CN111743888A - Application of (2Z,4E) -2, 4-decadienoic acid in preparing medicine for treating inflammation caused by influenza virus - Google Patents
Application of (2Z,4E) -2, 4-decadienoic acid in preparing medicine for treating inflammation caused by influenza virus Download PDFInfo
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
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- 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]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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Abstract
The invention provides the use of (2Z,4E) -2, 4-decadienoic acid in the manufacture of a medicament for the treatment of inflammation caused by an influenza virus, wherein the influenza virus is the H1N1 influenza virus. The (2Z,4E) -2, 4-decadienoic acid is separated from paecilomyces hepiali mycelium of Cordyceps sinensis. The (2Z,4E) -2, 4-decadienoic acid of the invention can effectively treat inflammation caused by influenza virus.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to application of (2Z,4E) -2, 4-decadienoic acid in preparation of a medicine for treating inflammation caused by influenza virus.
Background
Influenza viruses are mononegavirale RNA viruses, have a size of about 80-120nm, and are classified into four types, i.e., a (a), B (B), C (C), and D (D), depending on antigenic determinants of influenza virus Nucleoprotein (NP) and Membrane Protein (MP). Among them influenza viruses of types a 1, 3 and 5 (H1, H3 and H5) are common virus subtypes that infect humans. Influenza a virus infection can cause respiratory infectious diseases, placing a heavy burden on human health and global economic health.
Antiviral therapy is a key approach to remedying influenza infection, but currently, clinically available antiviral drugs are only neuraminidase inhibitors (NAIs). Clinical studies show that the NAIs can effectively inhibit virus replication of respiratory systems of influenza A infected patients, but the disease death rate is still high. The main reason is that NAIs have no obvious improvement effect on excessive inflammatory reaction generated by the body triggered by virus infection. This excessive immune response is mainly manifested by the recruitment of a large number of innate immune cells (macrophages and neutrophils, etc.) as well as the expression of inflammatory factors (TNF-alpha, IL-6, IL-8, IFN-alpha, IFN-beta, IFN-gamma, IP-10, MCP-1, MIG, etc.) in the patient's lung tissue. Targeting excessive immune responses has been considered as a key to the treatment of influenza infection, a necessary supplement to the use of antiviral drugs.
Disclosure of Invention
The present invention is directed to solving the above problems and provides a technical solution capable of effectively treating inflammation caused by influenza virus.
In order to achieve the above object, the present invention provides the use of (2Z,4E) -2, 4-decadienoic acid for the preparation of a medicament for the treatment of inflammation caused by influenza virus.
The use according to the invention, wherein the influenza virus is the H1N1 influenza virus.
The application of the invention, wherein the chemical structural formula of the (2Z,4E) -2, 4-decadienoic acid is as follows:
preferably, the (2Z,4E) -2, 4-decadienoic acid is isolated from paecilomyces hepiali mycelia of Cordyceps sinensis.
The use according to the invention, wherein said (2Z,4E) -2, 4-decadienoic acid inhibits the expression of the inflammatory factors TNF-alpha, IL-6, IL-8 and IP-10 caused by said influenza virus.
The use according to the invention, wherein the inflammation is an inflammatory condition caused by an inflammatory factor.
The experimental result shows that (2Z,4E) -2, 4-decadienoic acid has inhibitory activity on the expression of inflammatory factors induced by influenza virus, so that the compound can be used for effectively treating inflammation caused by the influenza virus.
Drawings
FIG. 1 shows the inhibitory effect of (2Z,4E) -2, 4-decadienoic acid on the expression of inflammatory signaling pathways caused by infection of A549 cells with H1N1 influenza virus.
Detailed Description
The present invention will be further described with reference to the following examples. It should be understood that the following examples are illustrative of the present invention only, and are not intended to limit the scope of the present invention.
