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Gene & Protein in Disease In silico insights on fisetin’s antidepressant effects

increased risk of suicide. As a major mental illness, MDD discovery, particularly in the development of plant-based
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has a profound impact on both individuals and society as herbal medicines for complex diseases. 20,21
a whole. The World Health Organization has raised grave Building on the importance of traditional pharmacology,
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concerns over the alarming increase in the prevalence of this study aims to explore the possible target genes and
MDD and other mental disorders worldwide. In addition, proteins involved, as well as the specific molecular cascades,
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the prevalence of MDD has increased in the wake of the associated with the TCM compound FT in the treatment
COVID-19 pandemic. MDD is marked by intense and of MDD. This investigation utilized integrated network
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common emotional symptoms such as feelings of guilt and pharmacology and in silico molecular docking techniques.
a lack of pleasure; cognitive symptoms like low self-esteem; After identifying the common targets between FT and
and physical symptoms including loss of energy, insomnia, MDD, we used protein-protein interaction (PPI) analysis
irritability, and fatigue. MDD remains one of the most to find the hub genes within the network. Subsequently,
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prevalent mental health conditions, impacting cognitive we utilized the Kyoto Encyclopedia of Genes and Genomes
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abilities, quality of life, and overall health. Nonetheless, (KEGG) and Gene Ontology (GO) enrichment methods to
the etiology of MDD is not fully understood. clarify the possible molecular pathways by which FT could
Extensive research conducted over the course of several deliver its therapeutic benefits in treating MDD.
decades has centered on the development and evaluation
of pharmacological interventions for the management of 2. Materials and methods
MDD. Although selective serotonin reuptake inhibitors 2.1. Pharmacology and toxicological properties
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are often prescribed for treating MDD, many patients find
them ineffective and experience various adverse effects and After obtaining the structure of FT from PubChem database,
tolerance. This underscores the need for antidepressants that we analyzed the physicochemical properties and drug-
provide a rapid onset of action, improved tolerability, greater likeness (DL) of the compound using two platforms: TCMSP
efficacy, and a reduced side effect profile. Consequently, (https://old.tcmsp-e.com/tcmsp.php) and SwissADME
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there has been growing interest in multi-target drugs, which (http://www.swissadme.ch/). These tools were employed to
offer the advantage of additive and synergistic effects. 9 assess the compound’s absorption, distribution, metabolism,
and excretion characteristics. Furthermore, the toxicity of
Chinese herbal medicine is recognized for its multi- FT was evaluated using the ProTox-II platform (accessible
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pathway and multi-target approach to treating diseases. at: https://tox-new.charite.de/).
Fisetin (FT, 3,7,3′,4′-tetrahydroxyflavone), a well-known
flavonoid with antioxidant properties, is abundantly found 2.2. Target prediction for ingredient
in vegetables and fruits and is an active component of We utilized prediction tools, such as the Super Pred and
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traditional Chinese medicine (TCM) known as Cotinus Swiss Target Prediction platforms, to identify potential
coggygria. Scientific evidence has demonstrated the targets of FT. The Canonical SMILES of FT was used
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diverse pharmacological effects of FT, including its anti- with the Swiss Target Prediction platform (accessible
angiogenic, anti-cancer, anti-aging, and neuroprotective at: http://www.swisstargetprediction.ch/), a web-based
properties. Due to these characteristics, FT has been platform specifically designed for the target identification of
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proposed as a potentially effective treatment for several small molecules. This platform maintains a high predictive
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neuropsychological disorders, including Huntington’s performance level, listing the correct target within the
disease, stroke, and Alzheimer’s disease (AD). 14,15 However, top 15 for over 70% of tested external compounds. We
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its antidepressant effects have yet to be investigated. In also used another platform, SuperPred (accessible at:
theory, FT’s anti-inflammatory properties could help https://prediction.charite.de/), with a prediction probability
reduce the chronic, low-grade inflammation seen in threshold >70%, to find the targets of FT. The gene
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individuals with MDD. Additional research has shown symbols of the potential targets were obtained by searching
that FT supports the protection and survival of neurons the UniProt databases (accessible at: http://www.uniprot.
and enhances memory in mice. 17,18 org/uniprot/). Finally, we removed any duplicate entries
TCM requires the utilization of big data to identify and prepared the finalized list of targets for further analysis.
all relevant targets and pathways associated with active
components and diseases. Network pharmacology, an 2.3. Target prediction for disease
interdisciplinary field combining bioinformatics and To identify genes associated with MDD, we employed
pharmacology, offers a systematic approach toward a the keyword “major depressive disorder or depression” in
comprehensive exploration of the complex pharmacological our search across the following three distinct databases:
effects of drugs. This approach is gaining traction in drug GeneCard (accessible at: https://www.genecards.org/),
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Volume 4 Issue 1 (2025) 2 doi: 10.36922/gpd.4846