CN116036241A - Application of epidermal growth factor in preparing medicine for treating gastric ulcer - Google Patents
Application of epidermal growth factor in preparing medicine for treating gastric ulcer Download PDFInfo
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- CN116036241A CN116036241A CN202310128348.8A CN202310128348A CN116036241A CN 116036241 A CN116036241 A CN 116036241A CN 202310128348 A CN202310128348 A CN 202310128348A CN 116036241 A CN116036241 A CN 116036241A
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- epidermal growth
- growth factor
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- medicament
- gastric
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Abstract
The invention provides application of an epidermal growth factor in preparing a medicament for treating gastric ulcer. The EGF is extracted from artificial or natural sources, including EGF, HEGF, rhEGF, sh-EGF, rh-oligopeptides-1, and sh-oligopeptides-1. The medicine is a medical composition comprising an active agent, an auxiliary agent, a dispersing agent, a wetting agent and/or a suspending agent. The carrier of the epidermal growth factor is water, colloid, hyaluronic acid, natural oil and/or glucose. The medicine is one of capsule, tablet or oral liquid. The invention also provides application of the epidermal growth factor in preparing food for promoting health of digestive tract. The invention provides an application of Epidermal Growth Factor (EGF) in gastric ulcer treatment and gastrointestinal tract health care.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of the medicine in preparation of medicines for treating gastric ulcer.
Background
Gastric ulcers are chronic ulcers that occur between the pylorus and the cardia of the stomach, a common, frequently occurring disease worldwide. Gastric ulcers are ulcers which are formed by gastric acid and pepsin erosion and defence by losing balance between their erosive and defensive actions, gastric acid self-digestion of mucous membrane, helicobacter Pylori (HP) infection, weakening of gastric mucous membrane self-protective barrier, and erosion.
Common medications for gastric ulcers include: antacid drugs such as aluminum hydroxide, aluminum magnesium carbonate, calcium carbonate, magnesium oxide, etc.; h2 receptor antagonists such as famotidine, roxatidine, lafutidine, nizatidine, and the like; proton Pump Inhibitors (PPI) such as lansoprazole, rabeprazole, omeprazole, pantoprazole, and esomeprazole, etc.; anti-helicobacter pylori agents such as clarithromycin, metronidazole, amoxicillin, and the like; gastric mucosa protectants such as bismuth potassium citrate, sucralfate, colloidal bismuth tartrate capsule, teprenone, etc.
However, most commonly used drugs have certain side effects, for example, omeprazole may cause digestive tract symptoms such as abdominal pain and diarrhea, influence calcium absorption, increase the risk of fracture caused by calcium and phosphorus metabolism, increase the risk of anemia caused by inhibition of gastric acid secretion, and the like.
Disclosure of Invention
In view of the above, the first aspect of the present invention proposes the use of an epidermal growth factor in the preparation of a medicament for treating gastric ulcers.
Furthermore, the EGF is extracted from artificial or natural sources, including EGF, HEGF and rhEGF, sh-EGF, rh-oligopeptides-1 and sh-oligopeptides-1.
Further, the molecular weight of the epidermal growth factor is 6.0-6.2kDa.
Further, the medicament is a pharmaceutical composition comprising an active agent, an adjuvant, a dispersing agent, a wetting agent and/or a suspending agent.
Further, the carrier of the epidermal growth factor is water, colloid, hyaluronic acid, natural oil and/or glucose.
Further, the medicine is one of a capsule, a tablet or an oral liquid.
In a second aspect, the invention provides the use of an epidermal growth factor in the manufacture of a food for promoting gut health.
The invention provides an application of Epidermal Growth Factor (EGF) in gastric ulcer treatment and gastrointestinal tract health care, and can achieve the effect of gastric ulcer treatment. EGF can be used as a natural growth promoting factor of gastrointestinal mucosa and has the advantage of small side effect.
Drawings
The accompanying drawings assist in a further understanding of the present application. For convenience of description, only parts related to the related invention are shown in the drawings.
FIG. 1 is a graph showing the change of the surface of gastric mucosal tissue of an experimental mouse according to an embodiment of the present invention;
FIG. 2 is a view showing pathological sections of gastric mucosal tissue of an experimental mouse according to an embodiment of the present invention.
