CN114681442A - Active ingredient of antiallergic fermented product and application thereof - Google Patents
Active ingredient of antiallergic fermented product and application thereof Download PDFInfo
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- CN114681442A CN114681442A CN202011642612.2A CN202011642612A CN114681442A CN 114681442 A CN114681442 A CN 114681442A CN 202011642612 A CN202011642612 A CN 202011642612A CN 114681442 A CN114681442 A CN 114681442A
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Abstract
Description
Technical Field
The present invention relates to the use of at least one of the compounds of formulae (I) to (IV) and pharmaceutically acceptable salts thereof, in particular those for combating allergy and/or assisting in the regulation of allergic conditions:
background
The term "allergy" generally refers to a symptom of excessive reaction of a human body to an originally harmless substance, and examples of substances (also referred to as "allergens") that may cause allergy include pollen, dust, food, mold, animal dander, insects, chemicals, and the like. When a human body overreacts to the above allergens, B lymphocytes produce a large amount of IgE, and the IgE activates mast cells and basophils, so that the mast cells and the basophils release a large amount of histamine to generate a series of immune reactions, which cause allergic diseases such as asthma, allergic rhinitis, allergic conjunctivitis, allergic gastroenteritis, atopic dermatitis, urticaria and the like, and in severe cases, the allergic shock is caused, thereby endangering life.
There are two hundred million people in mainland China with allergic constitution, and allergic population is rapidly rising. Drugs currently used clinically to inhibit allergic reactions include antihistamines, steroids, decongestants, mast cell stabilizers, leukotriene receptor antagonists, etc., however, most drugs relieve only a portion of the symptoms and often have side effects. Taking the commercially available antihistamines as an example, the first generation antihistamines (e.g., pheniramine, hippriphen, pheniramine, and pheniramine) generally cause sleepiness, attention deficit, dry mouth, constipation, and other side effects, while the second generation antihistamines (e.g., pheniramine, alexan, and pheniramine) are not suitable for patients with kidney disease because they are metabolized through the kidney. Therefore, the industry is still working on the research of anti-allergic related products. In particular, allergy has been classified by the world health organization (WTO) as a major research and prevention focus in the 21 st century, further illustrating the urgency of the aforementioned needs.
Disclosure of Invention
The inventor researches to find that the compounds shown in the formulae (I) to (IV) can effectively inhibit histamine generation and histamine secretion, so that the compounds can be used for resisting allergy and/or assisting in adjusting allergic constitution.
Therefore, an object of the present invention is to provide a use of an active ingredient for preparing a composition for anti-allergy and/or auxiliary adjustment of allergic constitution, wherein the active ingredient is at least one of the following compounds (I) to (IV) and pharmaceutically acceptable salts thereof:
preferably, the composition provided by the invention is used for inhibiting histamine generation and/or histamine secretion; more preferably, the composition is used to inhibit inflammatory reactions. Preferably, the composition is a pharmaceutical composition or a food composition. Wherein the food composition is used for assisting in regulating allergic constitution, and is a health food, functional food, nutritional supplement or special nutritional food. The pharmaceutical composition is used for reducing the incidence of asthma, allergic rhinitis, allergic conjunctivitis, allergic enterogastritis, atopic dermatitis, and/or urticaria, or for improving asthma, allergic rhinitis, allergic conjunctivitis, allergic enterogastritis, atopic dermatitis, and/or urticaria. Preferably, the pharmaceutical composition is in a dosage form for oral, respiratory, transdermal, intramuscular or hematological administration, or transmucosal administration.
Drawings
FIGS. 1A to 1D show NMR spectra of compounds of formulae (I) to (IV), respectively;
FIG. 2 shows the relative histamine contents of "group I" to "group IV" on a "control" basis, wherein the basophils of the "control" were cultured in a medium without the compound of the present invention and the basophils of the "group I" to "group IV" were cultured in a medium containing the compounds of the formulae (I) to (IV), respectively (. < 0.05; < 0.01. compared to the control).
Detailed Description
Some specific embodiments according to the present invention will be described below; this invention may, however, be embodied in many different forms without departing from the spirit thereof, and the scope of the invention should not be construed as limited to the embodiments set forth herein or defined by the claims.
