CN117771232A - Application of apigenin in preparation of medicines for treating inflammation - Google Patents
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Abstract
The invention belongs to the field of medical application, and discloses application of apigenin in preparation of a medicament for treating inflammation. Experimental results show that mice induced by DSS have typical UC symptoms, obvious diarrhea and hematochezia, after apigenin intervention, UC symptoms are reduced, and diarrhea and hematochezia conditions are obviously improved compared with model groups. Measurement of myeloperoxidase activity the myeloperoxidase activity in the colon of apigenin mice was significantly down-regulated after 5 days of dosing compared to model group, confirming by pharmacological related experiments that API inhibited mast cell overactivation by MRGPX2 receptor on mast cells to alleviate DSS-induced UC. Therefore, MRGPRX2 can be used as a receptor for treating ulcerative colitis, and apigenin can be used for preparing medicines for treating inflammation.
Description
Technical Field
The invention belongs to the technical field of medical application, and particularly relates to application of apigenin in preparation of a medicament for treating inflammation.
Background
Ulcerative colitis is a complex, idiopathic, inflammatory gastrointestinal disease of the colon, the main target organ of which is colorectal, and typical manifestations of the clinic include bloody diarrhea with or without mucus, rectal urgency, tenesmus, and varying degrees of abdominal pain, as well as possibly involvement of the upper digestive tract, with complications in esophageal, gastric, and duodenal mucosal lesions. UC is considered a global disease and is of bimodal age distribution, with high incidence in children aged 2-3 years, followed by 50-80 middle aged and elderly people. The prevalence and incidence of UC has increased since the middle of the twentieth century, and the incidence has increased more rapidly in specific populations (children). The ulcerative colitis has low mortality rate, is easy to relapse and is difficult to cure, and the clinical medicines for treating the ulcerative colitis at the present stage mainly comprise aminosalicylate, corticosteroid, immunomodulator, oral micromolecule and biological agents, have certain defects and shortages or bring burden to the economy of patients. The pathogenesis of UC is multifactorial, such as genetic abnormalities, altered dietary patterns, intestinal barrier dysfunction, dysregulation of microbiota, and abnormal host immune response, among others. Currently, the clinical treatment of UC is mainly directed to immune responses and pro-inflammatory factors, alleviating symptoms. Exploring effective interventions for other factors may help develop new therapeutic approaches. Therefore, searching for a target for UC treatment and performing more effective and safer treatment on patients are extremely important.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention aims to provide an application of apigenin in preparing a medicament for treating inflammation.
In order to achieve the above purpose, the invention is realized by adopting the following technical scheme:
use of apigenin in the manufacture of a medicament for the treatment of inflammation.
Further, the medicament is a medicament for colitis.
Further, the medicament is a medicament for treating ulcerative colitis.
Further, the drug targets the receptor MRGPX2 on mast cells.
Further, the medicament is capable of antagonizing mast cells.
Further, the agent is capable of inhibiting CPA3 expression levels.
Further, the agent is capable of inhibiting ADM expression levels.
Further, the medicament is a medicament for treating DSS-induced inflammation.
An antiallergic agent is a preparation prepared from apigenin and pharmaceutically acceptable auxiliary materials.
Further, the preparation is a tablet, a capsule, a granule, an injection or a pill.
