CN108619245B - New application of guava leaves and total flavonoids in guava leaves - Google Patents
New application of guava leaves and total flavonoids in guava leaves Download PDFInfo
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- CN108619245B CN108619245B CN201810324191.5A CN201810324191A CN108619245B CN 108619245 B CN108619245 B CN 108619245B CN 201810324191 A CN201810324191 A CN 201810324191A CN 108619245 B CN108619245 B CN 108619245B
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Abstract
The invention relates to application of guava leaf total flavonoids in preparing a medicine for preventing and treating pancreatitis. The invention further provides a pharmaceutical composition for preventing and treating pancreatitis, which comprises effective treatment dose of guava leaf total flavonoids as an active ingredient and a pharmaceutically acceptable carrier. Animal experiments show that the guava leaf total flavonoids inhibit excessive proliferation of pancreatic stellate cells and relieve pancreatic fibrosis degree by inhibiting activation of a P2X7R mediated NLRP3 inflammatory body signal pathway, have good effect of preventing and treating pancreatitis, have no toxic or side effect, and can be used for preparing medicaments for preventing and treating pancreatitis.
Description
Technical Field
The invention relates to the field of medicines, in particular to a traditional Chinese medicine for preventing and treating pancreatitis and a total flavone extract thereof.
Background
Pancreatitis can be acute (emerging, short-term) or chronic (sustained, long-term).
Acute Pancreatitis (AP) is a common disease that results in significant morbidity and mortality. Organ failure and systemic inflammatory response syndrome occur in the early stage of onset, and infection of necrotic tissues occurs in the later stage. At present, the treatment and prognosis of acute pancreatitis are still challenging, and have the characteristics of high fatality rate, high disability rate and high cost. Acute pancreatitis usually begins immediately after injury to the pancreas begins, with episodes usually being very mild, mild episodes lasting a short time and usually recovering completely when the pancreas returns to its normal state, and repeated episodes of acute pancreatitis result in chronic pancreatitis.
Chronic Pancreatitis (CP) is clinically manifested by recurrent epigastric pain and pancreatic endocrine-exocrine insufficiency, with a tendency to increase year by year, which seriously harms human health. Moreover, clinically recurrent, continuously progressing CP is at considerable risk of developing pancreatic cancer (about 10%), with a very poor prognosis of pancreatic cancer, accounting for 8 th among the total cancer mortality, with developed countries living high at 4 th, and most patients dying within one year after diagnosis. To date, the pathogenesis, pathophysiology, and clinical course of CP is still not well understood, and no ideal therapeutic regimen is available. It has been found that CP has a different etiology, but the pathological changes are similar, i.e., chronic inflammation that continues to progress eventually leads to irreversible damage to the pancreatic acinar and islet cells, which are gradually replaced by fibrous tissue, resulting in significant dysfunction of the endocrine and exocrine pancreatic functions. Pancreatic fibrosis is an important pathological process of CP, and can lead to loss of pancreatic functional tissue, narrowing or dilation of pancreatic ducts, acinar cell atrophy, pancreatic duct stones, and inflammatory cell infiltration. Inhibiting the development of pancreatic fibrosis can effectively alleviate CP symptoms and become an effective means for preventing CP malignant transformation. However, the pathogenesis of pancreatic fibrosis is complex, and at present, no medicine for effectively inhibiting pancreatic fibrosis exists.
The traditional Chinese medicine treatment has the characteristics of multilevel, multiple targets, small toxic and side effects and the like, and has unique advantages for preventing and treating chronic diseases. Guava leaf is a Chinese medicine with oxidation resistance, spasm resistance, allergy resistance, inflammation resistance and diabetes resistance, the main components of the extract are tannin, triterpene, volatile oil, polysaccharide, ketone compounds and the like, wherein flavonoid is the main bioactive component. In the prior art, the anti-tumor activity of the total flavonoids in guava leaves is reported in partial documents mainly aiming at the blood sugar reducing effect of the total flavonoids in guava leaves, but related documents and patents on the prevention and treatment effect of pancreatitis are not found.
Disclosure of Invention
The first purpose of the invention is to disclose a new application of guava leaves.
The second purpose of the invention is to disclose a new application of guava leaf total flavonoids.
