CN116726012A - Use of NNMT in diagnosis and treatment of inflammatory bowel disease - Google Patents

Use of NNMT in diagnosis and treatment of inflammatory bowel disease Download PDF

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Publication number
CN116726012A
CN116726012A CN202310256048.8A CN202310256048A CN116726012A CN 116726012 A CN116726012 A CN 116726012A CN 202310256048 A CN202310256048 A CN 202310256048A CN 116726012 A CN116726012 A CN 116726012A
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inflammatory bowel
nnmti
bowel disease
nnmt
disease
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付妤
陈超越
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Tongji Medical College of Huazhong University of Science and Technology
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Tongji Medical College of Huazhong University of Science and Technology
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Abstract

The invention belongs to the field of biological medicine, and particularly discloses an application of NNMT in diagnosis and treatment of inflammatory bowel disease. Use of NNMTi in the manufacture of a medicament for the prevention and treatment of inflammatory bowel diseases, including crohn's disease and ulcerative colitis. Use of an agent for detecting NNMT expression levels in the preparation of a product for diagnosing or detecting inflammatory bowel disease. The invention provides a new treatment scheme for inflammatory bowel disease, and further researches the treatability of NNMTi on Crohn's disease and ulcerative colitis through a DSS mouse model; and simultaneously, a new scheme is provided for detecting inflammatory bowel diseases.