As used in this specification (and particularly in the claims), the terms "a," "an," "the," and similar referents are to be construed to cover both the singular and the plural; by "individual" is meant a human or non-human mammal (e.g., dog, cat).
It is known that histamine is closely related to allergic and inflammatory reactions, and when histamine secretion in human body increases, a large amount of histamine binds to receptors on respiratory tract, gastrointestinal tract, skin and/or eye tissue and induces a series of allergic and inflammatory reactions, thereby causing redness, swelling, itching, etc. of eyes, skin and respiratory tract, or causing discomfort of gastrointestinal tract. The foregoing can be seen, for example: the document of M V White, The role of histamines in allologic diseases, J Allergy Clin Immunol 1990 Oct; 86(4Pt 2): 599-; 379-87, which are incorporated herein by reference in their entirety. Therefore, if secretion of antihistamine is effectively inhibited, an antiallergic effect and/or an effect of assisting in regulating allergic constitution can be achieved, and symptoms of allergic diseases such as asthma, allergic rhinitis, allergic conjunctivitis, allergic enterogastritis, atopic dermatitis, urticaria and the like can be improved and the incidence of the above diseases can be reduced.
Cordyceps militaris (Cordyceps militaris), also known as Cordyceps militaris, has similar efficacy to Cordyceps sinensis, can be propagated by artificial culture, and is often used as substitute of Cordyceps sinensis. Fructus Amomi (Fructus Amomi) is a collective name of fruits of various plants in the family zingiberaceae, common varieties comprise Amomum villosum (amonum villosum), hainan sand (amonum longiligulare) and Amomum xanthioides (amonum xanthioides), and the Fructus Amomi is known to be used for miscarriage prevention and the like. Red date (Ziziphus jujube Miller) is a common medicinal material in a Chinese herbal medicine formula, has quite good curative effect no matter fresh fruits or dried fruits, and modern medicine also proves that the red date has the effects of improving anemia, cough, neurasthenia, insomnia and hypertension. Apple (Malus pumila) contains a large amount of dietary fiber and vitamin C, and has weight reducing and antioxidant effects.
The inventor of the present invention finds that after cordyceps militaris, fructus amomi, red dates and apples are mixed and extracted, the extract is fermented in the presence of saccharomyces cerevisiae, lactobacillus plantarum and acetic acid bacteria strains to provide an extracted fermented product, and further, the extracted fermented product is purified and separated to obtain the compounds of the following formulas (I) to (IV), wherein the compounds have the effects of inhibiting the generation of histamine and the secretion of histamine:
the invention therefore relates to the use of at least one of the compounds of formulae (I) to (IV) and of a pharmaceutically acceptable salt thereof for preparing a composition for anti-allergy and/or for aiding in the regulation of allergic conditions. Preferably, the composition may be a pharmaceutical composition or a food composition.
The pharmaceutical composition provided by the present invention can be used for systemic administration or local administration, and can be delivered by various Drug Delivery Systems (DDS), and suitable drug delivery systems include oral drug delivery systems (oral drug delivery systems), transdermal drug delivery systems (transdermal drug delivery systems), injectable drug delivery systems (injectable drug delivery systems), inhalation drug delivery systems (inhalation drug delivery systems), transmucosal drug delivery systems (transmucosal drug delivery systems), and the like. For example, but not limited thereto, the pharmaceutical composition provided by the present invention can be delivered by liposome (liposome), microcapsule (microcapsule), nanoparticle (nanoparticle), microneedle (microneedle), etc. to achieve the purposes of improving bioavailability, controlling drug release rate, precise drug administration to a lesion, reducing drug side effects, etc.
The pharmaceutical composition provided according to the present invention may take any convenient form, without particular limitation, and take a corresponding convenient form depending on the intended use; for example, but not limited thereto, the pharmaceutical composition can be administered to a subject in need thereof by oral administration, transdermal administration (e.g., patch, ointment, etc.), intravenous injection (including drip infusion and bolus injection), intramuscular injection, subcutaneous injection, arterial injection, intraperitoneal injection, administration via the respiratory tract (e.g., spray, nasal drop, etc.), administration via the mucous membrane (e.g., eye drops, oral lozenge, etc.). Depending on the form of use and the use, a pharmaceutically acceptable carrier may be selected to provide the pharmaceutical composition, wherein the carrier is well known to those skilled in the art and includes excipients, diluents, adjuvants, stabilizers, absorption enhancers, disintegrants, solubilizers, emulsifiers, antioxidants, binders, tackifiers, dispersants, suspending agents, lubricants, hygroscopic agents, and the like.
