CN109620820B - Application of p-hydroxybenzoic acid in preparing medicine for treating inflammatory bowel disease - Google Patents
Application of p-hydroxybenzoic acid in preparing medicine for treating inflammatory bowel disease Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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Abstract
The invention discloses application of p-hydroxybenzoic acid in preparing a medicament for treating inflammatory bowel disease. Under the condition that the dosage is obviously lower than that of mesalazine, the p-hydroxybenzoic acid can obviously inhibit the increase of disease activity index score of enteritis model mice induced by dextran sodium sulfate, improve the reduction of colon length of colitis model mice, reduce MPO activity of colon of mice and reduce the infiltration of colitis model colon tissue inflammatory cells. Therefore, the p-hydroxybenzoic acid can relieve the inflammatory reaction of a DSS-induced inflammatory bowel disease model mouse, improve the severity of inflammatory bowel disease, and can be used for preparing a medicament for treating inflammatory bowel disease.
Description
Technical Field
The invention relates to application of p-hydroxybenzoic acid, in particular to application of p-hydroxybenzoic acid in preparing a medicament for treating inflammatory bowel diseases.
Background
Inflammatory Bowel Disease (IBD) is an idiopathic inflammatory bowel disease mainly affecting the ileum, rectum and colon, and clinically manifested as diarrhea, abdominal pain and even bloody stool. Inflammatory bowel disease includes Ulcerative Colitis (UC) and Crohn's Disease (CD). Ulcerative colitis is a continuous inflammation of the mucosal layer and submucosa of the colon, and the disease usually affects the rectum first and gradually spreads to the whole colon; crohn's disease is a non-continuous, full-thickness inflammation that affects the entire digestive tract, the most commonly affected areas being the terminal ileum, colon and perianal. UC, a typical inflammatory bowel disease, is better in young and strong years of 30-40 years old, has no sex difference, is manifested by clinical symptoms such as diarrhea, abdominal pain, mucopurulent bloody stool and the like, is complicated by multiple intestinal perforation, polyp, ulcer and the like, has a long course of disease and a high cancer rate, and seriously affects the life quality and survival of patients. Epidemiological studies have shown that UC incidence in european regions is 505/100000 high, in canadian regions 248/100000 and in the united states 214/100000. With the change of life style and diet rules, the incidence of UC in Asia and middle east is increasing year by year.
Currently, drug therapy and surgical resection are the main methods for controlling UC, and the following 5 types of commonly used therapeutic drugs are available: (1) aminosalicylates, such as sulfasalazine and mesalamine; (2) glucocorticoids, such as dexamethasone and beclomethasone dipropionate; (3) immunosuppressants such as 6-mercaptopurine and cyclosporine; (4) biologics such as the TNF-alpha inhibitor infliximab; (5) anti-infective drugs such as metronidazole and ciprofloxacin. The medicines mainly relieve local inflammation of colon and prevent disease progression by inhibiting abnormal immune response, but have the defects of unstable curative effect, more adverse reactions, poor tolerance, unsuitability for long-term administration, high price and the like. Therefore, the finding of the anti-UC medicament with definite curative effect, less adverse reaction and controllable quality has important value.
Disclosure of Invention
The invention aims to provide application of p-hydroxybenzoic acid in preparing a medicament for treating inflammatory bowel diseases.
Through a large number of experiments, the applicant finds that, under the condition that the dosage is obviously lower than that of mesalazine, the p-hydroxybenzoic acid can obviously inhibit the increase of Disease Activity Index (DAI) scores of enteritis model mice induced by dextran sodium sulfate, improve the reduction of the length of the colon of the colitis model mice, reduce the MPO activity of the colon of the mice and relieve the infiltration of inflammatory cells of colon tissues of the colitis model mice. Therefore, the p-hydroxybenzoic acid can relieve the inflammatory reaction of a DSS-induced inflammatory bowel disease model mouse, improve the severity of inflammatory bowel disease, and can be used for preparing a medicament for treating inflammatory bowel disease.
