Composition for promoting gastric mucosa injury repair and preparation method thereof

文档序号:13456 发布日期:2021-09-21 浏览:45次 中文

阅读说明:本技术 一种促进胃粘膜损伤修复的组合物及其制备方法 (Composition for promoting gastric mucosa injury repair and preparation method thereof ) 是由 廖群 刘文君 李诒光 许锦珍 边林林 刘慧莹 袁蓉 于 2020-12-18 设计创作,主要内容包括:本发明公开了一种促进胃粘膜损伤修复和抑制幽门螺杆菌的组合物及其制备方法,该组合物包含下述原料制成:小麦低聚肽、猴头菇、牡蛎肽和岩藻多糖;还可进一步添加石斛、白芨胶和益生菌等原料。本发明组合物在修复胃粘膜同时,能够增强机体的抗氧化能力及免疫力,抑制幽门螺杆菌,减轻炎症反应,促进溃疡的愈合,改善病人症状。(The invention discloses a composition for promoting gastric mucosa injury repair and inhibiting helicobacter pylori and a preparation method thereof, wherein the composition is prepared from the following raw materials: wheat oligopeptide, hericium erinaceus, oyster peptide and fucoidin; optionally herba Dendrobii, bletilla gum and probiotic bacteria. The composition can enhance the oxidation resistance and immunity of organisms, inhibit helicobacter pylori, relieve inflammatory reaction, promote ulcer healing and improve symptoms of patients while repairing gastric mucosa.)

1. The composition is characterized by comprising the following raw materials in parts by weight: 1-15 parts of wheat oligopeptide, 0.1-5 parts of hericium erinaceus, 0.5-10 parts of oyster peptide and 0.1-8 parts of fucoidin.

2. The composition according to claim 1, characterized by comprising the following raw materials in parts by weight: 3-10 parts of wheat oligopeptide, 0.5-3 parts of hericium erinaceus, 0.8-5 parts of oyster peptide and 0.5-5 parts of fucoidin.

3. The composition according to claim 2, characterized by comprising the following raw materials in parts by weight: 5 parts of wheat oligopeptide, 1 part of hericium erinaceus, 1 part of oyster peptide and 2.5 parts of fucoidin.

4. The composition according to claim 1, characterized in that it further comprises the following raw materials in parts by weight: 1-12 parts of dendrobium and 0.5-10 parts of bletilla hyacinthine gum.

5. The composition according to claim 4, characterized in that it further comprises the following raw materials in parts by weight: 3-10 parts of dendrobium and 2-7 parts of bletilla hyacinthine gum.

6. The composition according to claim 5, characterized in that it further comprises the following raw materials in parts by weight: one or two of 6 parts of dendrobium and 4 parts of bletilla hyacinthine gum.

7. The composition according to claim 1, characterized in that the composition further comprises 0.7-4.6 parts of probiotics, wherein the probiotics are selected from any one or more of lactobacillus acidophilus, lactobacillus casei, bifidobacterium bifidum and streptococcus thermophilus.

8. The composition according to claim 7, wherein the lactobacillus acidophilus is contained in an amount of 0.2 to 0.8 parts by weight.

9. The composition according to claim 7, wherein the lactobacillus casei is present in an amount of 0.2 to 2 parts by weight.

10. The composition according to claim 7, characterized in that it comprises 0.1 to 1 part by weight of Bifidobacterium bifidum.

11. The composition according to claim 7, wherein the hot streptococcus is contained in an amount of 0.2-0.8 parts by weight.

12. Use of a composition according to any one of claims 1 to 11 for the preparation of a food or a pharmaceutical product for promoting the repair of lesions of the gastric mucosa.

13. Use of a composition according to any one of claims 1 to 11 for the manufacture of a food or pharmaceutical product for inhibiting helicobacter pylori.

Technical Field

The invention belongs to the field of medicine and food health care, and particularly relates to a composition for promoting gastric mucosa injury repair and a preparation method thereof.

Background

The stomach is one of the important organs of the human body, and the main physiological function of the stomach is to receive and digest food, which is the basic guarantee for the normal life of human beings. Has important effect on the health development of human body and mind. However, nowadays with increasingly faster pace of life, many people in the workplace frequently use strong tea and coffee for refreshment when working and staying up at night, and people also smoke and drink without restriction due to the need of remuneration, and also have irregular diet of part of people, often drink too much food or eat too cold or too hot food, and these bad life styles often cause damage to gastric mucosa, and in the past, various stomach diseases can be caused. Therefore, for more and more sub-healthy people with gastric mucosa injury, the composition for promoting the repair of the gastric mucosa injury is provided, and the positive significance is achieved.

