Retinoic acid regulates the ubiquitin–proteasome system in a middle cerebral artery occlusion animal model

Abstract

Background Retinoic acid is a major metabolite of vitamin A and exerts beneficial effects including anti-oxidant and anti-inflammatory activities in neurons. The ubiquitin–proteasome system is an important biological system that regulates cell survival. Ubiquitination regulates protein degradation and plays an important role in oxidative stress. Deubiquitinating enzymes cleave ubiquitin from proteins and control ubiquitination-induced degradation. We detected decreases in ubiquitin carboxy-terminal hydrolase L1, ubiquitin thioesterase OTUB1, and proteasome subunit alpha types 1 and 3 in cerebral ischemic damage. In this study, we investigated whether retinoic acid regulates the expression of deubiquitinating enzymes ubiquitin carboxy-terminal hydrolase L1, ubiquitin thioesterase OTUB1, and proteasome subunit alpha types 1 and 3 in cerebral ischemic injury. Right middle cerebral artery occlusion (MCAO) was performed to induce cerebral ischemic damage in male rats. Retinoic acid (5 mg/kg) or vehicle was intraperitoneally injected every day from 4 days before surgery. Neurological behavioral tests were performed 24 h after MCAO, and right cerebral cortical tissues were collected. Results MCAO damage caused neurological behavioral dysfunction, and retinoic acid alleviated these deficits. The identified proteins decreased in MCAO animals with vehicle, while retinoic acid treatment attenuated these decreases. The results of proteomic study were confirmed by a reverse transcription-PCR technique. Expressions of ubiquitin carboxy-terminal hydrolase L1, ubiquitin thioesterase OTUB1, and proteasome subunit alpha types 1 and 3 were decreased in MCAO animals treated with vehicle. Retinoic acid treatment alleviated these MCAO-induced reductions. The ubiquitin–proteasome system plays an essential role in maintaining cell function and preserving cell shape against ischemic damage. Conclusions These findings suggest that retinoic acid regulates ubiquitin- and proteasome-related proteins including ubiquitin carboxy-terminal hydrolase L1, ubiquitin thioesterase OTUB1, and proteasome subunit alpha types 1 and 3 in a brain ischemia model. Changes in these proteins are involved in the neuroprotective effects of retinoic acid.

Role of the OTUB1/IRF7/NOX4 axis in oxidative stress injury and inflammatory responses in mice with Parkinson's disease

“…Besides, OTUB1 promotes nuclear factor‐κB‐mediated production of inflammatory cytokines in dendritic cells 27 . However, other studies have reported the anti‐oxidative and anti‐apoptosis role of OTUB1 in other neurological disorders, such as cerebral ischemic damage and intracerebral haemorrhage 28,29 . Therefore, we deduced that OTUB1 plays a dual role in neuroprotection in a disease context‐dependent manner.…”

“…27 However, other studies have reported the anti-oxidative and antiapoptosis role of OTUB1 in other neurological disorders, such as cerebral ischemic damage and intracerebral haemorrhage. 28,29 Therefore, we deduced that OTUB1 plays a dual role in neuroprotection in a disease context-dependent manner. Generally, our findings supported the view that OTUB1 inhibition plays a protective role in PD mice by inhibiting OSI and inflammatory responses.…”

Identification of changed proteins by retinoic acid in cerebral ischemic damage: a proteomic study

“…Our previous study showed that retinoic acid alleviates neuronal disorder and infarction, and exerts neuroprotective effects against cerebral ischemia following MCAO [ 20 ]. Previous studies have shown that administration of retinoic acid before and after MCAO surgery has neuroprotective effects [ 22 , 23 , 47 , 59 ]. We administered retinoic acid before MCAO surgery to demonstrate the preventive effect of retinoic acid on ischemic damage induced by MCAO.…”

Post-Translational Modification of ZEB Family Members in Cancer Progression

“…Ubiquitination regulates the activity and levels of proteins. It is associated with various disease such as cancer, autoimmunity and inflammation [ 112 , 113 ]. Therefore, understanding of ubiquitination processes could provide opportunities for the development of new therapeutics [ 114 ].…”