For example, the pharmaceutical composition can be provided in a form suitable for oral administration by any convenient method, such as oral liquid forms including syrups, oral liquids, suspensions, elixirs, and the like, and oral solid forms including powders, granules, buccal tablets, dragees, enteric tablets, chewable tablets, effervescent tablets, film-coated tablets, capsules, sustained release tablets, and the like. The pharmaceutical compositions provided according to the present invention may contain any pharmaceutically acceptable carrier that does not adversely affect the desired benefits of the active ingredient, i.e., at least one of the compounds of formulae (I) through (IV) and pharmaceutically acceptable salts thereof. By way of example, but not limitation, examples of pharmaceutically acceptable carriers for liquid dosage forms include: water, saline, dextrose (dextrose), glycerol, ethanol or the like, oils (e.g., olive oil, castor oil, cottonseed oil, peanut oil, corn oil, and germ oil), glycerol, polyethylene glycols, and combinations of the foregoing; examples of pharmaceutically acceptable carriers for such solid dosage forms include: cellulose, starch, kaolin (kaolin), bentonite (bentonite), sodium citrate, gelatin, agar, carboxymethylcellulose, gum arabic, algin, glycerol monostearate, calcium stearate, and combinations thereof.
Any pharmaceutically acceptable carrier that does not adversely affect the desired benefits of the active ingredients of the present invention (i.e., at least one of the compounds of formulae (I) through (IV) and pharmaceutically acceptable salts thereof) may also be included in dosage forms suitable for transdermal administration, for example: water, mineral oil, propylene glycol, polyethylene oxide, liquid paraffin, sorbitan monostearate, and polysorbate 60. The pharmaceutical composition can be provided in a form suitable for transdermal administration by any convenient method, such as, but not limited to, emulsions, creams, oils, gels (e.g., hydrogels), pastes (e.g., dispersion creams, ointments), lotions, sprays, and patches (e.g., microneedle patches).
The injection solution or the drop solution suitable for injection may contain one or more components such as isotonic solution, saline buffer (such as phosphate buffer or citrate buffer), solubilizer, emulsifier, 5% sugar solution, and other carriers in the pharmaceutical composition provided by the present invention, and the pharmaceutical composition is provided in the form of intravenous infusion solution, emulsion intravenous infusion solution, dry powder injection, suspension injection, or dry powder suspension injection. Alternatively, the pharmaceutical composition may be prepared as a pre-injection solid and the pre-injection solid dissolved or emulsified in another solution or suspension prior to administration to a subject in need thereof to provide the desired injection.
With respect to the pharmaceutical composition for administration to the respiratory tract, the pharmaceutical composition may be aerosolized, optionally using any convenient method, to facilitate the entry of the pharmaceutical composition into the respiratory tract. For example, but not limited thereto, the pharmaceutical composition may be administered via a nebulizer (nebulizer), or a pressurized container (e.g., nasal spray). Alternatively, the pharmaceutical composition may be prepared as a nasal drop.
As for the pharmaceutical composition for transmucosal administration, the pharmaceutical composition provided according to the present invention may contain one or more of a penetrant, a surfactant, a viscosity modifier, a pH modifier, a preservative, a stabilizer, an osmotic pressure modifier, and other carriers, and the pharmaceutical composition may be provided in the form of an eye drop, an eye ointment, an oral lozenge, a suppository, a nasal spray, a nasal drop, and the like.
The food composition provided according to the present invention may be a beverage, a solid food, or a semi-solid food, and may be provided in the form of a health food, a functional food, a nutritional supplement, or a special nutritional food. For example, but not limited thereto, the food composition may be dairy products, meat processed products, breads, wheats, biscuits, ices, lozenges, capsules, juices, teas, sparkling water, alcoholic beverages, sports beverages, nutritional beverages, infant formula, and the like. Preferably, the food composition is provided in the form of a health food or health food.
