CN102949404B - Vanillic acid glucoside derivative purposes in treatment of systemic autoimmune disease - Google Patents

Vanillic acid glucoside derivative purposes in treatment of systemic autoimmune disease Download PDF

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CN102949404B
CN102949404B CN201110235674.6A CN201110235674A CN102949404B CN 102949404 B CN102949404 B CN 102949404B CN 201110235674 A CN201110235674 A CN 201110235674A CN 102949404 B CN102949404 B CN 102949404B
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vanillic acid
acid glucoside
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systemic
autoimmune disease
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CN102949404A (en
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殷红
董俊兴
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Institute of Materia Medica of CAMS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Abstract

The application in the medicine of preparation treatment of systemic autoimmune disease of the disclosure of the invention vanillic acid glucoside derivative as shown in the formula (I).Preferably systemic autoimmune disease is selected from systemic lupus erythematosus (sle), rheumatoid arthritis, systemic sclerosis, mouth xerophthalmia scheorma syndrome, polymyositis.

Description

Vanillic acid glucoside derivative purposes in treatment of systemic autoimmune disease
Technical field
The present invention relates to the vanillic acid glucoside new use in the autoimmune diseasees such as systemic lupus erythematosus On the way.
Background technology
Autoimmune disease refers to that body produces autoantibody and/or for self to self component generation immunne response The effector T cell of antigen, causes autologous tissue or cell injury and dysfunction.Owing to antigen antibody complex is deposited on The reasons such as blood vessel wall cause whole body multiple organ injury's, are also called systemic autoimmune disease, including systemic red yabbi Skin ulcer (SystemicLupus Erythematosus, SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), mouth eye are dry Dry syndrome (SS) etc..Its basic feature is that blood samples of patients antinuclear antibody is positive, uses immunosuppressant treatment to have certain effect.
As a example by the most serious systemic lupus erythematosus (sle).SLE is a kind of to involve self of skin and whole body multisystem Immune disease, the definite cause of disease is still not clear.Primary disease is common with young women, and the state of an illness is often slow to be heavily alternately present, and morbidity form is many Sample, afflicted organ, lesion degree and complication are different.China's prevalence is about 70/,100,000, confirmed cases more than 50% The important organ such as liver, kidney is impaired.SLE still can not effect a radical cure, but can effectively alleviate the state of an illness through treatment.Conventional medicine has: 1) hydroxyl Chloroquine: for the slight case of only skin involvement.2) glucocorticoid: the treatment of hormone standard course for the treatment of is for acute, outbreak diseases Example, or main organs is by for a long time, is the key agents treating primary disease at present.3) immunosuppressant: after being mainly used in hormone decrement Effectively but expense is excessive serious side effects occurs for disease relapse or hormone, and lupus nephritis, lupus encephalopathy etc. are difficult to alone The case that hormone controls.Conventional have cyclophosphamide, cyclosporin, mycophenolate, azathioprine, leflunomide, tacrolimus, And the many glycosides of Chinese herb triperygium wilfordii etc., many of which is label medicine for external use.Existing immunosuppressant life-time service can produce bone marrow Suppression, reduces the resistance infection of human body, affects glucose-lipid metabolism the most to some extent.Therefore, comparatively safe, for B lymph The target biology medicine of cell is considered as orientation treatment from now on.Rituximab for RA treatment is a kind of anti- CD20 monoclonal antibody, does not reaches treatment terminal although by II phase clinic and is not approved by the FDA in the United States, and the outer SLE medication of its label is still Significantly continuing.Baily monoclonal antibody (belimumab) is humanization IgG1 type anti-bone-marrow-derived lymphocyte stimulating factor (B lymphocyte Stimulator, BlyS) monoclonal antibody, can be combined with the BlyS receptor on B cell surface high special, make generation self resist The bone-marrow-derived lymphocyte apoptosis of body, IgG hypergammaglobulinemia normalization.FDA approval on March 9th, 2011 Baily monoclonal antibody be used for treating active stage, The lupus erythematosus (SLE) of autoantibodies, becomes after oxychloroquine first granted SLE first-line treatment medicine over 56 years.According to Analyzing, the only SLE patient of China, India and state of Mexico three has just exceeded 2,200,000 people, and wherein only has few some patients energy Enough afford the biotherapeutics of costliness.Therefore, cheap glucocorticoid and immunosuppressant will be as SLE Primary treatment medicine exist.New, mechanism of action clearly, determined curative effect and the little small molecule immune inhibitor of side effect Not only clinical needs, bring benefit also can to numerous SLE patient and other system autoimmune disorders.
