CN113244307B - Application of fruit extract of Gugongguo in preparing medicine for preventing and treating stomach diseases - Google Patents
Application of fruit extract of Gugongguo in preparing medicine for preventing and treating stomach diseases Download PDFInfo
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- CN113244307B CN113244307B CN202010088118.XA CN202010088118A CN113244307B CN 113244307 B CN113244307 B CN 113244307B CN 202010088118 A CN202010088118 A CN 202010088118A CN 113244307 B CN113244307 B CN 113244307B
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
- A61K2236/333—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/39—Complex extraction schemes, e.g. fractionation or repeated extraction steps
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/50—Methods involving additional extraction steps
- A61K2236/51—Concentration or drying of the extract, e.g. Lyophilisation, freeze-drying or spray-drying
Abstract
The invention provides application of a fruit extract of a fruit of solid common fruit in preparing a medicament for treating and/or preventing stomach diseases. Experiments prove that: the fruit extract of fructus Mali Pumilae has effects of treating atrophic gastritis and repairing gastric mucosa injury, and has definite curative effect. The invention discloses a new application of medicinal materials of Gugong fruits.
Description
Technical Field
The invention belongs to the field of traditional Chinese medicines, and in particular relates to application of a fruit extract of fructus polygoni multiflori in preparing medicines for preventing and/or treating stomach diseases.
Background
Gastric diseases refer to organic or functional diseases occurring in the stomach. Clinically, chronic gastritis, peptic ulcer, gastric cancer and the like are common. The etiology of gastric diseases is very complex, including physical and chemical stimuli, infections, toxins, genetics, mental factors, developmental disorders, surgical effects, etc. Gastritis (gastitis) refers to inflammation of the gastric mucosa caused by various causes, and is one of the most common digestive system diseases. The acute and chronic gastritis can be classified into acute and chronic gastritis according to the clinical onset of the acute and chronic gastritis; according to the cause, it can be classified into helicobacter pylori-associated gastritis, stress gastritis, autoimmune gastritis, etc. The pathological changes of gastritis caused by different causes are also different, and generally include three processes, namely, epithelial damage, mucosal inflammatory reaction and epithelial regeneration. Acute gastritis is classified into simple gastritis, erosive gastritis, hemorrhagic gastritis, corrosive gastritis, suppurative gastritis and chronic gastritis according to their pathological changes, and chronic gastritis is classified into three categories of non-atrophic gastritis, atrophic gastritis and special gastritis.
Chronic atrophic gastritis is one of the common and frequently occurring diseases of the digestive system and is a chronic digestive system disease characterized by atrophy of the gastric mucosa epithelium and glands, reduced numbers, thinning of the gastric mucosa, thickening of the mucosal base layer, or concomitant pyloroglandular and intestinal glandular metaplasias, or atypical hyperplasia (Dixon MF, genta RM, yardley JH et al Classification and grading of gastritis: the updated Sydney System [ J ]. Am J Surg Pathol,1996,20 (10): 1161-1181;Rugge M,Correa P,Dixon MF et al Gastric mucosal atrophy: interobserver consistency using new criteria for classification and grading [ J ]. Alimentary Pharmacology & Therapeutics,2002,16 (7): 1249-1259.). The chronic inflammation is closely related to the occurrence and development of tumors (Eckmann L, nebelsiek T, fingerle AA et al Opposing functions of IKKbeta during acute and chronic intestinal inflammation [ J ]. PANS,2008,105 (39): 58-63.), and the cancer yield of chronic gastritis is obviously higher than that of non-gastritis patients. According to the theory proposed by Correa for normal gastric mucosa-superficial gastritis-atrophic gastritis-intestinal metaplasia-dysplasia-intestinal gastric Cancer (Correa P.A human model of gastric carcinogenesis [ J ]. Cancer Res., 1988,48 (13): 3554-3560.), intestinal metaplasia and dysplasia are considered as premalignant lesions (Jencks DS, adam JD, borum ML, et al, overlay of Current Concepts in Gastric Intestinal Metaplasia and Gastric Cancer [ J ]. Gastroenterol Hepatol,2018,14 (2): 92-101.). Research shows that chronic atrophic gastritis with precancerous lesions greatly increases the incidence of gastric cancer. The new incidence rate of gastric cancer of the crowd in China is 42.7 ten thousand, the new incidence rate accounts for 47.19 percent of the world, the death incidence rate is 0.69, and according to the latest statistical research, the proportion of stomach malignant tumors in various malignant tumor related death factors is always high (Zheng Rongshou, zhang Saiwei, chen Moqing and the like, the disease and death analysis of malignant tumors in China in 2013 [ J ], chinese tumors, 2017 (1): 1-7). Thus, delaying and preventing even reversing the pathological progression of the precancerous lesion can effectively prevent the occurrence of gastric cancer.
