The orphan nuclear receptor Nurr1 agonist amodiaquine mediates neuroprotective effects in 6-OHDA Parkinson's disease animal model by enhancing the phosphorylation of P38 mitogen-activated kinase but not PI3K/AKT signaling pathway.

Recent studies implicate the defects or altered expression of the orphan nuclear receptor Nurr1 gene in the substantia nigra in Parkinson's disease pathogenesis. In an attempt to corroborate the treatment-modifying disease that would replicate the effect of Nurr1, it has been found that amodiaquine and Nurr1 had the same chemical scaffolding, indicating a crucial structure-activity relationship. Interestingly, amodiaquine stimulate the transcriptional function of Nurr1 by physical interaction with its ligand-binding domain (LBD). However, the signaling route by which Nurr1 is activated by amodiaquine to cause the protective effect remains to be elucidated. We first demonstrated that amodiaquine treatment ameliorated behavioural deficits in 6-OHDA Parkinson's disease mouse model, and it promoted dopaminergic neurons protection signified by Tyrosine hydroxylase (TH) and dopamine transporter (DAT) mRNA; Tyrosine hydroxylase (TH) protein expression level and the immunoreactivity in the substantia nigra compacta. Subsequently, we used inhibitors to ascertain the effect of amodiaquine on Akt and P38 Mapk as crucial signaling pathways for neuroprotection. Wortmannin (Akt Inhibitor) induced a significant reduction of Akt mRNA; however, there was no statistical difference between the amodiaquine-treated group and the control group suggesting that amodiaquine may not be the active stimulant of Akt. Western blot analysis confirmed that the phosphorylated Akt decreased significantly in the amodiaquine group compared to the control group. In the same vein, we found that amodiaquine substantially increased the level of phosphorylated P38 Mapk. When P38 Mapk inhibited by SB203580 (P38-Mapk Inhibitor), the total P38 Mapk but not the phosphorylated P38 Mapk decreased significantly, while tyrosine hydroxylase significantly increased. These results collectively suggest that amodiaquine can augment tyrosine hydroxylase expression via phosphorylated P38 Mapk while negatively regulating the phosphorylated Akt in protein expression.

SOX1 Is a Backup Gene for Brain Neurons and Glioma Stem Cell Protection and Proliferation.

Failed neuroprotection leads to the initiation of several diseases. SOX1 plays many roles in embryogenesis, oncogenesis, and male sex determination, and can promote glioma stem cell proliferation, invasion, and migration due to its high expression in glioblastoma cells. The functional versatility of the SOX1 gene in malignancy, epilepsy, and Parkinson's disease, as well as its adverse effects on dopaminergic neurons, makes it an interesting research focus. Hence, we collate the most important discoveries relating to the neuroprotective effects of SOX1 in brain cancer and propose hypothesis worthy of SOX1's role in the survival of senescent neuronal cells, its roles in fibroblast cell proliferation, and cell fat for neuroprotection, and the discharge of electrical impulses for homeostasis. Increase in electrical impulses transmitted by senescent cells affects the synthesis of neurotransmitters, which will modify the brain cell metabolism and microenvironment.

Down-Regulated CUEDC2 Increases GDNF Expression by Stabilizing CREB Through Reducing Its Ubiquitination in Glioma.

Abnormally high expression of glial cell line-derived neurotrophic factor (GDNF) derived from glioma cells has essential impacts on gliomagenesis and development, but the molecular basis underlying increased GDNF expression in glioma cells remain unclear. This work aimed to study the molecular mechanisms that may explain the accumulation of GDNF in glioma. Firstly, we observed that cAMP response element-binding protein (CREB), known as an important transcription factor for binding of GDNF promoter region, was highly expressed with an apparent accumulation into the nucleus of glioma cells, which may contribute to the transcription of GDNF. Secondly, CUE domain-containing protein 2 (CUEDC2), a ubiquitin-regulated protein, could increase the amount of binding between the E3 ligase tripartite motif-containing 21 (TRIM21) and CREB and affect the CREB level. Like our previous study, it showed that there was a significantly down-regulation of CUEDC2 in glioma. Finally, our data suggest that GDNF expression is indirectly regulated by transcription factor ubiquitination. Indeed, down-regulation of CUEDC2, decreased the ubiquitination and degradation of CREB, which was associated to high levels of GDNF. Furthermore, abundant CREB involved in the binding to the GDNF promoter region contributes to GDNF high expression in glioma cells. Collectively, it was verified the GDNF expression was affected by CREB ubiquitination regulated by CUEDC2 level.

Identification of COL1A1 as an invasion­related gene in malignant astrocytoma.

Malignant astrocytoma (MA) is the most common and severe type of brain tumor. A greater understanding of the underlying mechanisms responsible for the development of MA would be beneficial for the development of targeted molecular therapies. In the present study, the upregulated differentially expressed genes (DEGs) in MA were obtained from the Gene Expression Omnibus database using R/Bioconductor software. DEGs in different World Health Organization classifications were compared using the Venny tool and 15 genes, including collagen type I α1 chain (COL1A1) and laminin subunit γ1 (LAMC1), were revealed to be involved in the malignant progression of MA. In addition, the upregulated DEGs in MA were evaluated using functional annotations of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes with the Database for Annotation, Visualization, and Integrated Discovery tool. The results indicated that invasion­associated enrichment was observed in 'extracellular matrix' (ECM), 'cell adhesion' and 'phosphoinositide 3­kinase­protein kinase B signaling pathway'. Subsequently, the analysis of the protein­protein interactions was performed using STRING and Cytoscape software, which revealed that the ECM component was the invasion­associated module and its corresponding genes included COL1A1, LAMC1 and fibronectin 1. Finally, survival Kaplan­Meier estimate was conducted using cBioportal online, which demonstrated that COL1A1 expression affected the survival of and recurrence in patients with MA. Moreover, the results of in vitro Transwell assay and western blot analysis revealed that the depleted levels of COL1A1 also decreased the expression of several proteins associated with cell invasion, including phosphorylated­signal transducer and activator of transcription 3, matrix metalloproteinase (MMP)­2, MMP­9 and nuclear factor­κB. On the whole, the present study identified the invasion­related target genes and the associated potential pathways in MA. The results indicated that COL1A1 may be a candidate biomarker for the prognosis and treatment of MA.