Vanillic acid glucoside was once isolated in the plants such as european plum, but in addition to antioxidant activity, other biological activity is not Appear in the newspapers.Chancing in test, vanillic acid glycosides compound has immunosuppressive activity.Subsequently by plant extract and chemistry Synthetically prepared compound, for pharmacological evaluation after structural identification.
Summary of the invention
The technical problem to be solved in the present invention is to provide the medicine of a kind of new treatment of systemic autoimmune disease, this Class medicine has excellent curative effect and toxic and side effects is low.
For solving the technical problem of the present invention, the present invention adopts the following technical scheme that: be specifically to provide such as formula (I) The application in the medicine of preparation treatment of systemic autoimmune disease of the shown vanillic acid glucoside derivative；
Wherein: R1Selected from H or M, M selected from alkali metal or alkaline-earth metal；
R2Alkyl for H, C1-6；The substituted acyl group of C1-6 alkyl；
R3For
Preferably alkali metal is selected from Li, Na or K.
Preferably alkaline-earth metal is selected from Mg, Ca or Ba.
The alkyl of preferred C1-6 is selected from CH3, CH2CH3, CH2CH2CH3。
The preferred substituted acyl group of C1-6 alkyl is selected from COCH3, COCH2CH3, COCH2CH2CH3。
Preferred compound of formula I is selected from following group:
Compound shown in above-mentioned Formulas I can be extracted by conventional phytochemical method or by conventional medicine The method learned is synthetically prepared.Such as using vanillic acid and monosaccharide as raw material, synthetically prepared by conventional vitochemical method.
Heretofore described systemic autoimmune diseases closes including but not limited to systemic lupus erythematosus (sle), rheumatoid Joint inflammation, systemic sclerosis, mouth xerophthalmia scheorma syndrome, polymyositis.
The present invention the pharmacological tests prove that the compound shown in Formulas I can substantially suppress mice spleen T of In vitro culture, B Lymphopoiesis, hence it is evident that suppression mice delayed hypersensitivity generation, and can substantially reduce active dna induction be System property lupus erythematosus syndrome sample mice serum anti-ds-DNA antibody level, reduces the IgG immune complex deposition in nephridial tissue And Renal tissues damage.Therefore the compound shown in Formulas I can be used for treating systematicness self exempt from as a kind of new immunosuppressant Epidemic is sick, especially systemic lupus erythematosus (sle), rheumatoid arthritis, systemic sclerosis, mouth xerophthalmia scheorma syndrome, multiple flesh Scorching.
Accompanying drawing explanation
The impact that mice spleen lymphocytes proliferation is reacted by Fig. 1 vanillic acid glucoside
Fig. 2. vanillic acid glucoside reduces SLE syndrome sample kidney of mouse IgG immune complex deposit
A1～A3 model group animal nephridial tissue diffusivity damage, glomerule hypertrophy, mesangial cell, blood capillary and Renal tubules, blood vessel hyperfluorescence (++++)；B1 vanillic acid glucoside 1.1mg/Kg group, only thin vessels moderate fluorescence (+～++)；B2 Vanillic acid glucoside 3.3mg/Kg group, hyperfluorescence in thin vessels, glomerule, renal tubules are slight fluorescence (++)；B3 prednisolone 5mg/Kg group, glomerule, renal tubules are slight fluorescence (+).
Detailed description of the invention
Below by the preferred embodiment of vanillic acid glucoside representational in compound of formula I and combine accompanying drawing specifically Bright various aspects and features of the invention.It should be appreciated by those skilled in the art, these embodiments are only intended to illustration purpose, And do not limit the scope of the invention.Protection scope of the present invention is the most limited by the claims.Without departing substantially from claims Under conditions of scope, those skilled in the art can carry out various modifications and improvements to various aspects of the present invention, and these are repaiied Change and improvement falls within protection scope of the present invention.Such as, the vanillic acid glucose used in embodiment is replaced with other Compound of formula I, be those of ordinary skill in the art it will be appreciated that and realize.