The guava leaf total flavonoids can be prepared according to the prior art, and the invention also provides an optimized extraction and detection method: on the basis of a single-factor test, by taking the extraction time, the material-liquid ratio and the ethanol consumption as independent variables and taking comprehensive scores of hyperin, quercetin-3-O-beta-D-arabinopyranoside, quercetin-3-O-alpha-L-arabinofuranoside and extract yield as dependent variables, a Box-Behnken design-response surface method is adopted to optimize the guava leaf total flavone reflux extraction process and carry out a verification test. The optimized extraction process is stable and feasible, the detection method is stable, and the quality is controllable.
Pharmacological tests prove that the guava leaf total flavonoids have the effect of preventing and treating acute pancreatitis and chronic pancreatitis. Compared with the normal group, the pancreatic injury is aggravated after the ranolanin injection (P is less than 0.001), and the levels of Caspase-1, NLRP3, alpha-SMA, IL-1 beta and IL-18 are increased (P is less than 0.01). The content of collagen I (ColI) and collagen III (ColIII) around pancreatic histiocytes is higher than that of a normal group (P is less than 0.001) through sirius red staining. Compared with the model group, the oxATP group and the TFPGL group with low dosage have reduced inflammatory injury and fibrosis degrees, and are expressed by reduced sirius red staining degree (P is less than 0.05), and reduced levels of Caspase-1, NLRP3, alpha-SMA, IL-1 beta and IL-18 (P is less than 0.05).
The guava leaf total flavonoids can be prepared into any pharmaceutically acceptable conventional dosage forms, such as capsules, tablets, granules, powder, oral liquid, pills and other preparations, according to the conventional preparation process. In order to make the above dosage forms possible, pharmaceutically acceptable excipients, such as: fillers, disintegrants, lubricants, suspending agents, binders, sweeteners, flavoring agents, preservatives, bases, and the like. The filler comprises: starch, pregelatinized starch, lactose, mannitol, chitin, microcrystalline cellulose, sucrose, etc.; the disintegrating agent comprises: starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch, crospolyvinylpyrrolidone, low-substituted hydroxypropylcellulose, croscarmellose sodium, etc.; the lubricant comprises: magnesium stearate, sodium lauryl sulfate, talc, silica, and the like; the suspending agent comprises: polyvinylpyrrolidone, microcrystalline cellulose, sucrose, agar, hydroxypropyl methylcellulose, and the like; the adhesive comprises starch slurry, polyvinylpyrrolidone, hydroxypropyl methylcellulose, etc.; the sweetener comprises: saccharin sodium, aspartame, sucrose, sodium cyclamate, glycyrrhetinic acid, and the like; the flavoring agent comprises: sweeteners and various essences; the preservative comprises: parabens, benzoic acid, sodium benzoate, sorbic acid and its salts, benzalkonium bromide, chloroacetidine acetate, eucalyptus oil, etc.; the matrix comprises: PEG 6000, PEG 4000, insect wax, etc.
The present invention is further described in the following description of the specific embodiments, which is not intended to limit the invention, but various modifications and improvements can be made by those skilled in the art according to the basic idea of the invention, within the scope of the invention, as long as they do not depart from the basic idea of the invention.
Drawings
FIG. 1 high performance liquid chromatogram of total flavonoids of guava leaf (A) and reference substance (B)
FIG. 2 histological evaluation of pancreatic injury and fibrosis before and after treatment with total flavonoids from guava leaves and oxATP
FIG. 3 evaluation of pancreatic fibrosis by picric acid sirius red staining (upper view is lower view of polarizer, lower view is lower view of optical lens)
FIG. 4 immunohistochemical detection of α -SMA, NLRP3 and Caspase-1 expression in pancreatic tissue (. times.200)
Detailed Description
Example 1 extraction and content determination of total flavonoids from guava leaves
The method comprises the steps of ethanol reflux extraction, reduced pressure recovery of a reagent, concentration, filtration, petroleum ether treatment, ethyl acetate extraction and the like. In the TFPGL content measurement, rutin is used as a standard substance to measure a light absorption value, the concentration is used as a horizontal coordinate, and the absorbance is used as a vertical coordinate, so that a standard curve is drawn. Measuring absorbance of the sample at 500nm (the rutin standard has strong absorbance value at 500nm, and is set as measurement wavelength) by ultraviolet spectrophotometry, and substituting into standard curve regression equation to calculate to obtain total flavone content of 19.8%.
