-O-β-D-glucoside
(Luteolin 3’-O-β-D-glucoside)
SOC-15 apigenin-7-O-B-D-glucoside SOC-16 luteolin 7-O-β-D-pyranglucoside
Apigenin 7-O-β-D-glucoside) (luteolin 7-O-β-D-glucoside)
SOC-17 5,4 '-dihydroxy-6,7-methylene-dioxy isoflavone
(5，4’-dihydroxy-6，7-methylenedioxy isoflavone)
SOC-18 luteolin 7-O-[β-D-apiose (1 → 2)]-β-D-glucoside
{luteolin 7-O-[2-(β-D-apiofuranosyl)-β-D-glucopyranoside]}
We adopt the rat gout model due to the micro-crystal type uric acid sodium, Oteracil Potassium induced mice hyperuricemia model, the uricopoiesis method is measured the activity test of xanthine oxidase vitro inhibition, the superoxide ion method of formation is measured xanthine oxidase vitro inhibition activity test and the test of pyrogallol autoxidation, found that chromocor compound and coumarin compound in the celery seed (Apium graveolens L.) have the formation of the uric acid of inhibition, promote urate excretion and antiinflammatory action.Therefore, chromocor compound in the celery seed and coumarin compound can be used to prepare the purposes of preventing and treating gout medicine or food or anti-inflammatory drug.
Advantage of the present invention is: the celery seed acetic acid ethyl ester extract that the present invention has found chrysoeriol first and contained this chemical compound has the effect of significant inhibition uricopoiesis, is the competitive inhibitor of xanthine oxidase.Coumarins and flavone compound can also reduce rat blood serum uric acid amount in the celery seed of the present invention, can be used for preparation and prevent and treat gout medicine, anti-inflammatory drug or health food.
The invention will be further described below in conjunction with the drawings and specific embodiments; it is not limitation of the invention; according to prior art well known in the art; embodiments of the present invention are not limited to this; therefore all this areas of having done according to the disclosure of invention be equal to replacement, all belong to protection scope of the present invention.
Description of drawings
Fig. 1 for be substrate with the xanthine of low concentration to the XO of chrysoeriol suppress active Lineweaver-burk mapping (0 μ M ,-; 0.5 μ M, *; 2.5 μ M, △; 5 μ M,; 10 μ M, zero).
The specific embodiment
Herba Apii graveolentis dry seed 10kg with 95% (V/V) ethanol percolate extraction, collects 15 times of amount percolates, and extracting solution is evaporated to nearly no ethanol in 55 ℃, thick extractum.After extractum added 1 times of water gaging dilution suspendible, the petroleum ether (60～90 ℃) with diluent 1/3rd volumes extracted 3 times, told petroleum ether and reclaimed the petroleum ether extract of petroleum ether.Water layer reuse 1/3rd volume ethyl acetate extractions 4 times are told ethyl acetate and are reclaimed ethyl acetate and get the celery seed acetic acid ethyl ester extract, and this extract mainly contains the celery seed coumarin and the flavone compound component is represented with (CFE).Flavonoid content is 55-65% in the extract, and the content of Coumarins is 5-10%.
Embodiment 2 celery seed flavonoids and coumarin compound preparation method
Herba Apii graveolentis dry seed 10kg with 75% (V/V) ethanol percolate extraction, collects 20 times of amount percolates, and extracting solution is evaporated to nearly no ethanol in 55 ℃, thick extractum.After extractum added 2 times of water gagings dilution suspendibles, the petroleum ether (60～90 ℃) with diluent 1/3rd volumes extracted 2 times, told petroleum ether and reclaimed the petroleum ether extract of petroleum ether.Water layer reuse 1/3rd volume ethyl acetate extractions 4 times are told ethyl acetate and are reclaimed ethyl acetate and get the celery seed acetic acid ethyl ester extract, and this extract mainly contains the celery seed coumarin and the flavone compound component is represented with (CFE).Flavonoid content is 55-65% in the extract, and the content of Coumarins is 5-10%.
Embodiment 3 celery seed flavonoids and coumarin compound preparation method
Herba Apii graveolentis dry seed 10kg with 4 times of amount 95% (V/V) ethanol heating extraction 3 times, heated 1 hour at every turn; Collect extracting solution, be evaporated to nearly no ethanol in 55 ℃, thick extractum.After extractum added 1 times of water gaging dilution suspendible, the petroleum ether (60～90 ℃) with diluent 1/3rd volumes extracted 3 times, told petroleum ether and reclaimed the petroleum ether extract of petroleum ether.Water layer reuse 1/3rd volume ethyl acetate extractions 4 times are told ethyl acetate and are reclaimed ethyl acetate and get the celery seed acetic acid ethyl ester extract, and this extract mainly contains the celery seed coumarin and the flavone compound component is represented with (CFE).Flavonoid content is 55-65% in the extract, and the content of Coumarins is 5-10%.