Detailed Description
The present application is described in further detail below with reference to the drawings and examples. The specific embodiments described herein are offered by way of illustration only, and not by way of limitation. Embodiments and features of embodiments in this application may be combined with each other without conflict.
Epidermal growth factor (hereinafter, EGF), a small molecule polypeptide consisting of 53 amino acids, was originally found in the submandibular glands of mice and urine of humans, has been intensively studied for decades. EGF is capable of promoting mitosis during cell culture, i.e., inducing DNA synthesis and cell division, and is detectable in body fluids and in many organs throughout the body. EGF can act on the "neural precursor cell line" at very low nanomolar concentrations, demonstrating its proprietary receptor system. Meanwhile, EGF has been shown to promote cell growth and development. And plays an important role in preventing oxidative stress and apoptosis due to blood flow restriction.
In the early 1980 s, an animal experiment found that, after destroying the major salivary glands of rats, a large area of ulcer wounds appeared in the stomach, meaning that "EGF secreted by the submandibular gland" had a protective effect on the gastric mucosa. Particularly, after the rat is subjected to salivary gland resection, the protection function of EGF is more prominent; compared to the control group, the salivary gland resected rats had reduced DNA and RNA synthesis in the "oxygenic mucosa". In aqueous extracts of salivary gland tissue, it was observed that cell growth of rat acid-secreting mucosa was significantly affected. In another rat experiment, which studied the role of EGF secreted by the mandibular gland, it was shown that saliva containing EGF at physiological concentration significantly reduced the area of gastric ulcer wounds, while saliva without EGF had no effect on gastric ulcer wounds. In rats where salivary glands are resected and ulcers are induced by "cysteamine" (cysteamine) agents, the use of exogenous EGF inhibits "gastrin" and lowers gastric pH, also reversing the decrease in blood flow in the mucosa.
Not only salivary glands, endogenous EGF is produced via the mucosa of the digestive tract, and its receptor is widely present in the epithelial cells of the digestive tract. In previous rat experiments, it was demonstrated that the expression level of EGFR receptor (EGFR) varies at the tissue level during gastroesophageal reflux wound healing. On day 14 after countercurrent treatment with strong acid, both mRNA and protein expression levels of EGF receptor were significantly increased, and the presence of EGF receptor was observed after labeling of most esophageal epithelial basal cells with "immunohistochemical staining" (immunohistochemically staining). Damage caused by reverse flow of strong acid results in an increase in basal cell number, i.e., promotion of cell proliferation and an increase in expression of EGF receptor, meaning that an increased response of EGF receptor to EGF is urgent and critical in the healing process of esophageal mucosa.
EGF receptor is expressed throughout the digestive tract. In normal intact esophageal mucosa, most of the EGF receptor is present in the basal and acanthocyte layers, gradually decreasing toward the "shallow epithelial layer". To cope with the "EGF reduction in damaged gastroesophageal mucosa", the site on the digestive tract that receives EGF (binding sites) can be used as a functional site (functional site) of the luminal EGF. Exogenous EGF, due to its low molecular weight, is accessible to receptors deep in the basal layer by absorption and diffusion, and furthermore, ulcers may lead to the exposure of proliferating cells to the basal layer. Previous experimental and clinical studies have shown that EGF is beneficial in maintaining digestive tract health.
Expression of EGF receptor in patients with "inflammatory digestive tract diseases", such as: patients with inflammatory bowel disease, crohn's disease, ulcerative colitis are under a great degree of negative regulation. The expression level of EGF receptor is inhibited in digestive tract lesions, indicating that EGF-related response is weakened in those diseases. In murine models of colitis, EGF significantly improved the "apical tight junction channel" (apical tight junction) between epithelial cells, reducing mucosal inflammatory responses, and thus alleviating ulcerative lesions. The use of EGF does not cause the deterioration of 'colonitis-related colorectal cancer', but rather inhibits neutrophil infiltration in the mucosa, promoting the mucosa of the lesion area to remain intact. More importantly, EGF was used to significantly reduce a variety of inflammatory cytokines in serum, including interleukin-6 (IL-6) and serum tumor necrosis factor-alpha (TNF-alpha). Endogenous EGF can maintain the homeostasis of the digestive tract, strengthen the integrity of the intestinal barrier, prevent injury, and play an important role in promoting ulcer wound healing.