According to the clinical symptoms of the chronic atrophic gastritis, the chronic atrophic gastritis can be attributed to the categories of "gastric fullness", "distention and fullness", "stomachache" and other diseases in traditional Chinese medicine (Tan Bao, jiang Zhaogong, zhixue Feng, research progress of traditional Chinese medicine treatment of the chronic atrophic gastritis [ J ], shanxi traditional Chinese medicine, 2019, 35 (6): 58-60.). At present, a great deal of literature reports prove that the traditional Chinese medicine therapy can treat atrophic gastritis, can lighten or eliminate partial intestinal epithelial metaplasia and abnormal hyperplasia and even cure the gastric cancer, blocks the development of the gastric cancer, and can effectively reduce the incidence rate and the death rate of the gastric cancer.
The Gugong fruit is a folk medicinal material of Yi nationality and is derived from Gugong fruit (Rose odorata Sweet var. Gugong fruit is mostly used as a medicine, has flat nature and sour taste, has the effect of relieving diarrhea with astringents, is commonly used for treating diarrhea, bacillary dysentery and other diseases (Ren Jie, he Anxin, miao medicine-Gugong fruit A Jiang Zhiji- "Changkang capsule" quality standard research [ J ], chinese national folk medicine journal, 1998, 31:41-42, changshu tablet quality standard, national drug administration 2002-2004 trial standard). The whole fruit of the ripe fruit of the Gugong fruit is black, and the taste is fragrant and sweet. The fruit of Gugong fruit is rich in volatile oil, triterpene, phenolic acid, protein, amino acid and minerals, etc. So far, the research of the fruit is less, only the report (the quality standard of Changshu tablet, the trial standard of the national drug administration 2002-2004) that the fruit is rich in SOD and triterpene components and the fruit wine development is carried out by taking the solid fruit as the raw material is clarified, but the research on the drug effect of the solid fruit extract is not seen so far.
Disclosure of Invention
The invention aims to provide a medicament for preventing and/or treating stomach diseases. The research of the invention discovers that the extract of the fruit of the solid common fruit has the prevention and/or treatment effects on gastric cancer, gastric precancerous lesions and gastritis transformation caused by atrophic gastritis and can be used for developing new medicines for preventing and/or treating stomach diseases.
In one aspect, the invention provides the use of an extract of fruit of gugongguo in the manufacture of a medicament for the treatment and/or prophylaxis of gastric disorders. Wherein the gastric disease is selected from one or more of chronic gastritis, gastric mucosa injury, gastric precancerous lesion, gastritis transformation or gastric cancer.
Preferably, the chronic gastritis is chronic atrophic gastritis; more preferably, the chronic atrophic gastritis is chronic atrophic gastritis with enterogastric gastritis or chronic atrophic gastritis with dysplastic gastritis.
Preferably, the fruit extract of the fruit is an ethanol extract or an aqueous ethanol extract, for example, an aqueous ethanol extract having a volume ratio of 50-95%.
Preferably, the tannin content of the fruit extract is not less than 20% by weight, and the total triterpene content is not less than 10% based on the total weight of the fruit extract; more preferably, the content of tannins of the fruit extract is 20-40% by weight and the total triterpene content is 10-20% by weight, based on the total weight of the fruit extract.
Further preferably, the preparation method of the fruit extract of the gugongguo comprises the following steps:
(1) Adding ethanol or ethanol water solution into the fruit of the solid male fruit, and reflux extracting;
(2) Filtering the extract obtained in the step (1), and concentrating under reduced pressure until the sugar degree is 10-40.
Preferably, in step (1) of the above preparation method, the extraction is carried out 2 to 3 times, each for 1 to 3 hours; preferably, the mass ratio of the solid male fruit to the ethanol or the ethanol water solution is 1: (4-8).
Preferably, in step (2) of the above preparation method, the filtration is filtration using a 80-120 mesh sieve.
Preferably, the medicament for treating and/or preventing stomach diseases comprises the extract of the fruit plant, and pharmaceutically acceptable carriers, auxiliary materials and/or diluents.
Preferably, the medicament for treating and/or preventing stomach diseases is a tablet, capsule, pill, powder or suspension.
In yet another aspect, the present invention provides a method of treating and/or preventing gastric disorders, the method comprising administering the extract of fruit of the fruit tree to a subject in need thereof. Wherein the gastric disease is selected from one or more of chronic gastritis, gastric mucosa injury, gastric precancerous lesion, gastritis transformation or gastric cancer. Preferably, the chronic gastritis is chronic atrophic gastritis; more preferably, the chronic atrophic gastritis is chronic atrophic gastritis with enterogastric gastritis or chronic atrophic gastritis with dysplastic gastritis. Preferably, the composition is administered at a dose of 0.9g to 6.6g per day, more preferably at a dose of 4.5g per day, for an adult of 60 kg.