In addition, any suitable dietary supplement may be included in the food compositions provided according to the present invention, depending on the form of use and the requirements. Food additives that may be used include, for example, but are not limited to, preservatives, bactericides, antioxidants, bleaches, color retention agents, bulking agents, nutritional additives, coloring agents, flavoring agents (e.g., sweeteners), viscosity agents, binders, food industry chemicals, emulsifiers, and quality improving, brewing, and food manufacturing agents.
The proposed dosage, standard and condition of use, or the proposed matter for co-administration with other food or medicine can be marked on the external package of the health food, functional food, nutritional supplement food or special nutritional food provided by the invention, so that the user can take the food by himself without the guidance of doctor, pharmacist or related medical practitioner without safety concerns.
The pharmaceutical composition or food composition provided according to the present invention may further contain, as necessary, additives in a suitable amount, for example, a toner, a colorant, and the like, which improve the feeling of the composition in use, and a buffer, a preservative, an antiseptic, an antibacterial agent, an antifungal agent, and the like, which improve the stability and storability of the composition.
The pharmaceutical or food compositions provided according to the present invention may optionally additionally contain one or more other active ingredients (e.g., antihistamines, steroids, decongestants, mast cell stabilizers, leukotriene receptor antagonists, probiotics, vitamins) to further enhance the efficacy of the composition or to increase the flexibility of use and formulation of the formulation, provided that the other active ingredients do not adversely affect the efficacy of the active ingredients of the invention (i.e., at least one of the compounds of formulae (I) through (IV) and pharmaceutically acceptable salts thereof).
The pharmaceutical or food compositions provided according to the invention contain, based on the total weight of the composition, at least about 0.0001, 0.0002, 0.0003, 0.0004, 0.0005, 0.001, 0.0015, 0.002, 0.0025, 0.003, 0.0035, 0.004, 0.0045, 0.005, 0.0055, 0.006, 0.0065, 0.007, 0.0075, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 80, 70, 90, or more of the pharmaceutically active compounds of formula I (I) and any useful amount thereof selected from the range of the foregoing compounds: about 0.0001 wt% to about 90 wt%, about 0.001 wt% to about 25 wt%, about 0.01 wt% to about 10 wt%, about 0.01 wt% to about 5 wt%, about 0.05 wt% to about 1 wt%, and about 0.05 wt% to about 0.5 wt%.
The pharmaceutical composition or food composition provided by the present invention can be administered at different frequencies such as once a day, several times a day, or once a few days, depending on the need, age, weight, and health condition of the individual to be administered and the purpose of administration. The content of the active ingredient (i.e., at least one of the compounds of formulae (I) to (IV) and pharmaceutically acceptable salts thereof) in the pharmaceutical composition or food composition provided according to the present invention may also be adjusted according to practical application requirements, for example: adjusting to the dosage which should be taken or externally applied every day.
The invention will now be further illustrated by the following examples. These examples are provided for illustration only and are not intended to limit the scope of the present invention.
Examples
[ preparation examples ]
In the following preparation examples, the materials and equipment used were as follows:
1. nuclear Magnetic Resonance Spectrometer (Nuclear Magnetic Resonance Spectrometer, NMR): the 1D and 2D spectra were obtained using 400MHz Varian 400FT-NMR, and chemical shifts (chemical shift) are expressed in δ in ppm.
2. Mass Spectrometer (Mass Spectrometer, MS) tandem Mass spectrometry-two-dimensional ion trap tandem fourier transform Mass spectrometry and ESI-MS/MS: measured using a Bruker amaZon SL system in m/z.
4. high Performance Liquid Chromatography (High Performance Liquid Chromatography, HPLC): high Performance Liquid Chromatography (HPLC) is a Hitachi chromatograph 5260 series; the elution solvent delivery is Hitachi chroma master 5110; the tubular column thermostat is Hitachi chroma 5310; the photodiode Array Detector (DAD) is a Hitachi chromatograph 5430, and the detection wavelength is 250 nm.
6. column Chromatography (Column Chromatography) packing material:
(1)Sephadex LH-20(Pharmacia,Piscataway,NJ,USA);
(2)Diaion HP 20(Mitsubishi Chemical Co.,Japan);
(3)Merck Kieselgel 60(40 63um,Art.9385);
7. thin Layer Chromatography (Thin Layer Chromatography):
(1)TLC aluminium sheets(Silica gel 60F 254,0.25mm,Merck,Germany);
(2)TLC aluminium sheets(RP 18F 254S 0.25mm,Merck,Germany)。
8. ultraviolet Lamp (UV Lamp): UVP UVGL 25, wavelength 254nm and 365 nm.