In the case of highly recurrent gastrointestinal ulcer, helicobacter pylori infection is often combined, and according to the result of histoimmune examination, EGF and EGFR receptor expression of the antrum (antrum) of the disease are found to be significantly increased, but EGF secretion in saliva is not particularly increased, and EGFR receptor expression returns to normal value after successful elimination of helicobacter pylori by antibiotics, and EGF continues to maintain similar concentration as in healthy subjects after infection. The local high demands of EGF at the problem occurrence are shown for gastrointestinal mucosal lesions, whereas according to previous cancer experimental models, there is no known risk of carcinogenesis with exogenous EGF.
Thus, several studies have demonstrated the potential of Epidermal Growth Factor (EGF) in the treatment of gastric ulcers.
Example one
This example demonstrates the effect of EGF in the treatment of gastric ulcers by the animal model of alcohol-induced gastric ulcers. To analyze the gastric protective effect of EGF in mice, the inventors designed animal experiments to induce acute gastric injury in Balb/c mice by oral administration of 75% ethanol and pre-administer EGF (10. Mu.g/400 ul) three days prior to induction. Omeprazole is a proton pump inhibitor and is widely used clinically in diseases caused by gastric hyperacidity, such as gastric ulcer lesions. Therefore, omphalzole was used as the positive control group for the test of this example. After induction with ethanol, mice were sacrificed. And taking down the gastric mucosa tissue of the mouse, and observing the surface change and histopathological section of the gastric mucosa tissue. The specific experimental method is as follows:
step1: animal disease pattern and sample treatment procedure
All animal protocols were performed according to approved methods and according to laboratory animal ethics and recommendations. Purchased from national laboratory animal center. Male Balb/c mice (6-7 weeks old;20-25 g) were divided into four groups:
group one: normal mice group;
group two-ETOH group (ulcer mode group): three consecutive days of water consumption followed by 400ml of 75% ethanol 12 hours after the third day of feeding;
group three-EGF group (sample experimental group): three consecutive days of EGF (400 ul/day, 10. Mu.g EGF) followed by 400ml of 75% ethanol 12 hours after the third day of feeding;
group four-ome group (drug positive control group): three days of omeprazole (20 mg/kg) was orally administered in succession, followed by 400ml of 75% ethanol at 12 hours after the third day of feeding.
Step2: ulcer index study
Mice were sacrificed 4 hours after 75% ethanol administration, stomach tissue was removed, and then the mice' stomach was opened longitudinally, expanded, fixed, and washed with saline. Lesions in the mucosa were examined at 10 x magnification to assess the status of ulcers, as well as the number and severity of each gastric ulcer. The stomach of each animal was recorded with photographs. The ulcer index per animal was calculated using the following scoring system as a record of mucosal lesions from congestion, bleeding to complete erosion:
0, no disease; 1-2, small lesions; 3-4, small ulcers; 5-6, large ulcers; 7. full is an ulcer.
Step3: histological analysis
Rats were sacrificed 4 hours after 75% ethanol administration, stomach tissue was removed, samples of the mice' stomach were fixed in 10% formalin, and wax blocks were made. Serial sections with a thickness of 5 μm were prepared and subjected to conventional hematoxylin and eosin (H & E) staining. Hemorrhagic lesions, epithelial cell lesions and oedema of the gastric mucosa and concomitant leukocyte infiltration were scored, with lesion levels ranging from grade 1 to grade 5 depending on severity:
1 = minimum (< 1%); 2 = slight (1-25%); 3 = medium (26-50%); 4 = moderate/severe (51-75%); 5 = severe/high (76-100%).
Step4: statistical analysis
The ulcer index and the histologically observed lesion index were obtained from individual animals, and the average value of each group was calculated. Data are expressed as mean ± SEM. One-way anova with post hoc Tukey's test was performed on multiple experimental groups using GraphPad Prism v5.0 software (GraphPad Software, inc., san Diego, calif., USA). The statistically significant difference assay p-value was set to 0.05.
