Cysteine and homocysteine can be exploited by GPX4 in ferroptosis inhibition independent of GSH synthesis.

Ferroptosis is inhibited by glutathione peroxidase 4 (GPX4), an antioxidant enzyme that uses reduced glutathione (GSH) as a cofactor to detoxify lipid hydroperoxides. As a selenoprotein, the core function of GPX4 is the thiol-dependent redox reaction. In addition to GSH, other small molecules such as cysteine and homocysteine also contain thiols; yet, whether GPX4 can exploit cysteine and homocysteine to directly detoxify lipid hydroperoxides and inhibit ferroptosis has not been addressed. In this study, we found that cysteine and homocysteine inhibit ferroptosis in a GPX4-dependent manner. However, cysteine inhibits ferroptosis independent of GSH synthesis, and homocysteine inhibits ferroptosis through non-cysteine and non-GSH pathway. Furthermore, we used molecular docking and GPX4 activity analysis to study the binding patterns and affinity between GPX4 and GSH, cysteine, and homocysteine. We found that besides GSH, cysteine and homocysteine are also able to serve as substrates for GPX4 though the affinities of GPX4 with cysteine and homocysteine are lower than that with GSH. Importantly, GPX family and the GSH synthetase pathway might be asynchronously evolved. When GSH synthetase is absent, for example in Flexibacter, the fGPX exhibits higher affinity with cysteine and homocysteine than GSH. Taken together, the present study provided the understanding of the role of thiol-dependent redox systems in protecting cells from ferroptosis and propose that GSH might be a substitute for cysteine or homocysteine to be used as a cofactor for GPX4 during the evolution of aerobic metabolism.

Increased activation of the hippocampus during a Chinese character subvocalization task in adults with cleft lip and palate palatoplasty and speech therapy.

This study aimed to explore brain activation in patients with cleft lip and palate (CLP) using a Chinese character subvocalization task, in which the stimuli were selected from a clinical articulation evaluation test. CLP is a congenital disability. Individuals with CLP usually have articulation disorder caused by abnormal lip and palate structure. Previous studies showed that primary somatosensory and motor areas had a significant difference in activation in patients with CLP. However, whether brain activation was restored to a normal level after palatoplasty and speech rehabilitation is not clear. Two groups, adults after palatoplasty with speech training and age-matched and sex-matched controls, participated in this study. Brain activation during Chinese character subvocalization task and behavioral data were recorded using functional MRI. Patients with CLP responded to the target significantly more slowly compared with the controls, whereas no significant difference in accuracy was found between the groups. Brain activation had similar patterns between groups. Broca's area, Wernicke's area, motor areas, somatosensory areas, and insula in both hemispheres, and the dorsolateral prefrontal cortex and the ventrolateral prefrontal cortex in the right hemisphere were activated in both groups, with no statistically significant difference. Furthermore, the two-sample t-test showed that the hippocampus in the left hemisphere was activated significantly in patients with CLP compared with the controls. The results suggested that the hippocampus might be involved in the language-related neural circuit in patients with CLP and play a role of pronunciation retrieval to help patients with CLP to complete the pronunciation effectively.