The fruit extract of the solid common fruits is mainly obtained by extracting mature fruits of natural solid common fruits, and has the advantages of simple extraction method, mature technology, higher extraction rate and low cost.
The present inventors have made a series of experiments, proved that the extract of the fruit of the solid common fruit has the functions of treating the chronic atrophic gastritis repairing gastric mucosa injury and gastric precancerous lesions, and the efficacy of preventing the conversion of gastritis to gastric cancer.
Drawings
Embodiments of the present invention are described in detail below with reference to the attached drawing figures, wherein:
FIG. 1 shows the effect of extract of fruit of Guo Male (FOE) on the levels of TNF- α (A), IL-1β (B) and IL-6 (C) in Lipopolysaccharide (LPS) -induced RAW264.7 cells;
FIG. 2 shows the effect of FOE on expression of Nrf2, keap1 and HO-1 proteins in LPS-induced RAW264.7 cells (#p <0.01vs control; (< 0.01vs LPS group);
FIG. 3 shows the effect of FOE on NF-. Kappa. B p65 and p-IKKK alpha-I protein expression in LPS-induced RAW264.7 cells (#p <0.01vs control; p <0.01vs LPS group);
FIG. 4 shows the protective effect of extract of fruit of Gugongguo on alcohol-induced gastric mucosal lesions in rats;
FIG. 5 shows the therapeutic effect of extract of fruit of Gugongguo on rats with chronic atrophic accompanied by enterogastric gastritis;
figure 6 shows the therapeutic effect of extract of fruit of gugongguo in rats with chronic atrophic accompanied by dysplastic gastritis.
Detailed Description
In order to explain the present invention in more detail, the present invention will be further described with reference to specific examples. However, the scope of the present invention is not limited thereto.
EXAMPLE 1 determination of tannin content
Instrument: island jin 1601 spectrophotometer; HZQ-QX electric motor oscillator (Donglian electronic technology development Co., ltd.)
Standard and reagent: gallic acid reference substance (content 98%); casein (chemically pure); sodium carbonate; sodium tungstate; sodium molybdate; lithium sulfate (all of the above reagents were analytically pure).
Preparing a phosphomolybdic tungstic acid reagent: taking 100g of sodium tungstate, 25g of sodium molybdate, adding 700mL of water to dissolve, adding 100mL of hydrochloric acid and 50mL of phosphoric acid, heating and refluxing for 10h, cooling, adding 150g of lithium sulfate, 50mL of water and 0.2mL of bromine, boiling to remove residual bromine (about 15 min), cooling, adding water to dilute to 1000mL, and filtering to obtain the sodium tungstate.
Drawing a casein method standard curve:
preparation of reference substance solution
Precisely weighing gallic acid standard substance 0.050g, placing into a 100mL brown volumetric flask, adding water for dissolution, fixing volume, mixing, precisely sucking 5.0mL, placing into a 100mL brown volumetric flask, fixing volume, and mixing well for use (each mL contains gallic acid 0.025 mg).
Drawing of a Standard Curve
Precisely measuring 0.5mL, 1.0mL, 2.0mL, 3.0mL, 4.0mL and 5.0mL of the reference substance solution, respectively placing the reference substance solution and the reference substance solution into 25mL brown volumetric flasks, respectively adding 1mL of the phosphomolybdic tungstic acid test solution, respectively adding 11.5mL, 11mL, 10mL, 9mL, 8mL and 7mL of water, diluting to a scale with 29% sodium carbonate solution, shaking uniformly, standing for 30min, taking the corresponding reagent as a blank, measuring absorbance at 760nm wavelength according to ultraviolet-visible spectrophotometry (appendix IV A of second edition 2005 of China), taking concentration (mg/mL) as an abscissa, and drawing a standard curve.
The linear regression equation is y= 4.0662X-0.0434 (r=0.9997)
Determination of total phenols: taking 1.0mL of solid common fruit extract, diluting 400 times, precisely measuring 2.0mL, placing in a 25mL brown volumetric flask, and calculating according to the method under the preparation item of a standard curve, from the step of adding 1mL of phosphomolybdic tungstic acid test solution, respectively adding 10mL of water, measuring absorbance according to the method, substituting into a linear regression equation, and calculating to obtain the solid common fruit extract.