In addition, it should be noted that unless specifically stated otherwise, various materials used in example below and reagent are all these Material conventional in field and reagent, can be either commercially available by conventional；Method therefor is those skilled in the art Known conventional method.
Embodiment 1. vanillic acid glucoside has significantly suppression to mice spleen T, the B lymphocyte proliferation of In vitro culture Effect
1.1 materials and methods
Cleaning grade BALB/c mouse, male, body weight (19 ± 2) g, purchased from Chinese Academy of Medical Sciences's Experimental Animal Center. LPS, ConA, DMSO, MTT Sigma product.RPMI 1640 complete medium 100U/L Han penicillin, streptomycin 100U/L, paddy Glutamine 2mM and 10% hyclone.De-neck puts to death mice, aseptic takes spleen, prepares Pi lymphocyte suspension routinely, uses RPMI1640 complete medium adjusts cell 8 × 109/ L, 0.1mL/ inoculate in hole 96 orifice plates.It is separately added into ConA (final concentration of 2.5mg/L) or LPS (final concentration of 10mg/L), and vanillic acid glucoside (final concentration of 1X10-9-1X10-5Mol/L), The multiple hole of each concentration 6.37 DEG C, 5%CO2Incubator is cultivated.After 44 hours, every hole adds MTT (5g/L) 10 μ L, continues to incubate Educate 4h, inhale gently after being centrifuged and abandon supernatant, add DMSO 100 μ L, measure absorption value at 570nm by microplate reader.
1.2 result of the test
The propagation of the mice Pi T lymphocyte that ConA is induced by vanillic acid glucoside has obvious inhibitory action, 1X10-9、1X10-6And 1X10-5Under mol/L concentration, suppression ratio is respectively 71%, 48% and 57% (p ＜ 0.05 is shown in Table 1 and figure 1).The propagation of the mice Pi bone-marrow-derived lymphocyte that LPS is induced by vanillic acid glucoside also has certain inhibitory action, 1X10-10- 1X10-7Suppression ratio 24%-29% (being shown in Table 2 and Fig. 1) under mol/L concentration.
The impact of the mice spleen T-lymphproliferation response that CoA is induced by table 1 vanillic acid glucoside
(* * p ＜ 0.01, * * * p ＜ 0.001vs matched group)
The impact of the mice spleen B-lymphproliferation response that LPS is induced by table 2 vanillic acid glucoside
(* p ＜ 0.05vs matched group)
Embodiment 2. vanillic acid glucoside has obvious inhibitory action to mice delayed hypersensitivity
2.1 materials and methods
Balb/c mice, male, 18-20g, purchased from Chinese Academy of Medical Sciences's Experimental Animal Center.Random packet, often organizes 3 Only, adaptability starts experiment after raising one week.Sensitization mBSA (Sigma) injects with normal saline to 5mg/mL, with equal-volume Freund's complete adjuvant (CFA, Sigma) is fully emulsified.In addition to Normal group, every mouse web portion intradermal injection emulsifying agent 100 μ l.It is administered sensitization and plays gastric infusion every day on 5th, 0.2ml/, continuous 3 times.Normal and model control group gives distilled water, examination Test medicated incense oxalic acid glucoside 1.1,3.3,10,20mg/Kg 4 dosage groups of body weight, positive drug indomethacin 3.3,10mg/Kg body Weigh 2 dosage groups.After again attacking last administration 2 hours, the left sufficient intradermal injection normal saline 25 μ l of mice, right sufficient intradermal injection mBSA(5mg/mL)25μl.After 24hr, de-neck puts to death animal, and the left and right lower limb of clip are weighed, and calculates swelling (mg/10g body weight) And inhibitory rate of intumesce.Win thymus, spleen is weighed simultaneously, calculates organ index.
2.2 result of the test
MBSA attacks sensitized mice again can cause obvious delayed hypersensitivity, indomethacin (3.3,10mg/Kg) Being respectively provided with obvious inhibitory action with vanillic acid glucoside (3.3mg/Kg), suppression ratio is respectively 34.6,66.6 and 48.0%. Indomethacin significantly raised mouse spleen index, and vanillic acid glucoside to the thymus of mice and index and spleen index all without obvious shadow Ring.Refer to table 3.
The impact on mice delayed hypersensitivity of the table 3 vanillic acid glucoside
(* p ＜ 0.05, * * p ＜ 0.01vs model control group)
The systemic lupus erythematosus (sle) syndrome sample mouse antibodies water that active dna is induced by embodiment 3. vanillic acid glucoside The improvement result of gentle Renal tissues damage
3.1 materials and methods
