CN116514701A - Indolic acid derivative for relieving colonitis and application thereof - Google Patents

Indolic acid derivative for relieving colonitis and application thereof Download PDF

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Publication number
CN116514701A
CN116514701A CN202310499686.2A CN202310499686A CN116514701A CN 116514701 A CN116514701 A CN 116514701A CN 202310499686 A CN202310499686 A CN 202310499686A CN 116514701 A CN116514701 A CN 116514701A
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China
Prior art keywords
des
mice
dss
colonitis
colon
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Pending
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CN202310499686.2A
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Chinese (zh)
Inventor
许庆彪
侯金秀
司文瑾
李健雄
黄威鸣
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Hubei Huntide Biotech Co ltd
Huazhong Agricultural University
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Hubei Huntide Biotech Co ltd
Huazhong Agricultural University
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Priority to CN202310499686.2A priority Critical patent/CN116514701A/en
Publication of CN116514701A publication Critical patent/CN116514701A/en
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04Indoles; Hydrogenated indoles
    • C07D209/30Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses an indolic acid derivative for relieving colonitis and application thereof. The 5-methoxy-2-methyl-3-indoleacetic acid (DES) provided by the invention has no toxic or side effect on animals. The DES provided by the invention can obviously reduce DAI index of mice during DSS induced colonitis and lighten the shortening of colon. The DES provided by the invention can relieve obvious damage to colon tissues of mice induced by DSS, wherein the obvious damage comprises replacement of individual intestinal gland disappearance by proliferated connective tissue, reduction of goblet cell quantity and small quantity of lymphocyte infiltration around the mice. The concentrations of the pro-inflammatory cytokines TNF- α, IL-6, IL-8 and IL-1β were significantly reduced in colon tissue of DES-intervention group mice compared to model group mice. DES intervention reduces serum immunoglobulin IgA, igG concentrations.

