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Application of PPAR alpha-UGT (peroxisome proliferator activated receptor alpha-uridine diphosphate glucuronosyl transferase) pathway inhibitor in treating inflammatory bowel diseases

An inflammatory bowel disease and inhibitor technology, applied in the field of new drug research and development, can solve the problems of impairing the patient's immune defense ability, increasing the risk of malignant lesions, and reducing the patient's ability to resist infection.

Inactive Publication Date: 2013-06-12
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the limitation of the selectivity and specificity of the above-mentioned drugs, it will inevitably damage the patient's immune defense ability while treating the disease, resulting in a decrease in the patient's anti-infection ability and an increase in the risk of malignant lesions

Method used

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  • Application of PPAR alpha-UGT (peroxisome proliferator activated receptor alpha-uridine diphosphate glucuronosyl transferase) pathway inhibitor in treating inflammatory bowel diseases
  • Application of PPAR alpha-UGT (peroxisome proliferator activated receptor alpha-uridine diphosphate glucuronosyl transferase) pathway inhibitor in treating inflammatory bowel diseases
  • Application of PPAR alpha-UGT (peroxisome proliferator activated receptor alpha-uridine diphosphate glucuronosyl transferase) pathway inhibitor in treating inflammatory bowel diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0011] Example 1. Replication of DSS-induced chronic colonic inflammation mouse model

[0012] Experimental materials: 20 g of SPF male C57BL / 6 mice (8 weeks old), provided by the Experimental Animal Center of the Academy of Military Medical Sciences;

[0013] Dextran sulfate (DSS, 36000-50000) was purchased from MP Company.

[0014] experimental method:

[0015] 1. The experimental mice need to adapt to the standardized animal room environment for at least 7 days, give standard animal feed, drink autoclaved water, and change the litter in time (2-3 times a week).

[0016] 2. Prepare 2.5% DSS solution: Use autoclaved water to prepare 2.5% DSS solution according to the weight-to-volume ratio. The prepared DSS solution can be stored in a refrigerator at 4°C for one week.

[0017] 3. After the start of the experiment, according to the daily drinking volume of each mouse 5ml, pour the DSS solution of the 2-day drinking water into the mouse water bottle each time. If there is any...

Embodiment 2

[0021] Example 2.qRT-PCR gene expression detection

[0022] Experimental materials: Trizol (Takara, Japan), reverse transcription reagents (Takara, Japan), SYBR Green I PCR kit (Takara, Japan), Bio-Rad CFX series fluorescence quantitation instrument (Biosystems, Bedford, MA).

[0023] Experimental method: Total RNA was extracted with Trizol (Takara, Japan), and the RNA concentration and purity were determined. Reverse transcription was performed using a reverse transcription reagent (Takara, Japan). And with quantitative PCR instrument: Thermal Cycler Dice TM Experiments were performed on Real Time System (Takara, Japan). Primer sequences are shown in Table 1. SYBR Green I PCR kit (Takara, Japan) was used for gene expression research. A three-step method was adopted, the reaction system was 20 μL, the annealing temperature was 60°C, and each sample was repeated three times, and the data processing was performed by ΔΔC t Law.

[0024] Table 1 qRT-PCR primer sequences

...

Embodiment 3

[0027] Embodiment 3.Western Blot detection

[0028] Experimental materials: Bio-Rad electrophoresis instrument; Bio-Rad gel imager. FXR, FGF15, Cyp7a1 antibodies and corresponding secondary antibodies were purchased from Santa Cruz Biotechnology (Santa Cruz, CA). GAPDH antibody was purchased from SunShine Biotechnology (Nanjing, China). Cell lysate: 10mM Tris-HCl (pH7.5), 1mM EGTA, 1mM MgCl2, 1mM β-ME, 1% glycerine, protease inhibitor (containing 1mM DTT and 2mM PMSF).

[0029] experimental method:

[0030] 1. Take an appropriate amount (80-100mg) of fresh tissue samples or properly preserved tissue samples, add 1ml of total protein extraction reagent (or nucleoprotein extraction reagent) containing protease inhibitors, and extract total protein (or nuclear protein extraction reagent) after homogenization protein).

[0031] 2. Protein quantification: Follow the operation instructions of the BCA protein quantification kit to determine the concentration of the sample.

[00...

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Abstract

The invention provides an application of a PPAR alpha-UGT (peroxisome proliferator activated receptor alpha-uridine diphosphate glucuronosyl transferase) pathway inhibitor in treating inflammatory bowel diseases, belongs to the field of new medicine research and development, and in particular relates to discovery of the treatment effect of the PPAR alphas-UGT pathway inhibitor, which is used for relieving hepatic and gall disease complications of inflammatory bowel diseases by controlling the steady equilibrium of bile acid, and reducing the risk that inflammatory bowel diseases are transformed to colon cancer. The application proves that the PPAR alpha-UGT pathway can be remarkably activated in a DSS colonitis mouse due to the detection to mice in intestine PPAR alpha and downstream typical target genes of a normal group and DSS (dextran sodium sulfate) induced colonitis mice by a qRT-PCR (quantitative real-time polymerase chain reaction) technology; and the application discovers and proves that an FXR-FGF15 (farnesoid X receptor-fibroblast growth factor15) negative feedback pathway of bile acid is remarkably inhibited in the colonitis mouse and bile acid synthesis is remarkably increased due to the qRT-PCR technology and an immunohistochemical technology. Therefore, activation of the PPAR alpha-UGT pathway is an initial factor of homeostasis imbalance of bile acid in inflammatory bowel diseases, and the PPAR alpha-UGT pathway inhibitor is expected to become a new target for researching and developing medicines for treating vicious transformation of inflammatory bowel diseases and complications thereof.

Description

technical field [0001] The invention relates to the field of new drug research and development, specifically the application of PPARα-UGT pathway inhibitors to reduce the complications of hepatobiliary diseases of inflammatory bowel diseases and reduce the risk of colon cancer transformation by controlling the homeostasis of bile acids. Background technique [0002] UGT is a biphasic metabolic enzyme located on the endoplasmic reticulum, which can catalyze the combination of a highly lipophilic aglycone and a sugar donor glucuronic acid (UDPGA), thereby increasing the polarity of the lipophilic substrate. Glucuronidation products of most compounds (endogenous substances such as bile acids, bilirubin, steroid hormones, biogenic amines; exogenous substances such as food ingredients, drugs, environmental toxins, carcinogens, etc.) Active reaction, and the increase in water solubility is conducive to its excretion from urine and bile. It has been reported in the literature that...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61P1/00A61P1/16
Inventor 王广基郝海平周雪妍谢杨
Owner CHINA PHARM UNIV
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