9. Solvent (solvent) (purchased from merck): n-hexane (n hex)ane), ethyl acetate (ethyl acetate), n-Butanol (n Butanol), methanol (methanol), methanol-d4(resolution hierarchy 99.5%), sulfuric acid solution (H)2SO4)。
Preparation of A antiallergic extract fermented product
A-1 mixing fructus Jujubae (Ziziphus jujube Miller), fructus Mali Pumilae (Malus pumila), Cordyceps Militaris (Cordyceps Militaris), Actinolitum (Amommum villosum), and water at a ratio of 1: 1: 1: 1: 40 (i.e. the weight of water is 10 times of the total weight of the red dates, the apples, the cordyceps militaris and the fructus amomi), and soaking and extracting for 1 hour at 95 ℃ to obtain an antiallergic extract. Then, before the extract was cooled to room temperature, 10 wt% of glucose was added to the extract according to the total weight of red date, apple, cordyceps militaris, amomum villosum and water to obtain a culture solution (in this case, the pH of the culture solution was 5.4, and the sugar degree value was 10.7 ° Bx).
A-2 after the culture medium is cooled to room temperature, adding 0.1 wt% of Saccharomyces cerevisiae (BCRC 20271) to the culture medium, and fermenting for 1 day to form a first primary fermentation liquid. And adding 0.05 wt% of Lactobacillus plantarum (Lactobacillus helveticus) TCI357 to the culture solution, and fermenting for 1 day to form a second primary fermentation solution. Finally, 5 wt% of acetic acid bacteria (Acetobacter aceti) BCRC11688 relative to the culture solution is added into the second primary fermentation broth, and fermentation is carried out for 5 days, so as to provide the anti-allergic extraction fermentation broth. The fermentation stages were all carried out at 30 ℃. The pH of the anti-allergic extraction broth was 4.05 and the sugar value was 2.0 ℃ Bx, indicating that most of the sugars were reacted.
B preparation of the Compounds of formulae (I) to (IV)
B-1 the anti-allergic extraction fermentation broth (20L) provided in A-2 was taken, ethyl acetate and water (equal ratio 1:1) were used as solvents, liquid phase partition extraction was performed 3 times, the extracts obtained by the three extractions were combined and concentrated under reduced pressure and dried to obtain ethyl acetate layer extract (5.6g) and aqueous layer extract. The aqueous layer extract was extracted by liquid phase partition 3 times with n-butanol and water (equal ratio 1:1) as solvents, and the extracts obtained by the three extractions were combined and concentrated under reduced pressure and dried to give an n-butanol layer extract (27.2g) and an aqueous layer extract (143.0 g).
B-2 the n-butanol layer extract (27.2g) from B-1 was taken and separated using Diaion HP-20 as chromatography material and pure water as starting eluent (then increasing the methanol ratio to 100% methanol) to give 3 fractions (AAB-F1 to AAB-F3). Taking the 2 nd layer (AAB-F2), performing Sephadex LH-20column chromatography (Sephadex chromatography) with methanol as eluent, and spot-spotting and combining by Thin Layer Chromatography (TLC) to obtain 12 divided layers (AAB2-1 to AAB 2-12).
B-3 the AAB2-3 from B-2 was taken and subjected to RP-HPLC purification using methanol and water (1:3) as the mobile phase to give the compound of formula (I) (4.9mg) and the compound of formula (II) (1.6 mg). After chemical structure analysis is carried out by hydrogen-nuclear magnetic resonance spectroscopy (1H-NMR) and electrospray ionization mass spectrometry (ESIMS), the compound shown in the formula (I) is Cordycepin (Cordycepin), and the compound shown in the formula (II) is pyroglutamic acid (L-pyroglutamic).
B-4 the compound of formula (IV) (1.6mg) was obtained by RP-HPLC purification of AAB2-9 provided in B-2 using methanol and water (33:67) as the mobile phase. After chemical structure analysis by hydrogen-nuclear magnetic resonance spectroscopy (1H-NMR) and electrospray ionization mass spectrometry (ESIMS), the compound of formula (IV) was confirmed to be Chlorogenic acid (Chlorogenic acid).
