CN113368097A - Application of puerarin in preparation of medicine for preventing and/or treating irritable bowel syndrome and medicine - Google Patents
Application of puerarin in preparation of medicine for preventing and/or treating irritable bowel syndrome and medicine Download PDFInfo
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- CN113368097A CN113368097A CN202010678934.6A CN202010678934A CN113368097A CN 113368097 A CN113368097 A CN 113368097A CN 202010678934 A CN202010678934 A CN 202010678934A CN 113368097 A CN113368097 A CN 113368097A
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Abstract
The invention discloses an application of puerarin in preventing, treating and/or relieving irritable bowel syndrome, wherein the puerarin can restore a blocked cell cycle and promote the proliferation of intestinal epithelial cells by up-regulating the level of phosphorylated extracellular regulated protein kinase (p-ERK); can be used for participating in repair of intestinal epithelial barrier by up-regulating expression of tight junction protein (occlusion), inhibiting hyperfunction of hypothalamus-pituitary-adrenal axis (HPA axis) by down-regulating receptor protein expression of hypothalamus corticotropin releasing factor (CRF1), and improving gastrointestinal motility and visceral hypersensitivity. Experiments prove that the puerarin has obvious curative effect on irritable bowel syndrome, quick response and small side effect, and is a high-efficiency, safe, stable and wide-source irritable bowel syndrome treatment medicine. The invention provides a new medicine source for preventing and treating irritable bowel syndrome and complications thereof.
Description
Technical Field
The invention belongs to the field of medicine and health, relates to a medicine or health-care product for preventing, treating and/or relieving gastrointestinal diseases, and particularly relates to an application of an effective component of a traditional Chinese medicine kudzu in medicines or health-care foods for preventing and treating irritable bowel syndrome.
Background
In modern society, people's learning, working and living pressure gradually increases, living habits become irregular, dietary structure imbalance, long-term stress, anxiety, depression and the like often cause gastrointestinal dysfunction, brain-intestine regulation disorder, intestinal flora disorder and other health problems, and Irritable Bowel Syndrome (IBS) is one of the intestinal dysfunction diseases which has sustained or intermittent attacks and changes abdominal pain, abdominal distension, defecation habits and (or) stool characteristics into clinical manifestations and lacks gastrointestinal structure and biochemical abnormalities. The patients are mainly young and middle-aged, the onset age is usually 20-50 years old, and women are more common than men and are often accompanied with other gastrointestinal dysfunction diseases such as functional dyspepsia. IBS is divided into four clinical types of diarrhea type, constipation type, mixed type and indeterminate type according to the characteristics of stool, and diarrhea is the main type in China.
Irritable Bowel Syndrome (IBS) is classified into the categories of diseases such as abdominal pain, diarrhea, constipation, depression and the like in traditional Chinese medicine, liver depression, spleen deficiency and kidney-yang deficiency are main pathogenesis, modern medicine considers that the IBS belongs to a functional gastrointestinal tract disease, and abdominal pain, abdominal distension, defecation habit, stool character change and the like are clinical manifestations, but no gastrointestinal tract structure and biochemical abnormality exist. IBS mainly comprises four subtypes, namely diarrhea type (IBS-D), constipation type (IBS-C), diarrhea and constipation mixed type (IBS-M) and amorphous type (IBS-U), is common in teenagers, has a higher prevalence rate in women than in men, and mainly has the diarrhea type in China, so that the work and life quality of patients are seriously influenced. Currently, the pathogenesis of irritable bowel syndrome is still unclear with respect to the specific cause, and thus effective therapeutic measures are still lacking. The medicine is mainly treated by anticholinergic medicine, antidiarrheal, antispasmodic, 5-hydroxytryptamine medicine, antidepressant and the like, but the effect is poor.
Although the pathogenesis of IBS remains unclear to date, studies have shown that disturbances in bi-directional communication of the brain-gut axis, increased visceral sensitivity, low grade inflammation, and increased intestinal permeability play important roles in mediating the process of IBS formation. Corticotropin Releasing Factor (CRF) is a key regulatory peptide that mediates the stress response of hypothalamic-pituitary-adrenal axis (HPA), participates in brain-gut axis interaction, and in the pathogenesis of IBS by affecting gastrointestinal motility, visceral hypersensitivity, etc. The intestinal Tight Junction (TJ) barrier plays a key role in the pathogenesis of intestinal and systemic diseases, and disruption of the TJ barrier and increased paracellular permeability lead to penetration of pro-inflammatory molecules into the lumen, activation of the mucosal immune system, and ultimately, persistent inflammation and tissue damage. occludin, as a TJ transmembrane protein, plays an important role in maintaining TJ barrier function. Low grade inflammation is found in colon tissues and peripheral blood of IBS patients, and inflammatory factors IL-6, IL-1 beta and TNF-alpha play important roles in the low grade inflammation. After ERK (extracellular regulatory protein kinase) is activated by upstream protein, ERK1/2 phosphorylation can be further activated, and the ERK is involved in various biological reactions such as cell proliferation and differentiation, cell morphology maintenance, cytoskeleton construction, cell apoptosis, cell canceration and the like. It has been shown that the ERK signaling pathway plays a crucial role in mediating the intestinal permeability enhancement of IBS.