Embodiment 4 celery seed flavonoids and coumarin compound preparation method
Herba Apii graveolentis dry seed 10kg with 5 times of amount 75% (V/V) ethanol heating extraction 4 times, heated 1.5 hours at every turn; Collect extracting solution, be evaporated to nearly no ethanol in 55 ℃, thick extractum.After extractum added 2 times of water gagings dilution suspendibles, the petroleum ether (60～90 ℃) with diluent 1/3rd volumes extracted 3 times, told petroleum ether and reclaimed the petroleum ether extract of petroleum ether.Water layer reuse 1/3rd volume ethyl acetate extractions 4 times are told ethyl acetate and are reclaimed ethyl acetate and get the celery seed acetic acid ethyl ester extract, and this extract mainly contains the celery seed coumarin and the flavone compound component is represented with (CFE).Flavonoid content is 55-65% in the extract, and the content of Coumarins is 5-10%.
Embodiment 5 silica gel column chromatographies prepare celery seed coumarin and flavone compound monomer
Celery seed acetic acid ethyl ester extract (CFE) 80g (pressing the preparation of embodiment 1 method), silica gel (200～300 orders, the yellow affair silica gel of Yantai sesame development experiments factory product) column chromatography is separated (φ 10 * 120cm, 1000g), and petroleum ether-ethyl acetate (50: 1,25: 1,9: 1,8: 2,1: 1) gradient elution, every 1000ml collects, be divided into part for 1-30, pillar reuse eluent ethyl acetate behind the gradient elution, every 500ml collects, and being divided into is 10 parts.Behind the decompression and solvent recovery, in the 5th, 7 and 11 part, can obtain compound S OC-2, the crystallization of SOC-3 and SOC-4.The 14th part once more silica gel column chromatography separate that (φ 4 * 40cm 100g), can obtain compound S OC-6, SOC-1 and SOC-5 behind petroleum ether-ethyl acetate (20: 1,15: 1,10: the 1) gradient elution.The the 17th, 18 and 20 part obtains compound S OC-7, SOC-13 and SOC-17.The 22nd, 24,26 and 27 parts obtain chemical compound and obtain compound S OC-8, SOC-11, SOC-10 and SOC-12.The 30th part obtains chemical compound and obtains compound S OC-9.The eluent ethyl acetate part, after 1,2 and 3 part of merging, (φ 2.5 * 40cm 100g), behind methanol-water (8: the 2) eluting, obtains compound S OC-14 and SOC-15 to the separation of C18 reversed-phase silica gel column chromatography once more.The eluent ethyl acetate part, after the 5th, the 6 and 7 part of merging, C once more
18((φ 2.5 * 40cm 100g), behind methanol-water (8: the 2) eluting, obtains compound S OC-16 and SOC-18 to reverse phase silica gel in the column chromatography separation.Above chemical compound is through mass spectrograph (Mat-212 magnetic-type) and nuclear magnetic resonance analyser (Bruker DRX-500 type) is measured and contrast the chemical constitution of having determined them with document.
Embodiment 6 uricopoiesis methods are measured xanthine oxidase vitro inhibition activity
1. material and method
(1) reagent
Xanthine (xanthine) is available from U.S. Sigma company; Allopurinol (allopurinol) is available from U.S. Sigma company; Xanthine oxidase (xanthine oxidase) is available from Roche company; Pyrophosphoric acid sodium salt (sodiumpyrophosphate decahydrate ace reagent) is available from ICN Biomedical company;
Chrysoeriol, apigenin and luteolin make by embodiment 5 separation and purification.
(2) measure uricopoiesis
Add 50 μ g/ml samples or positive control allopurinol (1 μ g/ml) in the 1mmol xanthine solution, add 0.1U/ml xanthine oxidase (XO), add sodium pyrophosphate buffer solution (80mmol/1, pH value 8.5) in the reaction system to final volume 1ml, reaction is beginning to add xanthine oxidase, 37 ℃ of reaction 5min, automatic clinical chemistry analyzer (Hitachi-7600-020) measures the uricopoiesis amount, with the uricopoiesis amount of 5min as response speed.