Determination of non-adsorbed polyphenols: precisely measuring 25mL of sample solution, adding the sample solution into a 100mL conical flask with a plug, which is filled with 0.6g of casein, sealing, placing the flask in a water bath at 30 ℃ for heat preservation for 1 hour, shaking the flask at constant temperature, taking out the flask, cooling the flask, shaking the flask uniformly, filtering the flask, discarding the primary filtrate, precisely measuring 2.0mL of continuous filtrate, placing the flask in a 25mL brown measuring flask, and obtaining the sample solution according to the method under the preparation item of a standard curve, wherein from the step of adding 1mL of phosphomolybdic tungstic acid sample solution, respectively adding 10mL of water, measuring absorbance according to the method, substituting the absorbance into a linear regression equation, and calculating the sample solution.
The content of tannins was calculated as follows: tannin content = total phenol amount-amount of non-adsorbed polyphenols
For specific tannin content determination see the examples below.
Example 2 total triterpene content determination
Test materials: absolute ethanol, 95% ethanol, glacial acetic acid, perchloric acid, vanillin, concentrated sulfuric acid and the like are all analytically pure reagents; ursolic acid standard reference (China medicine biological products institute); UV-1601 ultraviolet visible spectrophotometer (Shimadzu corporation).
The test method comprises the following steps: (1) And determining the optimal detection wavelength of the ursolic acid reference substance and drawing a standard curve.
Accurately weighing 4.0mg of ursolic acid reference substance baked to constant weight, adding absolute ethyl alcohol for dissolution, and then fixing the volume to 50mL, wherein the mass concentration is 0.08mg/mL. Taking a certain amount of ursolic acid reference substance solution into a 10mL test tube, adding 0.2mL of newly prepared vanillin-5% glacial acetic acid and 0.8mL of perchloric acid, heating in a water bath at 60 ℃ for 15min, cooling with ice water, adding 5mL of glacial acetic acid, standing, and scanning with a UV-1601 ultraviolet spectrophotometer within a wavelength range of 200-700 nm to show that the ursolic acid has maximum absorbance at 550 nm. Then 0.2, 0.4, 0.6, 0.8, 1.0 and 1.2mL of the reference substance solution are respectively sucked precisely, treated by the same method, absorbance is measured at 550nm, a regression equation is obtained according to the absorbance (A) and the mass of the ursolic acid, and a standard curve of the ursolic acid reference substance is drawn. The regression equation is obtained by linear regression calculation, wherein y=0.1015x+0.0065, the linear correlation coefficient r= 0.9992, and the ursolic acid mass and absorbance show good linear relation within the range of 0.016-0.096 mg.
(2) Preparation and content determination of extract sample solution.
50mg of the extract of the fruit of the solid Male fruit is weighed, placed in a 100mL volumetric flask, dissolved with 95% ethanol and scaled. Accurately transferring 1.0mL into a 25mL volumetric flask, and fixing the volume by 95% ethanol to obtain the sample to-be-detected liquid. And then accurately transferring 0.5mL of the liquid to be detected, measuring the absorbance of the liquid to be detected according to the method (1), solving the triterpene mass corresponding to the absorbance through a regression equation, and calculating the total triterpene content.
For specific total triterpene content determinations see the examples below.
EXAMPLE 3 preparation of fruit extract of Gugongguo
500g of solid male fruits are used as raw materials, and the mass ratio is 1:6, adding the mixture into 50% ethanol water solution, carrying out reflux extraction for 1 hour, extracting for 3 times, and sieving with a 80-120 mesh sieve to obtain an extract; collecting the extractive solution, concentrating under reduced pressure at 60deg.C and vacuum degree of 0.06-0.08 MPa to obtain concentrate with sugar degree of 10, and drying to obtain extract with extraction rate of 13.5%. Wherein the content of tannin is 34%, and the content of total triterpene is 10.4%.
EXAMPLE 4 preparation of fruit extract of Gugongguo
500g of solid male fruits are used as raw materials, and the mass ratio is 1:4, adding the raw material solid male fruits into a 95% ethanol water solution, carrying out reflux extraction for 3 hours, extracting for 2 times, and sieving with a 80-120 mesh sieve to obtain an extract; collecting the extractive solution, concentrating under reduced pressure at 30deg.C and vacuum degree of 0.06-0.08 MPa to obtain concentrate with sugar degree of 40, and drying to obtain solid fructus Mali Pumilae fruit extract with extraction rate of 12.1%, tannin content of 22% and triterpene content of 17.5%.
EXAMPLE 5 preparation of fruit extract of Gugongguo
500g of solid common fruits are taken as raw materials, the raw materials of the solid common fruits are added into 70% ethanol water solution according to the mass ratio of 1:8, reflux extraction is carried out for 2 hours, extraction is carried out for 2 times, and the mixture is sieved by a sieve of 80-120 meshes, thus obtaining extract; collecting the extractive solution, concentrating under reduced pressure at 50deg.C and vacuum degree of 0.06-0.08 MPa to obtain concentrate with sugar degree of 25, and drying to obtain extract with extraction rate of 18.5%. The extract of fruit of fructus Sorbi Pohuashanensis has a tannin content of 27% and a total triterpene content of 13.6%.