Through the experiment, the effect result of EGF on ethanol induced acute gastric injury can be obtained:
first, EGF can significantly slow down the ulceration of gastric mucosal tissue. FIG. 1 is a graph showing the change of the surface of gastric mucosal tissue of the experimental mice in this example, and the gastric mucosal tissue of the ulcer pattern group (ETOH group) shows the symptoms of a large area hemorrhagic ulcer in terms of anatomical observation (FIG. 1-A). The gastric mucosal ulcer index, the extent of lesions, was significantly reduced in mice pretreated with EGF and Omeprazole for three days compared to the ulcer model group (ETOH) lacking any treatment (FIG. 1-B).
Secondly, EGF provides protection effect for stomach wall structure. FIG. 2 is a view of pathological sections of gastric mucosal tissue of the experimental mice in this example, and the ethanol resulted in significant pathological changes in the gastric epithelial tissue of the mice, including hemorrhagic lesions, epithelial cell loss, swelling, and leukocyte infiltration (edema with leucocytes) (FIG. 2-A). However, in the groups pretreated with EGF and Omeprazole, respectively, ethanol-induced gastric epithelial tissue damage was significantly slowed, significantly protecting the stomach wall structure compared to the group of ulcers without any treatment (ETOH), and tissue section staining showed that the stomach wall was nearly intact, with little difference compared to the normal group of mice (FIG. 2-A). The bleeding lesions of the gastric mucosa, as well as the index of epithelial cell lesions, also reached a degree of improvement of the significant statistical difference (fig. 2-B).
The experimental results intuitively show that EGF can effectively improve gastric mucosal injury induced by ethanol, so that the gastric ulcer treatment effect can be achieved through the epidermal growth factor.
Embodiment two
In this embodiment, the epidermal growth factor is not limited in source, and may be extracted from artificial or natural sources, including but not limited to epidermal growth factor (EGF, oligo-1), human epidermal growth factor (hEGF, human Oligopeptide-1), recombinant human epidermal growth factor (rhEGF, sh-EGF, rh-Oligopeptide-1, sh-Oligopeptide-1), etc.
Embodiment three
In this embodiment, the acceptable carrier for the EGF is not particularly limited, and includes but is not limited to active agents, adjuvants, dispersants, wetting agents, suspending agents, and the like, and the group consisting of water, colloids, hyaluronic acid, natural oils, glucose, and the like, to complete the correspondence of the diversified substrates.
Embodiment IV
In this example, the epidermal growth factor enters the human body through any of the carriers described in the second example, and the treatment of gastric ulcer is completed.
Embodiment five
EGF is an important gastrointestinal mucosa protective factor. In the experiment of the first murine model, EGF binding to EGF receptor was demonstrated to promote gut health by promoting gut maturation and maintaining gut epithelial cells in a constant fashion. In this example, the EGF is used to promote health of the digestive tract.
The invention provides the efficacy of EGF in maintaining the health of the digestive tract, especially in treating gastric ulcer, and opens up a new direction of EGF application.
While the present application has been particularly shown and described with reference to a preferred embodiment, 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 application as defined by the appended claims.
Claims (7)
1. The use of epidermal growth factor in the preparation of a medicament for treating gastric ulcers.
2. The use of an epidermal growth factor according to claim 1, wherein said epidermal growth factor has a molecular weight of 6.0-6.2kDa in the manufacture of a medicament for treating gastric ulcers.
3. The use of an epidermal growth factor according to claim 1, wherein said epidermal growth factor is extracted from synthetic or natural sources, including epidermal growth factor EGF, human epidermal growth factor hEGF and recombinant human epidermal growth factors rhEGF, sh-EGF, rh-oligopeptides-1, sh-oligopeptides-1.
4. The use of epidermal growth factor according to claim 1, in the manufacture of a medicament for the treatment of gastric ulcers, wherein said medicament is a pharmaceutical composition comprising an active agent, an adjuvant, a dispersing agent, a wetting agent and/or a suspending agent.
5. The use of an epidermal growth factor according to claim 1, wherein the carrier of said epidermal growth factor is water, colloid, hyaluronic acid, natural oils and/or glucose for the preparation of a medicament for the treatment of gastric ulcers.
6. The use of an epidermal growth factor according to claim 1, in the manufacture of a medicament for treating gastric ulcers, wherein said medicament is one of a capsule, a tablet or an oral liquid.
7. The use of epidermal growth factor in the preparation of a food for promoting digestive tract health.
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