BALB/c mouse is put to death in the extraction of splenocyte activation and genomic DNA, and the aseptic spleen that takes, it is thin that routine prepares spleen Born of the same parents' suspension, trypan blue counting (survival rate ＞ 95%), adjust cell 2X10 with RPMI 1640-20% hyclone9/ L, adds Con A makes final concentration of 3mg/L, and every bottle of 20mL adds in culture bottle, in 37 DEG C, uprightly cultivates, after 48h in 5%CO2 incubator Take out, centrifugal collection activating cell.Utilize Animal genome DNA a large amount of rapid extraction test kit (vast Tyke, Beijing bio-based Because of technology company), the preparation of active dna is carried out according to test kit operating procedure.Systemic lupus erythematosus (sle) syndrome sample mice mould Type set up BALB/c mouse, 6wk, female.Mice random packet, often group 6, model group and the immunity of medicine group row, blank group It is left intact.Immune programme for children is: Intradermal multi-point injection, once every 2 weeks, each 0.1mg/0.2mL, 3 times altogether.Exempt from first DNA dry powder is added normal saline to 2mg/mL by epidemic disease, fully emulsified with equal-volume Freund's complete adjuvant after injection.2nd immunity note Penetrate DNA and incomplete Freund's adjuvant emulsifying agent；3rd immunity is DNA suspension.In sensitization process eye socket take blood examination survey serum resist Ds-DNA antibody horizontal.It is administered after the 3rd immunity the 8th day and starts gastric infusion every day, 0.2mL/10g body weight, totally 15 times.It is administered Dosage is respectively vanillic acid glucoside 1.1,3.3 and 10mg/Kg body weight；Positive control drug prednisolone acetate 5mg/Kg；Mould Type group and Normal group give pure water.After last is administered, plucks eyeball and take blood execution animal；Take serum test antibodies；Take breast Gland, spleen, liver are weighed calculating organ index；Take kidney and carry out pathological examination so that 4% formalin is fixing.Anti-ds-DNA antibodies resists Detection 96 hole ELISA Plate (COSTAR) of body, every hole adds 100 μ L salmon dsDNA (Sigma, 50mg/L) 4 DEG C and is coated overnight, PBS-0.5%Tween 20 washes plate, and 2mg/mL BSA-PBS adsorbs, and adds 100 μ L dilute serums, use goat-anti-after washing plate Mouse IgG-HRP (eBioscience) and enzyme linked immunosorbent assay (ELISA) detection kit (Wuhan doctor's moral), according to examination Agent box operational approach measures 450nm OD value (microplate reader, Labsystems).Renal tissue immunopathology checks mouse kidney Fix with 4% formalin, 5 μm paraffin sections.Conventional slicing treatment, uses goat anti-mouse IgG-FITC (eBioscience) the immune complex fluoroscopy of nephridial tissue IgG, the basic unstressed configuration of blind histological scores: 0=are carried out；1= Stove glomerule is slight fluorescence；The a number of glomerule of 2=light moderate fluorescence, renal tubules light moderate fluorescence；The a large amount of kidney of 3=is little Ball, renal tubules, invade profit inflammatory cell in intensity fluorescent；4=glomerule large area hyperfluorescence, fluorescence display diffusivity glomerule, kidney Tubular necrosis.
3.2 result of the test
After (1) the 3rd immunity the 7th day, all immune group mice serum anti-ds-DNA antibody levels were obviously higher than blank Matched group, shows modeling success.
(2) after being administered 15 days, 1.1, the 3.3 and 10mg/Kg body weight vanillic acid glucoside administration anti-ds-of group mice serum DNA antibody level is respectively 0.368 ± 0.047,0.303 ± 0.060,0.328 ± 0.053 (OD), with model group 0.445 ± 0.110 compares reduction substantially (p=0.149, p ＜ 0.05 and p ＜ 0.05, n=6, table 4).
The effect to SLE syndrome sample mice serum anti-ds-DNA antibody of the table 4 vanillic acid glucoside
(* p ＜ 0.05, * * p ＜ 0.01vs model control group)
(3), after being administered 15 days, model group kidney of mouse immunopathology evaluation score value is 3.2 ± 0.9 (n=6), three The evaluation score value of administration group (1.1,3.3 and 10mg/Kg body weight) is respectively 1.6 ± 0.7 (n=6), 2.5 ± 0.8 (n=6), 2.8 ± 1.1 (n=2), all have decline compared with model group, and wherein 1.1mg/Kg dosage group changes substantially (p ＜ 0.01, table 5, Fig. 2).
The impact on SLE syndrome sample kidney of mouse immune complex deposit of the table 5 vanillic acid glucoside
(* * p ＜ 0.01vs model control group)
Result above shows, vanillic acid glucoside can substantially reduce the systemic lupus erythematosus (sle) of active dna induction and combine Simulator sickness sample mice serum anti-ds-DNA antibody level, reduces IgG immune complex at the deposition of nephridial tissue and Renal tissues damage.
In sum, vanillic acid glucoside can substantially suppress mice spleen T of In vitro culture, B lymphocyte proliferation, bright The generation of aobvious suppression mice delayed hypersensitivity, and the systemic lupus erythematosus (sle) that can substantially reduce active dna induction is comprehensive Simulator sickness sample mice serum anti-ds-DNA antibody level, reduces IgG immune complex at the deposition of nephridial tissue and Renal tissues damage.Fragrant Oxalic acid glucoside can be as a kind of new immunosuppressant, for controlling of the autoimmune diseasees such as systemic lupus erythematosus (sle) Treat.