IBS is a chronic and relapsing gastrointestinal disease and there is currently no cure. The drugs for treating IBS mainly comprise anticholinergic drugs, prokinetic drugs, opioid drugs, antispasmodics, 2, 3-benzodiazepine receptor modulators, adrenocortical hormones, 5-hydroxytryptamine drugs, antidepressants and the like. In addition, hypnotic therapy, psychotherapy, acupuncture, low FODMAP diet, prebiotics and probiotics, etc. are also used for IBS treatment. Current drug therapy methods aim at reducing the severity of symptoms, however, due to the significant side effects of the drug, the quality of life of the patient is greatly reduced. The traditional Chinese medicine is used as a supplement and substitute medicine for IBS, has small side effect and good tolerance of patients compared with a synthetic medicine, and is more and more concerned by researchers.
Puerarin is the main effective component of Pueraria lobata Ohwi of Leguminosae, and is isoflavone compoundSub-formula is C21H20O9Molecular weight 416.28, melting point: 187 ℃ 189 ℃, white to yellowish crystalline powder, soluble in methanol, slightly soluble in ethanol, slightly soluble in water, insoluble in chloroform or diethyl ether.
Puerarin has pharmacological effects of vasodilation, heart protection, neuroprotection, bone formation promotion, blood sugar reduction, anti-inflammation, antioxidation, etc., and is commonly used for treating cardiovascular disease and cerebrovascular disease, diabetes, osteonecrosis, Parkinson disease, Alzheimer disease, depression, colon cancer, etc. However, puerarin has no report on the treatment of irritable bowel syndrome.
Disclosure of Invention
The invention aims to solve the technical problems in the process of preventing and treating the existing irritable bowel syndrome, and provides a new application of puerarin in preparing medicines for preventing and/or treating the irritable bowel syndrome, wherein the puerarin has obvious performance and efficacy in preventing and treating gastrointestinal diseases, especially the irritable bowel syndrome, has wide application prospects in treating and preventing the irritable bowel syndrome, and provides a new way for new medicinal applications of the puerarin and preparations thereof.
In order to achieve the purpose of the invention, the invention provides an application of puerarin in preparing a medicament or health-care product for preventing, relieving and/or treating gastrointestinal diseases.
Wherein the gastrointestinal disease is gastric ulcer or irritable bowel syndrome.
In particular, the gastrointestinal diseases are diarrhea type, constipation type and diarrhea and constipation mixed type and atypical irritable bowel syndrome, preferably diarrhea type irritable bowel syndrome.
In the process of screening natural active ingredients with the effects of preventing and treating irritable bowel syndrome, the inventor finds that puerarin has strong effect of reversing disorder of intestinal microbial flora and promoting normal proportion of the microbial flora; promoting the proliferation and repair of intestinal epithelial cells, and can be used for preventing and treating gastrointestinal diseases, especially irritable bowel syndrome.
Wherein, the medicine consists of puerarin and a pharmaceutically acceptable carrier.
In particular, the puerarin has a purity of more than 90%, preferably more than 95%.
In particular, pharmaceutically acceptable carriers are generally approved by health care professionals for this purpose and as inactive ingredients of medicaments. A compilation of pharmaceutically acceptable carriers can be found in tools such as The Handbook of Pharmaceutical excipients (Handbook of Pharmaceutical excipients, 2 nd edition, edited by A.Wade and P.J.Weller; published by American Pharmaceutical Association, Washington and The Pharmaceutical Press, London, 1994).
Wherein, the medicament is selected to be administered by oral, sublingual, transdermal, intramuscular, subcutaneous, mucocutaneous, urethral, vaginal or intravenous routes.
In particular, the medicament is in the form of an oral preparation, an injection or a topical preparation.
In particular, the oral preparation is selected from tablets, capsules, pills, powders, granules, syrups or solutions; the injection is selected from injection solution or freeze-dried powder for injection; the topical preparation is selected from cream, ointment, spray, aerosol, patch, gel or cataplasm.