Description

Indolic acid derivative for relieving colonitis and application thereof
Technical Field
The invention relates to the field of colonitis, in particular to an indolic acid derivative for relieving colonitis and application thereof.
Background
Inflammatory Bowel Disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract consisting of ulcerative colitis and crohn's disease clinically. IBD has become increasingly popular worldwide in recent years. IBD has been found to be associated with deregulation of the gut microbiota. It was found that changes in microbiota modulate the host immune system by modulating tryptophan (Trp) metabolism. Furthermore, bacterial Trp metabolites (indoles, tryptamines, etc.) have profound effects on gut microbiota composition, microbial metabolism, host immune system-gut microbiota interactions. Indole is a major bacterial Trp metabolite that regulates bacterial movement, biofilm formation, antibiotic resistance, and its production is catabolized by tryptophan enzymes as a key molecule between microbial and host metabolism. The effect of indole acid derivatives on intestinal microbiota and intestinal homeostasis is reported. The streptococcus mutans is capable of producing an indole acid derivative to promote intestinal epithelial barrier function and reduce inflammatory response to inhibit inflammation. The indole acid derivatives enhance IL-10 production and mucin gene expression following LPS stimulation. Mucin can be used as an energy source by symbiotic bacteria and IL-10 can act as an anti-inflammatory cytokine. Thus, the indole acid derivative has an important anti-inflammatory function in the intestinal tract, stimulating the production of the indole acid derivative to promote an anti-inflammatory response has a therapeutic effect. Aschersonia can metabolize Trp to indopropionic acid, thereby protecting mice from DSS-induced colitis.
In recent years, the anti-inflammatory activity of indoleacetic acid derivatives has been attracting attention from researchers at more and more countries, but the anti-inflammatory mechanism of the indoleacetic acid metabolites is not clear.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides an indole acid derivative for relieving colonitis and application thereof. In order to achieve the above purpose, the technical scheme of the invention is as follows:
the invention provides an indolic acid derivative for relieving colonitis, which is 5-methoxy-2-methyl-3 indoleacetic acid (DES).
The invention also provides an application of the 5-methoxy-2-methyl-3-indoleacetic acid in preparing medicines or foods for preventing or treating colonitis.
Further, the colitis is Dextran Sodium Sulfate (DSS) -induced colitis.
Still further, the concentration of DES in the medicament or foodstuff is from 0.1 to 0.4mg/mL.
Still further, the concentration of DES in the medicament or foodstuff is 0.2mg/mL.
The invention also provides application of the DES in preparing a medicament for treating diarrhea of piglets, lambs or calves.
The invention also provides a product for preventing or treating colonitis, which contains DES with the concentration of 0.1-0.4 mg/mL.
Further, the product contained DES at a concentration of 0.2mg/mL.
Still further, the product is a pharmaceutical or food or feed.
The invention has the beneficial effects that:
(1) The indole acid derivative provided by the invention, namely 5-methoxy-2-methyl-3-indoleacetic acid (DES), has no toxic or side effect on animals.
(2) The DES provided by the invention can obviously reduce DAI index of mice during DSS induced colonitis and lighten the shortening of colon.
(3) The DES provided by the invention can relieve obvious damage to colon tissues of mice induced by DSS, wherein the obvious damage comprises replacement of individual intestinal gland disappearance by proliferated connective tissue, reduction of goblet cell quantity and small quantity of lymphocyte infiltration around the mice.
(4) The concentrations of the pro-inflammatory cytokines TNF- α, IL-6, IL-8 and IL-1β were significantly reduced in colon tissue of DES-intervention group mice compared to model group mice.
(5) DES intervention reduced serum immunoglobulin IgA, igG concentrations compared to model mice.
Drawings
FIG. 1 is a graph of DAI index, colon morphology and colon length for different groups of mice;
FIG. 2 is a graph showing colon tissue HE staining and intestinal tissue injury scores of different groups of mice;
FIG. 3 is a graph showing the cytokine levels of mice of different groups.
Detailed Description
The present invention is described in further detail below in conjunction with specific embodiments for understanding by those skilled in the art.
EXAMPLE 1DES control Effect on DSS-induced mouse colitis
(1) C57BL/6 mice (16-18 g) 30 were randomly divided into 3 groups, each designated as: a Control group (Control), a modeling group (DSS), and a DES intervention group (dss+des); 10 per group were employed.
(2) Processing a blank Control group (Control), a modeling group (DSS) and a DES intervention group (DSS+DES); the processing method of the DES intervention group (DSS+DES) comprises the following steps: on days 1-17 of the experiment, 200 μl of DES solution was infused daily into DES intervention group (dss+des), and distilled water was freely drunk; wherein, on the 8 th to 14 th days of the experiment, 3% DSS solution is required to be drunk;
the processing method of the building module (DSS) comprises the following steps: on the 1 st to 17 th days of the experiment, 200 mu L of physiological saline is infused into the stomach every day, and distilled water is freely drunk; wherein, on the 8 th to 14 th days of the experiment, 200 mu L of 3% DSS solution of stomach is additionally filled, and 3% DSS water is freely drunk;
the processing method of the blank Control group (Control) is as follows: during the experiment, 200 mu L of normal saline for stomach is infused into the control group every day, and distilled water is freely drunk.
During the molding period, each group of mice was tested for diarrhea index changes.
After the modeling was completed, the blank Control group (Control), the modeling group (DSS), and the DES intervention group (dss+des) were sacrificed, the whole colon (cecum end to anus) was rounded, the colon length was measured, and the appearance of the colon was observed. Distal colon tissue 1cm was fixed, dehydrated, embedded, HE stained, and colon tissue HE stained from different groups of mice was observed and scored.
At the end of the modeling period, the DAI index of the DSS mice was raised to 5.6, while the DAI index of the DES intervention group (dss+des) mice was lowered to 3.2 (see fig. 1A).
From FIGS. 1B and C, it can be seen that the colon length of the normal group mice is 6.1cm, the colon length of the DSS model group mice is only 5.2cm, and the colon length of the DES intervention group (DSS+DES) is significantly increased to 6.1cm.
From fig. 2A, it can be seen that the colon tissue structure of DES intervention group (dss+des) is similar to that of normal group, and the intestinal tissue is clear in each layer; the epithelium of the mucosal layer is intact, the epithelial cells are normal in morphology, and no obvious inflammatory changes are seen. Whereas DSS-induced inflammatory lesions in the colon tissue were evident in mice, the colon tissue lesion score was also significantly lower in DES intervention group (dss+des) than in DSS group (see fig. 2B).
Thus, DES can relieve symptoms of acute colitis and colon tissue damage, significantly alleviating colitis.
Example 2 immunomodulatory effects of DES on DSS-induced colitis mice the procedure of steps (1) - (2) of example 1 is followed;
killing mice after molding obtained in step (2) in example 1, taking blank Control group (Control), molding module (DSS), and DES interventionGroup%Dss+des) colon tissue detects biochemical indexes in the supernatant of the colon tissue according to a colon tissue biochemical index determination method, wherein the biochemical indexes comprise TNF-alpha content, IL-6 content, IL-8 content, IL-1 beta content and serum IgA and IgG content.
As can be seen from FIGS. 3A-D, DSS treatment increased the concentrations of the pro-inflammatory cytokines TNF- α, IL-6, IL-8 and IL-1β, whereas DES treatment significantly decreased the concentrations of TNF- α and IL-6, IL-8 and IL-1β. In addition, DES intervention reduced serum immunoglobulin IgA and IgG concentrations (see figures 3E and F). Thus, immune response in the gut is significantly improved following DES intervention, alleviating excessive immune system activation by DSS.
Other parts not described in detail are prior art. Although the foregoing embodiments have been described in some, but not all, embodiments of the invention, it should be understood that other embodiments may be devised in accordance with the present embodiments without departing from the spirit and scope of the invention.