2. experimental result
By calculating the xanthine oxidase inhibitory activity power that the uricopoiesis suppression ratio detects given the test agent.Chrysoeriol (SOC-7), apigenin (SOC-13) and luteolin (SOC-12) are external to have remarkable inhibiting activity to xanthine oxidase (XO).
Further detect chrysoeriol (SOC-7), these three monomers of apigenin (SOC-13) and luteolin (SOC-12) when variable concentrations to the vitro inhibition activity of xanthine oxidase, its experimental result shows that its inhibitory action is dose-dependence, with inhibitor concentration to suppression ratio map three's 50 3nhibitory dose (IC
50), suppress activity intensity: chrysoeriol (IC
505.6 allopurinol (IC μ M),
506.8 apigenin (IC μ M),
509.5 luteolin (IC μ M),
5010.5 μ M).(above numerical value is the meansigma methods that detects three times, has passed through statistical procedures: SAS statistics software).
By changing concentration of substrate, detect enzymatic reaction speed, to chrysoeriol Lineweaver-Burk mapping (Fig. 1), to detect its enzyme suppressor mode, the result shows that chrysoeriol has significantly suppressed the generation of uric acid, is the competitive inhibitor of xanthine oxidase.
Embodiment 7 superoxide ion method of formation are measured XO and are suppressed active and the experiment of pyrogallol autoxidation
1. material and method
(1) medicine and reagent
Xanthine (xanthine); Allopurinol (allopurinol); Tetrazolium nitro nitroblue (Nitro BlueBtetrazolium); Superoxide dismutase (superoxide dismutase) is available from U.S. Sigma company; Xanthine oxidase (xanthine oxidase represents with XO) is available from Roche company; Pyrogallol is available from Shanghai Chemical Reagent Co., Ltd., Sinopharm Group;
(2) utilize superoxide ion to cause NBT chromogenic assay xanthine oxidase activity
Reaction system is divided into three groups, wherein model group only adds xanthine (50 μ mol/l), xanthine oxidase (0.1U/mol) and NBT (50 μ mol/l), and on the basis of model group, add the chrysoeriol (SOC-7) of 20,40 and 60 μ g/ml in the experimental group respectively again by the concentration of sample chrysoeriol (SOC-7), positive controls adds the allopurinol of 1 μ g/ml on the model group basis, add phosphate buffer (50mmol/l, pH value 7.2) in the reaction system to final volume 600 μ l.Reaction is beginning to add xanthine oxidase, room temperature reaction 5min, under 560nm, measure optical density with the CE-2021 spectrophotometer, wavelength 560nm,, compared after the optical density value that experimental group and positive controls are recorded is calculated its suppression ratio divided by the optical density value of model group as response speed with the optical density recruitment of per minute.Xanthine is dissolved in 1 μ mol/l NaOH, other components dissolved are in 50mmol/l phosphate buffer and solution that 0.1mmol/LEDTA joins [Valentao P., Fernandes E., Carvalho F., et al.Antioxidant activity ofcentaurium erythraea infusion evidenced by its superoxide badical scavenging and xanthineoxidase inhibitory activity[J] .J.Agric.Food Chem., 2001,49:3476-3479].
(3) pyrogallol autoxidation test
It is model group, chrysoeriol (SOC-7) sample sets (being further divided into 20,40 and 60 μ g/ml concentration groups by its concentration) that experiment is divided into three groups, and positive control SOD (100u/ml) group.Before adding pyrogallol, add the material in sample sets and the positive controls earlier, behind 25 ℃ of constant temperature 20min, add the pyrogallol of 25 ℃ of preheatings, shake up rapidly, in the impouring optical path 1cm cuvette, measure light absorption value A at wavelength 420nm place immediately
O, A
The chrysoeriol sampleAnd A
SODSuppression ratio=(A
O-A
The chrysoeriol sample/ A
SOD) A
O* 100%
[40]
(4) influence of the foundation of hyperuricemia model and chrysoeriol
Male Kunming strain mice, body constitution amount 18～22g, be divided into 6 groups at random, every group 10, be sham operated rats, model group, high, medium and low dosage chrysoeriol (SOC-7) group and allopurinol group, high, medium and low dosage intraperitoneal injection every day is 1 time in the experiment, and continuous 3d, the dosage of high, medium and low dosage group chrysoeriol (SOC-7) are respectively 10,20,30mgkg
-1, allopurinol dosage is 2mgkg
-1Administration in the end one day, model group gives the equal volume normal saline, 1h before the last 1d administration, all organize equal lumbar injection 900mgkg except that sham operated rats
-1Oteracil Potassium, the 1h posterior orbit is got blood, with automatic clinical chemistry analyzer measure uric acid level in the serum [Wang Haidong, Ge Fei. the Herba Antenoronis Neofiliformis (Herba Antenoronis Filiformis) extract is to the influence [J] of hyperuricemia mice. CHINA JOURNAL OF CHINESE MATERIA MEDICA, 2002,22 (12): 939-9].