The medicament in the present invention exists in the form of tablet, capsule, pill, powder, granule, syrup, solution, injection, spray, aerosol, patch, gel, cataplasm, etc., i.e., the pharmaceutical preparation includes the form of tablet, capsule, pill, powder, granule, syrup, solution, injection, spray, aerosol, patch, gel, cataplasm, etc., but is not limited to the above form.
The puerarin in the invention can be used alone or in the form of a pharmaceutical composition containing puerarin when used for preventing, alleviating or treating irritable bowel syndrome.
The invention provides a pharmaceutical preparation and a corresponding pharmaceutical dosage form for preventing, relieving or treating irritable bowel syndrome, which take puerarin as an active ingredient. The medicinal preparation takes the puerarin as an effective active ingredient and comprises other pharmaceutically acceptable carrier components.
In another aspect, the invention provides a medicament or health product containing puerarin for preventing or/and treating gastrointestinal diseases.
Wherein the gastrointestinal disease is gastric ulcer or irritable bowel syndrome.
In particular, the gastrointestinal diseases are diarrhea type, constipation type and diarrhea and constipation mixed type and atypical irritable bowel syndrome, preferably diarrhea type irritable bowel syndrome.
Particularly, the ratio of the weight of the puerarin to the total weight of the medicine or the health-care product is 0.01-10: 100.
the drug of the present invention can be prepared into various dosage forms, such as tablets, capsules, pills, powders, granules, syrups, solutions, injections, sprays, aerosols, patches, gels, cataplasms, etc., by methods known in the art.
The present invention also provides a method for treating irritable bowel syndrome, comprising administering to a subject a therapeutically effective amount of puerarin, which is 0.01-10 mg/kg-d, preferably 0.1-5 mg/kg-d.
As used herein, unless otherwise indicated, the term "therapeutically effective amount" is the amount of a drug required to produce an effective effect; the "therapeutically effective amount" is adjustable and variable and ultimately determined by the medical practitioner, taking into account factors including the route of administration and the nature of the formulation, the general condition of the recipient's weight, age, etc., and the nature and severity of the condition being treated.
Compared with the prior art, the invention has the following obvious advantages:
1. the invention explores the new medicinal value of the known compound puerarin, is used for the new application of treating the irritable bowel syndrome (the puerarin has significance for reducing the defecation times of diarrhea-type irritable bowel syndrome rats, increasing the discharge time of glass globules and reducing the viscus sensitivity), and can be prepared into the medicine or health-care food for preventing, conditioning and/or treating the irritable bowel syndrome, thereby developing a new field for the clinical application of the puerarin.
2. The puerarin of the invention has obvious effects of preventing and treating irritable bowel syndrome, especially diarrhea-predominant irritable bowel syndrome, the method of combining mother-child separation and colonic acetic acid stimulation is adopted to establish diarrhea-predominant irritable bowel syndrome animal models, animal experiments are carried out through oral routes, and the results show that: (1) the puerarin can obviously reduce the defecation times of rats, increase the discharge time of glass beads, increase the erection times and the total movement distance, reduce the visceral sensitivity and present an obvious dose-effect relationship; (2) through 16S rRNA sequencing analysis of the feces, the puerarin can reduce the ratio (F/B) of firmicutes to bacteroidetes, and reverse modeling-induced microbiota ecological disorder through the influence on the abundance of the microbiota such as bacteroides, lactobacillus, Prevotella, ruminococcus, streptococcus digestans and the like, so that the intestinal microbiota of the rat tends to be normal; (3) puerarin can restore the blocked cell cycle by increasing the level of p-ERK, promote the proliferation of intestinal epithelial cells, inhibit the hyperfunction of HPA axis by regulating the protein content of hypothalamic CRF1 receptor and colon tight junction protein occludin, participate in the repair of intestinal epithelial barrier, and show that the puerarin has stronger therapeutic action in diarrhea-predominant irritable bowel syndrome.
3. The puerarin has strong pharmacological action, obvious effect of preventing, conditioning and treating irritable bowel syndrome, quick response, small toxic and side effect and good safety, can be taken for a long time, can analyze the action mechanism of the puerarin for treating the irritable bowel syndrome by modern pharmacology, and has good medicinal prospect.
4. The product of the invention has rich raw material sources, low price, safe clinical use, simple preparation process, small dosage and convenient use, can be prepared into various dosage forms, and is easy to popularize.
5. The invention can adopt puerarin with single component to prepare the medicine for preventing and treating irritable bowel syndrome, and can also adopt the formula of puerarin and other medicines together to prepare the compound medicine for treating the irritable bowel syndrome with multiple targets.
