CN101642450A - New application of dicaffeoylquinic acid - Google Patents
New application of dicaffeoylquinic acid Download PDFInfo
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Abstract
The invention provides an application of dicaffeoylquinic acid for the preparation of drugs of cerebral neuroprotection and the drugs can be used for curing ischemic strokes. The invention also provides a drug composite of cerebral neuroprotection. Drug effect tests and researches show that dicaffeoylquinic acid component is a new kind of effective ingredients which can protect cerebral nerve better, can both promote the survival of cerebral cortical neurons in vitro and the antioxidation and has a certain function of passing blood-brain barrier.
Description
Technical field
The present invention relates to the new purposes of dicaffeoylquinic acid, particularly, is the purposes in the protectant medicine of preparation cranial nerve, belongs to field of medicaments.
Background technology
Apoplexy has another name called apoplexy, be with unexpected confused servant, hemiplegia, crooked mouth and tongue, speech not smoothgoing puckery or in silence, hemianesthesia is primary symptom, and have onset anxious, change fast characteristics, good sending out in a kind of disease of person in middle and old age, be the common frdquently encountered disease of middle-aged and elderly people, human existence and health in serious threat.Primary disease is equivalent to ischemic cerebrovascular (the Ischemic Cerebral vascular Disease of western medicine, ICVD), also claim Ischemic Stroke, have higher case fatality rate and disability rate, human beings'health and life security (Rao Mingli in serious threat, woods generation and. cerebrovascular disease. People's Health Publisher, 2002.172).As a kind of commonly encountered diseases, frequently-occurring disease, ICVD especially the limitation cerebral infarction with three big diseases that cause death of heart disease, malignant tumor majority state arranged side by side.Epidemiological study finds, China belong to one of this disease hotspot (Chen Jie. the epidemiology of cerebral infarction. practical cardio-cerebral-pulmo angiopathy magazine .2000,8 (3): 179~181).Motherland's medical science thinks, its sick position of apoplexy is at brain, and is closely related with the heart, kidney,liver,spleen, is the card of deficiency in origin and excess in superficiality, the etiology and pathogenesis complexity, and deficiency in origin is deficiency of the liver and kindey, deficiency of vital energy insufficiency of blood; Mark is real to be liver-wind stirring up internally, fire and wind stirring up each other, and burning hot interior strongly fragrant, the phlegm-damp heap soil or fertilizer over and around the roots is contained, and finally causes the internal resistance of the expectorant stasis of blood, and with the mechanism of qi superinverse, upset empties, and hoodwinks key clearly, becomes excess in the upper and deficiency in the lower, the critical syndrome that negative and positive are not maintained mutually.The symptom of its suddenly confused servant's syncope can be included the category that key closes coma in again.According to statistics, in the syndrome-classification of apoplexy, syndrome of blood stasis is taken the status as the leading factor, account for more than 73% of apoplexy (Tao Genyu, Du Xiaoquan. the status [J] of benefiting QI for activating blood circulation method in the cerebral infarction disease. ShanXi Chinese Medicine Academy journal, 1998,21 (3): 1).Though the pathogenesis of cerebral infarction is complicated, to sum up to get up, principal contradiction is stagnation of blood stasis.Over nearly 10 years, in, doctor trained in Western medicine bound pair stasis cerebral infarction carried out deep clinical and experimentation, the curative effect of stasis cerebral infarction disease obtains certainly substantially, its clinical report is also more.
