Neuroprotective role of FOXA1 in Parkinson's disease: Involvements of NF1 transcription activation and MAPK signaling pathway inhibition.

Forkhead box A1 (FOXA1), a member of the forkhead family of transcription factors, plays a crucial role in the development of various organ systems and exhibits neuroprotective properties. This study aims to investigate the effect of FOXA1 on Parkinson's disease (PD) and unravel the underlying mechanism. Transcriptome analysis of PD was conducted using three GEO datasets to identify aberrantly expressed genes. A mouse model of PD was generated by injecting neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP), resulting in reduced FOXA1 expression. FOXA1 decline was also observed in 1-methyl-4-phenylpyridinium-treated SH-SY5Y cells. Artificial upregulation of FOXA1 improved motor abilities of mice according to rotarod and pole tests, and it mitigated tissue damage, cell loss, and neuronal damage in the mouse substantia nigra or in vitro. FOXA1 was found to bind to the neurofibromin 1 (NF1) promoter, thereby inducing its transcription and inactivating the mitogen-activated protein kinase (MAPK) signaling pathway. Further experimentation revealed that silencing NF1 in mice or SH-SY5Y cells counteracted the neuroprotective effects of FOXA1. In conclusion, this research suggests that FOXA1 activates NF1 transcription and inactivates the MAPK signaling pathway, ultimately ameliorating neuronal damage and motor disability in PD. The findings may offer novel ideas in the field of PD management.

Colonic L-cell impairment in aged subjects with type 2 diabetes leads to diminished GLP-1 production.

AIMS: Glucagon-like peptide 1 (GLP-1) is produced by the L subtype of enteroendocrine cells (EECs). Patients with type 2 diabetes (T2D) exhibit reduced incretin effect, but the pathophysiology and functional change of the L-cells remain unclear. Deciphering the mechanisms of the biological changes in L-cells under T2D conditions may assist in the research of gut-based strategies for T2D therapy. METHODS: We investigated the fasting serum GLP-1 levels and the distribution of colonic L-cells in young and aged participants with and without T2D. Additionally, we established an aged male T2D Wistar rat model subjected to a long-term high-fat and high-fructose (HFHF) diet. Histological investigations and single-cell RNA sequencing (scRNA-seq) analyses were performed to explore the mechanisms underlying functional changes in the colonic EECs. RESULTS: We observed a decline in circulating GLP-1 levels and a reduced number of colonic L-cells in elderly patients with T2D. The mechanisms underlying impaired L-cell formation and disturbed GLP-1 production were revealed using aged T2D rats induced by a long-term HFHF diet. The scRNA-seq results showed that the transcription factors that regulate L-cell commitment, such as Foxa1, were downregulated, and the expression of genes that participate in encoding GLP-1, GLP-1 posttranslational processing, hormone secretion, and nutrient sensing was disturbed. CONCLUSIONS: Taken together, the reduced L-cell lineage commitment and disturbed L-cell functions might be the major cause of the reduced GLP-1 production in aged populations with T2D. Our study provides new insights for identifying novel targets in colonic L-cells for improving endogenous GLP-1 production.

Up-regulated microRNA-132 reduces the cognition-damaging effect of sevoflurane on Alzheimer's disease rats by inhibiting FOXA1.

OBJECTIVE: Some studies have implied the damaging effect of sevoflurane (sevo) on cognitive function in Alzheimer's disease (AD). This research was conducted to explore the effect of microRNA (miR)-132/forkhead-box A1 (FOXA1) axis on cognitive ability of sevo-treated AD rats. METHODS: The condensed-matter Aß1-40-induced AD rats were injected with miR-132- or FOXA1-related plasmids, followed by inhalation with 3% sevo. Then, the cognitive functions of AD rats were assessed. miR-132 and FOXA1 levels in hippocampal tissues of AD rats, and their interaction were identified. RESULTS: miR-132 expression was reduced and FOXA1 mRNA and protein levels were elevated in AD rats. miR-132 targeted FOXA1. Sevo treatment impaired cognitive function in AD rats. Elevated miR-132 or inhibited FOXA1 attenuated sevo-mediated injury in AD rats. Overexpressed FOXA1 rescued the effect of elevated miR-132 in AD rats with sevo treatment. CONCLUSION: Up-regulated miR-132 reduces the cognition-damaging effect of sevo on AD rats by inhibiting FOXA1.