(5) statistical procedures
SAS statistics software, the result all x ± s represent.The t check of data is in groups adopted in experiment in the body.
2. experimental result
(1) chrysoeriol (SOC-7) is to the influence of xanthine oxidase activity
Cause NBT determination of color superoxide ion growing amount by superoxide ion, show that chrysoeriol (SOC-7) has significant inhibitory effect to xanthine oxidase, calculates its half-inhibition concentration (IC
50) be 3.2 μ M.
(2) chrysoeriol (SOC-7) is to the influence (table 1) of hyperuricemia mice serum uric acid level
Model group mice serum uric acid level has been compared obvious rising with sham operated rats, the high, medium and low dosage group of chrysoeriol is compared with model group, and remarkable decline is all arranged, and illustrates that chrysoeriol (SOC-7) also has the uric acid resisting effect in vivo.
Table 1 chrysoeriol is to the result that influences with uric acid level in the uricase inhibition Oteracil Potassium processing mice serum
| Group | Mice (only) | Dosage (mgkg -1) | Serum uric acid level (μ molml -1) |
| Model group | 10 | - | 0.305±0.089 |
| Sham operated rats | 10 | - | 0.075±0.200# |
| Chrysoeriol (SOC-7) | 10 | 10 | 0.260±0.076 * |
| Chrysoeriol (SOC-7) | 10 | 20 | 0.235±0.066 ** |
| Chrysoeriol (SOC-7) | 10 | 30 | 0.216±0.048 ** |
| The allopurinol group | 10 | 2 | 0.139±0.037 ** |
Chrysoeriol and model group are relatively
*P＜0.05,
*P＜0.01; Model group and sham operated rats compare: #P＜0.05.
The anti-inflammatory activity research of embodiment 8 celery seed flavonoids and coumarin kind compound
1. material and method
(1) medicine and reagent:
Celery seed acetic acid ethyl ester extract (CFE) (flavonoid and Coumarins) is pressed the preparation of embodiment 1 method.
The aspirin enteric coatel tablets: Qinyang, Henan pharmaceutical factory produces, lot number: 20030314, and specification: 0.3g/ sheet.
Uric acid: Shanghai Foxing Changzheng medical science Co., Ltd, lot number: G041003.
Uric acid calibration solution: Shanghai Foxing Changzheng medical science Co., Ltd, lot number: G031191.
Experiment test instrument: rat foot claw tester: the semi-automatic enzymatic analysis instrument of Crony-800 type.
The preparation of crystallite uric acid sodium (MSU): get 8 gram uric acid and place 1600ml boiling water, transfer PH to 7.4, reheat to 95 degree, the room temperature cooling is also stirred gently, filters, and gets crystallite uric acid sodium, 200 ℃ of sterilizations are in the preceding suspension that is made into 100mg/ml with anhydrous normal saline.
(2) laboratory animal and grouping and dosage
Influence to rat paw edema: SD Sprague Dawley rat, 30, male and female half and half, 180～230 grams.Be divided into 3 groups at random, 10 every group, be respectively the normal saline matched group, aspirin matched group (0.25g/kg), CFE treatment group (1g/kg).
The rat urate excretion is influenced: 30 of SD rats, be divided into 3 groups at random, 10 every group, be respectively the normal saline matched group, aspirin matched group (0.25g/kg), CFE organizes (1g/kg).
(3) celery seed acetic acid ethyl ester extract (CFE) is measured the influence of pedal swelling
Under the sterile working, the MSU suspension 0.1ml that has prepared is injected in the subcutaneous inflammation that causes of the right back toes of rat, cause scorching preceding 30 minutes and give gastric infusion earlier, volume is 10ml/kg, and pedal swelling rate (basic value E (%)=(Vt-Vn)/vn * 100Vn and Vt represent respectively and cause the average swelling degree that the scorching sufficient sole of the foot volumetric values in front and back and inhibitory rate of intumesce I (%)=(Ec-Et)/Ec * 100 Et and Ec are represented administration group and matched group respectively) is measured in administration after 24 hours.