Li Zusheng, dicaffeoylquinic acid (dicaffeoylquinic acids, DCQ) pharmacological experiment study progress, 2004 the 10th the 4th phases of volume of medical science summary, reported, reported the dicaffeoylquinic acid caffeic acid (caffeic acid) that to be a class do not waited by quininic acid (quinc acid) and number by the phenolic acids natural component that esterification comprehensively forms, extensively be present in the fruit trees such as Chinese medicine such as plant kingdom such as Flos Lonicerae, Flos Inulae, Herba Xanthii and Folium Camelliae sinensis, Fructus Crataegi.All multiactions such as the antioxidation of present report DCQ, antiinflammatory, antiviral, fibrosis, inhibition smooth muscle contraction, blood fat reducing.As number of patent application: 99105113.0, denomination of invention: 1, the preparation method of 5-two-O-coffeic acyl quininic acid derivative discloses 1, the preparation method of 5-two-O-coffeic acyl quininic acid derivative; Application number: 03141616.0, denomination of invention: breviscapine and dicaffeoylquinic acid drug regimen and application thereof disclose effective site breviscapine and dicaffeoylquinic acid combination and the new purposes in the acute and chronic hepatopathy of treatment thereof extracted in the Herba Erigerontis; Application number: 03117754.9, denomination of invention: erigeron breviscapus and preparation method thereof and the application in pharmacy disclose preparation method and the application in treatment cardiovascular and cerebrovascular disease, senile dementia disease, the high fat disease of control medicinal that erigeron breviscapus effective site comprises scutellarin and dicaffeoylquinic acid.Application number: 96101141.6, denomination of invention: the application of di-caffee acyl-oxy-quininic acid in pharmacy discloses 3,4-dicaffeoylquinic acid, 3, the application in cardiovascular and cerebrovascular disease of the preparation of 5-dicaffeoylquinic acid and drug regimen.Application number: 03117753, denomination of invention: Erigeroster B and preparation method thereof and the application in pharmacy disclose new caffeic acid ester compounds Erigeroster B, extraction separation method and conduct treatment cardiovascular and cerebrovascular diseases medicament.
Still do not have the report dicaffeoylquinic acid at present and be used for the protectant purposes of cranial nerve; also not with 1; 5-dicaffeoylquinic acid, 4; 5-dicaffeoylquinic acid, 3; 4-dicaffeoylquinic acid, 3, dicaffeoylquinic acids such as 5-dicaffeoylquinic acid be raw material separately or the relevant report of drug combination.
Summary of the invention
Technical scheme of the present invention has provided the new purposes of dicaffeoylquinic acid, particularly, is the purposes in the protectant medicine of preparation cranial nerve.The present invention also provides a kind of cranial nerve protective agent pharmaceutical composition.
The invention provides the purposes of dicaffeoylquinic acid in the protectant medicine of preparation cranial nerve.
Wherein, described medicine is the medicine of treatment cerebral infarction.
Wherein, described dicaffeoylquinic acid is 1,5-dicaffeoylquinic acid, 4, and 5-dicaffeoylquinic acid, 3,4-dicaffeoylquinic acid, 3, the 5-dicaffeoylquinic acid,
Structure is as follows:
1, the 5-dicaffeoylquinic acid
4,5-dicaffeoylquinic acid 3,4-dicaffeoylquinic acid
3, the 5-dicaffeoylquinic acid.
The invention provides a kind of drug composite of cerebral neuroprotection; it is by 1; 5-dicaffeoylquinic acid, 4; 5-dicaffeoylquinic acid, 3; 4-dicaffeoylquinic acid, 3; in the 5-dicaffeoylquinic acid a kind of its more than one be mixed into active component, add the medicament that acceptable accessories or adjuvant composition are prepared from.
Further preferably, it is by 1,5-dicaffeoylquinic acid, 4, and 5-dicaffeoylquinic acid, 3,4-dicaffeoylquinic acid, 3, the medicament that the 5-dicaffeoylquinic acid is prepared from for the active component compatibility, its weight proportion is:
1,5-dicaffeoylquinic acid 1-10 part, 4,5-dicaffeoylquinic acid 1-10 part, 3,4-dicaffeoylquinic acid 1-10 part, 3,5-dicaffeoylquinic acid 1-10 part.
Wherein, described 1,5-dicaffeoylquinic acid and 3, the 4-dicaffeoylquinic acid derives from Herba Erigerontis Erigeron breviscapus (Vant.) Hand.-Mazz. medical material, concrete extraction separation method is with 95% ethanol 60L, 70% ethanol 20L ethanol percolation, and vacuum decompression reclaims ethanol.Ethyl acetate layer extractum, normal pressure silica gel column chromatography and anti-phase C18 column chromatography purification repeatedly can obtain 1,5-dicaffeoylquinic acid and 3,4-dicaffeoylquinic acid.