Patent document CN110124008A, composition of wheat peptide and fucoidan, and methods for preparing and using the same, discloses a combination of wheat peptide and fucoidan, which aims to relieve diabetic nephropathy and drunkenness symptoms after excessive drinking, and reduce damage or injury of alcohol to gastrointestinal mucosa. Patent document CN104382954A discloses a composition for preventing and treating gastric mucosal injury, which comprises hericium erinaceus, chitosan and wheat oligopeptide, but the composition has no inhibition effect on helicobacter pylori.

At present, the reports of the composition prepared from wheat oligopeptide, hericium erinaceus, oyster peptide and fucoidin on the aspects of promoting gastric mucosa injury repair and inhibiting helicobacter pylori do not exist.

Disclosure of Invention

The invention aims to provide a composition for repairing gastric mucosa, enhancing the oxidation resistance and immunity of the body, inhibiting helicobacter pylori, relieving inflammatory reaction and promoting ulcer

Can heal the disease and improve the symptoms of the patient.

The composition is mainly prepared from wheat oligopeptide, hericium erinaceus, oyster peptide and fucoidin, wherein the hericium erinaceus can be dried hericium erinaceus or hericium erinaceus extract; the composition may further comprise one or more of herba Dendrobii, bletilla gum and probiotic bacteria.

In order to achieve the purpose, the technical scheme of the invention is as follows:

the composition is characterized by comprising the following raw materials in parts by weight: 1-15 parts of wheat oligopeptide, 0.1-5 parts of hericium erinaceus, 0.5-10 parts of oyster peptide and 0.1-8 parts of fucoidin.

Preferably, the composition mainly comprises 3-10 parts of wheat oligopeptide, 0.5-3 parts of hericium erinaceus, 0.8-5 parts of oyster peptide and 0.5-5 parts of fucoidin.

More preferably, the composition mainly comprises 5 parts of wheat oligopeptide, 1 part of hericium erinaceus, 1 part of oyster peptide and 2.5 parts of fucoidin.

The raw materials of the composition further comprise one or two of 1-12 parts of dendrobium and 0.5-10 parts of bletilla hyacinthina gum.

Preferably, the raw materials of the composition further comprise one or two of 3-10 parts of dendrobium and 2-7 parts of bletilla hyacinthine gum.

More preferably, the raw materials of the composition further comprise one or two of 6 parts of dendrobium and 4 parts of bletilla hyacinthine gum.

The raw materials of the composition further comprise 0.7-4.6 parts of probiotics, wherein the probiotics are selected from any one or more of lactobacillus acidophilus, lactobacillus casei, bifidobacterium bifidum and streptococcus thermophilus.

Preferably, the lactobacillus acidophilus is contained in the composition in a weight part of 0.2-0.8 part.

Preferably, the lactobacillus casei is contained in the composition by weight in 0.2-2 parts.

Preferably, the bifidobacterium bifidum is contained in the composition by 0.1 to 1 part by weight.

Preferably, the composition comprises 0.2 to 0.8 part by weight of the hot streptococcus.

In a preferred embodiment of the present invention, the composition of the present invention comprises the following raw materials in parts by weight: 1-15 parts of wheat oligopeptide, 0.1-5 parts of hericium erinaceus, 0.5-10 parts of oyster peptide, 0.1-8 parts of fucoidin and 1-12 parts of dendrobe; preferably, 3-10 parts of wheat oligopeptide, 0.5-3 parts of hericium erinaceus, 0.8-5 parts of oyster peptide, 0.5-5 parts of fucoidin and 3-10 parts of dendrobe; more preferably, the feed comprises 5 parts of wheat oligopeptide, 1 part of hericium erinaceus, 1 part of oyster peptide, 2.5 parts of fucoidin and 6 parts of dendrobium.

