CN114425050A - Application of 4-methylumbelliferone in preparation of antiallergic drugs - Google Patents
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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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
-
- 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
- A61P37/08—Antiallergic agents
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- Animal Behavior & Ethology (AREA)
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- Pharmacology & Pharmacy (AREA)
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- General Health & Medical Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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Abstract
The invention discloses an application of 4-methylumbelliferone in preparing an antiallergic medicament, wherein the chemical structural formula of the 4-methylumbelliferone is shown in the specification
In an in-vitro experiment, the method for researching the degranulation of RBL-2H3 and BMMCs in vitro and the method for researching the in-vivo experiment of a passive sensitization model PCA and an active systemic sensitization model ASA determine that the 4-methylumbelliferone can relieve the degranulation of IgE-mediated mast cells and effectively relieve the symptoms of local and systemic anaphylactic reactions of an organism.
Description
Technical Field
The invention relates to the technical field of biological medicines, and particularly relates to application of 4-methylumbelliferone in preparation of an antiallergic medicine.
Background
Allergy is a hypersensitive reaction state of a human immune system to substances in a normal environment, common allergic diseases such as asthma, allergic rhinitis, atopic dermatitis and the like are caused by anaphylactic reaction, and symptoms of the allergic diseases are mainly manifested as red and swollen skin, itching, watery nasal discharge, shortness of breath and the like, so that the persistent health threat is brought to the life of people. In addition, about one fifth of people in the world suffer from allergic diseases, the social and economic development is related to the increasing incidence rate of the allergic diseases, and the allergic diseases are classified as one of three diseases which are mainly prevented and controlled in the 21 st century by the World Health Organization (WHO), which is a current major problem in the world.
The induction and maintenance of allergic reaction can not leave mast cells, which are mainly distributed at the joint of human body and external environment, such as respiratory tract, intestinal tract, urethral mucosa, etc., and are one of the main cells generating inflammatory reaction after contacting with allergen. When a specific allergen antigen is crosslinked with high affinity IgE receptor Fc epsilon RI on the surface of mast cells, the mast cells are rapidly induced to be activated and degranulated, various mediators and cytokines such as histamine, leukotriene, prostaglandin, TNF-alpha, IL-4 and the like are released, so that vasodilation, vascular permeability increase, low temperature, leukocyte aggregation, vascular permeability increase are caused, immune effector cells are induced to be recruited to the inflammatory focus part, and inflammatory reaction is promoted to occur. Therefore, inhibiting the activation of mast cells can reduce the occurrence of anaphylactic reaction, and is also an important reference for searching new antiallergic drugs.
Currently, clinically adopted antiallergic treatments such as antihistamine drugs, hormones and the like can only temporarily relieve the progress of allergic reaction, and various side effects such as somnolence, drowsiness, weakness, lassitude and the like are easily caused due to wide action range and large drug dosage. Although there are also more precise and effective specific treatment methods, the search for a drug with antiallergic effect is still a hot spot in the treatment of anaphylaxis because the treatment course is long, the cost is high, the curative effect is not exact and the drug is not widely used.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide the application of 4-methylumbelliferone in preparing the antiallergic drugs, and aims to solve the problems of large side effect and poor antiallergic effect of the conventional antiallergic drugs.
The technical scheme of the invention is as follows:
an application of 4-methylumbelliferone in preparing antiallergic medicine is provided, wherein the chemical structural formula of the 4-methylumbelliferone is shown in the specification
The use of (a), wherein the 4-methylumbelliferone achieves anti-type I hypersensitivity by inhibiting mast cell activation.
Has the advantages that: the invention provides a new application of 4-methylumbelliferone, namely the 4-methylumbelliferone is used for preparing an antiallergic medicament. In an in-vitro experiment, the method for researching the degranulation of RBL-2H3 and BMMCs in vitro and the method for researching the in-vivo experiment of a passive sensitization model PCA and an active systemic sensitization model ASA determine that the 4-methylumbelliferone can relieve the degranulation of IgE-mediated mast cells and effectively relieve the symptoms of local and systemic anaphylactic reactions of an organism.