B-5 the compound of formula (III) (5.6mg) was obtained by RP-HPLC purification of AAB2-11 provided in B-2 using methanol and water (1:4) as the mobile phase. After chemical structure analysis by hydrogen-nuclear magnetic resonance spectroscopy (1H-NMR) and electrospray ionization mass spectrometry (ESIMS), the compound of formula (III) was confirmed to be kaempferol-3-glucoside (Astragalin).
The chemical structural formulas of the compounds of formulae (I) to (IV) are shown in table 1 below, and their NMR charts are shown in figures 1A to 1D, respectively:
TABLE 1
Example 1: the effect of the compounds of the present invention in inhibiting histamine production and secretion
It is known that histamine is secreted mainly from mast cells and basophils in the human body. Proper histamine secretion helps prevent infection, but excessive or abnormal histamine can cause vasodilation, blood pressure drop, itching, diarrhea, and vomiting. To see whether the compounds of formulae (I) to (IV) of the present invention have the effect of inhibiting histamine production or secretion, experiments were conducted with DNP-HSA as an allergy-inducing agent and basophil RBL-2H3 as a cell model.
In this embodiment, the materials and equipment used are as follows:
RBL-2H3 cells (ATCC; Cat. CRL-2256)
2. Electric suction pipe (Beron; Cat.112108E)
3. Manual dispenser (Sartorius; Cat.725010, 725020, 725030, 725050, 725060)
4.CO2Incubator (ASTEC; Cat. SCA-165DS)
5. Constant temperature water bath (Yude; Cat. BH-130D)
6. Ultrapure Water production System (ELGA; Cat. classic DI)
7. Blood counting dish (Marienfeld; Cat. AP-0650010)
8. Vertical aseptic dustless operating table (Xin-table system; Cat. VCM-620)
9. Waste liquid suction apparatus (Yida medical-Tai system; Cat. DF-506K)
10. Inverted microscope camera system (ZEISS; Cat. Vert. A1)
11. Vertical rapid sterilizer (TOMIN; Cat. TM-329)
12.EpochTMMicropore plate spectrophotometric luminance meter (BioTek)
13. Cell culture solution: minimum Essential Medium (MEM) (Gibco; Cat.11095080) was added 15% FBS (Gibco; Cat.10437-028), 1% penicillin-streptomycin (Gibco; Cat.15140122).
14. 10X DPBS(Gibco;Cat.14200-075)
15. Trypan blue dead cell stain (Lonza; Cat.17-942E)
16.10X Trypsin (Gibco; Cat.15400-054)
17.Anti-DNP-IgE(monoclonal anti-dinitrophenyl antibody produced in mouse,IgGE isotype)(Sigma;Cat.D8406)
18.DNP-HSA(dinitrophenyl-human serum albumin)(Biosearch;Cat.D-5059)
19. ELISA kit for Histamine (ELISA kit for Histamine) (USCN; Cat. CEA927 Ge):
(1) standard (Standard)
(2) Standard diluent
(3) Detection agent A (detection reagent A)
(4) Detection agent B (detection reagent B)
(5) Test dilution A (assay dilution A)
(6) Test dilution B (assay dilution B)
(7) TMB substrate (TMB substrate)
(8) Stopping liquid (Stop solution)
(9)30X Wash buffer (Wash buffer)
(10) Pre-coated 96-well plate
(11) Sealing Plate film (Plate sealer)
(12) Instruction book
20.15 ml centrifuge tube (Protech; Cat. CT-15-PL-TW)
21.50 ml centrifuge tube (Protech; Cat. CT-50-PL-TW)
22. Micro-pipette tip (QSP; Cat.112NXL-Q, TW110-N-Q, 104-Q)
23.10 ml sterile Plastic straw (Simply. TM.; Cat. PC510-0200)
24.6 well cell culture dish (SimpleTM; Cat. PC306-0050)
25. Pasteur pipet (Kimble; Cat. M4230NO250SP4)
26.1.5 ml microcentrifuge tube (Biosigma; Cat. CL022B)
Before performing the experiment, the ELISA kit was subjected to the following treatments:
a. returning the reagent to room temperature;
b. with sterilized ddH2O10X DPBS diluted 10 fold to provide 1X DPBS;
c. diluting 10X trypsin with 1X DPBS by a factor of 10 to provide 1X trypsin;
d. DNP-HSA was prepared in serum-free MEM to a final concentration of 1. mu.g/ml (. mu.g/ml);
e. 20 ml of 30 XWash buffer was added to 580 ml of ddH2O, and mixed well to provide 1X wash buffer.