EXAMPLE 6 preparation of fruit extract of Gugongguo
500g of solid common fruits are taken as raw materials, the raw materials of the solid common fruits are added into 60% ethanol water solution according to the mass ratio of 1:6, reflux extraction is carried out for 2 hours, extraction is carried out for 2 times, and the mixture is sieved by a sieve of 80-120 meshes, thus obtaining extract; collecting the extractive solution, concentrating under reduced pressure at 40deg.C and vacuum degree of 0.06-0.08 MPa to obtain concentrate with sugar degree of 20, and drying to obtain solid fructus Mali Pumilae fruit extract with extraction rate of 17.6%. Wherein the content of tannin is 31%, and the total triterpene content is 11.2%.
Example 7 anti-inflammatory Activity of Guogong fruits based on lipopolysaccharide-induced inflammation model of RAW264.7 cells
(1) The experimental method comprises the following steps:
lipopolysaccharide LPS-induced inflammation model of RAW264.7 cells: taking cells in logarithmic growth phase according to 1×10 4 The number of individual wells/well was inoculated into 96-well plates and placed at 37℃with 5% CO 2 Culturing in an incubator for 24 hours. The cell state was observed, a blank group and a model group were set, the model group was added with 100. Mu.L/well of the culture solution followed by 10. Mu.L/well of the lipopolysaccharide solution (final concentration of 1, 5, 10, 20. Mu.g/mL per well), the blank group was added with the same volume of the culture solution, 6 duplicate wells were set per group, and the cell supernatant was collected. TNF-alpha is an initial cytokine of inflammatory reaction, so that we use the secretion level of TNF-alpha to screen the optimal concentration of lipopolysaccharide for inducing inflammation, and experimental results show that after 5 mug/mL of lipopolysaccharide stimulates cells, the secretion level of TNF-alpha reaches the highest, so that the subsequent experiment selects the concentration of lipopolysaccharide of 5 mug/mL to establish an inflammation model. The Lipopolysaccharide (LPS) concentrations mentioned below were all 5. Mu.g/mL.
Measurement of Nitric Oxide Synthase (NOS)And (3) determining: taking cells in logarithmic growth phase according to 1×10 5 The number of individual wells/well was inoculated into 24-well plates, placed at 37℃and 5% CO 2 After 24 hours of cultivation in an incubator, a blank group, a model group and an administration group were set, and 500. Mu.L/well of 25, 50, 100, 200, 400. Mu.g/mL of the solid male fruit extract prepared in example 6 was added to each administration group, followed by addition of LPS solution at a final concentration of 5. Mu.g/mL, 500. Mu.L/well of the culture solution to the model group, followed by addition of LPS solution to the blank group, and the culture solution was added to the same volume, and the same conditions were continued for 4 hours, 8 hours, 12 hours, 24 hours, 36 hours, and then supernatants were collected, and OD values were measured and converted into NOS enzyme activity values according to the nitric oxide synthase kit instructions.
Measurement of cytokines: taking cells in logarithmic growth phase according to 1×10 5 The number of cells/well was inoculated into a 24-well plate, cultured and dosed according to the method under the test item of Nitric Oxide Synthase (NOS), and the culture was continued, and the concentration level of each cytokine was measured according to the ELISA kit protocol.
Protein expression was detected by Western blotting (Western-Blot): taking cells in logarithmic growth phase according to 4×10 5 Inoculating the number of each hole into a 6-hole plate, setting a blank group, a dosing group and a model group (5 mug/mL of LPS), dosing after 24 hours, respectively dosing solid male fruit extracts with the concentration of 25, 50 and 100 mug/mL and 5 mug/mL of LPS, continuously culturing for 24 hours, discarding culture solution, washing twice with precooled PBS, adding 100 mug of protein lysate, collecting protein after 30 seconds, measuring the concentration of each group of protein by using BCA protein quantitative kit, drawing a standard curve, adding loading buffer solution according to the volume ratio of 1:4, mixing uniformly, boiling and storing at the temperature of minus 20 ℃ for standby. Preparing separating gel and concentrating gel according to experimental requirements by SDS-PAGE, loading sample, electrophoresis, transferring membrane, sealing, primary antibody and secondary antibody, detecting by chemiluminescence method, photographing, collecting photo, and performing gray analysis by using imageJ software.