Drawings
FIG. 1 is a graph showing the effect of puerarin on the 2h fecal pellet count and the glass bead elimination time of IBS-D model rats, wherein: FIG. 1A is the number of stool particles 2h prior to administration to IBS-D model rats; FIG. 1B shows the time of glass bead expulsion prior to administration to a rat model IBS-D; FIG. 1C is the number of stool particles for 2h on the second day after 2 weeks dosing for IBS-D model rats; FIG. 1D is the time of glass bead expulsion the next day after 2 weeks dosing in IBS-D model rats.
FIG. 2 is a graph showing the results of the effect of puerarin on the behavioural parameters of an open field experiment of IBS-D model rats, wherein FIG. 2A shows the number of erections before administration of IBS-D model rats; FIG. 2B shows the total distance traveled before administration of IBS-D model rats; FIG. 2C shows the number of erections after administration in IBS-D model rats; FIG. 2D shows the total distance traveled after administration of IBS-D model rats.
FIG. 3 is a graph showing the effect of puerarin on abdominal uplift and dorsal camber capacity thresholds in IBS-D model rats; wherein, FIG. 3A shows the threshold change of abdominal uplift and dorsal arch volume before drug treatment in IBS-D model rats; FIG. 3B shows the threshold change in abdominal uplift and dorsal arch volume following drug treatment in IBS-D model rats.
FIG. 4 is a graph showing the results of the effect of puerarin on the distal colon tissue of IBS-D model rats (H & E staining, scale: 200 μm), wherein A, B, C, D, E, F, G are blank control group, model group, positive drug group, puerarin low dose group, puerarin middle dose group, puerarin sub-high dose group, and puerarin high dose group, respectively.
FIG. 5 is a schematic diagram of a Western Blot analysis of the expression of ERK1+2, p-ERK, occludin and CRF1 proteins using GAPDH as an internal control, wherein the target protein in (A) is named as ERK1+2, p-ERK, occludin; (B) image J version 1.51n software carries out optical density analysis result chart on p-ERK1/ERK1+2 protein; (C) image J version 1.51n software carries out optical density analysis result chart on p-ERK2/ERK1+2 protein; (D) image J version 1.51n software carries out optical density analysis result graph on occludin protein; (E) western Blot analysis of the condensed electrophoretogram of the expression of CRF1 protein by taking GAPDH as an internal reference; (F) image J version 1.51n software CRF1 protein expression densitometry analysis results.
Detailed Description
The present invention and its advantageous effects are further illustrated below with reference to specific examples, which are only illustrative and not intended to limit the scope of the present invention. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.
The therapeutic effect of puerarin of the present invention for IBS-D is further illustrated by the following test examples, which include pharmacodynamic tests and mechanism-of-action verification tests of puerarin. The experimental procedures, for which specific experimental conditions are not indicated in the following examples, are generally carried out according to conventional conditions, or according to conditions recommended by the manufacturers.
Test example 1 pharmacodynamic study of Puerarin
1 Material
1.1 drugs and reagents
Puerarin (content > 98%), purchased from bioscience, Xianqi, China, batch number: k188904; using puerarin standard substance provided by Chinese medicine biological product verification to make comparison and making HPLC calibration, its content is 98.2%;
positive drug: pinaverium bromide (Dicetel), suwei pharmaceutical co ltd, france; batch number: h20160396;
mixing puerarin, positive drug and distilled water, making into solution, and intragastric administration.
1.2 animals
Rat: 21 healthy SD pregnant mice with a pregnancy period of 18 +/-2 days are purchased from Beijing Wittingli laboratory animals Co., Ltd, and the qualification number is SCXK (Jing) 2016-0006.
2 test methods and results
2.1 IBS-D model building
2.1.1 first stage: separating the new period mother and son (2-14 days):
newborn rats were separated from the mother rats for 3 hours (9:00am-12:00am) on the day of birth, designated day 1 (PND 1), during PND 2-PND 14, and the specific operation method: taking out the mother rat from the original cage, placing in a separate cage, and keeping the newborn rat in the original cage, keeping the temperature of the living environment at 28 + -2 deg.C, and placing the mother rat back into the original cage after the separation is finished. The blank control group was not isolated.
All rats were kept free to drink water during the experiment and were periodically padded and weighed. No operation was performed for 4 weeks after PND 15. Newborn rats and mother rats are bred together until PND 22 is weaned, and bred in cages after PND 30.
2.1.2 second stage: adult colonic acetic acid stimulation (PND 42-PND 56):
PND 42-PND 56, after the model group rat is anaesthetized by isoflurane, an anal tube (diameter: 1mm) lubricated by paraffin oil is inserted into a position 2cm away from the anus gently, 0.5mL of 0.5% acetic acid solution is filled into the colon, then the anal tube is pulled out slowly, the head of the rat is enabled to face downwards, the anus is pressed by hands, the tail of the rat is lifted for 30s so as to prevent the acetic acid from flowing out, then the rat is put back into the cage quickly, and after the rat is awakened, the rat can move freely and can take food and drink water. Rats in the placebo group had the same intervention as the model group except that the rats were given the same volume of 0.9% saline daily in the colon.