It is noted that some conventional technical procedures, reagents and apparatuses are not described in detail in the following examples for the sake of brevity and clarity, but it is understood that the conventional technical procedures, reagents and apparatuses are obvious to those skilled in the art if not specifically stated. For example, (2Z,4E) -2, 4-decadienoic acid used in the present invention can be obtained commercially or isolated as in example 1 below.
Example 1: isolation of (2Z,4E) -2, 4-decadienoic acid
Paecilomyces hepiali Cs-4 strain is separated from Cordyceps, and cultured by artificial submerged fermentation to obtain Paecilomyces hepiali mycelium.
166.6g of paecilomyces hepiali dry powder is extracted for 3 times in an ultrasonic bath by chloroform, and the mixture is concentrated to obtain 30ml of concentrated solution. The concentrate was subjected to silica gel column chromatography, eluting with n-hexane-ethyl acetate (95: 5 to 0:100 in volume ratio) and then chloroform-methanol-water (9: 1:0.1 to 8:2:0.2 in volume ratio) to give 38 fractions.
Fraction 5(1.9g) was further separated by forward silica gel column using petroleum ether-ethyl acetate (volume ratio 95:5 to 0:100) to give 12 subfractions.
Fraction 5-5(0.9g) was separated with n-hexane-ethyl acetate (volume ratio from 94:6 to 50:50) to give fraction 5-5-4(100 mg).
Fraction 5-5-4 was continued with petroleum ether-ethyl acetate (volume ratio from 94:6 to 50:50) to give 5-5-4-1(57 mg).
Then, 5-5-4-1 was purified by reverse column (methanol: water volume ratio from 70:30 to 100:0) to obtain 9mg of the objective fatty acid ((2Z,4E) -2, 4-decadienoic acid).
1H NMR(600MHz,CDCl3):7.35(1H,ddd,J＝11.3,15.0,1.0Hz,H-4),6.66(1H,t,J＝11.3Hz,H-3),6.11(1H,dt,J＝15.0,7.5Hz,H-5),5.57(1H,d,J＝11.3Hz,H-2),2.17(q,2H),1.40-1.45(m,2H),1.28-1.32(m,4H),0.88(t,J＝6.9Hz,3H)；13C NMR(150MHz,CDCl3):171.6,144.3,143.9,127.5,118.4,33.1,31.6,28.8,22.6,14.1。HRMS-ESI(m/z):[M+H]+calcd for[C10H17O2]+,169.1223found,169.1217。
Example 2: H1N1 influenza virus amplification
(1) Influenza virus inoculation of chick embryos
Diluting A/PR/8/34(H1N1) influenza virus with sterile normal saline containing penicillin and streptomycin, selecting SPF chick embryos with clear blood vessels, obvious fetal movement and obvious chorioallantoic membrane development boundary line at 9 days, using an egg inspection lamp to look at, scratching an inoculation part at the air chamber junction, avoiding embryo heads and blood vessels, using iodine and alcohol to disinfect the injection part, perforating by using a perforator, using an injector to suck 0.2mL of virus diluent to slowly inject the virus diluent into allantoic cavities of the chick embryos, using 0.2mL of each embryo to seal holes by paraffin, and then placing the inoculated chick embryos in a constant temperature box with the temperature of 35 ℃ and the saturation humidity for 48 hours. Embryo irradiation is carried out once every 12h, and dead chick embryos within 24h are discarded.
(2) Allantoic fluid of chick embryo for detoxification
The chick embryo is put in a refrigerator at 4 ℃ overnight, the eggshell at the air chamber part is disinfected, allantoic fluid is carefully sucked out, the allantoic fluid is centrifuged at 3000rpm for 20min, and supernatant is obtained.