Four chemical compounds of the present invention are known chemical compound; can extract by following document (I.Merfort.Caffeoylquinicacids from flowers of arnica Montana and arnicachamissonis[J] .Phytochemistry; 1992; 31 (6): 2111.H.Morshita.Chromatographic separation and identification of naturally occurringchlorogenic acids by ' Hnuclearmagnetic resonacespec-troscopy andmasss pectrometry[J] .Chromatography; 1984; 315:253.BarbaranTimmermann; Joseph Hoffmann.Constituents of chrysothamnuspaniculatus3:3; 4; 5-tricaffeoylquinicacid and 3; 4;-3; 5-and4; 5-dicaffeoylquinicacids[J] .J.Nat.Prod; 1983; 46 (3): 578. Teng Rong are big; Deng. spend the caffeoyl quinic acid composition in the Radix Morinae Bulleyanae in vain. the Wave Spectrum magazine; 2002,19 (2): 167 ~ 174)
Wherein, described preparation is: injection, drop pill or aerosol.
The present invention also provides pharmaceutical composition making the purposes for the treatment of in the medicine that is equipped with cerebral infarction.
A kind of pharmaceutical composition for the treatment of cerebral infarction provided by the invention can be realized: 1, extract each chemical compound from Herba Erigerontis, add the preparation that acceptable accessories or complementary composition are prepared from then by following technical solution.2, also can adopt the dicaffeoylquinic acid of commercially available or plant origin is raw material, adds the preparation that acceptable accessories or complementary composition are prepared from then.
Said medicine combination of the present invention can also can be extracted or preparation according to existing bibliographical information method available from commercially available commodity raw material.
The present invention also provides the application of this pharmaceutical composition in the medicine of the Cranial nerve injury as birth trauma of preparation treatment ischemic apoplexy sequelae, cerebrovascular disease.
Experimentation shows that the di-coffee mesitoyl quinine acid composition is the effective ingredient that a class has better cranial nerve protection, has to promote external cerebral cortex neurocyte survival and antioxidation, and has certain blood brain barrier ability that sees through; It is clear and definite to be used for the treatment of the cerebral infarction drug effect, provides a kind of new selection for clinical.
Obviously, according to foregoing of the present invention,,, can also make modification, replacement or the change of other various ways not breaking away under the above-mentioned basic fundamental thought of the present invention prerequisite according to the ordinary skill knowledge and the customary means of this area.
The specific embodiment of form is described in further detail foregoing of the present invention again by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
The specific embodiment
The preparation of embodiment 1 The compounds of this invention
Herba Erigerontis Erigeron breviscapus (Vant.) Hand.-Mazz. medical material (roguing grass) is used 95% ethanol 60L respectively, 70% ethanol 20L ethanol percolation, and vacuum decompression reclaims ethanol.Ethyl acetate layer extractum, normal pressure silica gel column chromatography and anti-phase C18 column chromatography purification repeatedly can obtain 1,5-dicaffeoylquinic acid and 3,4-dicaffeoylquinic acid.
Four kinds of chemical compounds of the present invention also can derive from commercially available kind, as 1,5-dicaffeoylquinic acid (the source bio tech ltd of middle mountain health), 4,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid (Shijiazhuang Yan Feng Pharmaceutical Technology Co., Ltd), 3, the self-control of 4-dicaffeoylquinic acid, purity is greater than 95%.
The preparation of embodiment 2 medicaments injections of the present invention
Get 1,5-dicaffeoylquinic acid 5g, 4,5-dicaffeoylquinic acid 5g, 3,4-dicaffeoylquinic acid 5g, 3,5-dicaffeoylquinic acid 5g, sodium chloride 85g, sodium sulfite 2g, add the dissolving of injection water, make 10000ml, be distributed into the injection that 3mg/2ml/ props up, intermediate detects, embedding, sterilization, labeling.
The preparation of embodiment 3 medicaments injections of the present invention
Get 1,5-dicaffeoylquinic acid 5g, 4,5-dicaffeoylquinic acid 50g, 3,4-dicaffeoylquinic acid 50g, 3,5-dicaffeoylquinic acid 50g, sodium chloride 85g, sodium sulfite 2g, add the dissolving of injection water, make 10000ml, be distributed into the injection that 3mg/2ml/ props up, intermediate detects, embedding, sterilization, labeling.