Claims (9)

1. An indoloic acid derivative for alleviating colitis, characterized in that: the indoloic acid derivative is 5-methoxy-2-methyl-3-indoleacetic acid.
2. Use of 5-methoxy-2-methyl-3-indoleacetic acid according to claim 1 for the preparation of a medicament or food for the prevention or treatment of colitis.
3. The use according to claim 2, characterized in that: the colitis is dextran sodium sulfate induced colitis.
4. A use according to claim 3, characterized in that: in the medicine or the food, the concentration of the 5-methoxy-2-methyl-3-indoleacetic acid is 0.1-0.4 mg/mL.
5. A use according to claim 3, characterized in that: the concentration of 5-methoxy-2-methyl-3-indoleacetic acid in the medicine or food is 0.2mg/mL.
6. Use of 5-methoxy-2-methyl-3-indoleacetic acid according to claim 1 for the preparation of a medicament for the treatment of diarrhea in piglets, lambs or calves.
7. A product for preventing or treating colitis, characterized in that: the concentration of the 5-methoxy-2-methyl-3-indoleacetic acid in the product is 0.1-0.4 mg/mL.
8. The product of claim 7, wherein: the concentration of 5-methoxy-2-methyl-3-indoleacetic acid in the product is 0.2mg/mL.
9. The product according to claim 7 or 8, characterized in that: the product is a drug or a food or a feed.
CN202310499686.2A 2023-05-06 2023-05-06 Indolic acid derivative for relieving colonitis and application thereof Pending CN116514701A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT270632B (en) * 1963-02-01 1969-05-12 Merck & Co Inc Process for the preparation of new α- (3-indolyl) acetic acids, their esters and salts
CN1384741A (en) * 1999-08-30 2002-12-11 范德比尔特大学 Selective COX-2 inhibitory novel esters from indolealkanols and novel amides from indolealkylamines
CN113975272A (en) * 2021-11-29 2022-01-28 西安交通大学 Application of indoleacetic acid (IAA) in preparation of medicine for preventing or treating inflammatory bowel disease

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT270632B (en) * 1963-02-01 1969-05-12 Merck & Co Inc Process for the preparation of new α- (3-indolyl) acetic acids, their esters and salts
CN1384741A (en) * 1999-08-30 2002-12-11 范德比尔特大学 Selective COX-2 inhibitory novel esters from indolealkanols and novel amides from indolealkylamines
CN113975272A (en) * 2021-11-29 2022-01-28 西安交通大学 Application of indoleacetic acid (IAA) in preparation of medicine for preventing or treating inflammatory bowel disease

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
G.P. KALASKAR等: ""Synthesis and evaluation of in vivo anti-inflammatory activity of indole-3-acetic acids"", 《INDIAN JOURNAL OF HETEROCYCLIC CHEMISTRY》, 31 December 2007 (2007-12-31), pages 325 - 328 *
YINGYIN XU等: ""Tremella fuciformis Polysaccharides Inhibited Colonic Inflammation in Dextran Sulfate Sodium-Treated Mica via Foxp3+ T Cells, Gut Microbiota, and Bacterial Metabolites"", 《TPS ALLEVIATED COLONIC INFLAMMATION》, vol. 12, 30 April 2021 (2021-04-30), pages 1 - 15 *

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