Example 2 acute toxicity of total flavonoids of guava leaves
1. The experimental method comprises the following steps:
the test design was performed on the dosing group and the placebo group, each group containing 24 animals, male and female. The administration group is administrated by intragastric administration with the dosage of 22.32g/kg and the administration volume of 40 ml/kg. The control group was gavaged with an equal volume of drinking water.
The appearance, mental state, respiration, skin fur, feces, eyes, ears, nose, mouth, genitals, and other general conditions of poisoning and death of the mice were observed and recorded daily. The body weight and food intake of the mice were measured once a week for 14 consecutive days.
2. The experimental results are as follows:
general and mortality observations: after administration, all animals had good mental and behavioral activity, clean skin and hair, normal stool and urine, normal weight increase, no abnormal food intake, and no other toxic reaction symptoms until day 14. After observation, no obvious abnormality of organs was observed in gross anatomy.
Weight: the difference between the body weight of the male mouse and the female mouse at each time point and the body weight of the male mouse and the female mouse at the control group has no statistical significance (P is more than 0.05), and the guava leaf total flavone has no obvious influence on the body weight of the mice after oral gavage administration.
Example 3 Multi-index effective surface method-optimized guava leaf total flavonase auxiliary extraction process
1. Chromatographic conditions and methods:
the chromatographic column is Agilent Eclipse XDB-C18(4.6mm × 250mm, 5 μm); a (methanol%), B (0.2% aqueous phosphoric acid%); gradient elution for 0-20.00 min, 37% A; 20.01-35.00 min, 70% A; the volume flow is 1 mL/min; the column temperature was 35 ℃; detection wavelength: 360 nm. Precisely absorbing 10 mu L of the test solution, measuring the peak areas of hyperin, quercetin-3-O-beta-D-arabinopyranoside and quercetin-3-O-alpha-L-arabinofuranoside in the test solution, calculating the content of the components, and converting the content of the total flavonoids in the guava leaves in the test solution by combining the percentage ratio of the chromatographic peak areas of the 3 components to the total peak area.
The total flavone content (mg/g) is 3 total flavonoid glycoside mass fractions/3 total flavonoid glycoside chromatographic peak area percentage sum multiplied by 100%
The chromatogram is shown in FIG. 1.
2. Single factor test
Investigation of enzyme dosage: taking 1.0g of guava leaf powder, precisely weighing, extracting at 30 ℃ for 30min, with a feed-liquid ratio of 1:25(g/mL), an ethanol concentration of 40%, enzyme dosages of 0, 0.1%, 0.2%, 0.5%, 1.0%, 1.5% and 2.0%, and determining the content of total flavonoids, wherein the results are respectively 4.17mg/g, 4.39mg/g, 4.86mg/g, 5.24mg/g, 8.48mg/g, 6.48mg/g and 5.92 mg/g. As a result, the total flavone content increases and then decreases with the increase of the enzyme dosage, and the total flavone content is the highest when the enzyme dosage is 1.0%. Therefore, the optimal amount of enzyme is chosen to be 1.0%.
Examination of extraction temperature: taking 1.0g of guava leaf powder, precisely weighing, using 0.5% of enzyme, extracting for 30min at a material-liquid ratio of 1:25(g/mL) and an ethanol concentration of 40%, extracting at 20, 30, 40, 50, 60 and 70 ℃ respectively, and determining the content of total flavonoids. As a result, the amounts were 5.04mg/g, 5.24mg/g, 6.07mg/g, 6.04mg/g, 5.13 mg/g and 3.56mg/g, respectively. The result shows that the content of the total flavone is obviously increased along with the increase of the extraction temperature, the content of the total flavone reaches the maximum at the extraction temperature of 40 ℃, the extraction temperature is continuously increased, and the content change of the total flavone tends to be smooth. Thus, an extraction temperature of 40 ℃ was chosen.
Examination of extraction time: taking 1.0g of guava leaf powder, precisely weighing, extracting with 0.5% enzyme at 30 deg.C and 1:25(g/mL) ethanol concentration of 40% at 15, 30, 45, 60, and 75min respectively, and determining total flavone content. As a result, the concentration was 4.60mg/g, 5.24mg/g, 4.33mg/g, 4.19mg/g and 4.85mg/g, respectively. As a result, the total flavone content increased with the increase of the extraction time and reached the maximum at 30min, and then the total flavone content decreased, probably because the ultrasonic time was too long and the enzyme activity was affected. Therefore, the extraction time was determined to be 30 min.