(4) celery seed acetic acid ethyl ester extract (CFE) is measured the influence of urate excretion
Under the sterile working, with the MSU suspension 0.1ml subcutaneous injection that has prepared, every day 2 times, continuous 10 days, 2 hours eye sockets were got blood and are surveyed serum uric acid concentration after the administration in the 11st day 1 time.
2. experimental result
Cause the gout outbreak by the sodian deposition of micro-crystal type uric acid in joint tissue and set up rat model, observe influence and the uricotelism of celery seed acetic acid ethyl ester extract (CFE) pedal swelling due to the uric acid.
(1) to the influence of rat paw edema rate and suppression ratio
A. rat paw edema rate:
Matched group causes scorching back 24 hours and causes scorching back 1 hour and compare at the sufficient sole of the foot, and the swelling degree does not have and alleviates; Compared the swelling degree in back 1 hour and obviously alleviate and CFE administration group causes scorching back 24 hours swelling degree and cause inflammation.See Table 2
Influence (%) N=10 of table 2 pair rat paw edema rate
| Time after the administration (hour) | |||||
| Group normal saline group aspirin |
1 11.6±5.68 21.0±8.17 15.2±5.98 | 3 15.9±4.93 18.5±9.53 20.2±7.55 | 5 24.7±8.57 16.5±0.41 21.7±6.74 | 7 18.1±5.69 12.6±7.78 18.0±7.67 | 24 12.9±7.65 9.68±5.67 10.6±6.83 |
B. to the influence of 24 hours suppression ratio of rat paw edema:
Credit is analysed by statistics, and positive control drug aspirin inhibitory rate of intumesce is 24.9%; The CFE inhibitory rate of intumesce is 10.1%, sees Table 3.
Influence (%) n=10 of table 3 pair rat paw edema 24h suppression ratio
| Group | Suppression ratio |
| Aspirin group CFE group | 24.9 20.1 |
(2) to the influence of rat blood serum uric acid level
Through gastric infusion continuous 10 days of every day 2 times, uric acid in the serum is measured in eyeball blood sampling back, compares with the normal saline matched group, and CFE group serum uric acid level significantly reduces (P＜0.05), sees Table 4.
The influence of table 4 pair rat blood serum uric acid
| Group | Uric acid level (umol/l) |
| Normal saline group aspirin group CFE group | 294.7±84.0 198.996±8.8 * 209.68±63.3 * |
*Compare with matched group P＜0.05.
Conclusion:
The result of the test of above embodiment 6-8 shows: by micro-crystal type uric acid sodium rat model, celery seed flavonoid and coumarin kind compound to the influence of pedal swelling due to the uric acid with and diuretic activity, can alleviate the pedal swelling that causes by MSU and play antiphlogistic effect, and can reduce rat blood serum uric acid amount.And generate two kinds of methods and detected xanthine oxidase vitro inhibition activity by measuring uricopoiesis and superoxide ion.Proved that further chrysoeriol (SOC-7) has certain uric acid resisting effect to the Oteracil Potassium mouse model.From present research data, Coumarins in the celery seed and flavone compound have possessed preparation and have prevented and treated gout medicine, anti-inflammatory drug or health food primary condition.Therefore, Coumarins and flavone compound can be used for preparation and prevent and treat gout medicine, anti-inflammatory drug or health food in the celery seed of the present invention.
Claims (9)
1. celery seed Coumarins and flavone compound are used for preparing the purposes of preventing and treating gout medicine, anti-inflammatory drug or health food.
2. purposes according to claim 1 is characterized in that: described celery seed Coumarins and flavone compound are the celery seed acetic acid ethyl ester extract.
3. purposes according to claim 2, it is characterized in that: described celery seed acetic acid ethyl ester extract prepares by the following method: Herba Apii graveolentis dry seed 10kg, with 15～20 times of amount 75～95% (V/V) ethanol percolate extraction or with 4～5 times of amount 75～95% (V/V) ethanol heating extraction 3～4 times, heated 1～1.5 hour at every turn; Extracting solution is evaporated to nearly no ethanol in 55 ℃, concentrated solution; Add 1～2 times of water gaging dilution suspendible in concentrated solution after, the petroleum ether (60～90 ℃) with diluent 1/3rd volumes extracts 2～3 times, tells petroleum ether and reclaims petroleum ether, gets petroleum ether extract; Water layer reuse 1/3rd volume ethyl acetate extractions 4 times are told ethyl acetate and are reclaimed ethyl acetate and get the celery seed acetic acid ethyl ester extract.