Drawings
FIG. 1 is a graph showing the degranulation results of 4-MU inhibition of RBL-2H3 in example 1;
FIG. 2 is a graph of the degranulation results of 4-MU inhibition of BMMC in example 2;
FIG. 3 is a graph of the results of anaphylaxis in the model for 4-MU inhibition of PCA in example 3;
FIG. 4 is a graph showing the results of 4-MU inhibition of anaphylaxis in ASA model in example 4.
Detailed Description
The invention provides an application of 4-methylumbelliferone in preparing an antiallergic medicament, and the invention is further described in detail below in order to make the purpose, technical scheme and effect of the invention clearer and clearer. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The invention provides an application of 4-methylumbelliferone in preparing an antiallergic medicament, wherein the chemical structural formula of the 4-methylumbelliferone is as follows:
the invention utilizes the research idea of 'new application of old medicine' to find a natural plant source molecule-coumarin derivative 4 capable of inhibiting mast cell activation, namely methyl umbelliferone (4-MU), the molecular formula of which is C10H8O3And the molecular weight is 176. 4-methylumbelliferone (4-MU) is mainly present in plants of the Umbelliferae and Compositae families, and 4-MU has been approved in Europe and Asia as a drug named hypmecromone for the treatment of biliary spasm, and is an orally administered dietary product.
The invention proves that the coumarin derivative 4-MU can obviously inhibit the activation of mast cells, has obvious effect of inhibiting degranulation of the mast cells, and can effectively inhibit the anaphylactic reaction of mouse individuals. This shows that 4-MU is expected to be used as an antiallergic drug and has a wide application prospect.
The invention is further illustrated by the following specific examples:
example 1
Inhibition of basophil degranulation by 4-MU in rats (RBL-2H 3):
basophils of mice are widely used in diagnosis of research allergy and immunotherapy, and RBL-2H3 is easy to culture and widely used in research on degranulation and signal pathways, mast cell stabilizers, physicochemical properties of Fc epsilon R and cytoskeletal interaction thereof. RBL-2H3 has high affinity IgE receptors that activate their secretion of histamine and other mediators by clustering or acting synergistically with calcium ionophores.
To verify the inhibitory effect of 4-MU on rat basophil (RBL-2H3) degranulation, the following embodiments were made:
cell culture: rat basophilic leukemia-2 h3 cell lines (RBLs) were purchased from Cellcook Biotechnology, Inc. (Guangzhou, China) and cultured in Dulbecco's Modified Eagle Medium (DMEM) containing 4.0mM l-glutamine, 1.0mM sodium pyruvate, 100U/ml penicillin, 100. mu.g/ml streptomycin, non-essential amino acids (Solarbio, Beijing, China), 10% fetal bovine serum (Gibco, Grand Island, N.Y.) at 37 ℃, 5% CO2, humidified chambers. BALB/c cultures were isolated using mouse femurs for Bone Marrow Mast Cells (BMMCs) and then cultured in RPMI-1640 medium supplemented with 100U/ml penicillin, 100. mu.g/ml streptomycin, 10% fetal calf serum, 10ng/ml IL3 and 10ng/ml SCF cytokine. The expression of cell surface CD117 and Fc epsilon RI after 4-6 weeks of culture is detected by flow cytometry, which indicates that the purity of MC is more than or equal to 95 percent.
CCK8 tested cells for toxic effects on 4-MU: cytotoxicity of 4-MU was determined using a cytometric kit according to the manufacturer's instructions (MedChem Express, Monmouth Junction, NJ). RBLs (2X 103/well) and BMMCs (1X 104/well) were incubated in 96-well plates for 24h after addition of 4-MU at an equal concentration gradient. Then, 10ul of CCK8 reagent was added thereto, and the resultant was incubated for 1 hour and then the absorbance (OD value) was measured in a microplate reader having a wavelength of 450 nm.
