CN111617070A - Application of dihydroartemisinin in preparation of medicine for treating inflammation caused by streptococcus suis virulence protein - Google Patents
Application of dihydroartemisinin in preparation of medicine for treating inflammation caused by streptococcus suis virulence protein Download PDFInfo
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Abstract
The invention provides an application of dihydroartemisinin in preparing a medicament for treating inflammation caused by streptococcus suis virulence protein. Dihydroartemisinin can effectively relieve inflammatory reaction of an organism caused by infection of streptococcus suis, has a good treatment effect, and has theoretical research and clinical application values in the aspect of tissue injury caused by streptococcus suis.
Description
Technical Field
The present invention relates to the field of pharmacy. Specifically, the invention relates to an application of dihydroartemisinin in preparing a medicament for treating inflammation caused by streptococcus suis virulence protein.
Background
The swine streptococcosis is a zoonosis caused by pathogenic swine streptococcosis, pigs are main hosts of the swine streptococcosis, but people who are related to live pig feeding and meat processing are susceptible people, and the pathogen is rarely transmitted among people. The main clinical symptoms of streptococcus suis are septicemia, meningitis, arthritis and the like, and can cause death of people in severe cases. The disease occurs in all countries in the world, Asia, Europe and North America are particularly serious, the situation that people infect the streptococcus suis disease in 2005 is avoided in the Sichuan province of China, wherein 215 people infect and 38 people die. Streptococci are oval gram-positive bacteria, and are divided into 33 serotypes according to capsular antigen specificity, with type 2 streptococcus suis being the most pathogenic. The streptococcus suis becomes common pathogenic bacteria in pig farms in China, seriously threatens the healthy development and public health safety of the live pig breeding in China, and is listed as a second-class animal epidemic disease in China at present. The streptococcus suis plays a pathogenic role mainly through virulence factors, and research on the virulence factors is always the focus of research. More than 70 virulence factors have been discovered and reported for their specific functions, with the most extensive and intensive studies on secreted and superficial virulence factors of S.suis type 2.
Lysozyme-released protein (MRP) was first discovered in 1989 by Vecht et al and successfully cloned in 1992, and was named after it appeared in the supernatant of lysozyme-treated pathogenic Streptococcus suis. MRPs share high homology with group A streptococcal M proteins and are also known as M-like proteins. The MRP is closely related to diseases such as meningitis and septicemia caused by streptococcus suis, and is used together with an Extracellular Protein Factor (EPF) to evaluate the pathogenicity and toxicity of the streptococcus suis strain. Recent studies have found that MRP can bind to fibrin in a host body to enhance the survival ability of Streptococcus suis and promote the further development of meningitis, and MRP-knocked-out strains can weaken the adhesion ability to human brain microvascular epithelial cells and reduce the ability of Streptococcus suis to penetrate tissue fiber disorders and the blood brain barrier.
Dihydroartemisinin (DhA) is a derivative of artemisinin, has strong and rapid killing effect on the erythrocytic stage of plasmodium, and can rapidly control clinical attack and symptoms.
However, no studies have been reported so far on the efficacy of dihydroartemisinin in the treatment of diseases caused by streptococcus suis.
Disclosure of Invention
The present invention aims to solve at least to some extent at least one of the technical problems of the prior art.
Therefore, the invention provides the application of dihydroartemisinin in preparing medicines. According to an embodiment of the invention, the medicament is for the treatment of a disease caused by streptococcus suis. The dihydroartemisinin can effectively relieve inflammatory reaction of an organism caused by infecting the streptococcus suis, has a good treatment effect, and has theoretical research and clinical application values in the aspect of tissue injury caused by the streptococcus suis.
According to an embodiment of the present invention, the use of dihydroartemisinin for preparing a medicament can also have the following additional technical features:
according to an embodiment of the invention, the dihydroartemisinin is used to inhibit the inflammatory response caused by the release of proteins by lysozyme of streptococcus suis.
According to an embodiment of the invention, the inflammatory response comprises: splenomegaly, inflammatory cell infiltration, increased levels of plasma inflammatory cytokines, macrophage and neutrophil proliferation in the spleen and peripheral blood, and activation of spleen inflammation-related signaling pathways. Dihydroartemisinin can effectively alleviate these inflammatory reactions, thereby serving a therapeutic purpose.
According to an embodiment of the invention, the dihydroartemisinin is used for reducing macrophage and neutrophil content in the spleen. Therefore, the inflammation reaction can be effectively relieved, and the treatment purpose is achieved.