Examination of ethanol volume fraction: taking 1.0g of guava leaf powder, precisely weighing, using 0.5% of enzyme, carrying out extraction at 30 ℃ for 30min at the enzymolysis temperature, wherein the material-liquid ratio is 1:25(g/mL), and the ethanol volume fractions are respectively 30%, 40%, 50%, 60% and 70%, and determining the content of total flavonoids. As a result, the amounts were 5.48mg/g, 5.24mg/g, 8.47mg/g, 6.27mg/g and 4.83mg/g, respectively. With the increase of the ethanol concentration, the content of the total flavone is increased firstly, the content of the total flavone is highest when the ethanol volume fraction is 50%, and the peak shape of a chromatographic peak is poor and the peak area is reduced with the continuous increase of the ethanol volume fraction. Thus, the extracted ethanol volume fraction was selected to be 50%.
3. Effect surface design test:
test design scheme and result determination: based on the result of the single-factor test, according to the design principle of the Box-Behnken test, factors with larger influence are selected, and the extraction time (A/min), the enzyme dosage (B/%) and the ethanol volume fraction (C/%) are independent variables. The factors and levels are shown in table 2, and the extraction process parameter investigation test arrangement and results are shown in table 3.
Model fitting and effect surface analysis: in terms of hyperoside amount (Y)1) Quercetin-3-O-beta-D-pyranAmount of arabinoside (Y)2) The amount of quercetin-3-O-alpha-L-arabinofuranoside (Y)3) Then, a weighted composite score (OD) was calculated, and the OD value was calculated as OD (1/3Y)1/Y1max+1/3Y3/Y3max+1/3Y2/Y2max) × 100, where Y1max、Y2max、Y3max is the maximum value of the corresponding component amount.
And (4) performing regression analysis on the fruits by using a Design-expert.V7.0.0 software by taking the OD value of the comprehensive score as a response value. In combination with the feasibility of operation, the optimal process is defined as extraction time 34min, enzyme dosage 0.93%, and ethanol volume fraction 52%.
Example 4 inflammatory response of guava leaf Total Flavonoids to acute pancreatitis
1. Method of producing a composite material
Firstly establishing a ranophangenin induced acute pancreatitis mouse model, observing the treatment effect of guava leaf total flavonoids on the model, and whether the pancreatic inflammatory reaction of animals of the acute pancreatitis model can be improved and the enzyme activity can be reduced. Animals: c57BL/6 mice, approximately 20 ± 2g in body weight; three experimental groups were randomized: a blank control group, an acute pancreatitis model group and a guava leaf total flavone group, wherein each group comprises 10 individuals (n is 10). The acute pancreatitis model is induced by intraperitoneal injection of ranophanin, which is dissolved in 0.9% physiological saline at a concentration of 5 μ g/m L. One needle of ranophagmycin is injected into the acute pancreatitis group and the guava leaf total flavone group every hour, and 6 needles are continuously injected, wherein each needle is 50 mug/kg of body weight. The blank control group was injected with an equal dose of physiological saline. The guava leaf total flavonoids begin three days before the molding. One hour after the last injection of ranophagmycin, all mice are subjected to eyeball removal and blood collection, after dissection, intestinal tract, pancreas and other samples are quickly collected and stored in liquid nitrogen, and then the mice are transferred to a refrigerator at the temperature of minus 80 ℃.
1.1 serum Amylase assay
Whole blood from the mice was collected and allowed to stand at room temperature for 30min to coagulate the blood, followed by centrifugation at 3000g at 4 ℃ for 10min, and the supernatant was aspirated and stored at-80 ℃. Serum amylase levels were determined by iodine-starch chromogenic method: the serum sample was incubated with the preheated substrate reaction solution at 37 ℃ for 7.5min, to the mixture, iodine solution and double distilled water were added, and the absorbance was measured using a spectrophotometer. Serum amylase activity (Ud L) was calculated.
1.2 determination of serum Lipase
The lipase level in the serum of the mouse is measured by adopting an ELISA method, compared with a control group, the serum lipase level of a model group is obviously increased, and a sample group fed with guava leaf total flavonoids before molding is obviously reduced compared with the model group and is close to the control group.