Release of β -aminoglycosidase: the degree of degranulation was determined by measuring the activity of beta-hexosidase. RBLs and BMMCs were incubated overnight with 50ng/mL of anti-DNP-IgE in complete medium for sensitization. IgE-sensitized cells were washed with Phosphate Buffered Saline (PBS), pretreated with 4-MU in Tyrode's buffer for 1 hour, and then incubated with 100ng/ml DNP-HSA at 37 ℃ for 30 minutes. The supernatant and the cell microspheres dissolved in Tyrode's buffer with 0.1% Triton X-100 were incubated with an equal volume of substrate solution (1mM 4-nitrophenyl-n-acetyl- β -d-glucopyranosamide) in 0.1M sodium citrate (pH 4.5) for 90 minutes at 37 ℃. The reaction was stopped with 150. mu.l stop solution (0.1M Na2CO3 and NaHCO 3). The product of β -hexosidase activity was measured by detecting absorbance at 405nm using a multiwell plate reader (Bio-Rad, Hercules, Calif.).
After activating RBL-2H3 cells through DNP-IgE mediated pathway, we further measure the release amount of beta-aminoglycoside which is a marker of mast cell activation, and find that 4-MU can inhibit RBL-2H3 degranulation in a dose-dependent manner, detailed results are shown in figure 1, and a in figure 1 shows that 4-MU has no cell proliferation inhibition effect on RBL-2H3 cells at the concentration of <100 MU M, which indirectly indicates that the concentration range has no toxic effect on RBL-2H3 cells; from fig. 1 b, it can be seen that 4-MU can inhibit the release of beta-aminoglycoside produced by IgE-induced cells at concentrations of 10 and 20. mu.M, indirectly indicating that 4-MU can inhibit the IgE-induced degranulation of mast cells.
Example 2
4-MU inhibits degranulation of bone marrow-derived mast cells (BMMCs):
cell culture: BMMCs were isolated from Balb/c mice (purchased from Guangdong provincial animal center for medical laboratory) and cultured in RPMI (Hyclone) 10% FBS (Gibico), 1% diabody, 10ng/ml IL-3 and SCF for 4-6 weeks.
CCK8 tested cells for toxic effects on 4-MU: BMMC (1X 104 per well) were plated in 96-well plates and T-5224 was added after 24 hours, respectively, and incubation continued for 24 hours. Then, 10ul of CCK8 reagent was added thereto, and the resultant was incubated for 1 hour and then the absorbance (OD value) was measured in a microplate reader having a wavelength of 450 nm.
Release of β -aminoglycosidase: BMMC is inoculated in a 24-well plate, incubated with anti-DNP IgE overnight for sensitization, incubated with 4-MU for 1h, stimulated with DNP-HSA (sigma) for 30mins, 50ul of supernatant is reacted with 50ul of substrate at 37 ℃ for 90mins, and absorbance is measured at 405 nm. After discarding the supernatant, 500ul 0.1% T-X100 was added to lyse for 20mins, after centrifugation, 50ul of the supernatant was reacted with 50ul of substrate for 90mins to determine the OD value. The release rate was 100% of the first OD value/(first OD value + second OD value).
Release of histamine: BMMC were inoculated into 24-well plates, incubated overnight with anti-DNP IgE for sensitization, 4-MU for 1h, and after 30mins stimulation with DNP-HSA (sigma), 100ul of supernatant was taken for histamine determination. Histamine determination was performed using a histamine determination kit (purchased from IBL International GmbH, germany).