According to an embodiment of the invention, the dihydroartemisinin is used for reducing the macrophage and neutrophil content in peripheral blood. Therefore, the inflammation reaction can be effectively relieved, and the treatment purpose is achieved.
According to an embodiment of the invention, the dihydroartemisinin is used for reducing the concentration of inflammatory factors in the plasma. Therefore, the inflammation reaction can be effectively relieved, and the treatment purpose is achieved.
According to an embodiment of the invention, the inflammatory factor is selected from at least one of the following: IL-1 alpha, IL-1 beta, IL-6, TNF-alpha, MCP-1 and GM-CSF. Therefore, the inflammation reaction can be effectively relieved, and the treatment purpose is achieved.
According to an embodiment of the invention, the dihydroartemisinin is used to reduce the expression of the gene TLR4 (Toll-like receptor 4). Therefore, the inflammation reaction can be effectively relieved, and the treatment purpose is achieved.
According to an embodiment of the invention, the dihydroartemisinin is used to inhibit NF- κ B and MAPK signaling pathway. According to another embodiment of the invention, the dihydroartemisinin is used for reducing the phosphorylation level of NF-kB proteins, JNK proteins and ERK proteins in the NF-kB and MAPK signaling pathway and reducing the phosphorylation level of JAK2 and STAT3 proteins in the JAK-STAT signaling pathway. Therefore, the inflammation reaction can be effectively relieved, and the treatment purpose is achieved.
According to the embodiment of the invention, the administration dose of the medicament is 2-8 mg/kg BW. Through the administration of 2-8 mg of dihydroartemisinin to each kilogram of body weight, inflammatory reaction can be effectively relieved, so that the treatment purpose is achieved.
According to an embodiment of the invention, the medicament comprises one or more pharmaceutically or dietetically acceptable excipients. For example, magnesium carbonate, magnesium stearate, talc, sugar or lactose. Therefore, the instant food is convenient to eat and can achieve a better treatment purpose. The dosage form of the medicine can be selected from one of mixture, injection, tablet, granule, syrup, capsule, oral liquid, aerosol and spray. Thus, different dosage forms can be adopted conveniently according to different administration objects. For example, tablets, granules, syrups, capsules and oral liquids may be used for convenience of administration, and the dosage form of the drug may be adjusted according to the absorption site of the drug and the release requirement of the drug, thereby improving the bioavailability of the drug and prolonging the release time of the drug. For severe patients, injection can be adopted, so that the requirement of large-dose administration is met, and the influence of gastrointestinal circulation on the effective components of the medicine is avoided.
The term "treatment" is used to refer to obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of complete or partial prevention of the disease or symptoms thereof, and/or may be therapeutic in terms of a partial or complete cure for the disease and/or adverse effects resulting from the disease. As used herein, "treatment" encompasses diseases in mammals, particularly humans, including: (a) preventing the onset of a disease (e.g., preventing a disease caused by streptococcus suis) or condition in an individual who is susceptible to the disease but has not yet been diagnosed with the disease; (b) inhibiting a disease, e.g., arresting disease progression; or (c) alleviating the disease, e.g., alleviating symptoms associated with the disease. As used herein, "treatment" encompasses any administration of a drug or compound to an individual to treat, cure, alleviate, ameliorate, reduce or inhibit a disease in the individual, including, but not limited to, administration of a drug containing dihydroartemisinin as described herein to an individual in need thereof.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Drawings
The above and/or additional aspects and advantages of the present invention will become apparent and readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings of which:
fig. 1 shows a schematic H & E staining of the effect of i.p. MRP and DhA on mouse spleen tissue morphology, according to one embodiment of the present invention, wherein the scale is 1mm, indicates red pulp and the arrows indicate white pulp.
FIG. 2 shows the effect of dihydroartemisinin on the number of mouse spleen macrophages and neutrophils induced by lysozyme released protein MRP according to an embodiment of the present invention, wherein A: CD64+CD11b+Macrophages; b: ly6G+CD11b+Neutrophils. The bar graph on the right side of the pseudo-color scatter plot represents the percentage of corresponding cells from 6 mice per group. Data are expressed as mean ± sem. n is 6. Different letters indicate significant difference between groups, P<0.05。
FIG. 3 shows the effect of dihydroartemisinin on lysozyme released protein MRP to induce the number of peripheral blood macrophages and neutrophils in mice according to one embodiment of the present invention. Wherein, A: CD64+CD11b+Macrophages; b: ly6G+CD11b+Neutrophils. The bar graph on the right side of the pseudo-color scatter plot represents the percentage of corresponding cells from 6 mice per group. Data are expressed as mean ± sem. n is 6. Different letters indicate significant difference between groups, P<0.05。
FIG. 4 shows the effect of dihydroartemisinin on lysozyme released protein MRP induced plasma inflammatory cytokine levels in mice according to one embodiment of the present invention. Wherein, A-H is the ELISA detection result of IL-1 alpha, IL-1 beta, IL-6, IL-10, TNF-alpha, MCP-1, IFN-gamma and GM-CSF in the plasma of the mouse in sequence. Data are expressed as mean ± sem. n is 6. Different letters indicate significant differences between groups, P < 0.05.