f. The detection agent A and the detection agent B were diluted 100 times with the detection diluent A and the detection diluent B, respectively, to provide working solutions of the detection agent A and the detection agent B.
g. Serial dilutions were performed on the standards: the standards were redissolved in 2 ml of standard dilution and left to stand for at least 10 minutes to allow the standards to dissolve sufficiently to provide a stock solution of the standards at a final concentration of 100 nanograms per milliliter (ng/ml). Preparing 5 new microcentrifuge tubes of 1.5ml, respectively adding 600 microliters of standard substance diluent into each microcentrifuge tube, then adding 300 microliters of standard substance stock solution into the first tube, uniformly mixing, taking 300 microliters from the first tube to the second tube, sequentially diluting to the 4 th tube, wherein the 5 th tube only contains the standard substance diluent. The final concentrations of the standard in the mixed solution in the 5 centrifuge tubes were 33.33 ng/ml, 11.11 ng/ml, 3.70 ng/ml, 1.23 ng/ml, and 0 ng/ml, respectively, through the above steps.
RBL-2H3 cells (1.5X 10)5Cells/well) were seeded in 24-well plates (each well containing 500. mu.l of medium) and placed in CO at 37 ℃2The culture was carried out overnight in an incubator. Then, the cells were divided into five groups, and cultured at 37 ℃ for 6 hours in the following culture media, respectively:
1. control group: cell culture broth (500 microliters total);
2. group I: cell culture broth (total 500. mu.l) containing the compound of formula (I) provided in preparation example B-3 at a concentration of 100. mu.m;
3. group II: cell culture broth (total 500. mu.l) containing the compound of formula (II) provided in preparation example B-3 at a concentration of 100. mu.m;
4. group III: cell culture broth (total 500. mu.l) containing the compound of formula (III) provided in preparation example B-5 at a concentration of 100. mu.m;
5. group IV: cell culture broth (total 500. mu.l) containing the compound of formula (IV) provided in preparation example B-4 at a concentration of 100. mu.m.
Next, the cells provided in each of the above groups were subjected to the following treatments: Anti-DNP-IgE was added to each well at a final concentration of 0.2. mu.g/ml and reacted for 30 minutes. Then, the liquid in each well was removed, and 500. mu.l of DNP-HSA solution was added, reacted at 37 ℃ for 30 minutes, and the supernatant in each well was collected for use.
50 microliters of the serially diluted standards, control supernatants, and group I through group IV supernatants were added to different wells of the pre-coated 96-well plate, and immediately 50 microliters of the working solution of detector A was added to each well. The 96-well plate was gently shaken and firmly covered with a sealing film, and the reaction was carried out at 37 ℃ for 1 hour. Then, the liquid in the 96-well plate was poured out, 350. mu.l of 1 Xwashing buffer was added to each well, and the liquid was poured out after standing for 1 to 2 minutes (the above washing step was repeated 3 times). After removing all the liquid in each well as much as possible, 100. mu.l of the working solution of the detection agent B was added to each well, and the 96-well plate was covered with a sealing plate film and allowed to react at 37 ℃ for 30 minutes. Then, the liquid in the 96-well plate was poured out, 350. mu.l of 1 Xwashing buffer was added to each well, and after standing for 1 to 2 minutes, the liquid was poured out (the above washing step was repeated 5 times). After removing all the liquid in each well, 90 μ l of the substrate solution is added to each well, covered with a new sealing film, and placed at 37 ℃ for reaction for 10 to 20 minutes (with the need of light shielding, and the action can not exceed 30 minutes). Add 50. mu.l of stop solution to each well and tap the 96 well plate to mix well and color the wells. Finally, o.d.450 values were measured by spectrophotometry and relative histamine content was calculated for each of the other groups based on the "control group" results, which are shown in fig. 2. The data were calculated with reference to the instructions in "ELISA kit for Histamine" (USCN; Cat. CEA927Ge) "and statistically analyzed using Excel software to test whether statistical significance was achieved with student's t (student's t-test).