1.3 determination of degree of edema in pancreatic tissue
The degree of edema in the pancreas was measured by the ratio of the weight of the fresh pancreas sample (wet weight) to the weight of the pancreas sample after drying (dry weight). And (3) shearing a part of fresh pancreatic tissue which is just taken out, removing fat, sucking and wiping the moisture on the surface of the pancreatic tissue by using filter paper, and weighing the wet weight by using an analytical balance. The pancreatic tissue is baked and dehydrated in an oven at 80 ℃, and the dry weight is weighed by an analytical balance after 48 hours. Calculating the dry-wet weight ratio of the pancreatic tissue:
pancreatic tissue wet dry weight ratio pancreatic wet weight-pancreatic dry weight pancreatic wet weight x 100%
1.4 pancreatic tissue myeloperoxidase Activity assay
Peroxidase (MPO) is a neutrophil activation and function marker, and MPO is commonly used in immunology to characterize neutrophil infiltration. The MPO enzyme activity is determined by the fact that MPO is present in a fixed amount of about 5% by dry weight of the cells per neutrophil, and that the enzyme has reducing properties. The hydrogen donor compound is reduced by MPO enzyme to generate a yellow compound, the absorbance is measured at the wavelength of 460nm through colorimetry, the yield of the product is calculated, and the activity of MPO is calculated.
2. Results
The results of the inflammatory response of guava leaf total flavonoids to acute pancreatitis are shown in table 1.
TABLE 1 inflammatory response of guava leaf Total Flavonoids to acute pancreatitis
Note: andthe ratio of the normal control group is,*P＜0.05，**P＜0.01，***p is less than 0.001; in comparison to the set of models,#P＜0.05，##P＜0.01，###P＜0.001。
example 5 Effect of guava leaf Total Flavonoids on fibrosis in mice with Chronic pancreatitis
Molding: 50C 57BL/6 mice were divided randomly into a normal group, a model group and an oxATP group (15. mu.g.kg)-1·d-1) TFPGL low dose group (0.186g kg)-1·d-1) TFPGL high dose group (0.372 kg)-1·d-1). The four groups of mice adopt repeated intraperitoneal injection of ranophanin to prepare a chronic pancreatitis mouse model, and the single injection dosage is 50 mug.kg-1Dissolving in 200 μ L physiological saline, injecting for 1, three or five times per week for 6 weeks, 1/h and 6/d.
Administration dose: after the last injection of ranolanin, oxATP (15. mu.g.kg) was administered to mice in the oxATP group and TFPGL low and high dose groups for 2 weeks, respectively-1·d-1Dissolved in 200. mu.L of physiological saline) and TFPGL (0.186, 0.372 g.kg)-1·d-1) And (5) performing intragastric administration. The animals in the control group were injected with the same amount of saline during the 8-week study period, and the injection time and frequency were the same as those in the model group. After the last injection is completed for 24 hours, all mice are killed by removing necks, part of pancreatic tissues are cut and placed in formalin for hematoxylin-eosin staining, sirius red picric acid staining and immunohistochemical experiments, and the other part of fresh tissues are used for enzyme-linked immunosorbent assay.
1. Mouse pancreatic tissue hematoxylin-eosin (HE) staining and pancreatic chronic inflammation fibrosis assessment:
after the formalin solution is used for fixing tissues for 24 hours, the tissues are dehydrated, embedded and sliced, and then are dewaxed, stained, dehydrated and mounted according to the conventional operation of HE staining. After airing the slices for 24h, pathological structural changes of pancreatic tissues are observed by a microscope.
Compared with the normal group, the pancreas of the model group mice can see obvious chronic inflammation and fibrosis (P is less than 0.001), and the chronic inflammation and fibrosis are expressed by gland atrophy, tissue fibrosis, tubular composite structure hyperplasia and inflammatory cell infiltration; the oxATP group and the TFPGL group with low and high dosage have obviously reduced cell infiltration, acinar atrophy and fibrosis degree scores compared with the model group (the P is less than 0.05). See fig. 2, table 2.