FIG. 5 shows the effect of dihydroartemisinin on lysozyme releasing protein MRP to elicit murine splenic Toll-like receptor 4(TLR4) protein levels according to one embodiment of the present invention. Wherein, A: protein expression levels of TLR2, TLR4 and MyD88 were determined by Western Blot. B: and (4) using ImageJ software to perform gray level analysis on the gray level analysis values of the bands of each group, and performing GAPDH gray level correction on the gray level analysis values and relative results after correction by a control group. Results are expressed as mean ± sem. n is 6.
FIG. 6 shows the effect of dihydroartemisinin on lysozyme releasing protein MRP to elicit the NF-. kappa.B and MAPK signaling pathways in mice according to one embodiment of the present invention. Wherein, A: western Blot was used to determine the levels of protein phosphorylation of NF-. kappa. B p65, JNK, p38, ERK. B: the relative results of the gray analysis values of each group of bands by using ImageJ software, the gray values of corresponding non-phosphorylated proteins are corrected, and then the gray values of the bands are corrected by a control group. Results are expressed as mean ± sem. n is 6.
FIG. 7 shows the effect of dihydroartemisinin on MRP-induced mouse spleen JAK-STAT signaling pathway in mice according to one embodiment of the present invention. Wherein, A: protein phosphorylation levels of JAK2, STAT3(Tyr705), STAT3(Ser727) were determined using Western Blot. B: the relative results of the gray analysis values of each group of bands by using ImageJ software, the gray values of corresponding non-phosphorylated proteins are corrected, and then the gray values of the bands are corrected by a control group. Results are expressed as mean ± sem. n is 6.
Detailed Description
The scheme of the invention will be explained with reference to the examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
Examples
Animal(s) production
Female C57BL/6 mice of 6 weeks old are raised in a laboratory without specific pathogens at a constant temperature of 22 ℃, are freely fed with drinking water in 12h light/dark cycle every day, the adaptation period is 2 weeks, and the weight of the mice is about 25g at the beginning of the test. The mouse feed is maintenance feed purchased from Beijing Huafukang Biotechnology Limited, and the drinking water is purified water. One week before the start of the experiment, mice were randomly divided into 10 groups by body weight, namely a control group, an MRP-treated group, an DhA-treated group, and a DhA + MRP-treated group, with 6 mice per group, randomly placed in two mouse cages, three mice per cage. The DhA-treated group and the DhA + MRP-treated group were intraperitoneally injected with 0.1mL of DhA-dissolved olive oil (DhA injection amount was 5 mg/kg. BW) 6 days after the start of the test, while the control group and the MRP-treated group were intraperitoneally injected with 0.1mL of olive oil not containing DhA as a control. On day 6 of the start of the experiment, the mice were deprived of feed, allowed free access to water and were starved for 24 h. On the 7 th day after the start of the test, 2.5 mg/kg. BW of MRP solution was prepared in PBS and the MRP-treated group and the DhA + MRP-treated group were intraperitoneally injected, while the control group and the DhA group were intraperitoneally injected with 0.1mL of PBS, and slaughter sampling was performed 12 hours after starvation (this test was repeated when the sample was insufficient)
Test animal sample Collection
Collecting mouse blood by eyeball-removing method in an anticoagulant blood collection tube, standing collected blood at room temperature for 30min, centrifuging at 1500g and 4 deg.C for 5min, collecting upper layer plasma, packaging, and storing in a refrigerator at-80 deg.C for a long time; the subsequent experiments were performed directly on the flow cytometric samples. The mice were sacrificed by cervical dislocation, opened abdominal cavity, and liver and spleen samples were taken in 1.5mL centrifuge tubes, rapidly cooled in liquid nitrogen, and stored in a refrigerator at-80 ℃ for a long time. Another spleen sample is taken and placed in OCT frozen section embedding medium, and is rapidly stored in a refrigerator at minus 80 ℃.
