CN108685900B - Application of atractylenolide III in resisting rotavirus - Google Patents
Application of atractylenolide III in resisting rotavirus Download PDFInfo
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Abstract
The invention relates to the technical field of atractylenolide III, in particular to application of atractylenolide III in resisting rotavirus. Application of atractylenolide III in resisting rotavirus is provided, in particular application of atractylenolide III in preparing medicine for resisting rotavirus. The application of the atractylenolide III in preparing the anti-rotavirus medicament is the first research of the applicant, and the atractylenolide III has the anti-rotavirus effect, fills the gap of the anti-rotavirus medicament, and has profound significance and value.
Description
Technical Field
The invention relates to the technical field of atractylenolide III, in particular to application of atractylenolide III in resisting rotavirus.
Background
Rotaviruses (RV) are the main causative agent of acute diarrhea in infants, about 60 million infants die of RV infection every year, and are mainly epidemic in autumn and winter, and the occurrence is not affected by sanitary conditions. The incidence of disease in developed countries is comparable to that in developing countries, but the mortality rate in developing countries is much higher than that in developed countries. RV is generally transmitted through a fecal-oral route, and the incubation period is 2-4 days. RV is thought to mainly invade villi of small intestinal cells, the most main symptom of a patient is diarrhea, the patient is emergent, the diarrhea is caused more than ten times to dozens of times a day, fever can be caused, specific lgM and lgG antibodies can quickly appear in blood after infection, secretory lgA can locally appear in intestinal tracts, the virus can be neutralized, and the RV has an effect on homotype virus infection. The course of the disease is 3-5 days or about a week. Recent studies have shown that RV infections are not restricted to the gut, but can also invade other systems, causing many complications such as shock, encephalopathy, cardiac damage and extrahepatic bile duct obstruction.
At present, no specific medicine for preventing and treating RV infection exists. In the aspect of RV vaccines, the RV vaccines are still in the research stage at home, the RV vaccines are expensive to market abroad, and the RV strains have limited prevention range due to the diversity. At present, oral rehydration recommended by WHO is mostly adopted clinically to relieve symptoms. Therefore, it is very important to discover and develop safe and effective drugs for preventing and treating rotavirus infection.
Atractylodes macrocephala lactone III (British name: Atractylenolide III (C15H20O 3)) is white needle crystal (structural formula shown below), is a main effective component of Atractylodes macrocephala (Atractylodes macrocephala Koidz) of Compositae, has the functions of resisting inflammation and tumor, improving dementia mouse model, regulating gastrointestinal peristalsis, promoting nutrient absorption and the like, but has less reports on the antiviral effect of Atractylodes macrocephala lactone III.
The structural formula of atractylenolide III.
Disclosure of Invention
The invention aims to provide application of atractylenolide III in resisting rotavirus aiming at the defects of the prior art.
In order to achieve the purpose, the invention adopts the following technical scheme:
provides the application of atractylenolide III in preparing anti-rotavirus medicaments.
In the rotavirus resisting medicine, the molar concentration of the atractylenolide III is 5 umol/L-80 umol/L.
In the rotavirus resisting medicine, the molar concentration of the atractylenolide III generating toxicity to cells is more than 80 umol/L.
The rotavirus resisting medicine is a preparation of tablets, granules, powder, capsules, pellets, liquid preparations, semisolid preparations, nano preparations, micro emulsions or liposomes.
The rotavirus resisting medicine comprises a composition or a compound preparation taking atractylenolide III as a component.
Compared with the prior art, the invention has the beneficial effects that:
the application of atractylenolide III in resisting rotavirus and the application of atractylenolide III in preparing anti-rotavirus medicines are the first researches of the applicant to discover that atractylenolide III has the anti-rotavirus effect, fill the blank of anti-rotavirus medicines and have profound significance and value.
Drawings
FIG. 1 is a graph showing the results of cytotoxicity experiments with atractylenolide III.