Description

Use of NNMT in diagnosis and treatment of inflammatory bowel disease
Technical Field
The invention belongs to the field of biological medicine, and particularly relates to an application of NNMT in diagnosis and treatment of inflammatory bowel disease.
Background
Inflammatory Bowel Disease (IBD), including Crohn's Disease (CD) and Ulcerative Colitis (UC), is a complex systemic inflammatory immune response caused by a variety of pathogenic factors that manifests as epithelial barrier dysfunction and mucosal immune response imbalance. The onset of IBD is a consequence of altered intestinal immune responses, and is highly affected by host microbiota in addition to genetic susceptibility. Recurrent chronic intestinal inflammation, which is self-sustaining over a long period of time, is likely to lead to the occurrence of colorectal cancer (CRC). Currently, IBD is at a high global incidence, placing a tremendous burden on medical resources, and is considered a major risk factor for colorectal cancer progression. A better understanding of the pathophysiology and molecular biochemistry of IBD onset and progression can provide a new corner for early diagnosis and treatment of IBD disease.
Nicotinamide N-methyltransferase (NNMT) is a cytoplasmic metabolizing enzyme that catalyzes the N-methylation of Nicotinamide (NAM) with s-adenosyl-1-methionine as a methyl donor, producing N1-Methylnicotinamide (MNA), releasing s-adenosyl-1-homocysteine (SAH). NNMT plays a key role in the nicotinic acid and nicotinamide metabolic pathways, and NNMT methylates NAM and facilitates its excretion from the body, thereby reducing the precursor substances for nicotinamide adenine dinucleotide (NAD+) synthesis. Most nad+ catabolic enzymes are inhibited by their product NAM concentration, but NNMT removes excess NAM, contributing to the sustained transduction of nad+ dependent pro-inflammatory signals. Inhibition of NNMT increases nad+ content. There is ample evidence that NAD+ has a regulatory effect on IBD. The role of NNMT inhibitor NNMTi in IBD has not been reported.
Disclosure of Invention
Aiming at the problems, the invention provides the application of NNMT in diagnosis and treatment of inflammatory bowel disease, mainly makes up for the undefined pathogenicity of NNMT in inflammatory bowel disease, also makes up for the study blank of NNMTi in treatment of inflammatory bowel disease, and further studies how to diagnose or detect inflammatory bowel disease and other problems.
In order to solve the problems, the invention adopts the following technical scheme:
the first aspect of the invention relates toNNMTi for preventing and treating inflammationApplication of medicine for treating sexual intestinal diseases is provided. Wherein control means prevention and treatment.
In some embodiments, the inflammatory bowel disease includes crohn's disease and ulcerative colitis.
In some ways, the NNMTi acts to improve intestinal permeability, repair barrier dysfunction in the intestine, improve oxidative stress and inflammatory damage to intestinal tissue.
In some aspects, the NNMTi isThis section focuses on a common NNMTi, but other mature NNMTi should be considered as viable as well, since the present invention verifies the effect of modulating NNMT expression levels on the alleviation of inflammatory bowel disease, which can be more effectively alleviated by inhibiting NNMT expression.
A second aspect of the invention relates toUse of an agent for detecting NNMT expression levels in the preparation of a product for diagnosing or detecting inflammatory bowel disease. Wherein, since NNMT expression level and occurrence of inflammatory bowel disease are in positive correlation, the reagent for detecting NNMT expression level can more specifically assist in diagnosing inflammatory bowel disease, and provide reference for diagnosing diseases. Of course, NNMT expression levels can also be used as an indicator in the diagnosis of inflammatory bowel disease. The reagent for detecting NNMT expression level should also comprise some high-throughput detection products.
In some embodiments, the inflammatory bowel disease includes crohn's disease, ulcerative colitis.
The reagent for detecting NNMT expression level comprises detection products such as primers, antibodies and the like. For example, primers for detecting NNMT expression level
An upstream primer: 5'-CCATCTGTTCTAAAAGAAGGGC-3' the number of the individual pieces of the plastic,
a downstream primer: 5'-GGAGGTGAAGCCTGATTCCA-3'.
The beneficial effects of the invention are as follows:
provides a new treatment scheme for inflammatory bowel disease, and further researches the treatability of NNMTi on Crohn disease and ulcerative colitis through a DSS mouse model; meanwhile, a new scheme is provided for detecting inflammatory bowel diseases.
Drawings
FIG. 1 shows NNMT expression in the intestinal tract and serum of IBD patients;
FIG. 2 is a graph of NNMTi alleviating intestinal inflammation in mice;
FIG. 3 is a graph of NNMTi increasing the expression of mouse intestinal barrier claudin;
FIG. 4 is a graph of NNMTi alleviating oxidative stress and inflammatory injury in the gut of mice.
Detailed Description
The invention is further described below:
1. material
1. Mice: c57BL/6J mice (purchased from Beijing vitamin Torilhua Co., ltd.) were kept under SPF conditions to 20-22g and about 8 weeks old.
2. NNMT inhibitor NNMTi (available from Med Chem Express Co., USA) with molecular formula C 10 H 11 IN 2 Molecular weight is 286.11Da; the purity was 99.64%.
Compound 1:
2. method of
1. A Dextran Sodium Sulfate (DSS) induced colitis mouse model was constructed, with NNMTi intervention.
(1) Grouping of experimental mice: male C57BL/6 mice were randomly divided into a control group, a DSS group, a DSS+1mg/kg NNMTi group and a DSS+10mg/kg NNMTi group, 6 mice/group were adaptively fed for 7 days, and their diet, activity, and urination and defecation conditions were observed and the body weight was weighed.
(2) Intervention of mice:
preparing a solvent: 10% DMSO+40% PEG300+5% Tween-80+45% physiological saline;
control group: normal water was freely drunk for 7 days, and 200ul of the above-mentioned formulation solvent was subcutaneously injected on days 0, 1, 2, 3, 4, 5, 6, 7;
DSS group: mice were given free access to 2.5% dss solution for 7 days, 200ul of the above formulation solvent was injected subcutaneously on days 0, 1, 2, 3, 4, 5, 6, 7;
DSS+1mg/kg NNMTi group and DSS+10mg/kg NNMTi group: mice were free to drink 2.5% DSS solution for 7 days, and 1mg/kg and 10mg/kg NNMTi were dissolved using the above-described formulation solvents, respectively. 200ul of the solution containing 1mg/kg and 10mg/kg NNMTi was subcutaneously injected on days 0, 1, 2, 3, 4, 5, 6, 7.
(3) Record of the general status of mice: after the beginning of the molding, the weight, the behavior of the feces (normal, pasty or watery feces) and the blood-carrying condition (no, occult or obvious macroscopic feces) and the activity condition (active or listlessness) of the mice were recorded every day.
(4) Mice were sacrificed and specimens were collected: on day 7, the mice are sacrificed, after the mice are anesthetized by pentobarbital sodium, the eyeballs are subjected to blood sampling, the abdominal cavity is opened along the midline of the abdomen, a complete straight colon is left from above the rectum to the ileocecum, and the colon length is measured and recorded; while spleen was left and weighed. The colon feces are washed, and the far-end colon tissue is taken and stored at the temperature of minus 80 ℃ for RT-qPCR, western-blot and oxidative stress detection.
(5) Mouse intestinal mucosa permeability assay: each mouse was subjected to intragastric lavage with 200. Mu.l of FITC-dextran 4kd (25 mg/ml), groups of mice were sacrificed after 4 hours of intragastric lavage, and about 500. Mu.l of whole blood samples were taken, left standing at room temperature for 2 hours, centrifuged at 4℃for 15 minutes using a centrifuge 3000rpm, and the supernatant was taken and the fluorescence levels in the serum were detected at 490nm and 520nm using a fluorescence spectrophotometer.
2. Primer sequences for RT-qPCR
Gene Upstream primer Downstream primer
HumanNNMT 5′-CCATCTGTTCTAAAAGAAGGGC-3′ 5′-GGAGGTGAAGCCTGATTCCA-3′
Mouseβ-actin 5'-GTTGGAGCAAACATCCCCCA-3' 5'-CGCGACCATCCTCCTCTTAG-3'
MouseIL-1β 5'-CCTCGTGCTGTCGGACCCATA-3' 5'-CAGGCTTGTGCTCTGCTTGTGA-3'
MouseTNF-α 5'-CCTGTAGCCCACGTCGTAG-3' 5'-GGGAGTAGACAAGGTACAACCC-3'
MouseIL-6 5'-TAGTCCTTCCTACCCCAATTTCC-3' 5'-TTGGTCCTTAGCCACTCCTTC-3'
MouseIFN-γ 5'-CCAGCGCCAAGCATTCAATGAG-3' 5'-GACAATCTCTTCCCCACCCCG-3'
3. Results
As in figure 1, the detection of increased expression of NNMT by RT-qPCR in colon tissue lesion tissue of IBD patients, whereas the expression changes were not evident in other tissues adjacent to colon tissue lesion; elevated expression of NNMT in the serum of patients with active IBD was detected by ELISA and correlated positively with CRP, ESR, NE% of the indicated inflammation level.
As in fig. 2, specific groupings of mice are seen in the methods section. The ratio of the daily body weight of each mouse to the body weight of the mouse on day 0 is measured and calculated, and the average value and standard deviation of each group are calculated; the results show that the average body weight of NNMTi group mice is heavier than that of DSS group and has statistical significance, and the body weight of the NNMTi treated mice with different doses has no statistical difference. Evaluating daily disease activity DAI for each mouse and calculating the mean and standard deviation for each group; the results show that the DAI values of the NNMTi group mice are smaller than those of the DSS group, the NNMTi group mice have statistical significance, and the DAI indexes of the mice under different doses of NNMTi treatment have no statistical difference. RT-qPCR detection shows that NNMTi group treatment successfully reduces NNMT expression of the intestinal tissues of mice. Colon tissues of each group of mice were HE stained and the tissue activity index HAI was evaluated, and colon tissues of NNMTi group mice were found to have HAI significantly lower than DSS group. The average spleen weight of the 10mg/kg NNMTi group mice is lighter than that of the DSS group, and the average colon length of the 10mg/kg group mice is longer than that of the DSS group, and the average spleen weight of the 10mg/kg NNMTi group mice has statistical significance.
As shown in FIG. 3, the four groups of mouse distal colon tissue zonal-junction proteins ZO-1 and occludins were examined by a western-blot method and normalized by the expression of GAPDH, and the column height represents the average value of the ratio of the protein expression level to the internal reference gene GAPDH, and the distance between the horizontal line above the column represents the standard deviation. The results showed that the protein expression of ZO-1 and occludin was increased to a different extent in NNMTi group compared to DSS group mice. FD4 reflects the intestinal permeability of mice, and NNMTi group has higher intestinal permeability than DSS group mice, which proves that NNMTi can repair the intestinal barrier of mice.
As shown in fig. 4, the total oxidative stress related index (T-AOC), glutathione (GSH), superoxide dismutase (SOD) and Malondialdehyde (MDA) of each group of mice were tested, and the results showed that NNMTi intervention alleviated oxidative stress damage of DSS mice colon tissue.
It will be apparent to those skilled in the art that various modifications to the above embodiments may be made without departing from the general spirit and concepts of the invention. Which fall within the scope of the present invention. The protection scheme of the invention is subject to the appended claims.