Hematoxylin-eosin staining
A pre-cooled cryomicrotome at-20 ℃ and the tissue sample embedded in the cryosection is placed in the cryomicrotome for equilibration of temperature. Slicing according to the frozen slicing process, wherein the slicing thickness is 5 mu m. The tissue slices were equilibrated at room temperature for 30min and thoroughly air dried, the slices were fixed with ice methanol for 10s, placed in hematoxylin stain for 5min, washed with weak alkaline water for 3 times, 30s each time. The slices were differentiated in 1% ethanol hydrochloride solution for 2s and rapidly washed with weak alkaline water for 3 times, each for 1 min. The sections were stained in eosin stain for 3min, washed 3 times with weak alkaline water, 1min each time. The sections were immersed once in 70% ethanol 2s, 95% ethanol 2s, absolute ethanol 2s, xylene I10s, xylene II 10s, then the slides were laid flat and neutral gum mounted dropwise, dried overnight, observed with an upright microscope 2X objective and photographed the next day.
Flow cytometry macrophage and neutrophil assay
For spleen samples: the spleen was cut in a 40 μm cell sieve, and the spleen was gently crushed using a syringe plunger, and single cells formed after crushing were passed through the sieve. And (4) extracting the mouse spleen leucocytes according to the specification of the mouse spleen leucocyte extraction kit. The leukocytes obtained from the spleen of each mouse were resuspended in 900. mu.L PBS containing 3% fetal bovine serum and the desired flow antibody was added, gently mixed, and left at room temperature for 30 min. Centrifugation, supernatant removal, PBS wash 3 times, after which the cell pellet is resuspended in PBS containing 3% fetal bovine serum and machine tested.
For peripheral blood samples: and (5) taking the anticoagulated blood of the mice, mixing uniformly, and subpackaging. Adding the required flow antibody into each tube, flicking and mixing uniformly, and standing at room temperature for 30 min. Add 1mL of erythrocyte lysate to the tube, reverse and mix well, and let stand for 15min at room temperature. Centrifugation, supernatant removal, PBS wash 3 times, with 3% fetal bovine serum PBS heavy suspension cell precipitation and machine detection.
Inflammatory cytokine ELISA detection
Standards were diluted in gradient and 25 μ L of standard/sample, 25 μ L of Assay Buffer and 25 μ L of mixed microspheres were added to a 96 well plate and mixed for 2h at room temperature. The supernatant was centrifuged off and the pellet was washed 2 times by adding 200. mu.L of washing buffer. Add 25. mu.L of detection antibody to each well and mix for 1h at room temperature. Add 25. mu.L of PE fluorescent dye to each well and mix for 0.5h at room temperature. The supernatant was centrifuged off, the pellet was washed 2 times with 200. mu.L of wash buffer and resuspended in 150. mu.L of wash buffer. And (3) detecting the heavy suspension microspheres by using a flow cytometer by taking the PE channel as a horizontal axis and the APC channel as a vertical axis, drawing a standard curve of each index according to a flow result by using special software, and calculating the concentration of the sample according to the standard curve.
Western blotting
Total spleen protein was extracted and protein concentration was measured by BCA method. The equivalent amount of protein (60. mu.g) was subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis at a polyacrylamide concentration of 10%, and after the electrophoresis was completed, the protein was transferred to a PVDF membrane. Blocking with 2.5% BSA at room temperature for 2 hours. The antibody was then incubated at 4 degrees overnight. After washing 3 times with TBST solution, the cells were incubated for 1 hour with goat anti-rabbit antibody (1:2000) conjugated with horseradish peroxidase. Color development was performed using an ECL chemiluminescence kit. Grey values were analyzed with ImageJ software.
Statistical analysis
Data are presented as mean ± SEMs and analyzed by one-way analysis of variance. Duncan's multiple comparisons were performed using GraphPadprism version 7.0 (GraphPad software, san Diego, Calif.) to determine differences, with P <0.05 considered significant.
Results of the experiment
As shown in FIG. 1, to investigate the in vivo alleviating effect of DhA on the inflammatory response of mice induced by MRP, the results showed that DhA pretreatment (5mg/kg BW, continuous for 6 days) was effective in alleviating inflammatory cell infiltration in white marrow of mouse spleen caused by intraperitoneal injection of 2.5mg/kg BW MRP, indicating that DhA could alleviate the inflammatory response of mouse spleen caused by MRP.
