Mechanistic study of Coriandrum sativum on neuritogenesis and synaptogenesis based on computationally guided in vitro analyses.

ETHNOPHARMACOLOGICAL RELEVANCE: Acceleration of neurite outgrowth and halting neurodegeneration are the most critical factors that are negatively regulated in various neurodegenerative diseases or injuries in the central nervous system (CNS). Functional foods or nutrients are considered alternative sources of bioactive components to alleviate various CNS injuries by promoting neuritogenesis and synaptogenesis, while their exact molecular mechanism remains unexplored. AIM OF THE STUDY: Coriandrum sativum L. (CS) is one of the popular herbs in the Apiaceae family, of which CNS modulating action is a well-documented traditionally but detailed study on memory boosting function yet remains unexplored. Consequently, this study aims to analyze the neurogenic and synaptogenic modulation of CS aqueous ethanol (CSAE) extract in the primary hippocampal neurons. MATERIALS AND METHODS: Primary hippocampal neurons were cultured and allowed to incubate with CSAE or vehicle. To observe the early neuronal differentiation, axonal and dendritic arborization, and synapse formation, neurons were immune-stained against indicated antibodies or stained directly with a lipophilic dye (1, 1'-dioctadecyl-3, 3, 3', 3'-tetramethyl indocarbocyanine perchlorate, DiL). Meanwhile, western blot was used to validate the synaptogenesis effect of CSAE compared to vehicle. Additionally, molecular docking and system pharmacology approaches were applied to confirm the possible secondary metabolites and pathways by which CSAE promotes neuritogenesis. RESULTS: Results show that CSAE can induce neuritogenesis and synaptogenesis at 30 µg/mL concentration. The treatment impacts early neuronal polarization, axonal and dendritic arborization, synaptogenesis, and synaptic plasticity via NMDARs expressions in primary neurons. In silico network pharmacology of CS metabolites show that the CSAE-mediated neurogenic effect is likely dependent on the NTRK2 (TrkB) mediated neurotrophin signaling pathway. Indeed, the observed neurogenic activity of CSAE is markedly reduced upon the co-treatment with a TrkB-specific inhibitor. Furthermore, molecular docking following binding energy calculation shows that one of the CS metabolites, scoparone, has a high affinity to bind in the BDNF mimetic binding site of TrkB, suggesting its role in TrkB activation. Scoparone was found to enhance neuritogenesis, but not to the same extent as CSAE. Moreover, the expression of TrkB signaling-related proteins (BCL2, CASP3, GSK3, and BDNF), which was found to be modulated by scoparone, was significantly affected by the co-treatment of TrkB inhibitor (ANA-12). These results further suggest that the modulation of neuritogenesis by scoparone is TrkB-dependent. CONCLUSIONS: This study provides deeper insights into the molecular mechanism of CS in boosting neuronal growth and memory function, which might implicate the prevention of many neurological disorders.

Structural and Dynamic Characterizations Highlight the Deleterious Role of SULT1A1 R213H Polymorphism in Substrate Binding.

Sulfotransferase 1A1 (SULT1A1) is responsible for catalyzing various types of endogenous and exogenous compounds. Accumulating data indicates that the polymorphism rs9282861 (R213H) is responsible for inefficient enzymatic activity and associated with cancer progression. To characterize the detailed functional consequences of this mutation behind the loss-of-function of SULT1A1, the present study deployed molecular dynamics simulation to get insights into changes in the conformation and binding energy. The dynamics scenario of SULT1A1 in both wild and mutated types as well as with and without ligand showed that R213H induced local conformational changes, especially in the substrate-binding loop rather than impairing overall stability of the protein structure. The higher conformational changes were observed in the loop3 (residues, 235-263), turning loop conformation to A-helix and B-bridge, which ultimately disrupted the plasticity of the active site. This alteration reduced the binding site volume and hydrophobicity to decrease the binding affinity of the enzyme to substrates, which was highlighted by the MM-PBSA binding energy analysis. These findings highlight the key insights of structural consequences caused by R213H mutation, which would enrich the understanding regarding the role of SULT1A1 mutation in cancer development and also xenobiotics management to individuals in the different treatment stages.