In another preferred embodiment of the present invention, the composition of the present invention comprises the following raw materials in parts by weight: 1-15 parts of wheat oligopeptide, 0.1-5 parts of hericium erinaceus, 0.5-10 parts of oyster peptide, 0.1-8 parts of fucoidin and 0.5-10 parts of bletilla hyacinthine gum; preferably, 3-10 parts of wheat oligopeptide, 0.5-3 parts of hericium erinaceus, 0.8-5 parts of oyster peptide, 0.5-5 parts of fucoidin and 2-7 parts of bletilla hyacinthine gum; more preferably, the composition comprises 5 parts of wheat oligopeptide, 1 part of hericium erinaceus, 1 part of oyster peptide, 2.5 parts of fucoidin and 4 parts of bletilla hyacinthine gum.

In another preferred embodiment of the present invention, the composition of the present invention comprises the following raw materials in parts by weight: 1-15 parts of wheat oligopeptide, 0.1-5 parts of hericium erinaceus, 0.5-10 parts of oyster peptide, 0.1-8 parts of fucoidin, 1-12 parts of dendrobe and 0.5-10 parts of bletilla hyacinthine gum; preferably, 3-10 parts of wheat oligopeptide, 0.5-3 parts of hericium erinaceus, 0.8-5 parts of oyster peptide, 0.5-5 parts of fucoidin, 3-10 parts of dendrobe and 2-7 parts of bletilla hyacinthine gum; more preferably, the composition comprises 5 parts of wheat oligopeptide, 1 part of hericium erinaceus, 1 part of oyster peptide, 2.5 parts of fucoidin, 6 parts of dendrobe and 4 parts of bletilla hyacinthine gum.

In a further preferred embodiment of the present invention, the composition of the present invention comprises the following raw materials in parts by weight: 1-15 parts of wheat oligopeptide, 0.1-5 parts of hericium erinaceus, 0.5-10 parts of oyster peptide, 0.1-8 parts of fucoidin, 1-12 parts of dendrobe, 0.5-10 parts of bletilla hyacinthine gum and 0.7-4.6 parts of probiotics; preferably, 3-10 parts of wheat oligopeptide, 0.5-3 parts of hericium erinaceus, 0.8-5 parts of oyster peptide, 0.5-5 parts of fucoidin, 3-10 parts of dendrobe, 2-7 parts of bletilla gum, 0.2-0.8 part of lactobacillus acidophilus, 0.2-2 parts of lactobacillus casei, 0.1-1 part of bifidobacterium bifidum and 0.2-0.8 part of streptococcus thermocatenus.

The wheat oligopeptide is a bioactive peptide separated from wheat protein hydrolysate, has multiple functions of oxidation resistance, inhibition, morphine action, immunoregulation and the like, can stimulate lymphocyte proliferation of an organism, enhances the saliva swallowing function of giant saliva cells, improves the capability of the organism for resisting infection of external pathogens, reduces the morbidity of the organism and the like. In recent years, many researchers find that wheat peptide is closely related to gastrointestinal tract health, and a certain dose of wheat peptide can improve the absorption and utilization of protein by rats, and the possible ways are as follows: promoting the growth of gastrointestinal epithelial cells; the up-regulation of the activity of small intestinal mucosa aminopeptidase and Na + -K + -ATP enzyme; the supplement of the wheat peptide can improve the oxidation resistance of the small intestine of the rat in the plateau training, reduce the generation of oxygen free radicals and effectively prevent the damage of the small intestine mucosa barrier caused by the long-term plateau training.

The hericium erinaceus is a fruiting body of a hericium erinaceus of the family of the dentistry, is an excellent food which is high in protein, low in fat and rich in minerals and vitamins, contains unsaturated fatty acid, can reduce the content of cholesterol and triglyceride in blood, regulates blood fat and is beneficial to blood circulation. According to the record of the compendium of materia Medica: has mild nature and sweet taste, and has the functions of benefiting five internal organs and promoting digestion. Modern researches have also shown that Hericium erinaceus has the effects of invigorating spleen, benefiting stomach, reducing cholesterol, nourishing, resisting cancer, and protecting liver.

The fucoidan of the present invention, also referred to as "fucoidan", is a water-soluble polysaccharide substance composed of fucose (fucose) containing sulfate groups. Fucoidin has multiple biological functions, such as resisting tumor, improving gastrointestinal tract, resisting oxidation, enhancing immunity, resisting thrombi, lowering blood pressure, and resisting virus.