(2) Experimental results:
in the concentration range of 25-200 mug/ml, the NO inhibition rate of the extract (FOE) of the fruit of the solid common fruit on RAW264.7 cells is gradually enhanced along with the increase of the concentration, and the IC thereof 50 At a rate of 26.15.+ -. 2.79. Mu.g/ml, inhibition at 200. Mu.g/mlUp to 99.50%.
As shown in FIG. 1, in the blank, the levels of TNF-alpha, IL-1β and IL-6 released by the cells were low, and the levels of TNF-alpha, IL-1β and IL-6 released were significantly increased (P < 0.01) after LPS stimulation. After the FOE with different concentrations acts on cells, the levels of TNF-alpha, IL-1 beta and IL-6 in cell supernatants are obviously reduced (P < 0.01), which proves that the FOE can relieve the degree of inflammatory factor release of inflammatory cells to a certain extent and has a certain anti-inflammatory effect.
As shown in fig. 2 and 3, the expression of NF- κ B p65 and p-ikkα/β proteins was significantly increased in the LPS model group compared to the blank group, and the administration group significantly reduced the expression of NF- κ B p65 and p-ikkα/β proteins and was dose dependent compared to the model group. These results indicate that FOE may exert anti-inflammatory effects via NF- κB signaling pathway by down-regulating protein expression of key signaling molecules such as Keap1, NF- κ B p65 and p-IKKKα/β, up-regulating Nrf2, HO-1, etc.
The experimental results show that the Chinese medicinal composition is a solid common fruit fruit extracts can be effectively based on NF- κB signaling pathway inhibits LPS-induced RAW264.7 cell inflammatory response, thereby exerting an anti-inflammatory effect.
Example 8 inhibition of gastritis to cancer metastasis by solid Malus fruit extract was observed based on a gastritis transformation model in which N-methyl-N-nitronitrosoguanidine (MNNG), a chemical mutagen, induces the formation of human gastric epithelial cells (GES-1)
(1) The experimental method comprises the following steps:
MNNG is purchased from beijing hundred profit biotechnology limited, brand-ladder love, specification 5g. GES-1 cells were purchased from Shanghai vivid and Biotechnology Inc. Phosphate Buffered Saline (PBS) was purchased from amerco, usa, under the specification 10L. Dimethyl sulfoxide (DMSO) was purchased from Amresco, USA, 500ml in size. Fetal Bovine Serum (FBS) was purchased from Amresco, USA, 100ml gauge. 3- (4, 5-dimethylthiazole-2) -2, 5-diphenyltetrazolium bromide (MTT) was purchased from Shanghai Biyun biotechnology Co., ltd., 500mg in size.
(2) Experimental protocol:
human gastric epithelial cells GES-1 were seeded at 1X 10 4 Number of individual wells/well to be seeded into 96-well platesIn DMEM medium containing 10% Fetal Bovine Serum (FBS) at 37deg.C with 5% CO 2 Is cultured for 24 hours under the condition of (2). The next day the old solution was aspirated, medium containing 10% FBS and no diabody was added, 5X 10 was added -5 MNNG-induced stimulation of (C), culturing in dark for 24h, and removing culture solution containing MNNG. The administration groups were given 25, 50, 100, 200, 400 μg/mL of solid male fruit extract solution, 3 duplicate wells per gradient; incubate for 48h, aspirate and discard the old solution, then add complete medium containing 0.5mg/ml MTT (containing 10% FBS, total volume 100. Mu.l/well), incubate for 4h at 37 ℃, discard the medium, add 100. Mu.l/DMSO, mix well for 10min with a horizontal shaker and detect absorbance with a microplate reader.
(3) Experimental results:
compared with normal control group, MNNG stimulated GES-1 cell activity is significantly enhanced, and fructus Mali Pumilae fruit extract has effect in significantly inhibiting MNNG induced GES-1 cell activity enhancement (P<0.05 Data analysis to determine half-Inhibitory Concentration (IC) of solid Male fruit extract FOE on gastritis transformed cells 50 ) 78.31+ -1.97 μg/ml, which shows that the extract of fruit of Gugongguo has inhibiting effect on transformed cells of gastritis.
