OGG1の小分子阻害剤は,炎症性遺伝子発現と炎症を抑制する

Torkild Visnes^1,2, Armando Cázares-Körner¹, Wenjing Hao³

¹Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, S-171 76 Stockholm, Sweden.

Science (New York, N.Y.)

|November 17, 2018

まとめ

8 - オキシグアニンDNAグリコシラーゼ1 (OGG1) をTH5487阻害剤で標的化すると,炎症が軽減されます. このアプローチはDNA修復を阻害し炎症性遺伝子発現と免疫細胞の増殖を減少させます

科学分野:

分子生物学
免疫学
生物化学

背景:

炎症は反応性酸素種とDNAの損傷,特に8-dihydro-8-oxoguanine (8-oxoG) を含む.
8-オクソガニンのDNAグリコシラーゼ1 (OGG1) は,8-オクソガニンを修復し,その欠乏は炎症に抵抗性を与える.

研究の目的:

炎症に対する治療戦略としてOGG1抑制を調査する.
臨床前モデルの新しいOGG1阻害剤TH5487の有効性を評価する.

主な方法:

選択的なOGG1活性サイト阻害剤であるTH5487の開発.
TH5487をマウスに投与し,その耐受性の評価.
OGG1- DNAの相互作用,核因子 κB (NF-κB) の結合,およびTNF-α刺激に対する遺伝子発現に対するTH5487の効果の分析.

主要な成果:

TH5487は,OGG1の8oxoGへの結合を効果的に阻害し,マウスではよく耐えます.
TH5487は,炎症性遺伝子のプロモーターにおけるTNF-α誘発OGG1- DNAの相互作用を防止する.
OGG1のTH5487による抑制は,NF- kB結合の減少,炎症性遺伝子発現の減少,マウスの肺における免疫細胞の増殖の減少につながる.

結論:

OGG1阻害による酸化DNA修復をターゲットにすることは,炎症状態の管理に有効な戦略です.
TH5487は,DNA修復経路を調節することによって,炎症を予防および治療する治療薬としての可能性を証明しています.

さらに関連する動画

10:17

Methodologies for Studying B. subtilis Biofilms as a Model for Characterizing Small Molecule Biofilm Inhibitors

Published on: October 9, 2016

16.3K

06:57

Author Spotlight: Advancing Gene Editing in Bamboo Leaves for Sustainable Plastic Alternatives

Published on: August 18, 2023

2.3K

関連する概念動画

01:42

What is Gene Expression?

196.7K

Overview
Gene expression is the process in which DNA directs the synthesis of functional products, that is, proteins. Cells can regulate gene expression at various stages. It allows organisms to generate different cell types and enables cells to adapt to internal and external factors.
Genetic Information Flows from DNA to RNA to Protein
A gene is a stretch of DNA that serves as the blueprint for functional RNAs and proteins. Since DNA is made up of nucleotides and proteins consist of amino...

196.7K

01:36

What is Gene Expression?

11.4K

A gene is a stretch of DNA that serves as the blueprint for functional RNAs and proteins. Since DNA is comprised of nucleotides and proteins are comprised of amino acids, a mediator is required to convert the information encoded in DNA into proteins. This mediator is the messenger RNA (mRNA). mRNA copies the blueprint from DNA by a process called transcription. In eukaryotes, transcription occurs in the nucleus by complementary base-pairing with the DNA template. The mRNA is then...

11.4K

01:58

Cell Specific Gene Expression

16.5K

Multicellular organisms contain a variety of structurally and functionally distinct cell types, but the DNA in all the cells originated from the same parent cells. The differences in the cells can be attributed to the differential gene expression. Liver cells, whose functions include detoxification of blood, production of bile to metabolize fats, and synthesis of proteins essential for metabolism, must express a specific set of genes to perform their functions. Gene expression also varies with...

16.5K

01:58

Cell Specific Gene Expression

5.6K

02:35

Chromatin Position Affects Gene Expression

24.8K

Chromatin is the massive complex of DNA and proteins packaged inside the nucleus. The complexity of chromatin folding and how it is packaged inside the nucleus greatly influences access to genetic information. Generally, the nucleus' periphery is considered transcriptionally repressive, while the cell's interior is considered a transcriptionally active area.
Topologically Associated Domains (TADs)
The 3-dimensional positioning of chromatin in the nucleus influences the...

24.8K

02:51

mRNA Stability and Gene Expression

6.7K

The structure and stability of mRNA molecules regulates gene expression, as mRNAs are a key step in the pathway from gene to protein. In eukaryotes, the half-life of mRNA varies from a few minutes up to several days. mRNA stability is essential in growth and development. The absence of the proteins regulating its stability, such as tristetraprolin in mice, can cause systemic issues, including bone marrow overgrowth, inflammation, and autoimmunity.
Cis-acting Elements involved in mRNA stability