Molding was continued for 2 weeks. The experiment was fixed at 9:00 am.
2.2 grouping and administration
After the molding is finished, all the molding groups of rats are subjected to viscera sensitivity test, the Brishol integral is more than 5 minutes, and the rats with significant difference compared with a blank control group when the AWR is 3 minutes are considered to be successfully molded. Rats successfully modeled were randomly divided into a Model group (Model), a pinaverium bromide group (Dicetel, 15mg/kg), and Puerarin (Puerarin) low (6mg/kg), medium (12mg/kg), sub-high (24mg/kg), and high (48mg/kg) dose groups, 15 of which were each administered by gavage at 1.0mL/100g, wherein the Model group and the blank Control group (Control) were administered with the same amount of physiological saline. The administration was started the next day after the end of molding and continued for 2 weeks.
2.3 taking materials and sample treatment
After the administration, the rats were anesthetized with chloral hydrate the next day, and blood was taken from the abdominal aorta, and plasma was collected and separated. The rats were sacrificed by dislocation of the cervical vertebrae, the hypothalamus was isolated and the feces were left as a sample. The proximal colon (2 cm from the ileocecal part) and the distal colon (8 cm from the anus) were cut out by 2cm, blood and impurities were washed with physiological saline, and a portion was fixed in 4% neutral formalin solution for histopathological section analysis. The rest part is cut open along the mesentery longitudinally, after being washed by normal saline, the intestinal mucosa at the near end and the far end is respectively scraped, and is put into a freezing tube, and after being frozen by liquid nitrogen, the intestinal mucosa is put into a refrigerator at minus 80 ℃ for storage and standby (the material drawing operation is carried out on ice).
2.4 results of pharmacodynamic studies
2.4.1 general observations and weight changes in rats
From the second stage of molding, the mental state, the gloss of the fur and the movement of the rat were observed every day. The body weights of the rats in each group were measured and recorded on days 1, 7, 14, 21 and 28, respectively, and the measurement results are shown in table 1.
Table 1 weight change of newborn rat (g, Mean ± SE, n ═ 8)
Note:##P<0.01vs Control；**P<0.01，*P<0.05vs Model。
as shown in Table 1, the rats in the blank control group had good mental status, had sausage-shaped stools, clear edges, and smooth and glossy fur; after the model is made, the weight of the rats of each model making group slowly increases, and has significant difference (P <0.01) compared with a blank control group, the excrement is in a soft block shape or paste-like excrement, the defecation frequency is increased, the rats are prone to pricking, listlessness, laziness in movement and lying, dull hair color and hair erection are caused, and the individual rats have the phenomenon of perianal unclean; after administration, the positive medicine group and the low, medium, sub-high and high-dose puerarin groups have obvious weight increase, and have significant difference (P <0.05) compared with a model group, the mental state is improved, the fur becomes smooth, and the diarrhea symptom is improved.
2.4.22 h measurement of stool particle number, stool integral and glass bead discharge time
The molding machine feeds the rat at 8:00 in the morning, fasts at 9:00, collects the feces of the rat at 10:00-12:00 and calculates the number of the feces grains for 2h on the day of molding completion (namely before each medicine); the group was fed 8:00, fasted 9:00, and collected from 10:00-12:00 the morning after 2 weeks of administration, and the number of feces grains was calculated for 2 hours, and the score of the feces was recorded according to the Brishol score standard, and the average score was calculated, and the statistical results are shown in Table 2.
The day after model building and the day after administration for 2 weeks, rats were anesthetized with isoflurane, and a glass bead with a diameter of 3mm was placed along the anus into the rectum 3cm from the anus, and then moved to a cage filled with clean filter paper to keep free food and water intake. The time was started after the rats were awakened, and the time for the removal of the glass beads in the rectum of the rats was recorded and fasted for 12h before the experiment. The statistics of the number of fecal pellets and the time to pellet output of rats before and after administration are shown in FIGS. 1A-D.
TABLE 2 Brishol typing integration criteria
Among them, types 1 and 2 are constipation, types 3 and 4 are normal, and types 5, 6 and 7 are diarrhea.
As shown in fig. 1A-D, after two weeks of continuous acetic acid stimulation, the number of 2h fecal pellets of each model-making rat was significantly increased, the time for discharging the glass beads was significantly shortened, and compared with the blank control group, the significant difference (P <0.01 or P <0.05) was observed, which indicates that the colonic transit frequency of IBS-D rats was increased after model making; after two weeks of continuous administration, the number of fecal particles in the low, medium, sub-high and high puerarin groups after 2h is obviously reduced (P <0.01 or P <0.05) compared with the model group, and the discharge time of the glass globules is prolonged, wherein the puerarin high dose group has significant difference (P <0.05), which shows that the colon transport function of IBS-D rats is improved after administration.