FIG. 2 is a graph showing the results of experiments on the direct inactivation of rotavirus with atractylenolide III at different concentrations.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects solved by the present invention more clearly apparent, the present invention is further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1.
The application of atractylenolide III in preparing anti-rotavirus medicament is provided. The application of atractylenolide III in preparing anti-rotavirus medicaments is the first research of the applicant to discover that atractylenolide III has the anti-rotavirus effect, fills the gap of anti-rotavirus medicaments, and has profound significance and value.
Example 2.
The application of atractylenolide III in preparing anti-rotavirus medicines is disclosed, wherein the molar concentration of atractylenolide III in the anti-rotavirus medicines is 5 umol/L-80 umol/L.
Example 3.
The application of atractylenolide III in preparing anti-rotavirus medicament is provided, wherein, in the anti-rotavirus medicament, the molar concentration of atractylenolide III generating toxicity to cells is more than 80 umol/L.
Example 4.
The application of atractylenolide III in preparing anti-rotavirus medicament is provided. Wherein the rotavirus resisting medicine is tablet, granule, powder, capsule, pellet, liquid preparation, semisolid preparation, nanometer preparation, microemulsion or liposome preparation.
Example 5.
The application of atractylenolide III in preparing anti-rotavirus medicament is provided. Wherein, the drug for resisting rotavirus comprises a composition or a compound preparation which takes atractylenolide III as a component.
Experiment:
first, experimental material
Experimental drugs:
atractylodes macrocephala lactone III (Kyorman SpA., 99.99% purity, batch number: MUST-17030203). Experimental reagent:
DMEM culture solution and fetal bovine serum are provided by GIBCO company;
MTT (4, 5, dimethylthiazole-2, 5, diphenyltetrazolium bromide), available from M1124Amresco Inc.;
the mixed solution of penicillin and streptomycin, trypsin, PBS and dimethyl sulfoxide were all provided by solarbio.
Preparing and subpackaging reagents:
(1) fetal bovine serum was dispensed into sterile 50ml centrifuge tubes and stored at-20 ℃.
(2) Trypsin was dispensed into sterile 10ml centrifuge tubes and stored at-20 ℃.
(3) The mixed solution of streptomycin and streptomycin is subpackaged in sterilized 10ml centrifuge tubes and preserved at the temperature of minus 20 ℃.
(4) MTT application liquid:
50mg of MTT powder and 10 mg of PBS10ml are stirred and dissolved, filtered by a 0.22 mu m filter membrane for sterilization, and are stored at minus 20 ℃ in dark for standby after being subpackaged.
Experimental equipment:
a 96-hole cell culture plate, an adjustable microsyringe, a cell culture bottle, a filter, a suction pipe, a thermostat and a disinfection pot;
clean bench SIK-202, available from Anhui Union clean plants;
o L YMP μm S inverted light microscope CKX 41;
enzyme linked immunosorbent assay (ELISA) DG 3022A;
carbon dioxide incubator, available from Thermo corporation, usa;
cells and viruses;
caco-2 cells (colon cancer cells), MA104 cells (rhesus monkey embryonic kidney cells), Wa strain rotavirus.
Second, Experimental methods
Cell and virus:
caco-2 cells and MA104 cells were grown and passaged in DMEM medium containing 10% fetal bovine serum, 100. mu.g/ml penicillin, 100. mu.g/ml streptomycin. The infectious virus is human Wa strain rotavirus suitable for cell culture proliferation.
(II) cytotoxicity test of drugs:
weighing 2mg of atractylenolide III sample, dissolving with DMSO (dimethyl sulfoxide), adding a proper amount of DMEM to dissolve, setting the final concentration of DMSO not to exceed 0.5% as a standard, setting a solvent control group, performing sterile operation in a clean bench, filtering and sterilizing with a disposable filter head, calculating the initial concentration, and calculating the final concentration of each drug to be 5 umol/L-640 umol/L.