The oyster peptide is prepared by enzymolysis of oyster protein, and has various physiological activities, such as antioxidation, ACE inhibition, anti-inflammation, bacteriostasis, immunity enhancement and the like. Researchers separate polypeptide with the molecular weight less than 10 kDa from the original Plasma (Plasma) of the oyster by an ultrafiltration means, and the oyster polypeptide is found to have a certain antibacterial effect through an antibacterial experiment, which shows that the oyster polypeptide has the antibacterial effect; the Concha Ostreae active peptide with molecular weight below 3 kDa can inhibit lymphocyte function, and has immunosuppressive effect.

The preparation method of the composition for promoting gastric mucosal injury repair provided by the invention comprises the following steps:

(1) weighing wheat oligopeptide, hericium erinaceus, oyster peptide, fucoidin, dendrobe, bletilla gum and probiotics according to the amount, and mixing to obtain a mixed material;

(2) adopting pharmaceutically acceptable carrier or excipient to prepare granules, tablets, capsules, soft capsules, dripping pills, pills or oral liquid according to the conventional pharmaceutical process; or adopting excipient or food additive acceptable on food to prepare food with various forms according to conventional food preparation process.

Compared with the prior art, the invention has the beneficial effects that: can improve immunity, inhibit helicobacter pylori, relieve inflammatory reaction, and promote ulcer healing.

The following experiments further illustrate the beneficial effects of the present invention.

Experiment one: clinical research on protective effect of the invention on gastric mucosa injury

1. Selection criteria for subjects

The test subject is a volunteer subject which meets the diagnosis standard of chronic superficial gastritis and is confirmed to be damaged by gastric mucosa by gastroscope screening.

Diagnosis standard of chronic superficial gastritis: prolonged course of disease, with different degrees of clinical symptoms such as dyspepsia, epigastric pain, heartburn, belching, acid regurgitation, abdominal distension, etc., and mild tenderness of the upper abdomen. The diagnostic standard of the chronic superficial gastritis fiberoptic gastroscope and the biopsy diagnostic standard are met. Patients with gastric ulcer were excluded.

2. Grouping and taking conditions

The subjects were treated with food in 180 cases, wherein 94 men and 86 women were treated with food at an average age of 38.5 (25-60), and the subjects were randomly divided into 6 groups and administered with 100mL of each dose 1 time a day for 30 consecutive days.

3. Test article

Test article 1: dissolving 5g of wheat oligopeptide, 1g of hericium erinaceus, 1g of oyster peptide and 2.5g of fucoidin in purified water, adding a proper amount of sweetening agent, and fixing the volume to 100mL to obtain the oral liquid.

Test article 2: 5g of wheat oligopeptide, 1g of hericium erinaceus, 4g of dendrobium, 1g of oyster peptide, 2.5g of fucoidin, 0.5g of lactobacillus acidophilus, 0.5g of bifidobacterium bifidum, 0.8g of lactobacillus casei and 0.45g of streptococcus thermophilus are dissolved in purified water, and a proper amount of sweetening agent is added to the purified water to achieve a constant volume of 100mL, so that the oral liquid is obtained.

Test article 3: dissolving 0.5g of lactobacillus reuteri powder, 2.9g of lactobacillus rhamnosus, 3g of fructo-oligosaccharide, 0.5g of wheat oligopeptide, 1g of tea polyphenol, 1.5g of astragalus extract, 0.5g of adenophora stricta extract and 0.1g of sodium bicarbonate in purified water, adding a proper amount of sweetening agent, and fixing the volume to 100mL to obtain the traditional Chinese medicine.

Test article 4: dissolving 0.5g of wheat oligopeptide, 1.252g of hericium erinaceus and 1g of chitosan in purified water, adding a proper amount of sweetener, and fixing the volume to 100mL to obtain the oral liquid.

Test article 5: dissolving 5g of wheat oligopeptide and 7.5g of fucoidin in purified water, adding a proper amount of sweetener, and fixing the volume to 100mL to obtain the product.