2.4.3 behavioural testing
Model group after the end of modeling, the administration group performed open-field behavioral activity tests on all rats 2 weeks after administration. The number of times of erection (1 cm from the ground for both forelimbs) and the total distance of movement of the rat within 5min were recorded. Experiments were performed between 9:00 and 13:00 a.m. to avoid interference with the circadian rhythms of the rats. Animal faeces were cleaned regularly during the experiment.
Statistical results of the open field behavioral activity test of rats before and after administration are shown in FIGS. 2A-D.
As shown in fig. 2A-D, after two weeks of acetic acid stimulation, the number of erections and total distance traveled of each model rat was significantly reduced, with significant differences (P <0.01 or P <0.05) compared to the blank control group, indicating that IBS-D model rats followed depressive-like behavior; after continuous administration for two weeks, compared with the model group, the erection times and the total movement distance of the rats in the low, medium, sub-high and high puerarin group are obviously increased (P is less than 0.01), which shows that the depression-like symptoms of the rats in each administration group are obviously improved, and the curative effect of the puerarin sub-high dose group is more obvious.
2.4.4 rat visceral sensitivity assay
After the model building group finishes the model building, the abdominal evacuation reflex (AWR) of the rat is evaluated by adopting a colon rectal distension method (CRD) after the administration of the administration group for 2 weeks: after a rat is anesthetized with isoflurane, the paraffin oil lubricated 8F catheter with the air bag is inserted into the colon and rectum for 6cm through the anus, and the catheter is fixed with the tail root of the rat by a medical adhesive tape at a position 1cm outside the anus. Placing the rat in an observation cage with the size of 20cm multiplied by 6cm multiplied by 8cm, gradually injecting physiological saline into the air sac when the rat adapts to the observation cage for 30min and is in a quiet state, respectively observing the volume threshold values causing the abdomen uplifting and back arching of the rat, repeating for 3 times, wherein the interval is 5min every time, the rectal expansion lasts for 20s every time, and averaging the data. To avoid circadian rhythm effects, the treatment is carried out between 13:00 and 17:00 in the afternoon. Rats were fasted for 18h prior to the experiment. The scores were made using the AWR behaviour score (referred to Al-char standard).
0 minute: no behavioral response when the rectum of the rat is expanded;
1 minute: when the rectum expands, the body is still, the head movement is reduced, and the initial perception threshold is defined;
and 2, dividing: when the rectum expands, the abdominal muscles slightly contract, but the abdominal muscles are not lifted off the desktop, and the pain sensation threshold is defined;
and 3, dividing: when the rectum expands, the abdominal muscles contract strongly and lift off the table top, which is defined as the pain threshold;
and 4, dividing: when the rectum dilates, the pelvis is lifted and the body is arched, which is defined as the threshold of maximum tolerance capacity of pain sensation.
A threshold minimum volume that elicits a 4-point behavioral response was chosen to assess visceral sensitivity.
As shown in fig. 3A-B, after two weeks of acetic acid stimulation, the volume thresholds for abdominal uplift and dorsal arching of the rats in each model group were significantly decreased, and compared with the blank control group, there was a significant difference (P <0.01), indicating that the visceral sensitivity of IBS-D rats was increased; after two weeks of continuous administration, the volume thresholds for abdominal uplift and dorsal arching (P <0.01 or P <0.05) were significantly increased in the low, medium, sub-high, and high puerarin-containing rats compared to the model group, indicating that the sensitivity of IBS-D rats to external stimuli was improved after administration.
2.4.5 rat Colon Pathology section analysis
Taking rat distal colon tissue for H & E staining of paraffin section, and observing pathological changes of rat colon tissue by an optical microscope. The results of H & E staining of distal colon tissue are shown in FIG. 4. The colon mucosa of the rats in the blank control group has complete structure and orderly arrangement of glands, and inflammatory cell infiltration and interstitial edema are not seen; part of colon of the model group is adhered to abdominal tissues, the colon is shortened, the arrangement of glands is loose and irregular, inflammatory cells are infiltrated in submucosa, and the inflammatory cells can be lymphocytes, neutrophils and eosinophils; the symptoms of the positive medicine group and the puerarin groups with low, medium, sub-high and high doses are improved, part of glands are arranged loosely, and the submucosa can be seen with mild hyperemia.