(3) HA method for measuring hemagglutination titer
Adding 25 mu L of PBS into 2-12 holes in the A-H row of a 96-hole hemagglutination plate, adding the chick embryo allantoic fluid to be detected into the first hole in the A-H row, diluting by two times, uniformly mixing to the 11 th hole, discarding 25 mu L, taking the 12 th hole as a negative control, adding 25 mu L of 1% chick red blood cell suspension into each hole, adding from low concentration to high concentration, uniformly mixing, standing at room temperature for 30min, and observing the agglutination condition of the chick red blood cells. Selecting clear allantoic fluid with hemagglutination titer greater than 1:256, mixing, centrifuging at 1500rpm for 10min, collecting supernatant, packaging, and freezing at-80 deg.C.
Example 3: cell median infectious amount (TCID) of virus50) Measurement of
MDCK cells were seeded in 96-well plates overnight, influenza virus diluted 10-fold in DMEM/F12 basal medium was added after the cells were confluent, 100 μ L/well with 6 replicate wells per concentration, and normal controls were set, and an equal amount of DMEM/F12 basal medium was added as a blank. Incubating in a 37 deg.C, saturated humidity, 5% carbon dioxide incubator for 2h, discarding the supernatant, washing with PBS twice, adding basic culture medium, and culturing for 48 h. The growth of the cells was observed daily and the development of CPE was recorded when the cells developed lesions (i.e., cytopathic effects, CPE) such as atrophy, rounding, sloughing, etc. Calculating TCID of each tested concentration of TA by Reed-Muench method50The value is obtained.
Example 4: (2Z,4E) -2, 4-decadienoic acid cytotoxicity evaluation
Cells in the log phase of growth (MDCK, A549 cells) were digested to adjust their cell density to 1 × 105Inoculating each cell/mL into a 96-well cell culture plate, culturing at 100 μ L/well for 18-22 h (after U937 cells grow to proper density, adding PM)A is stimulated for 48 hours), supernatant is discarded, a series of medicines with different concentrations (2Z,4E) -2, 4-decadienoic acid dissolved in DMSO is diluted by DMEM basic culture solution, the final content of the DMSO is less than or equal to 5 thousandths), a solvent control group (basic culture solution containing 5 thousandths of DMSO and no medicine) and a blank control group (basic culture solution and no medicine) are arranged, cells are continuously placed in an incubator to be cultured, after 24 hours of culture, MTT (0.5mg/mL) and 20 muL/hole are added, the mixture is uniformly mixed, light-shielding incubation is carried out for 4 hours, supernatant is discarded, Formazan (Formazan) crystals generated by dissolving 150 muL MSO are added, the crystals are placed on a low-speed oscillator to be shaken for 10 minutes, the crystals are fully dissolved, the OD value of the crystals is detected by an enzyme-labeled detector at the wavelength of 550nm, and the inhibition rate (normal group-administration group)/normal group × 100% is calculated.
Results of the experiment
half-Toxic Concentration (TC) of (2Z,4E) -2, 4-decadienoic acid on A549 cells and U937 macrophages50) 190.7. mu.M and 155.8. mu.M, respectively, and a concentration of 100. mu.M had no toxic effect on both cells (Table 1, Table 2).
Table 1: cytotoxicity of (2Z,4E) -2, 4-decadienoic acid on A549 cells ((2Z,4E) -2, 4-decadienoic acid)
n＝3)
| Concentration (μ M) | 0 | 31.25 | 62.5 | 125 | 250 | 500 | 1000 |
| Inhibition ratio (%) | 0.00±2.94 | 3.90±2.94 | 1.00±3.82 | 4.13±3.31 | 24.15±4.02 | 60.65±4.25 | 4.25±0.35 |
Table 2: (2Z,4E) -2, 4-decadienoic acid cytotoxicity on U937 macrophages: (
n＝3)
Example 5: inflammatory factor assay of cell culture supernatants
(1) Infection of 12-well plate monolayer A549 cells 105A TCID50H1N1 influenza virus, 37 ℃, 5% CO2After 2 hours of adsorption, the supernatant was discarded, washed twice with PBS, 1mL of drug (2Z,4E) -2, 4-decadienoic acid was added to each well at different concentrations (25, 50, 100. mu.M), and after 24 hours of action, the cell supernatant was collected into a l.5mLEP tube. The mixture was placed in a centrifuge with a 4 ℃ precooling at 13000rpm and centrifuged for 15min to discard the precipitated cell debris.