The purpose of the invention is realized by the following technical scheme:
application of p-hydroxybenzoic acid in preparing medicine for treating or preventing inflammatory bowel disease.
The invention also provides a medicament for treating or preventing inflammatory bowel disease, which takes p-hydroxybenzoic acid as an effective component and contains p-hydroxybenzoic acid with a therapeutically effective dose. The dosage form of the medicine can be pharmaceutically acceptable dosage forms, and the dosage forms are capsules, tablets, granules, suppositories, sustained-release agents and the like.
Preferably, the inflammatory bowel disease is ulcerative colitis.
Preferably, the inflammatory bowel disease is DSS-induced colitis.
Drawings
FIG. 1 is a graph of the effect of p-hydroxybenzoic acid on the DAI score of DSS-induced UC mice; wherein normal represents the normal group, DSS represents the model group, HHA (20mg/kg) represents the parahydroxybenzoic acid group, Mesalazine (200mg/kg) represents the Mesalazine group; in comparison with the normal group,##represents p<0.01; comparing with model group<0.05, represents p<0.01。
FIG. 2 is a graph of the effect of p-hydroxybenzoic acid on colon length of DSS-induced UC mice; in comparison with the normal group,##represents p<0.01; comparing with model group<0.05, represents p<0.01。
FIG. 3 is a graph of the effect of p-hydroxybenzoic acid on MPO activity in DSS-induced UC mice; wherein, in comparison with the normal group,##represents p<0.01; comparing with model group<0.05, represents p<0.01。
FIG. 4 is a graph of the effect of p-hydroxybenzoic acid on the pathomorphology of DSS-induced UC mice; wherein normal group, DSS group, HHA (20mg/kg) group, p-hydroxybenzoic acid group and Mesalazine (200mg/kg) group.
Detailed Description
The technical solution of the present invention will be further explained with reference to the specific embodiments.
In animal experiments, 2.5% Dextran Sulfate Sodium (DSS) solution is adopted to induce a C57BL/6 mouse to construct a UC model, the model mouse is administered with parahydroxybenzoic acid and a positive drug mesalazine by gavage, and the improvement effect of parahydroxybenzoic acid on UC is analyzed.
1. Material
1.1 Experimental animals
SPF grade C57BL/6 mice, female, 6-8 weeks old, with a weight of 20 + -2 g, purchased from Schlekschad laboratory animals GmbH, Hunan, license number: SCXK (xiang) 2016-: SYXK 2013-. Feeding in an environment with a temperature of 25 + -2 deg.C and a relative humidity of 55 + -10%, and freely taking food and drinking water. Is suitable for being used after being fed for one week.
1.2 Experimental reagents
P-hydroxybenzoic acid; mesalazine, shanghai love pharmaceutical co ltd, cat #: 151007; dextran sodium sulfate, MP Biomedicals corporation, usa, cat #: 160110; myeloperoxidase (MPO) kit, tokyo institute of bioengineering, lot number: 20170717, respectively; TRIzol reagent, Invitrogen, usa, cat #: 152104, respectively; other reagents are all commercially available analytical reagents, national drug group chemical reagents, Inc.
1.3 Experimental instruments
2. Experimental methods
2.1 establishment of mouse colitis model
To investigate the inhibitory effect of p-hydroxybenzoic acid on DSS-induced colitis in mice, mice were randomly divided into 5 groups: normal group (normal), model group (DSS), parahydroxybenzoic acid (HHA) group (20mg/kg), Mesalazine (Mesalazine) group (100mg/kg), 8 per group. The normal group freely drinks double distilled water; the remaining groups, except the normal group, were free to drink 2.5% DSS for 7 days, followed by tap water for 3 days.
The day of the start of molding was d1, and the body weight of the mouse at this time was recorded as the initial body weight. Gavage (0.1mL/10g) was started on the day of molding, once a day for 10 consecutive days. The dextran sodium sulfate, the p-hydroxybenzoic acid and the mesalazine are dissolved and administered by double distilled water.
