## 3 Results
### Functional Classification of DEGs in Response to GP Extracts
Of the 51 downregulated genes, a GO enrichment analysis revealed that nine genes associated with cell adhesion (GO:0007155) were strongly downregulated (Table S8 and Figure 9A). In addition, two genes related to the positive regulation of viral genome replication (GO:0045070) were strongly downregulated. We found that many downregulated genes were localized to diverse cellular components, such as the synapse (seven genes), neuron part (eight genes), apical part of the cell (four genes), an intrinsic component of the plasma membrane (nine genes), chloride channel complex (two genes), and exocyst (one gene) (Figure 9B). Figure 6: Summary of assigned gene ontology (GO) slim for 176 DEGs. The number of assigned (**A**) upregulated genes and (**B**) downregulated genes according to three categories for GO ontology, namely biological process, cellular component, and molecular function. Figure 8: Significantly enriched GO terms for 125 upregulated genes. Directed acyclic graphs (DAGs) display the most significant GO terms for upregulated genes according to **(A)** biological process and **(B)** cellular component. The DAG displays the hierarchical relationship of identified GO terms. The blue colored boxes indicate the most significant GO terms. The significance is indicated by the color intensity. Figure 7: Enriched gene set for 176 DEGs based on several functional databases. To identify enriched gene sets, enrichment analyses were conducted based on gene ontology (biological process, cellular component, and molecular function), KEGG, Panther, Reactome, and Wikipathway using the WebGestalt program. [PERSON] and red colored bars indicate down- and upregulated genes, respectively. \(p\) < 0.05 was used as a cutoff. An enrichment analysis using the 125 upregulated genes in the KEGG database revealed that folate biosynthesis ( hsa00790) was a significant metabolic pathway (Table S5). In contrast, among the 51 downregulated genes, five metabolic pathways, including neuroactive ligand-receptor interaction ( hsa04080), renin-angiotensin system ( hsa04614), maturity-onset diabetes of the young ( hsa04950), nicotinate and nicotinamide metabolism ( hsa00760), and mucin-type O-glycan biosynthesis ( hsa00512) were significantly enriched (Table S6). Enrichment analyses using the PANTHER database revealed that the circadian clock system (P00015) and vitamin D metabolism and activity pathways (P04396), were significantly enriched in the upregulated genes, while the plasminogen activating cascade (P00050) and axon guidance mediated by Slit/Robo (P00008) pathways were highly enriched in the downregulated genes. Reactome pathway analyses identified 38 and 24 enriched pathways for up- and downregulated genes, respectively. For instance, molecules associated with elastic fibers (R-HSA-2129379), collagen chain trimerization (R-HSA-8948216), and elastic fiber formation (R-HSA-1566948) were identified in the upregulated genes, whereas post-translational protein modification (R-HSA-597592), post-translational modification: synthesis of GPI-anchored proteins (R-HSA-163125), and protein methylation (R-HSA-8876725) were identified in the downregulated genes. Enrichment analysis against the Wikipathway database, providing biological pathways, revealed 18 and 5 enriched pathways for up- and downregulated genes, respectively. Among the upregulated genes were lung fibrosis (WP3624), dopaminergic neurogenesis (WP2855), biogenic amine synthesis (WP550), amino acid metabolism (WP3925), tryptophan metabolism (WP465), heme biosynthesis (WP561), and vitamin D metabolism (WP1531). Among the downregulated genes, splicing factor NOVA regulated synaptic proteins (WP4148), ACE Inhibitor pathway (WP554), and NAD+ biosynthetic pathways (WP3645) were identified. Figure 9: Significantly enriched GO terms for 51 downregulated genes. DAGs display the most significant GO terms for upregulated genes according to (**A**) biological process and (**B**) cellular component. The DAG displays the hierarchical relationship of identified GO terms.