Claims (7)

1. the answering in the medicine of preparation treatment of systemic autoimmune disease of the vanillic acid glucoside derivative as shown in formula (I) With；
Wherein:
R1Selected from H or M, M selected from alkali metal or alkaline-earth metal；
R2Alkyl for H, C1-6；The substituted acyl group of C1-6 alkyl；
R3For
Application the most according to claim 1, it is characterised in that described alkali metal is selected from Li, Na or K.
Application the most according to claim 1, it is characterised in that described alkaline-earth metal is selected from Mg, Ca or Ba.
Application the most according to claim 1, it is characterised in that the alkyl of described C1-6 is selected from CH3, CH2CH3, CH2CH2CH3。
Application the most according to claim 1, it is characterised in that the described substituted acyl group of C1-6 alkyl is selected from COCH3, COCH2CH3, COCH2CH2CH3。
Application the most according to claim 1, it is characterised in that described compound of formula I is selected from following group:
Application the most as claimed in one of claims 1-6, it is characterised in that described systemic autoimmune diseases is selected from being System property lupus erythematosus, rheumatoid arthritis, systemic sclerosis, mouth xerophthalmia scheorma syndrome, polymyositis.
CN201110235674.6A 2011-08-16 2011-08-16 Vanillic acid glucoside derivative purposes in treatment of systemic autoimmune disease Active CN102949404B (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101817746A (en) * 2010-05-19 2010-09-01 江西中医学院 Phenolic acid compound and use thereof in the preparation of anticomplementary medicaments

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GB0801032D0 (en) * 2008-01-21 2008-02-27 Univ York Immune modulation

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101817746A (en) * 2010-05-19 2010-09-01 江西中医学院 Phenolic acid compound and use thereof in the preparation of anticomplementary medicaments

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