The preparation of embodiment 4 medicaments injections of the present invention
Get 1,5-dicaffeoylquinic acid 50g, 4,5-dicaffeoylquinic acid 5g, 3,4-dicaffeoylquinic acid 5g, 3,5-dicaffeoylquinic acid 5g, sodium chloride 85g, sodium sulfite 2g, add the dissolving of injection water, make 10000ml, be distributed into the injection that 3mg/2ml/ props up, intermediate detects, embedding, sterilization, labeling.
Below further prove beneficial effect of the present invention by pharmacodynamics test.
Test example 1 The compounds of this invention is to the influence of In vitro culture cerebral cortex neurocyte survival
The present invention discloses 1,5-dicaffeoylquinic acid, 4,5-dicaffeoylquinic acid, 3,4-dicaffeoylquinic acid, 3, the drug efficacy study result of 5-dicaffeoylquinic acid.
Bed board: get 96 orifice plates, every hole adds 0.1mgmL-1 poly-D-lysine 50 μ L, and vibration is even, and the room temperature standing over night is standby.
Preparation cell suspension: the disconnected neck of neonatal rat is put to death, 75% alcohol-pickled sterilization, aseptic condition separates brain cortical tissue, removes the cerebrovascular film as far as possible, inserts in the ice Hanks liquid rinsing 3 times.Obtaining tissue is cut into the 1mm3 piece of tissue, and the trypsin with 0.25%+37 ℃ of digestion down of 0.05%II Collagen Type VI enzyme adds culture fluid and stops digestion behind the 30min, filter with 75 μ m cell screen clothes.With the centrifugal 8min of filtrate 1000rmin-1, abandon supernatant.Add complete culture solution (900mLL
-1The DMEM high glucose medium, 100mLL
-1Hyclone, L-glutaminate 0.45gL
-1, NaHCO3 3gL-1, HEPES 4.5gL-1, penicillin 1 * 105UL
-1, streptomycin 1 * 105UL
-1), suction pipe piping and druming makes it to be uniformly dispersed and makes single cell suspension.Liquid measure is cultivated in counting and adjustment makes every mL contain 1 * 106 cell.
Inoculated and cultured and medicine adding method: with cell suspension inoculation in through the bag quilt 96 orifice plates in, every hole 100 μ L change liquid after cultivating 24h, add cytosine arabinoside behind the 72h to suppress non-nerve growth, later every 2d half amount is changed liquid, 7d changes behind the liquid according to requirement of experiment, and what add various mass concentration gradients respectively respectively is subjected to reagent thing (establishing 5 dosage groups, by a certain percentage dilution), cumulative volume 200 μ L in every hole add culture fluid simultaneously and continue to cultivate as the blank group.
The MTT trace is colorimetry automatically: after adding drug effect 1d, every hole adds MTT liquid (tetramethyl azo azoles salt, 5mgmL
-1), after continuing to cultivate 4h, remove supernatant, PBS liquid rinsing 2 times, every hole adds dimethyl sulfoxide (DMSO) 150 μ L, fully vibration, room temperature leaves standstill 10min, measures absorption value in 492nm wavelength place with microplate reader.
The result shows that above chemical compound all has the effect that promotes external cerebral cortex neurocyte survival preferably.The results are shown in Table 1 ~ 3.
Table 13,5-DCQ and 1,5-DCQ is to the influence of In vitro culture cerebral cortex neurocyte survival
Table 2 erigeron breviscapus effective component is to the influence of In vitro culture cerebral cortex neurocyte survival
1,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid, 3, the saturating blood brain barrier result of study of 4-dicaffeoylquinic acid, the result shows 1,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid, 3, the 4-dicaffeoylquinic acid can see through external blood brain barrier model in various degree.The result of study of comprehensive above cranial nerve protection, 1,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid, 3,4-two caffeoyl quinines can see through the protective effect of blood brain barrier performance cranial nerve.