The test substance 6 comprises 2.8 g of pine pollen peptide, 0.6 g of sea cucumber peptide, 0.7g of oyster peptide, 0.4 g of soybean peptide, 0.3 g of rice peptide, 0.3 g of wheat peptide, 0.6 g of donkey-hide gelatin peptide, 0.4 g of pea peptide, 0.2 g of astragalus root, 0.2 g of fucoidin, 0.6 g of bletilla, 0.5g of dried ginger and 0.7g of inula flower, all the materials are sieved by a 40-mesh sieve and then dissolved in purified water, and a proper amount of sweetening agent is added to fix the volume to 100mL, so as to obtain the product.

4. The main observation indexes are as follows: improvement of clinical symptoms. The symptoms and signs of fullness in the stomach, pain, acid regurgitation, hiccup, belching, tongue pulse, etc. before and after treatment are recorded in detail. Second, before and after the treatment, the gastroscopy is carried out, and the color, bleeding point, congestion and erosion damage degree of the gastric mucosa are observed, and the change before and after the comparison is carried out.

5. The curative effect standard is as follows: the effect is shown: the epigastric pain and other symptoms disappear, and the gastroscopy is improved. Improvement: epigastralgia and other symptoms improve, and gastroscopy improves. No change in epigastric pain and other symptoms, no change in gastroscopy.

6. Results

The results show that the composition can improve the immunity of the organism, inhibit helicobacter pylori and effectively promote the repair of gastric mucosa.

Experiment two: in vivo helicobacter pylori resistance test of the present invention

1. Preparation and grouping of Hp infected mouse models: adaptively feeding Kunming mice for 1 week, fasting and water deprivation for 12h, randomly selecting 15 mice as normal control groups, and molding the rest mice: and (3) per mouse is sterilized by 0.2mL of ethanol after gastric lavage, and normal diet and drinking water are recovered after 2 hours. Then, the pretreated mice are fasted for 12h, and then each mouse is perfused with 0.5mL of Hp bacteria suspension (the bacteria liquid number is 1 multiplied by 109 CFU. mL)-1) This was repeated 4 times every 12 hours. Recovering drinking water after 2h after last gastric lavage. After 5 weeks, tail venous blood was taken and serological examination was performed by urease method, and the patients with positive Hp antibody were considered as successful model building. The mice successfully modeled were randomly divided into 7 groups of 15 mice each, namely a model control group and 1-6 groups of test objects (the formula of each test object is the same as that of experiment 1).

2. The administration condition is as follows: normal control group and model group were given physiological saline in equal amount, and the other groups were given corresponding test substance 1 time a day for 5 weeks.

3. Detection indexes are as follows: fasting for 24 hours after the last administration, killing the mice, and taking blood from eyeballs to perform a rapid urease test; the stomach of the rat is taken out under the aseptic condition, the rat is cut along the greater curvature of the stomach, the residue is washed by sterile physiological saline, and then the antrum part is cut along the longitudinal axis to take antrum tissue for bacteriological smear examination and histological examination so as to determine whether Hp exists.

1) Urease test: adding 100ul of serum or plasma to the test plate sample wells; the results were observed within 15-20 min.

2) Smear microscopy: the mucosa surface of the antrum of the stomach of the mouse is pasted on a glass slide for smear, and microscopic examination is carried out after gram staining.

3) Histological examination: the stomach tissue blocks were fixed with 4% formaldehyde and the tissue sections were subjected to HE staining and Giemsa staining, respectively.

Statistical analysis of experimental data was performed using SPSS software.

4. As a result:

note: p <0.01 for the normal group, and P <0.05 for the model group.

The above results show that: compared with a normal control group, the negative rate of the model control group has significant significance (P < 0.01), which indicates that the molding is successful. Compared with a model control group, the composition can effectively eliminate HP in the stomach of a mouse, and the difference has significance.

Detailed Description

The invention is further described below with reference to examples:

example 1

Weighing the following raw materials in parts by weight: 5 parts of wheat oligopeptide, 1 part of hericium erinaceus, 1 part of oyster peptide and 2.5 parts of fucoidin.

The preparation method comprises the following steps: adopting pharmaceutically acceptable carrier or excipient to prepare granules, tablets, capsules, soft capsules, dripping pills, pills or oral liquid according to the conventional pharmaceutical process;

or adopting excipient or food additive acceptable on food to prepare food with various forms according to conventional food preparation process.

Example 2

Weighing the following raw materials in parts by weight: 1 part of wheat oligopeptide, 0.1 part of hericium erinaceus extract, 0.5 part of oyster peptide and 0.1 part of fucoidin. The preparation method is the same as example 1.