TABLE 2 histological scoring of inflammatory injury of pancreatic tissue in each group: (
n＝10)
Note: compared with the control group, the compound of the formula,1)P<0.001; in comparison with the set of models,2)P<0.05。
2. pancreatic collagen content inspection and quantitative analysis:
the paraffin sections were stained with sirius kukoense red to assess the collagen content of pancreatic tissue. After the section is dewaxed, 0.1% (w/v) sirius red-saturated picric acid solution is dripped and dyed for 1h at room temperature, and hematoxylin is counterdyed for 10min after being washed by running water. Differentiation is carried out for 30s by 1% hydrochloric acid, tap water is alkalized, dehydration and transparency are carried out, and neutral resin is used for sealing. The type and expression level of collagen in pancreatic tissues were analyzed by a polarized light microscope, and the content of Col i and Col iii (expressed as areas of yellow-red and green collagen in the visual field) and the Collagen Volume Fraction (CVFs) were quantified by Image-Pro Plus 6 Image analysis software, wherein CVFs (area of green collagen + area of yellow-red collagen)/total area (area of visual field for photograph) × 100%.
The picric acid sirius red stain can specifically display collagen tissues under a polarizing microscope. Under the polarizer, collagen I (ColI) is yellow or red, and collagen III (ColIII) is blue-green or grey-blue. Under light, the visible model group, oxATP group, TFPGL low dose group, TFPGL high dose group collagen were specifically colored red, acinar and pancreatic islet atrophy, and replaced with collagen fibers. As can be seen under a polarizer, compared with a normal group, the chronic pancreatitis fibrosis formed after the ranulin is injected is mainly ColI, and the collagen content is obviously increased (P is less than 0.001); the TFPGL low and high dose groups ColI and ColIII collagen were decreased (P < 0.05) compared to the model group, with the TFPGL high dose group ColI significantly decreased (P < 0.01). See table 3, fig. 3.
TABLE 2 collagen content and CVFs changes in pancreatic tissues of each group: (
n＝10)
Note: compared with the control group, the compound of the formula,1)P<0.001; in comparison with the set of models,2)P<0.05，3)P<0.01。
3. caspase-1, NLRP3, alpha-SMA immunohistochemical staining of paraffin sections
The pancreas tissue paraffin section is dried at 60 ℃ for 30 minutes and then rewarmed at room temperature for 30 minutes. Paraffin section is placed in fresh xylene for dewaxing and ethanol gradient dehydration, and then 3% H2O2Incubate at room temperature for 10 min. After TBST rinsing for 5min multiplied by 3 times, the slices are placed in EDTA solution for microwave thermal restoration for 10 min. The goat serum was blocked for 1 hour and incubated with Caspase-1, NLRP3 or alpha-SMA (all diluted to 1:200 in goat serum working solution) overnight at 4 ℃. Rinsing with TBST for 5min × 3 times, incubating biotin-labeled goat anti-rabbit IgG for 1h at normal temperature, developing DAB for 10min, washing with TBST for multiple times, counterstaining with hematoxylin, dehydrating, clearing, sealing with neutral gum, and observing gene expression under the mirror.
Compared with the normal group, the pancreatic tissues of the model group have obviously increased expression of alpha-SMA, NLRP3 and Caspase-1 (P is less than 0.01); after the oxATP and the TFPGL act on the mice, the expression of alpha-SMA, NLRP3 and Caspase-1 in pancreatic tissues is reduced compared with that of a model group (P is less than 0.05), wherein the expression of the alpha-SMA, NLRP3 and Caspase-1 in the pancreatic tissues of a TFPGL high-dose group is obviously reduced compared with that of the model group (P is less than 0.01). See table 4, fig. 4.
TABLE 4 quantitative analysis of the optical density values of the groups of α -SMA, NLRP3 and Caspase-1 (S) ((S))
n＝10)
Note: compared with the control group, the compound of the formula,1)P<0.01; in comparison with the set of models,2)P<0.05，3)P＜0.01
4. enzyme linked immunosorbent assay (ELISA) for detecting IL-1 beta and IL-18 levels
Fresh pancreatic tissue was washed free of blood stain with pre-chilled PBS, 50mg was weighed, transferred to a 2ml centrifuge tube, and 500. mu.L of pre-chilled PTR buffer was added. The homogenate was homogenized for 10s using an ultrasonic cell disruptor, and the process was performed on ice. After incubating the tissue homogenate on ice for 20 minutes, centrifuge 18000g for 20min at 4 ℃, and pipette the supernatant into a new 2ml centrifuge tube. Protein concentration was measured by BCA method. The protein concentration of the sample was measured to be 13. mu.g/. mu.L-1～16μg·μL-1Protein was trimmed to the same concentration of 10. mu.g/. mu.L using PTR buffer-1. The IL-1 beta and IL-18 levels were determined using the ELISA kit protocol and the results are shown in Table 5.