Test example 2 external blood brain barrier modelling and saturating blood brain barrier
Because the existence of blood brain barrier, nearly all macromolecular drug and 98% small-molecule drug all can not enter brain and central nervous system, and medicine can cross over blood brain barrier and reach effective treatment concentration be vital.For seeking and further analyze the effective substance of Herba Erigerontis brain targeting neuroprotective, this experiment employing brain micro blood vessel endothelium cell of former generation and star spongiocyte co-culture model analog in vitro BBB.Use efficient liquid phase chromatographic analysis, different time points is measured the transmitance of The compounds of this invention in 8h.
1, material and instrument
Day island proper Tianjin LC-10A high performance liquid chromatograph, the SPD-10AV UV-detector; The SCL-10A system controller; The CBL calorstat, N2000 chromatographic data work station.Nitrogen evaporator (KL-512, Beijing Kang Lin science and technology limited Company): high speed centrifuge (centrifuge 5417c, eppendorf company): ultrasonic washing instrument (AS10200, Tianjin Ao Tesaiensi Instr Ltd.)
Methanol, acetonitrile (Fisher company, chromatographically pure), the described chemical compound of the method for embodiment 1: 1,5-dicaffeoylquinic acid (the source bio tech ltd of middle mountain health), 4,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid (Shijiazhuang Yan Feng Pharmaceutical Technology Co., Ltd), 3, the self-control of 4-dicaffeoylquinic acid, purity is greater than 95%.
2, method and result
2.1 sample preparation
Select leak test to test male hole and carry out the permeability experiment, to adding 1,5-dicaffeoylquinic acid, 4,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid, 3,4-dicaffeoylquinic acid (0.2mgmL in the pond
-1) be subjected to add in the pond 600 μ L AC culture fluid.From be subjected to the pond, carefully collected filtrate each 100 μ L, 50 μ L, 50 μ L, 50 μ L, 50 μ L respectively in-20 ℃ of preservations at the 0th, 1,2,4,8 hour, treat to do sample treatment after all samplings finish.Wherein 0 hour is blank, to being the initial concentration (referring to Fig. 5-1) for the pond for the medicinal liquid that adds in the pond.Each sample nitrogen is dried up (37 ℃), respectively to wherein adding methanol, supersound process 20min, it is centrifugal that (5000rmin-1 * 10min), get supernatant makes HPLC and analyzes need testing solution.
2.2HPLC analyze
Chromatographic condition: Tianjin, island LC-10A high performance liquid chromatograph; Chromatographic column: be the octadecylsilane chemically bonded silica post, Yi Lite SinoChrom ODS-BP 5 μ m (250 * 4.6mm) posts number: E1817666, flow velocity: 1mLmin
-1Column temperature: room temperature;
3,5-dicaffeoylquinic acid mobile phase is acetonitrile: 0.6% formic acid (20: 80).The detection wavelength is 330nm.
The accurate respectively 20 μ L need testing solutions injection high performance liquid chromatograph of drawing detects.
2.3 transmitance is calculated
According to the HPLC measurement result, get following formula and calculate transmitance.
A wherein
Be subjected to the pondFor being subjected to the peak area of pond sample, A
For the pondFor supplying pond peak area, V
Be subjected to the pondFor being subjected to cell body to amass V
For the pondFor long-pending for cell body.Result of calculation sees Table 4.
The saturating external BBBM composition transmitance of table 4
Tab.4The?permeability?of?compounds?on?the?in?vitro?BBB?model
Numbering | Chemical compound | For the pond peak area | For cell body long-pending (μ l) | 8h is subjected to the pond peak area | Be subjected to cell body to amass (μ l) | Transmitance (%) |
??1 | ??3,5-DCQ | ??256813.7 | ??300 | ??101640 | ??600 | ??79.15 |
??2 | ??1,5-DCQ | ??30541 | ??300 | ??8072.6 | ??650 | ??57.27 |
??3 | ??3,4-DCQ | ??35615 | ??300 | ??4692 | ??650 | ??28.54 |
??4 | ??4,5-DCQ | ??257202 | ??300 | ??27521 | ??650 | ??23.18 |
Above-mentioned test shows, 4, and 5-DCQ, 1,5-DCQ, 3,5-DCQ, 3,4-DCQ all can see through BBBM.Wherein 3,5-DCQ sees through the best results of BBBM.Above-mentioned evidence, four chemical compounds of the present invention all are cranial nerve protection effective ingredient of new saturating blood brain barrier.