Example 3

Weighing the following raw materials in parts by weight: 3 parts of wheat oligopeptide, 0.5 part of hericium erinaceus, 0.8 part of oyster peptide and 0.5 part of fucoidin. The preparation method is the same as example 1.

Example 4

Weighing the following raw materials in parts by weight: 10 parts of wheat oligopeptide, 3 parts of hericium erinaceus extract, 5 parts of oyster peptide and 5 parts of fucoidin. The preparation method is the same as example 1.

Example 5

Weighing the following raw materials in parts by weight: 15 parts of wheat oligopeptide, 5 parts of hericium erinaceus, 10 parts of oyster peptide and 8 parts of fucoidin. The preparation method is the same as example 1.

Example 6

Weighing the following raw materials in parts by weight: 5 parts of wheat oligopeptide, 0.5 part of hericium erinaceus extract, 2 parts of oyster peptide and 2.5 parts of fucoidin. The preparation method is the same as example 1.

Example 7

Weighing the following raw materials in parts by weight: 5 parts of wheat oligopeptide, 1 part of hericium erinaceus, 4 parts of dendrobium, 1 part of oyster peptide and 2.5 parts of fucoidin. The preparation method is the same as example 1.

Example 8

Weighing the following raw materials in parts by weight: 5 parts of wheat oligopeptide, 1 part of hericium erinaceus extract, 1 part of oyster peptide, 2 parts of fucoidin and 0.5 part of bletilla hyacinthine gum. The preparation method is the same as example 1.

Example 9

Weighing the following raw materials in parts by weight: 10 parts of wheat oligopeptide, 5 parts of hericium erinaceus, 6 parts of dendrobium, 1 part of oyster peptide, 2 parts of fucoidin and 7 parts of bletilla hyacinthine gum. The preparation method is the same as example 1.

Example 10

Weighing the following raw materials in parts by weight: 15 parts of wheat oligopeptide, 1 part of hericium erinaceus, 1 part of oyster peptide, 2 parts of fucoidin, 2 parts of lactobacillus casei and 1 part of bifidobacterium bifidum. The preparation method is the same as example 1.

Example 11

Weighing the following raw materials in parts by weight: 5 parts of wheat oligopeptide, 1 part of hericium erinaceus extract, 1 part of oyster peptide, 2.5 parts of fucoidin, 0.2 parts of lactobacillus acidophilus, 0.2 parts of lactobacillus casei, 0.4 parts of bifidobacterium bifidum and 0.6 parts of streptococcus thermophilus. The preparation method is the same as example 1.

Example 12

Weighing the following raw materials in parts by weight: 5 parts of wheat oligopeptide, 1 part of hericium erinaceus, 4 parts of dendrobium, 4 parts of bletilla hyacinthine gum, 1 part of oyster peptide, 2.5 parts of fucoidin, 0.8 part of lactobacillus acidophilus, 2 parts of lactobacillus casei, 1 part of bifidobacterium bifidum and 0.8 part of streptococcus thermocatenus. The preparation method is the same as example 1.

Example 13

Weighing the following raw materials in parts by weight: 5 parts of wheat oligopeptide, 1 part of hericium erinaceus, 3 parts of dendrobium, 2 parts of bletilla hyacinthine gum, 1 part of oyster peptide, 0.5 part of fucoidin, 0.2 part of lactobacillus acidophilus, 0.2 part of lactobacillus casei, 0.1 part of bifidobacterium bifidum and 0.2 part of streptococcus thermocatenus. The preparation method is the same as example 1.

Example 14

Weighing the following raw materials in parts by weight: 15 parts of wheat oligopeptide, 4 parts of hericium erinaceus, 12 parts of dendrobium, 10 parts of bletilla hyacinthine gum, 10 parts of oyster peptide, 8 parts of fucoidin, 0.5 part of lactobacillus acidophilus, 1 part of lactobacillus casei, 0.5 part of bifidobacterium bifidum and 0.5 part of streptococcus thermocatenus. The preparation method is the same as example 1.

8页详细技术资料下载
上一篇:一种医用注射器针头装配设备
下一篇:一种免疫增强组合物及其应用

网友询问留言

已有0条留言

还没有人留言评论。精彩留言会获得点赞!

精彩留言,会给你点赞!