Compared with the normal group, the concentrations of IL-1 beta and IL-18 protein in pancreatic tissues of mice in the model group are obviously increased (P is less than 0.01). Compared with the model group, the concentration of IL-beta and IL-18 protein in the pancreatic tissue of the mouse shows a descending trend (P is less than 0.05) after the oxATP and TFPLGL are treated.
TABLE 5 determination of IL-1. beta. and IL-18 protein concentrations in pancreatic tissue
Note: compared with the control group, the compound of the formula,1)P<0.01; in comparison with the set of models,2)P<0.05
5. statistical data analysis
The data shown in the experiment were repeated at least three times, and one section was prepared for each group of 10 animals. Statistical analysis of data was performed using SPSS 22.0. Data ± represent values of standard deviation. The single-factor analysis of variance is adopted for the comparison between the mean values of the measured data, the LSD-t method is adopted for the comparison between groups, and the paired sample t test is adopted for the comparison between two groups. P < 0.05 is statistically significant.
After the ranophanin is injected for six weeks continuously, HE staining, sirius red staining and alpha-SMA immunohistochemical staining results show that pancreatic tissues of mice show obvious inflammatory manifestations such as pancreatic fibrosis, acinar atrophy, inflammatory cell infiltration and the like. The collagen of the model groups Col I and Col III is obviously increased, and the collagen of Col I is taken as the main collagen. The protein expression levels of NLRP3 and Caspase-1 are obviously increased, and the fibrosis degree of the mouse is consistent with the expression trends of NLRP3 and Caspase-1 protein in an NLRP3 inflammatory body signal channel. Model group α -SMA immunohistochemistry showed that the staining sites were localized around acinar cells and near ductal, vascular regions, consistent with the distribution of Pancreatic Stellate Cells (PSCs) in pancreatic tissue. After P2X7R antagonist and guava leaf total flavone treatment, compared with a model group, HE staining, picric acid sirius red staining and alpha-SMA immunohistochemical staining all show that the pancreatic fibrosis degree of mice is inhibited to a certain extent, and NLRP3, Caspase-1, IL-1 beta and IL-18 protein expression is reduced, which indicates that the guava leaf total flavone can indirectly reduce modification and activation of proinflammatory factors such as IL-1 beta, IL-18, IL-33 and the like through inhibiting the activity of NLRP3 inflammasome, thereby reducing the activation of PSCs. The NLRP3 inflammasome can also promote the expression of TGF beta I and TGF beta III and has interaction with a TGF beta-Smad signaling pathway, and the fact that the guava leaf total flavone can inhibit the NLRP3 inflammasome activation to indirectly inhibit the expression of TGF beta 1 is predicted, so that the generation of extracellular matrix is reduced.
In conclusion, the P2X7-NLRP3 signal channel is activated during the chronic pancreatitis, and proinflammatory factors IL-1 beta and IL-18 activate maturation and PSCs, which are closely related to the progression of pancreatic fibrosis. The guava leaf total flavonoids can inhibit activation of NLRP3 inflammasome and obviously improve the ranulin-induced chronic pancreatitis fibrosis.
Claims (5)
1. Application of guava leaf total flavonoids in preparing medicine for preventing and treating pancreatitis is provided.
2. Use according to claim 1, characterized in that: application of guava leaf total flavonoids in preparing medicine for preventing chronic pancreatitis is provided.
3. Use according to claim 1, characterized in that: application of guava leaf total flavonoids in preparing medicine for treating chronic pancreatitis is provided.
4. Use according to any one of claims 1 to 3, characterized in that: the prevention and treatment of pancreatitis is to inhibit the hyperproliferation of pancreatic stellate cells and relieve the degree of pancreatic fibrosis by inhibiting the activation of P2X7R mediated NLRP3 inflammatory body signal pathway.
5. Use according to any one of claims 1 to 3, characterized in that: the total flavonoids of guava leaves are derived from the extract of the leaves of guava (Psidium guajava L.) belonging to Myrtaceae.
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| JP2016182110A (en) * | 2015-03-25 | 2016-10-20 | 博正 王 | Edible composition for improving type 2 diabetes formed of guava fruit and trehalose and use thereof |
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| P2X7R拮抗剂对小鼠慢性胰腺炎的作用及机制研究;张桂贤等;《天津医药》;20161031;第44卷(第10期);第1238-1242页 * |
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