2.2 disease Activity index assessment
Observing the mental state, hair color, stool character, activity state, hematochezia and other conditions of the mice every day, recording the weight, diarrhea index and fecal occult blood condition of the mice, and calculating Disease Activity Index (DAI), wherein the DAI is (weight reduction + diarrhea index + fecal occult blood)/3. The DAI scoring criteria are detailed in table 1.
Table 1: DAI scoring criteria
And (3) occult blood detection: by adopting an o-toluidine method, a small amount of excrement is picked by a cotton swab, 0.3mL of o-toluidine glacial acetic acid solution is firstly dripped, then 0.3mL of 3% hydrogen peroxide solution is quickly dripped, and blue brown is positive within 2 min.
2.3 colonic MPO Activity assay
40mg of colon tissue is weighed, Phosphate Buffer Solution (PBS) is added to prepare 10% homogenate, the absorbance (OD) is measured at 460nm according to the instruction of an MPO kit, and the MPO content is calculated according to a formula. The calculation formula is as follows:
MPO viability units/g tissue ═ (assay tube OD value-control tube OD value) × 2/22.6 × sample size (g).
2.4 specimen Collection
Collecting blood from fundus venous plexus 1h after the last administration, standing at 4 deg.C for 2h, centrifuging (3500rpm,4 deg.C) for 15min, sucking upper layer serum, and subpackaging at-80 deg.C for freezing and storing. The colon was removed at a distance of 1cm from the anus, the length of the colon was measured with a ruler and photographed, the colon was washed 2 times with PBS, 0.4cm of the colon was taken from the end close to the rectum, fixed in 4% paraformaldehyde solution, and the remaining colon was frozen at-80 ℃.
2.4 Colon histopathological examination
Taking colon tissues fixed in 4% paraformaldehyde solution (not less than 24H), neutralizing with 5% sodium sulfate solution for 36H, washing with running water overnight, dehydrating with absolute ethanol, embedding in paraffin, dewaxing conventionally, staining with hematoxylin eosin (H & E), sealing with neutral resin, and observing pathological and histological changes of intestinal wall under an optical microscope, wherein the specific scores are as follows: (1) the severity of the intestinal wall inflammation, scored as 1, 2 and 3, represents mild, moderate and severe inflammation, respectively; (2) the severity of the lesions, scored as 1, 2 and 3, i.e., lesions located in the mucosal layer, mucosa and submucosa and transmural lesions; (3) the extent of crypt damage, scored as 1, 2, 3 and 4, was 1/3 crypt damage, 2/3 crypt damage, crypt loss but both surface epithelium intact and crypt surface epithelium are missing.
2.5 data analysis
All data are expressed as means ± s.e.m. and statistical differences between groups were tested using one-way ANONA and Dunnett's in the SPSS software. A p-value less than 0.05 is considered to be significantly different.
3. Results of the experiment
3.1 Effect of P-hydroxybenzoic acid on DSS-induced DAI scores in UC mice
Figure 1 is a graph of the effect of p-hydroxybenzoic acid on the DAI score of DSS-induced UC mice, showing that: DSS-induced colitis mice have a gradual increase in the disease activity index DAI, manifested primarily as weight loss, diarrhea and hematochezia. Compared with a normal group, the DAI score of the mice in the model group is obviously increased (p is less than 0.01); compared with the model group, the DAI of the p-hydroxybenzoic acid group and the mesalazine group is obviously reduced, and the inhibition effect of the p-hydroxybenzoic acid group (p is less than 0.01) on DSS-induced colitis is stronger than that of the positive drug (p is less than 0.05).
3.2 Effect of P-hydroxybenzoic acid on Colon Length of DSS-induced UC mice
Figure 2 is a graph of the effect of p-hydroxybenzoic acid on colon length of DSS-induced UC mice, showing that: compared with the normal group, the colon length of the DSS-induced colitis mouse is obviously shortened (p is less than 0.01). Compared with the model group, the colon shortening (p < 0.01) of the model mouse can be protected by the administration of p-hydroxybenzoic acid through the stomach, and the colon shortening inhibiting capacity of the p-hydroxybenzoic acid is stronger than that of the positive drug (p < 0.05).