Inflammatory lncRNA AK039862 regulates paraquat-inhibited proliferation and migration of microglial and neuronal cells through the Pafah1b1/Foxa1 pathway in co-culture environments.

Emerging evidences having suggested that particular lncRNAs have a potential effect on PD progression through provoking damage and inflammatory responses of microglia/ dopaminergic cells. In addition, paraquat can be accumulated in human body through various approaches and have an increased risk for Parkinson's disease. However, the specific role and mechanism of lncRNA related to neurotoxic in the progression of PD is unclear. In our study, a mouse PD model was established induced by the intraperitoneal injection of paraquat (5 mg/kg and 10 mg/kg) every three days (10 times). We determined differential expression of lncRNA AK039862 and its potential targeted genes Pafah1b1/Foxa1 in PD mouse model, then we used fluorescence in situ hybridization (FISH) to visualize the cellular distribution of AK039862. Short interfering RNAs (siRNAs) and overexpression plasmids were designed for knockdown or overexpression of AK039862. To simulate the coexisting dopaminergic cells and microglia cells in vitro, we applied several non-contact co-culture models, including conditioned medium and Transwell co-culture systems. Cytotoxicity of PQ was evaluated using bv2 cells with the concentrations: 30, 60 µM, and mn9d cells with the concentrations: 50, 100 µM. As a result, we depicted multiple interesting individual and interactive features of inflammatory lncRNA AK039862 involved in PQ-induced cellular functional effects. First, we detected that AK039862 contributed to the neuronal injury process in PQ-treated mice and co-localization of AK039862 with dopaminergic cells in vivo. And interestingly, we demonstrated that PQ significantly inhibited microglia and dopaminergic cells proliferation and microglia migration in vitro. Further research indicated that the PQ-induced low expression of AK039862 rescued microglia proliferation and migration inhibition via the AK039862/Pafah1b1/Foxa1 pathway. Meanwhile, AK039862 also participated in the interaction between microglia and dopaminergic cells with PQ treatment in non-contact co-culture models. In summary, we found that PQ inhibited the proliferation and migration of microglial cells, and elucidated AK039862 played a key role in PQ-induced neuroinflammatory damage through Pafah1b1/Foxa1. Finally, inflammatory AK039862 is involved in the complex communication between microglia and dopaminergic cells in the environment of PQ damage.

FOXA1 Induces E-Cadherin Expression at the Protein Level via Suppression of Slug in Epithelial Breast Cancer Cells.

Epithelial-to-mesenchymal transition (EMT) is an important process during embryonic development and tumor progression by which adherent epithelial cells acquire mesenchymal properties. Forkhead box protein A1 (FOXA1) is a transcriptional regulator preferentially expressed in epithelial breast cancer cells, and its expression is lost in mesenchymal breast cancer cells. However, the implication of this biased expression of FOXA1 in breast cancer is not fully understood. In this study, we analyzed the involvement of FOXA1 in EMT progression in breast cancer, and found that stable expression of FOXA1 in the mesenchymal breast cancer MDA-MB-231 cells strongly induced the epithelial marker E-cadherin at the mRNA and protein levels. Furthermore, stable expression of FOXA1 was found to reduce the mRNA and protein expression of Slug, a repressor of E-cadherin expression. FOXA1 knockdown in the epithelial breast cancer MCF7 cells reduced E-cadherin protein expression without decreasing its mRNA expression. In addition, FOXA1 knockdown in MCF7 cells up-regulated Slug mRNA and protein expression. Notably, similar to FOXA1 knockdown, stable expression of Slug in MCF7 cells reduced E-cadherin protein expression without decreasing its mRNA expression. Taken together, these results suggest that although FOXA1 can induce E-cadherin mRNA expression, it preferentially promotes E-cadherin expression at the protein level by suppressing Slug expression in epithelial breast cancer, and that the balance of this FOXA1-Slug axis regulates EMT progression.