(2) The assay buffer, wash buffer, sample diluent were allowed to stand at room temperature, others were placed on ice. After the sample had dissolved, the sample was centrifuged (cell debris removed from the supernatant) at 3000rpm for 15min 4 ℃. Preparation of 0.5%, 1% BSA (optional): 50mg (BSA) +10mL (DMEM), 50mg (BSA) +5mL (DMEM)0.22 μm filtration; and (5) diluting the standard substance.
(3)50 μ L of diluted (1 ×) magnetic beads/well; swirling for 10-20s before adding holes, and each row needs to be swirled;
(4) after adding the magnetic beads, washing the mixture for 1-2min by using 1 × Bio-Plex washing buffer solution twice; plate washing machine
(5) Samples, standards, blanks, Pre-vortex, 50. mu.L/well
(6) Tightly adhering the film, keeping the tinfoil away from light, and oscillating (850rpm +/-50 rpm for 30 min); preparing a detection antibody 10min in advance;
(7)1 × Bio-Plex Wash buffer 3 times (on magnetic rack);
(8)25 μ L detection antibody/well; swirling for 10-20s before adding holes, and each row needs to be swirled;
(9) tightly adhering the film, keeping the tinfoil away from light, and oscillating (850rpm +/-50 rpm for 30 min); prepare 1 XSA-PE 10min in advance, vortex 100 XSA-PE 5s, dilute to 1 XSA-PE in the dark.
(10)1 × Bio-Plex Wash buffer 3 times (on magnetic rack);
(11)50 μ L of 1 XSA-PE/well; swirling for 10-20s before adding holes, and each row needs to be swirled;
(12) the film was tightly adhered, the tinfoil was kept out of the sun, shaken (850 rpm. + -. 50rpm, 10min)
(13)1 × Bio-Plex Wash buffer 3 washes
(14) Maintenance of 96-well plates with 125. mu.L/well assay buffer
(15) Detecting on machine, data sorting and counting
Example 6: mechanism of action of (2Z,4E) -2, 4-decadienoic acid on inflammatory signaling pathways
A549 cells in logarithmic growth phase were collected and 2.0mL (1 × 10) per well was added to a six-well plate6Individual cells/well), the culture medium was discarded after the cell monolayer was grown to 90% confluence, washed twice with PBS, then infected with H1N1 influenza virus (m.o.i. ═ 0.1-1), incubated at 37 ℃ for 2H, the virus supernatant was discarded, washed twice with PBS, and TA ((2Z,4E) -2, 4-decadienoic acid) at various concentrations (25, 50, 100 μ M), 2 mL/well, was addedSetting three parallel samples for each tested concentration of a normal control group (without adding tested drugs and influenza viruses) and a virus control group (without adding tested drugs) and a drug control group (without adding influenza viruses) in an experiment, continuously culturing cells at 37 ℃, stopping culturing after 24h, extracting cell proteins, washing the cells for 2 times by using precooled PBS, then adding a proper amount of RIPA lysate (about 1 × 106 cells can use 100 and 150 mu L lysate), after freezing for 5min, scraping the cells by using a cell scraper, blowing and collecting the cell lysate, centrifuging a protein sample for 10min at 13,000rpm in a 4 ℃ centrifuge, sucking and storing a BCA (serum albumin) component, determining the protein concentration by using a BCA method, adjusting the sample concentration to be the same according to the determined protein concentration, adding 5 × sample buffer, uniformly mixing, and boiling for 10 min.
