Oxidative Stress and Its Modulation by Ladostigil Alter the Expression of Abundant Long Non-Coding RNAs in SH-SY5Y Cells

Abstract

Neurodegenerative disorders, brain injury, and the decline in cognitive function with aging are accompanied by a reduced capacity of cells in the brain to cope with oxidative stress and inflammation. In this study, we focused on the response to oxidative stress in SH-SY5Y, a human neuroblastoma cell line. We monitored the viability of the cells in the presence of oxidative stress. Such stress was induced by hydrogen peroxide or by Sin1 (3-morpholinosydnonimine) that generates reactive oxygen and nitrogen species (ROS and RNS). Both stressors caused significant cell death. Our results from the RNA-seq experiments show that SH-SY5Y cells treated with Sin1 for 24 h resulted in 94 differently expressed long non-coding RNAs (lncRNAs), including many abundant ones. Among the abundant lncRNAs that were upregulated by exposing the cells to Sin1 were those implicated in redox homeostasis, energy metabolism, and neurodegenerative diseases (e.g., MALAT1, MIAT, GABPB1-AS1, NEAT1, MIAT, GABPB1-AS1, and HAND2-AS1). Another group of abundant lncRNAs that were significantly altered under oxidative stress included cancer-related SNHG family members. We tested the impact of ladostigil, a bifunctional reagent with antioxidant and anti-inflammatory properties, on the lncRNA expression levels. Ladostigil was previously shown to enhance learning and memory in the brains of elderly rats. In SH-SY5Y cells, several lncRNAs involved in transcription regulation and the chromatin structure were significantly induced by ladostigil. We anticipate that these poorly studied lncRNAs may act as enhancers (eRNA), regulating transcription and splicing, and in competition for miRNA binding (ceRNA). We found that the induction of abundant lncRNAs, such as MALAT1, NEAT-1, MIAT, and SHNG12, by the Sin1 oxidative stress paradigm specifies only the undifferentiated cell state. We conclude that a global alteration in the lncRNA profiles upon stress in SH-SY5Y may shift cell homeostasis and is an attractive in vitro system to characterize drugs that impact the redox state of the cells and their viability.

The multifaceted perspectives on the regulation of lncRNAs in hepatocellular carcinoma ferroptosis: from bench-to-bedside

“…HDLBP was significantly upregulated in HCC tissues and this upregulation inhibited ferroptosis through stabilizing cytoplasmic ferroptosis-associated lncRNA (lncFAL) [ 131 ]. LncFAL decreased ferroptosis susceptibility through disrupting the ferroptosis suppressor protein 1 (FSP1)-TRIM69 interaction and competitively inhibiting the polyubiquitination and degradation of FSP1 [ 132 ]. These results advocate the considerable potential of targeting FSP1 as a promising therapeutic approach for HCC patients exhibiting upregulated expression of HDLBP or lncFAL, which also implies that targeting ferroptosis-suppressive lncRNAs could offer a novel therapeutic approach for HCC patients.…”

“…The lncRNA GABPB1-AS1 is the antisense transcript of GABPB1 mRNA [ 139 ]. The expression of GABPB1-AS1 might fluctuate in response to stress stimuli [ 132 , 140 ]. Qi et al [ 140 ] have revealed that erastin activated the transcription of GABPB1-AS1, which significantly reduced the expression of GABPB1, resulting in decreased PRDX5 peroxidase expression.…”

Conceptual Framework of the Design of Pleiotropic Drugs against Alzheimer’s Disease

“…This prodrug has been shown to inhibit both AChE and BuChE, which, by decarbamylating this molecule, releases a phenol derivative of rasagiline, a monoamine oxidase B inhibitor (MAO-B), which is also used in Parkinson's disease for its neuroprotective effect. Ladostigil has been involved in clinical trials against Alzheimer's disease and has led to the synthesis of numerous analogues [26][27][28]. Furthermore, based on the same principle, other pleiotropic prodrugs have been designed by exploiting cholinesterase inhibition to release various phenolic drugs, such as hydroxyquinoline with metal-chelator and Aβ inhibitory properties [29] or an indole derivative with 5-HT 6 R-antagonist properties [30].…”