Compared with the prior art, the invention has the following beneficial effects:
the invention discloses an application of apigenin in preparation of a medicine for treating ulcerative colitis, a DSS induced UC animal model is established by C57 mice, disease activity index evaluation is carried out on each group of mice during administration, diarrhea, hematochezia conditions and scoring of each group of mice are compared after 5 days of administration, MPO activity detection is carried out on colon of the mice, and pathological picture staining is carried out. The results show that mice induced by DSS all show typical UC symptoms, obvious diarrhea and hematochezia, after apigenin intervention, UC symptoms are lightened, diarrhea and hematochezia conditions are obviously improved compared with the model group, and macroscopic scores are obviously reduced compared with the model group (P < 0.001). Determination of myeloperoxidase activity was significantly down-regulated in the colon of apigenin group mice 5 days after dosing compared to model group. The staining results were seen: compared with the model group, five days after administration, the colon structure of the apigenin group is complete, the tissue injury is slight, the mucosal epithelium structure is complete, and the crypt structure is basically complete and regular. Apigenin is thought to significantly inhibit colon pathology in mice with UC model. By immunofluorescent staining, apigenin was found to significantly reduce infiltration of mast cells in colon tissue of mice. Pharmacological experiments prove that apigenin can block MRGPRX2-CPA3-PAMP-12-MRGPRX2 pro-inflammatory positive feedback loop in UC model to relieve inflammation symptoms by inhibiting MRGPRX 2-mediated mast cell activation. Therefore, MRGPRX2 can be used as a target point for treating ulcerative colitis, and apigenin can be used for preparing medicines for treating ulcerative colitis.
Drawings
FIG. 1 is the effect of API on the disease activity index of UC mice; n=6;
FIG. 2 is a graph modeling the effect of API on the disease activity index of UC mice on day six; data are expressed in mean±sem, n=6; in comparison with the NOR group of the devices, ### P<0.001; in comparison with the group of UCs, * P<0.05， ** P<0.01。
figure 3 is a representative picture of diarrhea and hematochezia status in each group of mice. Wherein, (a) a representative graph of diarrhea for each group of mice; (b) a representative plot of colon from each group of mice; (c) a local representation of the distal colon of each group of mice.
FIG. 4 is the effect of API on the colon length of UC mice; data are expressed in mean±sem, n=6; in comparison with the NOR group of the devices, ### P<0.001; in comparison with the group of UCs, * P<0.05， *** P<0.001。
FIG. 5 is the effect of API on MPO viability in the colon of UC mice; data are expressed in mean±sem, n=6; in comparison with the NOR group of the devices, ### P<0.001; in comparison with the group of UCs, ** P<0.01， *** P<0.001。
FIG. 6 is a representative picture of H & E staining results of colon tissue of mice. Wherein, (a) - (f) are colon tissue structures and morphologies of the mice under a low power microscope (magnification 40×, scale: 500 μm); (g) - (l) is a partial enlarged view (magnification 200×, scale: 200 μm), (a) is a negative control group, (b) is a UC model group, (c) is a sulfasalazine (positive drug) group, (d) is a 10mg/kg API group, (e) is a 20mg/kg API group, (f) is a 40mg/kg API group, (g) is a partial enlarged view of the graph (a), (h) is a partial enlarged view of the graph (b), (i) is a partial enlarged view of the graph (c), (j) is a partial enlarged view of the graph (d), (k) is a partial enlarged view of the graph (e), and (l) is a partial enlarged view of the graph (f).
FIG. 7 is the effect of API on mast cell activation in the colon of UC mice; (a) is the level of CPA3 in the colon of each group of mice; (b) ADM levels in the colon of each group of mice; (c) Is negative control group, UC model group and sulfasalazinePyridine (positive drug) group, 10mg/kg API group, 20mg/kg API group, 40mg/kg API group immunofluorescence staining results; data are expressed in mean±sem, n=6; in comparison with the NOR group of the devices, ## P<0.01， ### P<0.001; in comparison with the group of UCs, * P<0.05， ** P<0.01， *** P<0.001。
Detailed Description
The invention is described in further detail below with reference to the accompanying drawings.
Experimental drugs used in the examples of the present invention:
apigenin with molecular formula of C 15 H 10 O 5 CAS:520-36-5. Purchased from chicken Cinnamomum Biotechnology Co.
Experimental animals used in the examples of the present invention:
the C57 male mice of 4 to 6 weeks old were purchased from the department of medical laboratory animal center of the university of Western An traffic and produced license number: SCXK (Shaanxi 2023-002). Adopts a conventional separate-cage feeding mode to ensure sufficient amount of food and water.