Claims (7)
1, the purposes of dicaffeoylquinic acid in the protectant medicine of preparation cranial nerve.
2, purposes according to claim 1 is characterized in that: described medicine is the medicine of treatment cerebral infarction.
3, purposes according to claim 1 is characterized in that: described dicaffeoylquinic acid is 1,5-dicaffeoylquinic acid, 4, and 5-dicaffeoylquinic acid, 3,4-dicaffeoylquinic acid or 3, the 5-dicaffeoylquinic acid,
Structure is as follows:
1, the 5-dicaffeoylquinic acid
4,5-dicaffeoylquinic acid 3,4-dicaffeoylquinic acid
3, the 5-dicaffeoylquinic acid.
4, a kind of drug composite of cerebral neuroprotection; it is characterized in that: it is by 1; 5-dicaffeoylquinic acid, 4; 5-dicaffeoylquinic acid, 3; 4-dicaffeoylquinic acid, 3; the mixture of one or more in the 5-dicaffeoylquinic acid is an active component, adds the medicament that acceptable accessories or adjuvant composition are prepared from.
5, pharmaceutical composition according to claim 4 is characterized in that: it is by 1,5-dicaffeoylquinic acid, 4,5-dicaffeoylquinic acid, 3,4-dicaffeoylquinic acid, 3, the medicament that the 5-dicaffeoylquinic acid is prepared from for the active component compatibility, its weight proportion is:
1,5-dicaffeoylquinic acid 1-10 part, 4,5-dicaffeoylquinic acid 1-10 part, 3,4-dicaffeoylquinic acid 1-10 part, 3,5-dicaffeoylquinic acid 1-10 part.
6, according to any described pharmaceutical composition of claim 4-5, it is characterized in that: described preparation is: injection, drop pill or aerosol.
7, the purposes of any described pharmaceutical composition of claim 4-5 in the medicine of preparation treatment cerebral infarction.
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CN102266318A (en) * | 2011-05-23 | 2011-12-07 | 中国人民解放军第二军医大学 | Application of caffeoylquinic acid and derivatives thereof in preparing anticomplementary medicines |
CN103553922A (en) * | 2013-11-06 | 2014-02-05 | 天津科技大学 | Preparation of macranthoin G in eucommia ulmoides, and application of macranthoin G in neuroprotective medicine |
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CN108658843A (en) * | 2017-03-30 | 2018-10-16 | 上海医药工业研究院 | Acetobenzylamide piperidine amides analog derivative and its application as neuroprotection agent |
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102266318A (en) * | 2011-05-23 | 2011-12-07 | 中国人民解放军第二军医大学 | Application of caffeoylquinic acid and derivatives thereof in preparing anticomplementary medicines |
CN104434896A (en) * | 2013-09-12 | 2015-03-25 | 中国药科大学 | Application of dicaffeoylquinic acid derivative for preparing chemokine receptor 2b antagonist |
CN103553922A (en) * | 2013-11-06 | 2014-02-05 | 天津科技大学 | Preparation of macranthoin G in eucommia ulmoides, and application of macranthoin G in neuroprotective medicine |
CN108658843A (en) * | 2017-03-30 | 2018-10-16 | 上海医药工业研究院 | Acetobenzylamide piperidine amides analog derivative and its application as neuroprotection agent |
CN108658843B (en) * | 2017-03-30 | 2021-06-04 | 上海医药工业研究院 | Acetylbenzylamine piperidine amide derivative and application thereof as cerebral nerve protective agent |
CN108949743A (en) * | 2018-06-15 | 2018-12-07 | 翁炳焕 | A kind of full-length genome hybridizing clones method |
CN109674777A (en) * | 2019-01-16 | 2019-04-26 | 中国科学院成都生物研究所 | Application of the isochlorogenic acid class compound in preparation neurodegenerative disease and hypochondriacal drug |
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