Experimental example 2 study on mechanism of action of Puerarin in treating IBS-D
1. Effect of Puerarin on IBS-D rat intestinal flora
16S rRNA can be used as a characteristic nucleic acid sequence for revealing biological species and is considered as an index most suitable for phylogeny and classification and identification of bacteria.
In the experiment, IBS-D rat stool samples are collected, 16S rRNA sequence data of each sample is obtained through DNA extraction, PCR amplification, sample mixing and purification of PCR products, library building and sequencing and the like, and the species composition and community structure differences of the samples are further identified through OTU clustering, species annotation analysis, sample complexity analysis (Alpha Diversity), multi-sample comparative analysis (Beta Diversity), environmental factor correlation analysis and the like, so that 10 species with the highest flora expression abundance are obtained, as shown in Table 3. The sequencing was completed by Beijing Nuo He-derived bioinformatics science and technology Co.
Relative abundance of top 10 species ranked by maximum abundance at the Family (Family) level (%)
Table 3 shows the relative abundance of species ranked at the family level TOP 10, and the results show that the abundance of the species of intestinal fecal microbiota of rats in the model group varied greatly compared to the blank control group, with decreased abundance of species of muribacteriaceae (belonging to bacteroides, members of the S24-7 family), Akkermansiaceae (encephalitaceae), Bacteroidaceae (Bacteroidaceae), Prevotellaceae (Prevotellaceae), Ruminococcaceae (ruminococcus), Peptostreptococcaceae (Peptostreptococcaceae), christenseellaceae (belonging to clostridiaceae). After treatment with puerarin (24mg/kg), the abundance of species of Murebacteriaceae (belonging to Bacteroides, family members of S24-7), Bacteroidaceae (Bacteroides), Lactobacillus (Lactobacillaceae) was increased, and the abundance of species of Prevotellaceae (Prevotella, Ruminococcaceae (Ruminococcaceae), Peptostreptococcus (Peptostreptococcaceae), Christensella (belonging to Clostridia) was significantly decreased, as compared to the model group. Studies have shown that the increased abundance of Prevotellaceae in patients with depression, IBS, inflammatory bowel disease and obesity, the presence of this microorganism can accelerate the fermentation of other indigestible carbohydrates, leading to increased acetate production and a disturbed balance between energy intake, consumption and storage in the body. The prevotellaceae abundance in the model group rat feces is obviously increased, which shows that the animal model can cause the energy metabolism disorder of the rat, and the prevotellaceae abundance in the puerarin group rat feces is obviously reduced, which shows that the puerarin can improve the symptom of IBS by influencing the energy metabolism of the rat.
2. Western blot method for verifying action mechanism
After dry prediction of IBS-D rats, the rats were anesthetized and sacrificed, and the hypothalamic and distal colonic mucosal tissues were isolated and stored in a freezer at-80 ℃. In Western blot experiments, the samples are taken out of a refrigerator at the temperature of-80 ℃, protein lysate is added according to the proportion of 1:9(w/v), an ultrasonic disruptor is used for carrying out tissue homogenization, the homogenized samples are placed on a shaking table to be fully disrupted for 30min at the rotating speed of 70rpm, then the samples are placed at the temperature of 4 ℃ and 12000r/min, centrifugation is carried out for 10min, supernatant is taken and placed in a 1.5mL centrifuge tube, a BCA protein determination kit is used for carrying out protein quantification, and finally sterile PBS is used for adjusting the protein concentration to 5 mg/mL. Adding 5 Xloading buffer solution at a ratio of 4:1, boiling for 5min, cooling, and storing at-20 deg.C. Preparing 10% SDS-polyacrylamide separation gel and 5% SDS-polyacrylamide concentrated gel, and performing electrophoretic separation, wherein the loading amount of protein is 50 μ g; the electrophoresis conditions are as follows: the voltage of the concentrated gel is 80V for 30 min; the gel separation voltage is 100V, the gel separation voltage is 60min, the gel is transferred to a PVDF membrane by a wet method after electrophoresis, the temperature of a primary antibody (CRF1, ERK1+2, p-ERK, oclusion and GAPDH) is 4 ℃ overnight, a secondary antibody is incubated for 1h at room temperature after being cleaned, a color reagent is added after the secondary antibody is cleaned, a gel imaging analysis system scans, and the gel electrophoresis analysis result is shown in figure 5.
Compared with a blank control group, the colon P-ERK level and the occludin protein content of the rat in the model group are obviously reduced (P <0.01), the receptor level of hypothalamus CRF1 is obviously increased (P <0.01), compared with the model group, the colon P-ERK level and the occludin protein content of the low, medium and sub-high dose groups of puerarin are obviously increased (P <0.01), the receptor level of CRF1 is obviously reduced (P <0.01), which indicates that after the drug is administered, the hyperfunction state of the rat HPA axis is inhibited, the inhibition of the cell cycle of colon epithelial cells is relieved, the cells start to carry out mitosis, and the colon TJ barrier is gradually restored.