As shown in FIGS. 2A and B, to further explore DhA ability to alleviate inflammation caused by MRP, flow cytometry was used on macrophages in the spleen (CD 64)+，CD11b+) Neutrophil (Ly 6G)+，CD11b+) The content of cells was measured. The result shows that DhA can remarkably reduce the content (P) of spleen macrophages and neutrophils<0.05)。
As shown in FIGS. 3A and B, to further explore DhA ability to alleviate inflammation caused by MRP, macrophages in peripheral blood (CD 64) were treated using flow cytometry+，CD11b+) Neutrophil (Ly 6G)+，CD11b+) The content of cells was measured. The results show that DhA can significantly reduce the content of peripheral blood macrophages and neutrophils (P)<0.05)。
As shown in FIG. 4, to further verify DhA inhibition of the mouse inflammatory response induced by MRP, this section of the study used ELISA to detect the concentration of inflammatory factors in the mouse plasma. As shown in the figure, DhA can significantly reduce the plasma concentrations of IL-1 alpha, IL-1 beta, IL-6, TNF-alpha, MCP-1 and GM-CSF (P <0.05), but has no significant effect on the plasma concentrations of IL-10 and IFN-gamma. The results show that DhA can inhibit mouse inflammatory reaction caused by MRP by reducing plasma concentration of inflammatory factors.
As shown in FIG. 5, the occurrence of inflammatory reaction caused by Streptococcus suis is often accompanied by the activation of inflammation-related signaling pathways, and the molecular mechanism of alleviating inflammatory reaction is explored DhA from the molecular level by Western blot technique in the present experiment. The results show that DhA can significantly reduce the expression level of TLR4 (P <0.05), but has no significant effect on the expression levels of TLR2 and MyD 88.
As shown in FIG. 6, the occurrence of inflammatory reaction caused by Streptococcus suis is often accompanied by the activation of inflammation-related signaling pathways, and the molecular mechanism of alleviating inflammatory reaction is explored DhA from the molecular level by Western blot technique in the present experiment. The result shows that DhA can significantly reduce the phosphorylation levels of NF-kB and key proteins NF-kB, JNK and ERK of MAPK signal pathway (P <0.05), but has no significant effect on the phosphorylation level of P38.
As shown in FIG. 7, the occurrence of inflammatory reaction caused by Streptococcus suis is often accompanied by the activation of inflammation-related signaling pathways, and the molecular mechanism of alleviating inflammatory reaction is explored DhA from the molecular level by Western blot technique in the present experiment. The results show that DhA can significantly reduce phosphorylation levels (P <0.05) of JAK-STAT signal pathway key proteins JAK2 and STAT3(Tyr705), but has no significant effect on phosphorylation levels of STAT3(Ser 727).
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (10)
1. Use of dihydroartemisinin for the preparation of a medicament for the treatment of a disease caused by streptococcus suis.
2. Use according to claim 1, wherein dihydroartemisinin is used to inhibit the inflammatory response caused by the release of protein by lysozyme of Streptococcus suis.
3. The use according to claim 1, wherein the inflammatory response comprises: splenomegaly, inflammatory cell infiltration, increased levels of plasma inflammatory cytokines, macrophage and neutrophil proliferation in the spleen and peripheral blood, and activation of spleen inflammation-related signaling pathways.
4. Use according to claim 1, wherein dihydroartemisinin is used to reduce macrophage and neutrophil content in the spleen.
5. Use according to claim 1, wherein dihydroartemisinin is used to reduce the content of macrophages and neutrophils in the peripheral blood.
6. Use according to claim 1, wherein dihydroartemisinin is used to reduce the concentration of inflammatory factors in plasma;
optionally, the inflammatory factor is selected from at least one of: IL-1 alpha, IL-1 beta, IL-6, TNF-alpha, MCP-1 and GM-CSF.
7. Use according to claim 1, wherein dihydroartemisinin is used to reduce the expression of the TLR4 gene.
8. The use according to claim 1, wherein dihydroartemisinin is used to inhibit NF- κ B and MAPK signaling pathway;
optionally, the dihydroartemisinin is used for reducing the phosphorylation level of NF-kB and NF-kB proteins, JNK proteins and ERK proteins in a MAPK signal pathway and reducing the phosphorylation level of JAK2 and STAT3 proteins in a JAK-STAT signal pathway.
9. The use according to claim 1, wherein the medicament is administered in a dose of 2-8 mg/kg BW.
10. Use according to claim 1, wherein the medicament comprises one or more pharmaceutically or dietetically acceptable adjuvants.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116334109A (en) * | 2022-07-29 | 2023-06-27 | 西南大学 | Application of overexpression of AaMAPK6 gene in sweet wormwood herb in improving artemisinin content and method |
| CN116334109B (en) * | 2022-07-29 | 2024-04-05 | 西南大学 | Application of overexpression of AaMAPK6 gene in sweet wormwood herb in improving artemisinin content and method |
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