Cytotoxicity experiments Caco-2 cells were treated with 6 × 104Cell density of one/ml, added to 200. mu.l per well in 96 well cell culture plates. 5% CO at 37 ℃2Incubate until the cells grow into a monolayer. Sucking out growth liquid, and firstly, mixing the growth liquid according to the ratio of 1:1 and 1: 10. 1: 100. 1: 1000 was diluted with serum-free DMEM medium to obtain a series of concentrations of drug solution, and then 100. mu.l/well was added to a 96-well plate, and 6 wells were repeated for each concentration. Normal controls were supplemented with an equal volume of DMEM maintenance solution without serum only. 5% CO at 37 ℃2After incubation and continuous observation by light microscope, the cells at the three other drug concentrations were normal within 72 hours except for the change in cytotoxicity between the first and second drug concentrations. This indicates an effective concentration between 1:1 and 1: 100. According to the ratio of 1:1, 1: 2. 1: 4. 1: 8. 1: 16. 1: 32. 1: 64. obtaining a series of liquid medicines with concentration according to the proportion of 1:128, repeating the operation, and finding that the concentration is higher than 1: the drug concentration of 64 showed cytotoxic changes.
37℃5％CO2Incubating, continuously observing for 2d with optical microscope, sucking out the liquid medicine, keeping out of the sun, adding 5mg/ml MTT25 μ l/well (prepared with serum-free DMEM medium, keeping out of the sun), and keeping at 37 deg.C with 5% CO2After 4h incubation, centrifuging at 800r/ml, discarding the supernatant, adding 50 μ l DMSO/well, oscillating at room temperature for about 10min, dissolving the crystal, mixing, and detecting Optical Density (OD) of each well at 490nm wavelength on microplate reader) The value is obtained. The cell viability was determined according to the following equation.
The% cell viability is × 100% mean absorbance value of drug/cell control.
(III) virus proliferation and titer determination:
proliferation and titer determination of Wa strain RV was performed on MA104 cells. RV was inoculated when cells were grown to monolayer in culture flasks. Prior to virus inoculation, the cell monolayer was washed once with phosphate buffered saline (PBS, pH7) and twice with serum-free DMEM medium. Before inoculation, the original virus solution was removed from a-80 ℃ freezer, dissolved at 4 ℃, exposed to 10. mu.g/ml pancreatin at 37 ℃ for 30min, and the MA104 cells grown as a monolayer were washed twice with PBS. Then adding virus liquid after incubation with pancreatin, wherein the cell maintenance liquid after virus inoculation is a DMEM culture liquid without fetal bovine serum and containing 1 mu g/ml pancreatin. And (2) incubating the cells inoculated with the virus in a carbon dioxide incubator (containing 5% of carbon dioxide) at 37 ℃ until the virus infects MA104 cytopathic effect (CPE cytopathic effect) to be + + + up, putting the culture bottle into a culture flask for cryopreservation at-20 ℃, thawing at 4 ℃, repeatedly freezing and thawing for three times, centrifuging at low temperature and high speed of 12000r/min, taking the supernatant to obtain virus liquid, repeating the virus passage experiment in the cells by the same method, and harvesting the virus. Subpackaging and storing at-80 deg.C.
Viral infectivity titer determination was performed in 96-well plates using MA104 cells (microtiter method). Diluting the obtained product to 10 according to the ratio of 1:10 in a serum-free DMEM culture solution-110-210-3…10-6At equal serial concentrations, 96-well plates cultured as monolayers of MA104 cells were washed 2 times with PBS, and different dilutions of virus were added to 96-well cell culture plates, repeating for 8 wells at each concentration at 25 μ l/well. Setting normal control cells, 5% CO at 37 ℃2After 2h incubation, virus fluid was aspirated and cell culture medium without serum was added at 200. mu.l/well. 5% CO at 37 ℃2Incubation and continuous observation. When no CPE is continuously appeared in the virus wells with the lowest dilution capable of showing cytopathic CPE, counting the number of the virus wells with CPE appearing in each dilution, and calculating the TCID of the virus according to the Reed-M [ mu ] nch method50(Tissue culture infective dose)。
(IV) the anti-RV effect of the medicine:
in the experiment, the concentration of the TC90-95 drug is firstly selected for carrying out the following anti-RV experiment, and then the selected drug with the anti-RV effect is diluted by a DMEM culture solution (without serum) in a multiple ratio to examine the anti-RV effect at different concentrations.
