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Pharmaceutical application of tauroursodeoxycholic acid and acceptable salts thereof

A technology of tauroursodeoxycholic acid and inhibitor, which can be used in medical preparations containing active ingredients, drug combinations, anti-tumor drugs, etc. There are literature reports on the physiological effects of prevention and treatment of liver cancer, etc., to achieve the effects of easy acquisition, stability verification, and wide sources.

Inactive Publication Date: 2014-07-16
XIAMEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, Tauroursodeoxycholic Acid Capsules was approved for sale in China under the trade name taurolite in 2007. It is mainly used clinically for the treatment of gallbladder cholesterol stones, primary sclerosing cholangitis and chronic hepatitis C virus. There is no literature reporting that it has the physiological effect of preventing and treating liver cancer, and there is no literature reporting that it has a regulatory effect on the oncogene Yap and UPR signaling pathways

Method used

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  • Pharmaceutical application of tauroursodeoxycholic acid and acceptable salts thereof
  • Pharmaceutical application of tauroursodeoxycholic acid and acceptable salts thereof
  • Pharmaceutical application of tauroursodeoxycholic acid and acceptable salts thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Will 1-2x10 5 HepG2 cells (purchased from Shanghai Shengbo Medical Bioengineering Technology Co., Ltd.) were plated in one well of a 6-well plate, and the HepG2 cells were treated with the control solvent DMSO (dimethyl sulfoxide) and 250 μM TUDCA on the next day, and samples were collected 24 hours later , carry out the following experiments respectively:

[0036]1) Real-time quantitative fluorescent PCR: RNA was extracted, and real-time quantitative fluorescent PCR experiments were carried out using BioRad's iQ SYBR Green Supermix kit and iCycler iQ system (BioRad, Hercules, CA, USA), using the Gapdh gene as an internal reference, and each sample was set 3 replicates, using the delta-delta method to analyze the mRNA levels of Yap and the downstream target gene CTGF (Connection tissue growth factor, connective tissue growth factor) of the transcription factor TEAD in each sample, so as to determine the effect of TUDCA on the transcriptional coactivation activity of Yap...

Embodiment 2

[0042] Wild-type mice (from Xiamen University Experimental Animal Center) and Mst1 / 2 gene knockout (Mst1 / 2DKO) mice (from Harvard Medical School, USA) were taken and divided into TUDCA group and control group respectively. TUDCA (250mg / kg) was injected intraperitoneally once a week, and PBS was injected intraperitoneally twice a week in the control group; mice at different treatment times were dissected in batches, the total liver volume and the number and size of tumors were observed and compared, and wild animals were collected. A part of each of Mst1 / 2 DKO mice and Mst1 / 2 DKO mice were continuously injected with TUDCA or PBS to study the effect of TUDCA treatment on the survival rate and lifespan of Mst1 / 2 DKO mice.

[0043] The results showed that in TUDCA-treated Mst1 / 2DKO mice, the liver / body weight ratio of young mice ( figure 2 A), The size and number of tumors in aged mice were significantly reduced ( figure 2 B), whereas mice treated with the control solvent had n...

Embodiment 3

[0046] The mouse treatment method is the same as in Example 2. The expression and activity of Yap and UPR pathway elements in liver tissue samples of wild-type mice and Mst1 / 2DKO mice, and Mst1 / 2DKO mice treated with or without TUDCA (250 mg / kg) were compared by immunoblotting.

[0047] The results showed that Bip, PERK, p-PERK, p-eIF2α, and spliced ​​ATF6 were significantly up-regulated in Mst1 / 2DKO mouse liver tissue samples compared with control wild-type mice ( image 3 A), indicating that two branches of the UPR pathway, PERK-eIF2 and ATF6-XBP1, are activated. When TUDCA treated Mst1 / 2DKO mice, compared with untreated Mst1 / 2DKO mice, the levels of Bip, PERK and p-eIF2 decreased, while p-Yap increased and CTGF decreased ( image 3 B), illustrating that both Yap activity and activated UPR pathway were inhibited by TUDCA in Mst1 / 2DKO mice.

[0048] This example illustrates that TUDCA can effectively inhibit the activity of Yap and the activation of UPR pathway in Mst1 / 2DKO...

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Abstract

The invention discloses pharmaceutical application of tauroursodeoxycholic acid and acceptable salts thereof. The tauroursodeoxycholic acid can reduce the expression and activity of cancer genes Yap and inhibit the activity of a UPR (unfolded protein response) signal channel component; and as verified in two liver cancer models with Yap activation and UPR signal channel activation functions, the tauroursodeoxycholic acid has an effect of preventing and treating a liver cancer, and has a certain application prospect in preparation of a medicament for preventing and treating the liver cancer, particularly in preparation of a medicament for preventing and treating the liver cancer caused by Yap activation or UPR signal channel activation.

Description

technical field [0001] The invention relates to a pharmaceutical use of tauroursodeoxycholic acid and acceptable salts thereof. Background technique [0002] Liver cancer is one of the most common malignant tumors in the world, and it is a disease with high malignancy and poor prognosis. The annual incidence of liver cancer in China ranks first in the world, and liver cancer is the second leading cause of cancer death in my country and the third in the world. At present, there is still no effective treatment for liver cancer. Surgical resection combined with postoperative interferon and retinoic acid chemotherapy is mainly used in clinic. However, this method is often difficult to completely remove cancer cells, and the tumor is prone to recurrence and metastasis. The high cost of treatment and serious side effects have brought great economic and mental pressure to patients and their families. Therefore, it is necessary to further develop more economical and effective drug...

Claims

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Application Information

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IPC IPC(8): A61K31/575A61P35/00
Inventor 周大旺陈兰芬
Owner XIAMEN UNIV
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