The test results show that the puerarin can obviously reduce the defecation times of rats, increase the discharge time of glass beads, increase the standing times and the total moving distance and reduce the viscus sensitivity; meanwhile, puerarin can reduce the ratio (F/B) of firmicutes to bacteroidetes, and reverse modeling induced microbiota ecological disorder by the influence on the abundance of bacteroides, lactobacillus, prevotella, ruminococcus, streptococcus digestus and other microbiota, so that the intestinal microbiota of the rat tends to be normal; mechanism verification shows
Puerarin can restore the blocked cell cycle by increasing the level of phosphorylated extracellular regulated protein kinase (p-ERK), and promote the proliferation of intestinal epithelial cells; meanwhile, puerarin can regulate the protein content of hypothalamic CRF1 receptor and colon tight junction protein (occlusion), up-regulate the expression of the tight junction protein, inhibit the hyperfunction of HPA axis and participate in the repair of intestinal epithelial barrier; meanwhile, the composition can also inhibit the hyperfunction of hypothalamus-pituitary-adrenal axis (HPA axis) and improve the gastrointestinal tract motility and visceral hypersensitivity by down-regulating the expression of receptor protein of hypothalamus corticotropin releasing factor (CRF 1). Therefore, the puerarin has obvious treatment effect on irritable bowel syndrome, especially diarrhea-predominant irritable bowel syndrome, and can be used for preparing medicaments for the irritable bowel syndrome.
EXAMPLE 1 Puerarin tablets
1. The raw materials are prepared according to the following mixture ratio
Mixing puerarin and starch uniformly, granulating, adding pulvis Talci and magnesium stearate, mixing uniformly, and making into tablet, 0.2g each tablet.
Example 2 Puerarin capsules
1. The raw materials are prepared according to the following mixture ratio
Puerarin (purity greater than 98%) 100g
Vitamin C600 g
Starch 1000g
Mixing puerarin, vitamin C and starch uniformly, and making into capsule, 0.2g each capsule.
Example 3 Puerarin granules
Puerarin (purity greater than 98%) 50g
Vitamin C600 g
Sucrose powder 5000g
Mixing puerarin, vitamin C and sucrose powder uniformly, granulating, and bagging at 5g per bag.
Claims (9)
1. Application of puerarin in preparing medicine or health product for preventing, relieving and/or treating gastrointestinal tract diseases is provided.
2. The use according to claim 1, wherein the gastrointestinal disorder is gastric ulcer or irritable bowel syndrome.
3. The use of claim 1 or 2, wherein the medicament consists of puerarin and a pharmaceutically acceptable carrier.
4. Use according to claim 1 or 2, wherein the drug is selected for administration by the oral, sublingual, transdermal, intramuscular, subcutaneous, mucocutaneous, urethral, vaginal or intravenous route.
5. Use according to claim 1 or 2, wherein the medicament is in the form of an oral, injectable or topical formulation.
6. Use according to claim 5, wherein the oral formulation is selected from tablets, capsules, pills, powders, granules, syrups or solutions; the injection is selected from injection solution or freeze-dried powder for injection; the topical preparation is selected from cream, ointment, spray, aerosol or patch.
7. The use according to claim 1 or 2, wherein the puerarin is more than 90% pure.
8. A medicine or health-care product for treating irritable bowel syndrome is characterized by containing puerarin.
9. The medicament or health product of claim 8, wherein the ratio of the weight of the puerarin to the total weight of the medicament or health product is 0.01-10: 100.
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| CN102397372A (en) * | 2011-11-17 | 2012-04-04 | 云南云药科技股份有限公司 | Medicinal composition and pharmaceutical preparation and application thereof to treating irritable bowel syndrome |
| CN104306362A (en) * | 2014-09-25 | 2015-01-28 | 广州中医药大学 | Application of patchoulicalcohol in preparation of medicines for treating gastric motility disorders |
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| CN104306362A (en) * | 2014-09-25 | 2015-01-28 | 广州中医药大学 | Application of patchoulicalcohol in preparation of medicines for treating gastric motility disorders |
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| SI-YAN CHE ECT.: "Puerarin prevents epithelial tight junction dysfunction induced by ethanol in Caco-2 cell model", 《JOURNAL OF FUNCTIONAL FOODS》 * |
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| CN114796307A (en) * | 2022-03-29 | 2022-07-29 | 甘肃中医药大学 | Application of flos puerariae lobatae extract in preparing medicine for preventing and treating inflammatory bowel diseases |
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