(V) the effect of the medicine on virus-adsorbed cells:
the liquid medicine was added to a 96-well culture plate of Caco-2 cells grown as a monolayer, and each liquid medicine was repeated 6 wells at 100. mu.l/well. Normal cell control groups were set, and virus control groups were each supplemented with an equal volume of DMEM medium (no serum). 5% CO at 37 ℃2And (5) incubating for 2 h.
Sucking out the medicinal liquid, adding 100TCID except for normal control group50100 μ l/well of virus (virus reacted with 10 μ g/ml pancreatin at 37 ℃ for 30min), 5% CO at 37 ℃2Incubating for 2h, aspirating the virus, adding 200. mu.l/well of cell maintenance medium, 5% CO at 37 ℃2Incubation was followed by continuous observation.
After the cells had CPE at ++++ time, the maintenance solution was aspirated, 5mg/ml MTT50 μ l/well was added, incubated for 2h and the supernatant discarded. Add 25 μ l/well of DMSO and mix well with shaking at room temperature for about 10 min. Subsequently, the absorbance value is read by an enzyme linked immunosorbent assay at 570 nm.
The virus inhibition rate and therapeutic index of the drug were calculated according to the following formulas:
the inhibition ratio of the drug to the virus (mean absorbance value of drug group-mean absorbance value of virus control group)/(mean absorbance value of normal cell control group-mean absorbance value of virus control group) × 100% was repeated three times.
The Therapeutic Index (TI) is used as an evaluation index to measure the RV inhibition efficacy of the drug, and the TI is CC50/IC 50.
Note: observed under an optical microscope, without CPE, recorded as: a; CPE appeared in 25% of the cells and was recorded as: +; between 25% and 50% of the cells develop CPE, which is recorded as: + +; between 50% and 75% of the cells develop CPE, which is recorded as: + + + +; between 75% and 100% of the cells develop CPE, which is recorded as: ++++.
(VI) direct inactivation of the virus by the drug:
the drug was mixed with 100TCID50 in a virus solution (virus was exposed to pancreatin at a concentration of 10. mu.g/ml for 30min) in equal volume for 2 h.
This was added to 96-well culture plates grown as monolayers of Caco-2 cells, which were previously washed 2 times with PBS. Normal cell control groups were set, and virus control groups were each supplemented with an equal volume of DMEM only. 5% CO at 37 ℃2Incubating for 2h, then aspirating the mixture, adding 200. mu.l/well of cell maintenance medium, 5% CO at 37 ℃2And (4) continuously observing incubation, carrying out MTT detection by the method when the cells have CPE within the range of ++ - +++ and calculating the inhibition rate and the therapeutic index of the drug to the virus.
(VII) Effect of drugs on Virus biosynthesis:
(1) will 100TCID50The virus solution (virus was allowed to act with trypsin at a concentration of 10. mu.g/ml for 30min) was added to 100. mu.l/well in a Caco-2 cell 96-well culture plate grown as a monolayer, and the cells were washed 2 times with PBS before. And setting a normal cell control, and adding an equivalent volume of DMEM culture solution. 5% CO at 37 ℃2And (3) incubating for 2h, then sucking out the virus liquid, adding 100 mu l/hole of the virus liquid, setting virus control, and only adding an equal volume of DMEM culture solution.
(2)37℃5％CO2Incubating for 2 hr, sucking out the medicinal liquid, adding cell maintenance liquid 200 μ/well, and adding 5% CO at 37 deg.C2Incubation was followed by continuous observation.
(3) Namely, MTT detection is carried out when cell CPE is between ++ - +++ according to the method, and the inhibition rate and the therapeutic index of the drug to the virus are calculated.