Construction and treatment of ulcerative colitis mice model:
1. principle of experiment
The model is built by adopting a relatively mature and accepted preparation method of the ulcerative colitis mouse model at home and abroad, and the basic process is to replace drinking water of the mouse with 5% DSS aqueous solution to induce the mouse to generate ulcerative colitis. The stomach is irrigated with apigenin or salazosulfapyridine (positive medicine) every day for intervention treatment.
2. Experimental procedure
(1) The C57 mice were randomly divided into 6 groups, each group being 6, with the group names of negative control group, ulcerative colitis model group, 10mg/kg apigenin (low dose group), 20mg/kg apigenin group (medium dose group), 40mg/kg apigenin group (high dose group) and salazosulfapyridine group (positive drug group), respectively.
(2) Treatment of mice of each group, once daily, was performed by administering 5% DSS aqueous solution induction and gastric lavage intervention treatment daily starting from modeling:
a) Negative control group: each mouse was perfused with 0.2mL of saline, and the mice were weighed and scored for disease activity index prior to intragastric administration.
b) Ulcerative colitis model group: each mouse was perfused with 0.2mL of saline, and the mice were weighed and scored for disease activity index prior to intragastric administration.
c) Apigenin group: each mouse was perfused with 0.2mL of physiological saline containing 10mg/kg, 20mg/kg or 40mg/kg apigenin, and the mice were weighed and scored for disease activity index prior to lavage.
d) Sulfasalazine group (positive drug group): each mouse was gavaged with 0.2mL of 100mg/kg sulfasalazine solution, and the mice were weighed and scored for disease activity index prior to gavage.
3. Observation index
Macro scoring: after modeling day 6, diarrhea and hematochezia were observed for each group of mice and scores were recorded separately. The raters used a single blind method for the observation and evaluation of mice.
Colon tissue of mice is obtained: after killing the mice by cervical dislocation, fixing the mice on an anatomical plate, spraying 75% alcohol on the abdomen of the mice, cutting off the abdominal cavity of the exposed mice along the midline of the abdomen of the mice, finding out the colon of the mice, performing blunt separation, retaining the cecum, and completely cutting off the colorectal part of the mice to obtain colon tissue materials of the mice.
Measuring colon length: after the colon of the mouse was taken out, the length of the colon of the mouse was measured using a vernier caliper.
Detection of the activity of the MPO in the colon of the mice: colon was collected with dead mice on day 6 into 1.5ml EP tubes, weighed, and appropriate amounts of HTAB buffer were added based on tissue weight. Pre-chilled homogenised steel balls were added to the EP tube, homogenized at 70Hz for 10 minutes using a tissue homogenizer, 4 ℃,13400xg, centrifuged for 6 minutes and the supernatant collected. Freezing and preserving at-80 ℃ for standby. The activity of MPO in colon tissue of mice was examined according to a specific procedure.
Colon tissue staining of mice: a section of the colon at the distal end of the mouse colon was taken, treated to form a coil, fixed, and then immersed in 4% paraformaldehyde at 4℃for 24 hours. Washing with running water for 12h, dehydrating by a dehydrator, immersing paraffin into paraffin tissue blocks, and slicing the section of the sausage with the thickness of 5 μm for subsequent tissue staining.
Data processing and statistical analysis: all experimental data were statistically analyzed using statistical software Graphpad prism 8.0, data results were expressed as mean ± standard error (mean ± SEM), P <0.05 indicating significant differences.
Related pharmacological activity experiments of API on UC mice:
1. disease Activity index determination
From the beginning of the first day of modeling to the end of modeling (sixth day), the mice were scored for 3 aspects of stool morphology, hematochezia, and weight loss by the method described in the literature references (Cho E J, shin J S, noh Y S, et al, anti-inflammatory effects of methanol extract of in mice with ulcerative colitis [ J ]. Journal of Ethnopharmacology,2011,136 (3): 428-35.), the scoring criteria being shown in Table 1, and the results being shown in FIG. 1. The disease activity index on the sixth day of modeling was counted and the results are shown in fig. 2.
