Effects of quercetin and derivatives on NAMPT/Sirtuin-1 metabolic pathway in neuronal cells: an approach to mitigate chemotherapy-induced cognitive impairment.
Jeena John, Subham Das, Anu Kunnath, Jayesh Mudgal, Krishnadas Nandakumar
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引用次数: 0
Abstract
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.
期刊介绍:
Metabolic Brain Disease serves as a forum for the publication of outstanding basic and clinical papers on all metabolic brain disease, including both human and animal studies. The journal publishes papers on the fundamental pathogenesis of these disorders and on related experimental and clinical techniques and methodologies. Metabolic Brain Disease is directed to physicians, neuroscientists, internists, psychiatrists, neurologists, pathologists, and others involved in the research and treatment of a broad range of metabolic brain disorders.