Search

CN-121512985-B - Application of Slc36a1 agonist in preparation of medicines for preventing and/or treating colonitis

CN121512985BCN 121512985 BCN121512985 BCN 121512985BCN-121512985-B

Abstract

The invention provides an application of an Slc36a1 agonist in preparing a medicament for preventing and/or treating colonitis, and belongs to the technical field of biology. The invention applies 4-GBA or sarcosine to the colonitis model mice, and can obviously improve the clinical and histological phenotype of the colonitis induced by DSS. From colonocytes and mouse experiments, 4-GBA enhances intestinal mucosal barrier by up-regulating Slc36a1, promoting intestinal homeostasis. The invention takes 4-GBA or sarcosine molecules of the targeted Slc36a1 as a core, and breaks through the limitation of the existing treatment strategy by synchronously solving the linkage mechanism of stem cell regeneration-goblet cell differentiation-mucus barrier repair.

Inventors

  • WANG CHUO
  • YANG JIANMING
  • XIAO YAWEN
  • Song Ruofan

Assignees

  • 中国医学科学院医药生物技术研究所

Dates

Publication Date
20260512
Application Date
20260119

Claims (8)

  1. Application of 4-guanidyl butyric acid in preparing a medicament for preventing and/or treating colonitis.
  2. 2. The use of claim 1, wherein said 4-guanidino butyric acid upregulates Slc36a1 expression.
  3. 3. The use of claim 1, wherein the 4-guanidino butyric acid activates intestinal stem cell proliferation, induces goblet cell differentiation in a targeted manner, and upregulates MUC2 protein expression.
  4. 4. The use of claim 1, wherein the colitis comprises bacterial colitis and chemical colitis.
  5. 5. The use according to claim 1, wherein the effective dose of 4-guanidino butyric acid is 50-200mg/kg.
  6. 6. The use of claim 1, wherein the medicament comprises 4-guanidino butyric acid and a pharmaceutically acceptable carrier thereof.
  7. 7. The use according to claim 1, wherein the pharmaceutical dosage form comprises a powder, a granule, a capsule, a tablet, a pill, an injection.
  8. 8. The use according to claim 1, wherein the total active ingredient in the medicament is 0.5-95%.

Description

Application of Slc36a1 agonist in preparation of medicines for preventing and/or treating colonitis Technical Field The invention belongs to the technical field of biology, and particularly relates to application of an Slc36a1 agonist in preparation of a medicament for preventing and/or treating colonitis. Background Inflammatory Bowel Disease (IBD), particularly Ulcerative Colitis (UC), is a chronic recurrent bowel disease, the pathological features of which are destruction of intestinal barrier function, goblet cell depletion, depletion of mucus layers, and imbalance of crypt stem cell homeostasis. The current mainstream clinical treatment strategies rely mainly on immunosuppressants (e.g. corticosteroids) and biological agents (e.g. anti-TNF- α antibodies), but these drugs only temporarily reduce the inflammatory response and do not achieve substantial repair of the intestinal barrier. Long-term use often accompanies complications such as drug dependence, increased infection risk, systemic toxic and side effects and the like. At the mechanism level, the maintenance of intestinal barrier function depends on three major core elements, namely mucin MUC2 secreted by goblet cells forms a physical mucus barrier to prevent pathogen invasion, epithelial tight junction proteins (such as Occlutin and ZO-1) maintain intercellular tightness, and Lgr5 + intestinal stem cells continuously proliferate and differentiate to repair epithelial damage. Although the existing therapy can temporarily inhibit immune response, the triple repair mechanism is difficult to synchronously activate, so that the mucous membrane healing rate is low and the recurrence rate is high. Therefore, the development of novel therapeutic strategies that can simultaneously target barrier repair and stem cell regeneration is an urgent need in the IBD field. Disclosure of Invention In view of the above, the present invention aims to provide an application of the agonist of the Slc36a1 in preparing a medicament for preventing and/or treating colonitis, wherein the agonist of the Slc36a1 uses 4-guanylbutyric acid (4-GBA) or sarcosine molecules targeted to the Slc36a1 as a core, and achieves the purpose of treating colonitis by synchronously solving a linkage mechanism of stem cell regeneration-goblet cell differentiation-mucus barrier repair. In order to achieve the above object, the present invention provides the following technical solutions: The invention provides application of an Slc36a1 agonist in preparing a medicament for preventing and/or treating colonitis, wherein the Slc36a1 agonist comprises one or two of 4-guanylbutyric acid and sarcosine. Preferably, the Slc36a1 agonist upregulates Slc36a1 expression. Preferably, the Slc36a1 agonist activates intestinal stem cell proliferation, induces goblet cell differentiation in a targeted manner, and upregulates MUC2 protein expression. Preferably, the colitis includes bacterial colitis and chemical colitis. Preferably, the effective dose of the Slc36a1 agonist is 50-200mg/kg. The invention provides an application of Slc36a1 as a target in preparing a medicament for screening and preventing and/or treating colonitis. Preferably, the agent that upregulates expression of Slc36a1 has the effect of preventing and/or treating colitis. The invention provides a medicament for preventing and/or treating colonitis, which comprises the Slc36a1 agonist and a pharmaceutically acceptable carrier thereof. Preferably, the dosage forms of the medicine comprise powder, granules, capsules, tablets, pills and injection. Preferably, the total active ingredient in the medicament accounts for 0.5-95%. The invention has the beneficial effects that: The invention discloses a targeting pathway of 'Slc 36a1 agonist- & gt Slc36a 1- & gt stem cell activation +goblet cell differentiation' for the first time, and solves the problem that the existing therapy can not synchronously repair the intestinal mucosa barrier. The potential of the 4-GBA transporter Slc36a1 as a biomarker and a therapeutic target in ulcerative colitis is also provided. Aiming at colonitis treatment, a safe and well-targeted small molecule therapy is provided, which is different from the side effect risk of the traditional anti-inflammatory drug. Drawings FIG. 1 shows the results of a validation of 4-GBA for alleviating enteritis. DAI scoring, colon length measuring result, colon tissue HE staining result, D.AB-PAS staining result, immunohistochemical analysis result of MUC2 protein in colon tissue, F.C. rodenium infected mouse flow chart, colon tissue HE staining result, colon tissue bacteria content result, and feces bacteria content result. FIG. 2 is a 4-GBA safety verification of mice. A. Weight measurement of mice, colon length measurement, and HE staining of colon, liver, kidney and lung tissue. Figure 3 is a demonstration that 4-GBA significantly enhanced intestinal barrier function. A-C immunohistochemical staining analysis of the results of express