To further validate the pharmacological effect of 4-MU on mast cell activation, we used bone marrow derived mast cells (BMMCs). First, 4-MU was measured for its effect on BMMCs cell viability and T-5224 ≦ 50 μ M was found to have no toxic effect on cells. Next, we measured the release amount of beta-aminoglycoside, a marker of mast cell activation, which significantly inhibited the release amount of beta-aminoglycoside from BMMCs, as compared to the control group, and the detailed results are shown in FIG. 2. These data indicate that 4-MU can inhibit degranulation of BMMCs. As can be seen from the figure, 4-MU can inhibit beta-aminoglycosidase (shown as b in FIG. 2) and histamine (shown as c in FIG. 2) release induced by IgE in BMMC at concentration ranges (< 100. mu.M, shown as a in FIG. 2) without significant toxic side effects, indicating that 4-MU can inhibit IgE-induced mast cell degranulation.
Example 3
Effect of 4-MU on passive cutaneous allergic reactions in mice:
feeding of BALB/c mice: female mice (BALB/C4-5 weeks old) were purchased from Guangdong provincial medical laboratory animal center (Guangdong Foshan) and placed in a relatively stable SPF environment of temperature (24 + -1 deg.C) and humidity (55 + -10%) for 1 week. Mice were used to isolate bone marrow-derived mast cells (BMMC) and a passive skin allergy (PCA) model and an Active System Allergy (ASA) model were performed.
Mice were injected 500 ng/ear with anti-DNP-IgE. After 24h, 4-MU (50mg/kg) or ketotifen (50mg/kg, positive control) was administered intraperitoneally (i.p.) (N5/group) to the ear. After 1h, mice were injected intravenously with 200 μ g DNP-HSA PBS containing 0.5% Evans blue dye at the tail. Mice were euthanized 1h after DNP-HSA injection. The ear was taken and placed in 700. mu.l of formamide and extracted at 65 ℃ for 12 hours. Dye absorbance was measured at 620nm with a microplate reader (Thermo Fisher Scientific inc., Waltham, MA). Ears were fixed with 4% formaldehyde and embedded in paraffin. Tissue sections were stained with toluidine blue. The PCA model is an animal model that can be used to evaluate the effectiveness of drugs well.
The detailed results are shown in FIG. 3: IgE/Ag significantly induces PCA reaction, 4-MU has significant reduction effect on PCA reaction, and through the amount of diffused Evans blue dye and the thickness reaction of ears, the color of Evans blue gradually becomes lighter, the ears gradually become thinner and the anaphylactic reaction gradually decreases along with the increase of the dose of 4-MU.
Example 4
Effect of 4-MU on OVA-induced systemic anaphylaxis:
mice (N ═ 5/group) were sensitized with OVA mixed solution (100 μ g OVA +2mg aluminium adjuvant +200 μ l PBS) on days 0 and 7. 4-MU (50mg/kg) or ketotifen (10mg/kg) was injected intravenously on days 9, 11, and 13. On day 14, OVA (10mg/kg, i.p.) was injected and rectal temperature of the mice was measured every 10 minutes for 90 minutes. The mice were euthanized after 90 minutes, and blood samples were collected by orbital venous plexus bleeding and the amount of histamine released was quantified using enzyme linked immunosorbent assay (ELISA). The OVA-induced systemic anaphylaxis model is a mature model for researching antiallergic drugs.
The detailed results are shown in FIG. 4: after OVA injection, the rectal temperature of the mice decreased, and in the mice receiving OVA injection, 4-MU inhibited the decrease in rectal temperature, and the effect was similar to that of the ketotifen group (positive control group), indicating that 4-MU had the effect of inhibiting allergic reactions.
It is to be understood that the invention is not limited to the examples described above, but that modifications and variations may be effected thereto by those of ordinary skill in the art in light of the foregoing description, and that all such modifications and variations are intended to be within the scope of the invention as defined by the appended claims.
Claims (2)
1. An application of 4-methylumbelliferone in preparing antiallergic medicine is provided, wherein the chemical structural formula of the 4-methylumbelliferone is shown in the specification
2. The use according to claim 1, wherein the 4-methylumbelliferone achieves resistance to type I hypersensitivity by inhibiting mast cell activation.
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