Table 1: DAI scoring criteria
Results are expressed as mean ± SEM of 6 mice per group. * P is p<0.05,**p<0.01vs UC model group; ### p<0.001vs NOR。
effect of API on hematochezia and diarrhea in UC mice
Diarrhea, hematochezia are typical clinical symptoms of UC. The effect of the API on improving inflammatory symptoms of ulcerative colitis in UC mice was examined by observing and evaluating changes in diarrhea and hematochezia in UC mice before and after API intervention treatment, and the results are shown in fig. 3 (a), (b) and (c).
The diarrhea and hematochezia conditions of each group of mice were observed and recorded on the sixth day of the modeling, and scored according to a macro scoring table (table 2), and the results are shown in table 3, wherein the macro scoring (a) of the mice in the negative control group, the UC model group, the sulfasalazine (positive drug) group, the 10mg/kg API group, the 20mg/kg API group, and the 40mg/kg API group is 0.000± 0.000,5.333 ± 0.667,1.333 ± 0.333,2.667 ± 0.333,1.333 ± 0.494,1.333 ±0.422, respectively. Diarrhea and hematochezia conditions were significantly elevated (P < 0.001) in the UC model group compared to the negative control group, showing significant ulcerative colitis symptoms. The diarrhea and hematochezia conditions were significantly improved for both the API dosed and sulfasalazine groups at each concentration compared to the UC model group, with statistical differences (P < 0.001). Macroscopic scoring results indicate that the API has the effect of alleviating the symptoms of ulcerative colitis. The results are shown in Table 3:
table 2: macroscopic scoring criteria
Table 3: macroscopic scoring results
Results are expressed as mean ± SEM of 6 mice per group. * P<0.001vs UC model group; ### p<0.001vs NOR。
effect of API on the colon Length of UC mice
The disease severity of each group of mice was observed by measuring the colon length of the mice, and the results are shown in fig. 4, and compared with the negative control group (8.53+ -0.340 cm), the MPO activity (5.90+ -0.260 cm) in the colon tissue of the mice in the UC model group was significantly shortened, and the difference was statistically significant (P < 0.001), indicating that the construction of the UC mouse model was successful. MPO activities of the 10mg/kg API group, the 20mg/kg API group and the 40mg/kg API group are 6.782 +/-0.081 cm, 6.765+/-0.124 cm and 6.704 +/-0.160 cm respectively, which are obviously lower than that of the UC model group (P < 0.05), and the MPO intervention treatment can obviously relieve colon shortening of UC mice.
Effect of API on MPO Activity in the colon of UC mice
The MPO activity in the colon of each group of mice is detected by a specific detection method, and the result is shown in figure 5, compared with a negative control group (0.377+/-0.069U/mg), the MPO activity (1.644 +/-0.216U/mg) in the colon tissue of the mice in the UC model group is obviously increased, and the difference has statistical significance (P < 0.001), so that the construction of the UC mouse model is successful. MPO activities of the 10mg/kg API group, the 20mg/kg API group and the 40mg/kg API group are 0.691+/-0.135U/mg, 0.687+/-0.080U/mg and 0.540+/-0.131U/mg respectively, which are obviously lower than those of the UC model group (P < 0.001), and the inhibition effect of the API on MPO is gradually enhanced with the increase of the dosage of the drug.
Effect of API on pathological changes in the colon tissue of UC mice
After observing API intervention treatment through HE staining, the pathological changes of colon tissues of UC mice are observed. In FIG. 6, (a) - (f) are in order a negative control group, a UC model group, a sulfasalazine (positive drug) group, a 10mg/kg API group, a 20mg/kg API group, a 40mg/kg API group. The colon structure of apigenin group is more complete, the tissue injury is slight, the mucosal epithelium structure is more complete, and the crypt structure is basically complete and regular. The results indicate that the API dose-dependently inhibits colon pathological changes of mice with UC model.