4. according to claim 1 or 2 or 3 described purposes, it is characterized in that: described celery seed acetic acid ethyl ester extract contains following monomer: SOC-1: umbelliferone, SOC-2: xanthotoxol, SOC-3: bergapton, SOC-4:5,8-dimethoxy-6, the 7-furocoumarin, SOC-5:6-methoxyl group-umbelliferone, SOC-6: isoimpinellin and 10 flavone compound: SOC-7: chrysoeriol, SOC-8:5,7,3 ', 4 '-tetrahydroxy-3-methoxy flavone, SOC-9: chrysoeriol 7-O-β-D-glucoside, the SOC-10 Quercetin, SOC-11: kaempferol, the SOC-12 luteolin, the SOC-13 apigenin, SOC-14: luteolin 3 '-O-β-D-glucoside, SOC-15: apigenin 7-O-β-D-glucoside, SOC-16: luteolin 7-O-β-D-pyranglucoside, SOC-17:5,4 '-dihydroxy-6,7-methylene-dioxy isoflavone and SOC-18: luteolin 7-O-[β-D-apiose (1 → 2)]-β-D-glucoside.
5. chrysoeriol is used for preparing the purposes of preventing and treating gout medicine, anti-inflammatory drug or health food.
6. the compositions that contains chrysoeriol is used for preparing the purposes of preventing and treating gout medicine, anti-inflammatory drug or health food.
7. celery seed acetic acid ethyl ester extract, it is characterized in that preparing as follows: Herba Apii graveolentis dry seed 10kg, with 15～20 times of amount 75～95% (V/V) ethanol percolate extraction or with 4～5 times of amount 75～95% (V/V) ethanol heating extraction 3～4 times, heated 1～1.5 hour at every turn; Extracting solution is evaporated to nearly no ethanol in 55 ℃, concentrated solution; Add 1～2 times of water gaging dilution suspendible in concentrated solution after, the petroleum ether (60～90 ℃) with diluent 1/3rd volumes extracts 2～3 times, tells petroleum ether and reclaims petroleum ether, gets petroleum ether extract; Water layer reuse 1/3rd volume ethyl acetate extractions 4 times are told ethyl acetate and are reclaimed ethyl acetate and get the celery seed acetic acid ethyl ester extract.
8. celery seed acetic acid ethyl ester extract according to claim 7, it is characterized in that: described extract contains following chemical compound: SOC-1: umbelliferone, SOC-2: xanthotoxol, SOC-3: bergapton, SOC-4:5,8-dimethoxy-6, the 7-furocoumarin, SOC-5:6-methoxyl group-umbelliferone, SOC-6: isoimpinellin and 10 flavone compound: SOC-7: chrysoeriol, SOC-8:5,7,3 ', 4 '-tetrahydroxy-3-methoxy flavone, SOC-9: chrysoeriol 7-O-β-D-glucoside, the SOC-10 Quercetin, SOC-11: kaempferol, the SOC-12 luteolin, the SOC-13 apigenin, SOC-14: luteolin 3 '-O-β-D-glucoside, SOC-15: apigenin 7-O-β-D-glucoside, SOC-16: luteolin 7-O-β-D-pyranglucoside, SOC-17:5,4 '-dihydroxy-6,7-methylene-dioxy isoflavone and SOC-18: luteolin 7-O-[β-D-apiose (1 → 2)]-β-D-glucoside.
9. the preparation method of celery seed acetic acid ethyl ester extract, it is characterized in that: Herba Apii graveolentis dry seed 10kg, with 15～20 times of amount 7～95% (V/V) ethanol percolate extraction or with 4～5 times of amount 75～95% (V/V) ethanol heating extraction 3～4 times, heated 1～1.5 hour at every turn; Extracting solution is evaporated to nearly no ethanol in 55 ℃, concentrated solution; Add 1～2 times of water gaging dilution suspendible in concentrated solution after, the petroleum ether (60～90 ℃) with diluent 1/3rd volumes extracts 2～3 times, tells petroleum ether and reclaims petroleum ether, gets petroleum ether extract; Water layer reuse 1/3rd volume ethyl acetate extractions 4 times are told ethyl acetate and are reclaimed ethyl acetate and get the celery seed acetic acid ethyl ester extract.
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