Small molecule modulators of antioxidant response pathway.
Wooyoung Hur1, Nathanael S Gray
1Department of Cancer Biology, Dana-Farber Cancer Institute, 250 Longwood Ave, Boston, MA 02115, USA.
Current Opinion in Chemical Biology
|January 4, 2011
Summary
Nuclear factor E2-related factor 2 (Nrf2) activates antioxidant genes by targeting the Antioxidant Response Element (ARE). Non-carcinogenic inducers enhance Nrf2 activity, bolstering cellular defenses against oxidative stress and disease.
Area of Science:
- Molecular biology
- Cellular biology
- Pharmacology
Background:
- Nuclear factor E2-related factor 2 (Nrf2) is a key transcription factor regulating cellular defense mechanisms.
- Nrf2 controls the expression of antioxidant and protective genes via the Antioxidant Response Element (ARE).
- Activation of the Nrf2-ARE pathway enhances cellular resistance to oxidative stress and environmental toxins.
Purpose of the Study:
- To review small molecule activators of the Nrf2-ARE pathway.
- To summarize the biological activities of these activators in various disease models.
Main Methods:
- Literature review of small molecule Antioxidant Response Element (ARE) inducers.
- Analysis of their mechanisms of action, focusing on Keap1 interaction.
- Compilation of reported biological activities and protective effects.
Main Results:
- Identified various chemical classes of non-carcinogenic ARE inducers.
- Demonstrated that these inducers enhance Nrf2 transcriptional activity.
- Highlighted the role of S-alkylation of Keap1 cysteines in Nrf2 activation.
- Documented protective effects in multiple disease models.
Conclusions:
- Small molecule ARE inducers represent a promising therapeutic strategy.
- Targeting the Nrf2-ARE pathway offers a means to bolster cellular antioxidant defenses.
- Further research into these compounds could lead to novel treatments for oxidative stress-related diseases.
Related Concept Videos
01:20Radical Autoxidation
The oxidation of an organic compound in the presence of air or oxygen is called autoxidation. For example, cumene reacts with oxygen to form hydroperoxide. Autoxidation involves initiation, propagation, and termination steps. Many organic compounds are susceptible to autoxidation—especially ethers in the presence of oxygen, which form hydroperoxides. Even though this reaction is slow, old ether bottles contain small amounts of peroxide, which leads to laboratory explosions during ether...
01:17Oxidation of Phenols to Quinones
In the presence of oxidizing agents, phenols are oxidized to quinones. Quinones can be easily reduced back to phenols using mild reducing agents. The electron-donating hydroxyl group enhances the reactivity of the aromatic ring, enabling oxidation of the ring even in the absence of an α hydrogen.
o-hydroxy phenols are oxidized to o-quinones and p-hydroxy phenols to p-quinones. Such redox reactions involve the transfer of two electrons and two protons. The reversible redox property is crucial in...
o-hydroxy phenols are oxidized to o-quinones and p-hydroxy phenols to p-quinones. Such redox reactions involve the transfer of two electrons and two protons. The reversible redox property is crucial in...
02:39Positive Regulator Molecules
Mitotic cell division results in daughter cells that exactly resemble the parent cell. However, errors in the DNA replication or distribution of genetic material may lead to genetic mutations that may be passed down to every new cell formed from the resulting abnormal cell. Propagation of such mutant cells is restricted through checkpoint mechanisms present at different stages of the cell cycle. These checkpoints involve regulator molecules that either promote or demote cell cycle events.
01:45Positive Regulator Molecules
To consistently produce healthy cells, the cell cycle—the process that generates daughter cells—must be precisely regulated.
01:46Electron Transport Chain: Complex I and II
The mitochondrial electron transport chain (ETC) is the main energy generation system in the eukaryotic cells. However, mitochondria also produce cytotoxic reactive oxygen species (ROS) due to the large electron flow during oxidative phosphorylation. While Complex I is one of the primary sources of superoxide radicals, ROS production by Complex II is uncommon and may only be observed in cancer cells with mutated complexes.
ROS generation is regulated and maintained at moderate levels necessary...
ROS generation is regulated and maintained at moderate levels necessary...
01:27Redox Reactions
Redox reactions are vital biochemical processes that underpin energy metabolism in cells. These reactions involve the transfer of electrons between molecules, occurring in tandem as oxidation and reduction. Oxidation refers to the loss of electrons, while reduction denotes their gain. This coupling ensures the seamless flow of electrons through metabolic pathways. For example, in bacterial metabolism, glucose undergoes oxidation to carbon dioxide, while oxygen is simultaneously reduced to...