3.3 Effect of P-hydroxybenzoic acid on MPO Activity in DSS-induced UC mice
FIG. 3 is a graph of the effect of p-hydroxybenzoic acid on the MPO activity of DSS-induced UC mice, showing that: compared with the normal group, the MPO activity of the mice with DSS-induced colitis is obviously enhanced (p is less than 0.01). Compared with the model group, the gastric lavage of p-hydroxybenzoic acid significantly reduced the MPO activity of the colon of the model mice (p < 0.01), and the MPO activity reducing ability thereof was stronger than that of the positive drug (p < 0.05).
3.4 Effect of P-hydroxybenzoic acid on the pathological morphology of DSS-induced UC mice
As can be seen from FIG. 4, no significant pathological change was observed in colon tissues in the normal group of mice; the colon tissue lesion of the model group mice mainly affects the mucosa and the submucosa, inflammatory cell types are mainly mononuclear macrophages and neutrophils, and the partial mucosa full-layer necrosis of a severe inflammation area forms ulcer. Compared with the normal group, the model group mice have colon tissue inflammatory cell infiltration and crypt damage (p is less than 0.01). Gavage administration of p-hydroxybenzoic acid (p < 0.01) significantly reduced the above histopathological changes compared to the model group, which was more potent in reducing histopathology than the positive drug (200mg/kg, p < 0.05).
4. Conclusion and discussion
Under the condition that the dosage is obviously lower than that of mesalazine, the p-hydroxybenzoic acid obviously improves the weight reduction of a DSS-induced UC model mouse, inhibits the increase of DAI, reduces the reduction of the length of the colon of the mouse caused by the DSS, reduces the MPO activity of the colon of the model mouse, and simultaneously reduces inflammatory cell infiltration and tissue damage.
Claims (6)
1. Application of p-hydroxybenzoic acid in preparing medicine for treating or preventing inflammatory bowel disease.
2. The use according to claim 1, characterized in that said inflammatory bowel disease is ulcerative colitis.
3. The use according to claim 1, characterized in that said inflammatory bowel disease is DSS-induced colitis.
4. The use according to claim 1, wherein said medicament is in a pharmaceutically acceptable dosage form.
5. The use according to claim 4, wherein the dosage form is capsule, tablet, granule, suppository.
6. The use according to claim 4, wherein said dosage form is a sustained release formulation.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1907275A (en) * | 2005-08-02 | 2007-02-07 | 盛华（广州）医药科技有限公司 | Application of p-hydroxybenzoic acid and its analogue in the preparing process of medicine for preventing and treating skin mucous membrane virus infection |
| CN108553456A (en) * | 2016-12-29 | 2018-09-21 | 天津中医药大学 | The new application of benzoic acid and its derivative |
| CN109069456A (en) * | 2017-03-17 | 2018-12-21 | 马来西亚棕榈油委员会 | Anti-oxidant, anti-inflammatory composition with and application thereof |
-
2019
- 2019-01-30 CN CN201910091008.6A patent/CN109620820B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1907275A (en) * | 2005-08-02 | 2007-02-07 | 盛华（广州）医药科技有限公司 | Application of p-hydroxybenzoic acid and its analogue in the preparing process of medicine for preventing and treating skin mucous membrane virus infection |
| CN108553456A (en) * | 2016-12-29 | 2018-09-21 | 天津中医药大学 | The new application of benzoic acid and its derivative |
| CN109069456A (en) * | 2017-03-17 | 2018-12-21 | 马来西亚棕榈油委员会 | Anti-oxidant, anti-inflammatory composition with and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| Polyphenol metabolites from colonic microbiota exert anti-inflammatory activity on different inflammation models;Mar Lorrosa等;《MOLECULAR NUTRITION&FOOD RESEARCH》;20090831;第53卷(第8期);1044-1054 * |
| 溃疡性结肠炎患者血清PGE2、PAF水平变化及其临床意义;李玉生;《实用临床医药杂志》;20100608;第14卷(第11期);17-18 * |
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