Claims (8)

  1. Application of NNMTi in preparing medicine for preventing and treating inflammatory bowel disease.
  2. 2. The use according to claim 1, wherein the inflammatory bowel disease comprises crohn's disease and ulcerative colitis.
  3. 3. The use according to claim 1, wherein the NNMTi effect is manifested by an improvement of the permeability of the intestine, a repair of barrier dysfunction of the intestine, an improvement of oxidative stress and inflammatory lesions of the intestinal tissue.
  4. 4. The use according to claim 1, wherein said NNMTi is
  5. 5. Use of an agent for detecting NNMT expression levels in the preparation of a product for diagnosing or detecting inflammatory bowel disease.
  6. 6. The use according to claim 5, wherein the inflammatory bowel disease comprises crohn's disease, ulcerative colitis.
  7. 7. The use according to claim 5, wherein the reagent for detecting NNMT expression level comprises an antibody, a primer.
  8. 8. The use according to claim 7, wherein the primer is
    An upstream primer: 5'-CCATCTGTTCTAAAAGAAGGGC-3' the number of the individual pieces of the plastic,
    a downstream primer: 5'-GGAGGTGAAGCCTGATTCCA-3'.
CN202310256048.8A 2023-03-16 2023-03-16 Use of NNMT in diagnosis and treatment of inflammatory bowel disease Pending CN116726012A (en)

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