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<p><i>Background:</i>&#xa0;The cognitive alterations observed in individuals undergoing cancer treatments have garnered more attention recently. Chemotherapy can reduce nicotinamide adenine dinucleotide (NAD+) levels by inhibiting nicotinamide phosphoribosyl transferase (NAMPT). This reduction can make cancer cells more susceptible to oxidative damage and death and may also affect non-cancerous cells, particularly the brain cells. During chemotherapy-induced suppression, the downregulation of the NAMPT-mediated NAD+/Sirtuin 1 (SIRT1) pathway may cause dyscognition.&#xa0;<i>Objective:</i>&#xa0;This study aimed to assess the role of quercetin and analogues in chemobrain and the associated mechanisms.&#xa0;<i>Methods:&#xa0;</i>The potential of quercetin and its derivatives interaction with NAMPT and SIRT1 proteins was performed using computational studies followed by their <i>in vitro</i> evaluation in SH-SY5Y cells. Molecular docking and simulation studies of human SIRT1 and NAMPT proteins with quercetin and its derivatives were performed. Differentiated SH-SY5Y cell lines were treated with quercetin and selected derivatives against Methotrexate and 5-Fluorouracil (MF) toxicity, by subjecting to cytotoxicity assay, flow cytometry, and RT-PCR analysis.&#xa0;<i>Results:</i>&#xa0;Quercetin, Rutin, and Isoquercetin showed interactions necessary in the activation process of both proteins. Cytotoxicity and flow cytometric studies demonstrated that the phytochemicals shield the differentiated SH-SY5Y cells from MF toxicity. As determined by RT-PCR investigations, NAMPT and SIRT1 gene mRNA expression was higher in test drug-treated cells at quercetin (0.12, 0.6 µM), rutin, and isoquercetin (16, 80 µM) and lower in MF-treated cells.&#xa0;<i>Conclusion:</i>&#xa0;The treatment of phytochemicals alleviated CICI by targeting NAMPT and SIRT1 proteins, which could lead to the identification of effective treatment strategies for the chemobrain.</p> Graphical abstract <p></p>

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Effects of quercetin and derivatives on NAMPT/Sirtuin-1 metabolic pathway in neuronal cells: an approach to mitigate chemotherapy-induced cognitive impairment

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月14日

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  • Jeena John,
  • Subham Das,
  • Anu Kunnath,
  • Jayesh Mudgal,
  • Krishnadas Nandakumar

摘要

Background: The cognitive alterations observed in individuals undergoing cancer treatments have garnered more attention recently. Chemotherapy can reduce nicotinamide adenine dinucleotide (NAD+) levels by inhibiting nicotinamide phosphoribosyl transferase (NAMPT). This reduction can make cancer cells more susceptible to oxidative damage and death and may also affect non-cancerous cells, particularly the brain cells. During chemotherapy-induced suppression, the downregulation of the NAMPT-mediated NAD+/Sirtuin 1 (SIRT1) pathway may cause dyscognition. Objective: This study aimed to assess the role of quercetin and analogues in chemobrain and the associated mechanisms. Methods: The potential of quercetin and its derivatives interaction with NAMPT and SIRT1 proteins was performed using computational studies followed by their in vitro evaluation in SH-SY5Y cells. Molecular docking and simulation studies of human SIRT1 and NAMPT proteins with quercetin and its derivatives were performed. Differentiated SH-SY5Y cell lines were treated with quercetin and selected derivatives against Methotrexate and 5-Fluorouracil (MF) toxicity, by subjecting to cytotoxicity assay, flow cytometry, and RT-PCR analysis. Results: Quercetin, Rutin, and Isoquercetin showed interactions necessary in the activation process of both proteins. Cytotoxicity and flow cytometric studies demonstrated that the phytochemicals shield the differentiated SH-SY5Y cells from MF toxicity. As determined by RT-PCR investigations, NAMPT and SIRT1 gene mRNA expression was higher in test drug-treated cells at quercetin (0.12, 0.6 µM), rutin, and isoquercetin (16, 80 µM) and lower in MF-treated cells. Conclusion: The treatment of phytochemicals alleviated CICI by targeting NAMPT and SIRT1 proteins, which could lead to the identification of effective treatment strategies for the chemobrain.

Graphical abstract