(eight) statistical analysis
SPSS13.0 software is adopted, and One-Way ANOVA method is selected, and the OD value of the medicine group is compared with the OD value of the model group by mean. And (4) selecting a PROBIT regression method, and performing regression analysis on the drug concentration, the cell survival rate, the drug concentration and the inhibition rate of the drug on the virus. Obtaining the median cell survival concentration CC of the drug50Inhibitory concentration of drug on half of the virus-infected cells IC50And calculating the therapeutic index according to the therapeutic index TI which is the concentration of the cell median survival drug/the concentration of the median virus inhibiting drug.
Third, experimental results
(I) results of cytotoxicity test of atractylenolide III:
the experimental result of the cytotoxic effect (n ═ 3) of atractylenolide III on Caco-2 is shown in the attached drawing, and the result shows that no cytotoxicity occurs in atractylenolide III at the concentration of 5-80 umol/L, and obvious cytotoxicity occurs when the concentration is more than 160 umol/L.
(II) the experimental result of the atractylenolide III for preventing rotavirus invading cells:
MTT shows that the OD value of each drug concentration group is not significant compared with that of a virus control group, and P is more than 0.05(n is 3). The results show that the medicine has no effect of preventing rotavirus invading cells.
(III) the results of experiments on direct rotavirus inactivation by atractylenolide III:
TABLE 1 direct inactivation of RV organisms by atractylenolide III (n ═ 3)
The result shows that the effect of directly inactivating RV is larger along with the increase of the concentration of atractylenolide III in the range of 40-70 umol (as shown in figure 2), which shows that the effect of directly inactivating RV by atractylenolide III is enhanced (in a certain range) along with the increase of concentration, but the effect of preventing rotavirus from invading cells is not generated.
(IV) Effect of Atractylodes macrocephala lactone III on Virus biosynthesis:
MTT shows that the OD value of each drug concentration group is not significant compared with that of a virus control group, and P is more than 0.05(n is 3). The results show that the medicine has no obvious effect on the virus synthesis.
The results show that the effect of atractylenolide III on RV is achieved through a direct killing way of RV virus, no obvious influence is caused on the absorption and biosynthesis of RV, and the research provides experimental basis for developing atractylenolide III as a new drug for preventing RV.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention, and not for limiting the protection scope of the present invention, although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (5)
1. Application of atractylenolide III in preparing medicine for resisting rotavirus is provided.
2. The use of atractylenolide III as claimed in claim 1 for the preparation of anti-rotavirus drugs, wherein the molar concentration of atractylenolide III is 5 μmol/L-80 μmol/L.
3. The use of atractylenolide III as claimed in claim 1 for the preparation of anti-rotavirus agent, wherein the molar concentration of atractylenolide III toxic to cells is greater than 80 μmol/L.
4. The use of atractylenolide III according to claim 1 for the preparation of anti-rotavirus medicaments, characterized in that: the rotavirus resisting medicine is tablet, granule, powder, capsule, pellet, liquid preparation, semisolid preparation, nano or liposome preparation.
5. The use of atractylenolide III according to claim 1 for the preparation of anti-rotavirus medicaments, characterized in that: the rotavirus resisting medicine comprises a composition taking atractylenolide III as a component.
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Non-Patent Citations (3)
| Title |
|---|
| Atractylenolide I and Atractylenolide III Inhibit Lipopolysaccharide-induced TNF-α and NO Production in Macrophages;Cui-qin Li等;《PHYTOTHERAPY RESEARCH》;20070115;347–353 * |
| Atractylenolide III, a sesquiterpenoid, induces apoptosis in human lung carcinoma A549 cells via mitochondria-mediated death pathway;Tae-Hee Kang等;《Food and Chemical Toxicology》;20111231;514-519 * |
| Gastroprotective activity of atractylenolide III from Atractylodes ovata on ethanol-induced gastric ulcer in vitro and in vivo;Kun-Teng Wang等;《Journal of Pharmacy and Pharmacology》;20101231;381-388 * |
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