Effect of API on mast cell activation in the colon of UC mice
Mast cells, upon activation, modulate inflammatory responses by releasing specific cytokines and enzymes. The status of mast cell activation in the colon of UC mice was studied by detecting the level of CPA3 (mast cell release) and ADM (a precursor substance that generates the MRGPRX2 ligand PAMP-12 after hydrolysis of CPA 3) in the colon of mice. At the same time, the infiltration condition of mast cells in the colon of the mouse is observed by immunofluorescence staining
The results are shown in FIG. 7, wherein the analysis results in the graph (a) show that the CPA3 content in colon tissues of the mice in each concentration API administration group is significantly lower than that in the UC model group (P <0.01, P < 0.001); the analysis result in the graph (b) shows that the ADM content in colon tissues of the mice in the concentration API administration groups is significantly lower than that in the UC model group (P <0.05, P < 0.01); the above results indicate that the API can inhibit the expression levels of CPA3 and ADM, and act as an inhibitor of mast cell activation. In the figure, (c) shows the immunofluorescence staining results of the negative control group, the UC model group, the sulfasalazine (positive drug) group, the 10mg/kg API group, the 20mg/kg API group and the 40mg/kg API group in sequence. It was found that an increased number of mast cells and degranulation were observed in the colon tissue of UC mice, whereas API significantly antagonizes activated mast cells in UC.
Thus, diarrhea, hematochezia and symptoms of the mice are obviously reduced after apigenin intervention, and macroscopic scores are statistically different from model groups. DSS-induced diarrhea in UC, hematochezia, increased MPO activity, and shortened colon. API treated mice exhibited reduced diarrhea and hematochezia, reduced MPO activity and improved colon shortening. Reduced levels of CPA3 and ADM in the colon tissue of the mice and improved mast cell infiltration and degranulation. This study showed that the levels of CPA3 and ADM were reduced and that CPA3 hydrolyzed the ligand PAMP-12 produced by ADM to activate mast cells; the API is likely to reduce DSS-induced symptoms of UC inflammation. Therefore, the receptor MRGPRX2 of PAMP-12 on the mast cells can be used as a target point for treating ulcerative colitis, and apigenin can be used for preparing medicines for treating ulcerative colitis.
An antiallergic agent is a preparation prepared from apigenin and pharmaceutically acceptable auxiliary materials.
Wherein the preparation is tablet, capsule, granule, injection or pill.
An antiallergic composition comprising apigenin as main ingredient.
The above is only for illustrating the technical idea of the present invention, and the protection scope of the present invention is not limited by this, and any modification made on the basis of the technical scheme according to the technical idea of the present invention falls within the protection scope of the claims of the present invention.
Claims (10)
1. Use of apigenin in the manufacture of a medicament for the treatment of inflammation.
2. The use according to claim 1, wherein the medicament is a medicament for colitis.
3. The use according to claim 1, wherein the medicament is a medicament for the treatment of ulcerative colitis.
4. The use according to claim 1, wherein the medicament targets the receptor MRGPX2 on mast cells.
5. The use according to claim 1, wherein the medicament is capable of antagonizing mast cells.
6. The use according to claim 1, wherein the medicament is capable of inhibiting CPA3 expression levels.
7. The use according to claim 1, wherein said medicament is capable of inhibiting ADM expression levels.
8. The use according to claim 1, wherein the medicament is a medicament for the treatment of DSS-induced inflammation.
9. An antiallergic drug is characterized in that the drug is a preparation prepared from apigenin and pharmaceutically acceptable auxiliary materials.
10. An antiallergic agent as claimed in claim 8, which is in the form of a tablet, capsule, granule, injection or pill.
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