EXAMPLE 9 protection of fruit extract of Gugongguo against gastric mucosal lesions
The experimental method comprises the following steps: 60 SD male rats (provided and fed by the laboratory animal center of the military academy of civil liberation army of China, license number: SCXK- (army) 2012-0004, animal eligibility number: 1700515) with a body weight of 200+ -20 g were randomly divided into 6 groups, picric acid marks: blank (Control), model (Model), dachi (aluminum magnesium carbonate tablet: talcid) were purchased from Bayer pharmaceutical healthcare Co., ltd., positive Control (Talcid 8 mg/kg), solid male fruit extract high dose group (FOE-H0.5 g/kg), solid male fruit extract medium dose group (FOE-M0.25 g/kg) and solid male fruit extract low dose group (FOE-L0.125 g/kg). Each administration group was continuously fed by stomach irrigation for 7 days at a weight of 0.5mL/200g, and the same amount of distilled water was administered to the blank group and the model group, and fasted for 24 hours before molding. After the last administration for 30min, except for a blank group, 90% ethanol is infused into the stomach of each rat, 0.2mL/200g is added, an acute gastric mucosal injury model of the rat is built after l hours, the rat is sacrificed, materials are obtained, and the effect of the FOE (solid common fruit extract) with different concentrations on acute gastric mucosal injury caused by large-dose ethanol is observed.
TABLE 1 evaluation of the protective effect of extract of fruit of Equisetum arvense based on bleeding points and bleeding areas of gastric mucosa
After the rats are lavaged with 95% ethanol for 1 hour, the rats have obvious gastric mucosa injury phenomenon. The experimental results are shown in table 1 and fig. 3. Visual inspection shows that the rats in the blank group are not obviously abnormal, the stomach injury of the rats in the model group is serious, and mucous membrane congestion edema, hemorrhage and erosion appear. The FOE extracted from the fruit of the solid common fruit has obvious repairing effect in high, medium and low dosage administration groups. Compared with the model group, the FOE administration group has less strip-shaped damage in stomach tissue and less bleeding spots. Especially in the high dose group, bleeding points and bleeding areas are significantly reduced and lower than in the positive drug group. The result shows that the extract of the fruit of the solid common fruit has better protection effect on acute gastric mucosal injury induced by high-concentration ethanol, and shows dose dependency, and the protection effect of the extract of the fruit of the solid common fruit at high dose even exceeds that of a positive drug Gastrodia elata group (Talcid).
EXAMPLE 10 therapeutic Effect of fruit extract of Gugongguo on rats with chronic atrophic gastritis
The experimental method comprises the following steps: 60 SD male rats (SCXK- (army) 2012-0004, animal eligibility number 1700515, provided and raised by the center of laboratory animals of the national institute of Lesion, china) with a body weight of 200+ -20 g, were randomly divided into 6 groups, namely, a normal control group, a model group of chronic atrophic gastritis (chronic atrophic gastritis, CAG), an intervention group of celecoxib (Congo pharmaceutical Co., ltd.) as a positive drug (10 mg/kg), a high-dose group of solid fruit extract (FOE-H0.5 g/kg), a medium-dose group of solid fruit extract (FOE-M0.25 g/kg), and a low-dose group of solid fruit extract (FOE-L0.125 g/kg), each group of 10 animals. The model group, the positive medicine group and the administration group are respectively irrigated with sodium deoxycholate solution (20 mmol/L of sodium deoxycholate is irrigated with stomach every day, and the dosage is 6 ml/kg), and 0.1 percent ammonia water is freely drunk to induce the rats to generate chronic atrophic gastritis. And (3) continuous molding is carried out for 8 weeks, and the gastric mucosa of the rat with successful molding is atrophic to different degrees and accompanied by intestinal epithelial metaplasia. After the molding is finished, the gastric lavage administration is started, once a day, and the administration is continued for 4 weeks. The change in body weight and food intake of rats was observed during the experiment. After 4 weeks, the weight of the rats was increased, the food intake was also increased compared with that during molding, and the hair color and brightness of the rats were recovered. After the rat is subjected to the vertebroplasty and the sacrifice after the experiment is finished, the stomach tissue is rapidly taken out, the obtained stomach tissue is sheared along the greater curvature of the stomach, the obtained stomach tissue is washed by normal saline, the filter paper is sucked dry, and the obtained stomach tissue is fixed by paraformaldehyde solution. Tissue section preparation is carried out, finally HE staining is carried out, and pathological changes of stomach tissues of rats are observed under a microscope.
Experimental results: when observed under a light microscope, the gastric mucosa surface of the normal group of rats is smooth, the structural hierarchy is complete, the epithelial cells are closely arranged, and obvious inflammatory cell infiltration and erosion ulcer formation are avoided, and the normal group shown in fig. 4A is obtained. The model group of chronic atrophic gastritis is shown in figure 4B, in which lymphocyte, plasma cell, eosinophil infiltration and a large number of cup-shaped cells are seen in the gastric mucosa lamina propria, most inflammatory cells are gathered, intestinal epithelium grows, and local focal area is proliferated. The high dose group (see figure 4F) of the extract of the fruit of the solid common fruit obviously reduces the pathological state of the chronic atrophic gastritis compared with the model group, only a few lymphocytic, plasmatic and eosinophilic infiltrates were seen, the disappearance of intestinal metaplasia shows that the extract of the fruit of the solid common public fruits has therapeutic effect on the rat model with chronic atrophic accompanied by intestinal gastritis.