The specific procedures of immunoblot analysis with GAPDH (about 37kD) as internal control were as follows:
(1) SDS-PAGE electrophoresis: firstly, preparing gel, mounting an electrophoresis plate, sequentially filling separation gel (8% -12%) with proper concentration and volume, concentrating gel (5%) and pouring a proper amount of electrophoresis buffer solution; sequentially adding the processed samples and the protein Marker into the sample loading holes, wherein each sample is loaded with 20 mu g of sample; and then, starting electrophoresis at a constant voltage of 80V on the concentrated gel, increasing the voltage to 120V after the concentrated gel enters the separation gel after electrophoresis for 15min, continuing the electrophoresis until the bromophenol blue reaches the bottom of the separation gel, and turning off the power supply.
(2) Protein transfer: cutting 4 pieces of filter paper and a PVDF film for each piece of glue in advance, wherein the size of the PVDF film is slightly larger than that of the gel; soaking the PVDF membrane in methanol for 1min to activate the PVDF membrane, taking out the PVDF membrane, placing the PVDF membrane, filter paper and sponge in a membrane transferring buffer solution until the PVDF membrane is completely wet, and then taking the PVDF membrane out of an electrophoresis tank; sequentially placing and aligning the sponge, the filter paper, the PVDF membrane, the gel, the filter paper and the sponge from bottom to top in a membrane rotating instrument to form a sandwich structure, and driving out bubbles on the filter paper with the thickness of the upper layer; the film transferring instrument is assembled and connected with a power supply, and the temperature is low, 380mA constant voltage is kept for 120 min.
(3) And (3) sealing: the PVDF membrane was removed, blocked with 5% BSA/TBST solution at room temperature for 1h with shaking in a shaker, and washed 3 times with TBST, 5min each.
(4) Antibody incubation: pressing a primary antibody according to the ratio of 1: diluting at the ratio of 1000, adding the diluted solution into an antibody incubation box, putting the PVDF membrane into the antibody incubation box, incubating overnight at the temperature of 4 ℃ by a shaking table, and washing for 3 times by TBST; adding a secondary antibody (1: 5000) and incubating for 1h at room temperature in a dark place. TBST washing 3 times.
(5) Sweeping the membrane: the membrane-scanning analysis was performed with the (Tanon-5200) system and the image record was saved.
The experimental results show that: the (2Z,4E) -2, 4-decadienoic acid has obvious inhibition effect (25-100 mu M, p is less than 0.001) on the expression of TNF-alpha, IL-6, IL-8 and IP-10 caused by the infection of A549 cells and U937 macrophages by H1N1 influenza virus, and is shown in tables 3 and 4.
Table 3: (2Z,4E) -2, 4-decadienoic acid on the expression of inflammatory factors caused by infection of A549 cells with H1N1 influenza Virus (2Z,4E) -2, 4-decadienoic acid
n＝3)
Table 4: (2Z,4E) -2, 4-decadienoic acid on the expression of inflammatory factors caused by infection of U937 cells with H1N1 influenza Virus: (
n＝3)
The inhibition of phosphorylation of Toll-like receptor 3(TLR-3), retinoic acid-inducible gene I (RIG-I), p65 transcription factor (p-p65) and signal transduction and activator of transcription 2 (STAT 2) in inflammatory signaling pathways caused by infection of A549 cells with H1N1 influenza virus by (2Z,4E) -2, 4-decadienoic acid is shown in FIG. 1.
Claims (5)
- Use of (2Z,4E) -2, 4-decadienoic acid for the preparation of a medicament for the treatment of inflammation caused by influenza virus.
- 2. The use according to claim 1, wherein the influenza virus is the H1N1 influenza virus.
- 3. Use according to claim 1, characterized in that (2Z,4E) -2, 4-decadienoic acid has the following chemical formula:
- 4. the use according to claim 1, wherein the (2Z,4E) -2, 4-decadienoic acid is isolated from the mycelia of Paecilomyces hepiali of Cordyceps sinensis.
- 5. The use according to claim 1, wherein said (2Z,4E) -2, 4-decadienoic acid inhibits the expression of the inflammatory factors TNF- α, IL-6, IL-8 and IP-10 caused by said influenza virus.
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