From FIG. 2, it can be seen that the histamine content of groups I to IV after treatment with the compounds of formulae (I) to (IV) according to the invention is significantly reduced compared to the "control group". The above results show that the compounds of formulae (I) to (IV) of the present invention can effectively inhibit the production and secretion of histamine from basophils and inhibit inflammatory reaction, and therefore can be used for anti-allergy and/or auxiliary adjustment of allergic constitution, and can improve and reduce the incidence of allergic diseases such as asthma, allergic rhinitis, allergic conjunctivitis, allergic gastroenteritis, atopic dermatitis, urticaria, etc.
Claims (10)
1. Use of an active ingredient for the preparation of a composition for anti-allergy and/or for the auxiliary adjustment of allergic constitution, characterized in that: the active ingredient is at least one of compounds of formulae (I) to (IV) below and pharmaceutically acceptable salts thereof:
2. use according to claim 1, characterized in that: the composition is used for inhibiting histamine production and/or histamine secretion.
3. Use according to claim 1, characterized in that: the composition is used for inhibiting inflammatory reaction.
4. Use according to any one of claims 1 to 3, characterized in that: the composition is a pharmaceutical composition or a food composition.
5. Use according to claim 4, characterized in that: the food composition is used for assisting in regulating allergic constitution.
6. Use according to claim 4, characterized in that: the food composition is a health food, functional food, nutritional supplement or special nutritional food.
7. Use according to claim 4, characterized in that: the pharmaceutical composition is used for reducing the incidence of at least one of the following: asthma, allergic rhinitis, allergic conjunctivitis, allergic enterogastritis, atopic dermatitis, and urticaria.
8. Use according to claim 4, characterized in that: the pharmaceutical composition is used for improving at least one of the following: asthma, allergic rhinitis, allergic conjunctivitis, allergic enterogastritis, atopic dermatitis, and urticaria.
9. Use according to claim 7, characterized in that: the pharmaceutical composition is in a dosage form for administration orally, via the respiratory tract, transdermally, intramuscularly or bloody, or mucosally.
10. Use according to claim 8, characterized in that: the pharmaceutical composition is in a dosage form for administration orally, via the respiratory tract, transdermally, intramuscularly or bloody, or mucosally.
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6407066B1 (en) * | 1999-01-26 | 2002-06-18 | Elan Pharmaceuticals, Inc. | Pyroglutamic acid derivatives and related compounds which inhibit leukocyte adhesion mediated by VLA-4 |
CN105147656A (en) * | 2015-06-16 | 2015-12-16 | 洪铁 | Application of chlorogenic acid to preparing medicine for treating allergic rhinitis |
-
2020
- 2020-12-30 CN CN202011642612.2A patent/CN114681442A/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6407066B1 (en) * | 1999-01-26 | 2002-06-18 | Elan Pharmaceuticals, Inc. | Pyroglutamic acid derivatives and related compounds which inhibit leukocyte adhesion mediated by VLA-4 |
CN105147656A (en) * | 2015-06-16 | 2015-12-16 | 洪铁 | Application of chlorogenic acid to preparing medicine for treating allergic rhinitis |
Non-Patent Citations (4)
Title |
---|
MYOUNG-SCHOOK YOOU等: "Cordycepin Suppresses Thymic Stromal Lymphopoietin Expression via Blocking Caspase-1 and Receptor-Interacting Protein 2 Signaling Pathways in Mast Cells", BIOL. PHARM. BULL., vol. 39, no. 1, pages 90 - 96 * |
YUN-HO KIM等: "Astragalin Inhibits Allergic Inflammation and Airway Thickening in Ovalbumin-Challenged Mice", JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, pages 836 - 845 * |
娄俊丽等: "过敏性疾病与肠道菌群", 临床儿科杂志, vol. 27, no. 2, pages 196 - 198 * |
徐珒昭等: "焦谷氨酸对高盐饮食小鼠肠道健康及肠道菌群的作用", 食品与发酵工业, vol. 47, no. 2, pages 102 - 108 * |
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