EXAMPLE 11 therapeutic Effect of extract of Gugongguo fruit on rats with chronic atrophic accompanied by dysplastic gastritis
The experimental method comprises the following steps: 60 SD male rats with body weight of 200+ -20 g and SPF grade were randomly divided into 6 groups, a normal control group, a model group of chronic atrophic gastritis (chronic atrophic gastritis, CAG), a positive drug celecoxib intervention group (10 mg/kg) and a high dose group of solid male fruit extract (FOE-H0.5 g/kg), a medium dose group of solid male fruit extract (FOE-M0.25 g/kg) and a low dose group of solid male fruit extract (FOE-L0.125 g/kg), each group of 10 animals. The model group, the positive medicine group and the administration group are respectively irrigated with sodium deoxycholate solution (20 mmol/L of sodium deoxycholate is irrigated with stomach every day, the dosage is 6 ml/kg) and 60 percent ethanol, the stomach is irrigated with empty stomach twice a week, 0.1 percent ammonia water is freely drunk, the model is continuously manufactured for 12 weeks, and the gastric mucosa of the model rat is manufactured to shrink and be accompanied with intestinal epithelial metaplasia or abnormal hyperplasia with different degrees. After the molding is finished, the gastric lavage is started to perform drug intervention once a day. The change in body weight and food intake of rats was observed during the experiment. After 4 weeks of therapeutic administration, the rats had increased food intake and body weight compared to the modeling phase, and their hair color recovered to be bright, with a significant increase in mobility.
Experimental results: when the normal group rats are observed under an optical microscope, the gastric mucosa surface is smooth, the texture is clear, the epithelial cells are closely arranged, and no obvious erosion ulcer is formed, as shown in figure 5A. The chronic atrophic gastritis model group can be seen with partial kitchen mesenchymal bleeding, a large number of cupped cells are gathered, and the gland is moderately abnormal in shape, as shown in fig. 5B. The low dose group of extract of fruit of Gugongguo showed no abnormal proliferation of rat glands, little lymphocyte aggregation and eosinophil infiltration, as shown in FIG. 5C. The high dose group of the fruit extract of the gugongguo obviously lightens the pathological state compared with the model group, and has the function of restoring the normal state of rats. Some rats had little eosinophil infiltration, and glandular dysplasia disappeared, and moderate intestinal metaplasia was reduced to mild intestinal metaplasia or disappeared, see fig. 5D.
Claims (11)
1. Use of fruit extract of Gugongguo in preparing medicine for treating and/or preventing stomach diseases, wherein the stomach diseases are selected from one or more of chronic gastritis, gastric mucosa injury, gastric precancerous lesion, gastritis transformation or gastric cancer,
the preparation method of the solid male fruit extract comprises the following steps:
(1) Adding ethanol or ethanol water solution into the fruit of the solid male fruit, and reflux extracting;
(2) Filtering the extract obtained in the step (1), and concentrating under reduced pressure until the sugar degree is 10-40.
2. The use according to claim 1, wherein the chronic gastritis is chronic atrophic gastritis.
3. The use according to claim 2, wherein the chronic atrophic gastritis is chronic atrophic gastritis with enterogastric gastritis or chronic atrophic gastritis with dysplastic gastritis.
4. The use according to claim 1 to 3, wherein, the fruit extract of the solid common fruits is ethanol water solution extract with the volume ratio of 50-95%.
5. Use according to any one of claims 1 to 3, wherein the fruit extract has a tannin content of not less than 20% by weight and a total triterpene content of not less than 10% based on the total weight of the fruit extract.
6. The use according to claim 5, wherein the fruit extract has a tannin content of 20-40% by weight and a total triterpene content of 10-20% by weight, based on the total weight of the fruit extract.
7. The use according to claim 1, wherein in step (1) of the above preparation method, the extraction is carried out 2 to 3 times, each for 1 to 3 hours.
8. The process according to claim 1, wherein in step (1) of the process, the mass ratio of the solid male fruit to the ethanol or the ethanol water solution is 1: (4-8).
9. The use according to claim 1, wherein in step (2) of the above preparation method, the filtration is filtration using a 80-120 mesh sieve.
10. The use according to claim 1, wherein the medicament for the treatment and/or prevention of gastric diseases comprises the extract of fruit of the fruit plant, together with pharmaceutically acceptable excipients.
11. The use according to claim 10, wherein the medicament for the treatment and/or prophylaxis of gastric diseases is in the form of a tablet, capsule, pill, powder or suspension.
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