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Importance of Redox Homeostasis in Potential Treatment of Disease

Research team led by Dr Lee Wen Hwa of the Genomic Research Centre, Academia Sinica elucidate the roles of GPx7 and GPx8 in monitoring reactive oxygen species which can provide promising therapeutic use.

Many disease are associated with oxidative stress, the accumulation of reactive oxygen species (ROS). The human body has intrinsic mechanisms that activate antioxidant systems to modulate ROS and oxidative stress. Understanding the links between disease and oxidative stress can shed light on disease pathogenesis and potential novel therapeutic options.

In two separate studies the teams studied the molecular mechanisms and disease associations of GPx7 or NPGPx (Nonselenocysteine-containing phospholipid hydroperoxide glutathione peroxidase) and GP8x (Glutathione Peroxidases 8).

The study conducted on GPx7 primarily by Dr Hsieh Yung-Lin and Ph.D student, Su Fang-Yi, demonstrated that mice which had the GPx7 gene knockout displayed physical weakness and lead them to associate with Amyotrophic Lateral Sclerosis (ALS). Collaborating with Dr Tsai Li-Kai of National Taiwan University Hospital and Dr. Chen Kai-Yun of Taipei Medical University, the team found expression of GPx7 to be lower in ALS patients, further confirming clinical significance of GPx7 in ALS.

The team later went on to discover that protein modulation process, O-GlcNAcylation is affected when GPx7 gene is knocked out. This is due to its function in transferring oxidative signals to O-GlcNAcase (OGA) when GPx7 senses ROS to inhibit its enzymatic activity. It was then that the researchers treated GPx7 knockout mic with an OGA inhibitor to test its association with motor neuron degeneration. After three months of treatment the team saw an improvement in their movement and increase in O-GlcNAc levels. Besides the discovery of GPx7 molecular mechanism in oxidative stress, the researchers had created an animal model for studying the pathogenesis of motor neuron disease.

In another research led by Dr Lee Wen Hwa, together with Dr Hsu Jye-Lin, assistant professor from the Development Center for Immunology of China Medical University took a closer look at the molecular mechanisms of GPx8. Prolonged infections in the human gut can lead to severe ulcerative colitis, Crohn’s disease or even colon cancer.

With this in mind, the team set out to understand the role that GPx8 plays as a sensor in immune responses. Through animal tests, they identified two inhibitors where one is able to remove excess free radicals, and another inhibits caspase-4 activity. Both of which showed that it was able to reduce the severity of colitis in GPx8-deficient mice models. The two inhibitors displayed promising results in reducing inflammation and showed potential for further clinical trials.

The research teams looks forward to using their established animal models for further research and discoveries on potential therapies for age-related diseases that involve oxidative stress. [APBN]