Garg Asmita, Saroj Jyotshana, Tiwari Saurabh, Das Uttara, Shukla Neetu, Ghosh Jimut Kanti, Bandyopadhyay Sanghamitra
Systems Toxicology Group, Food, Drug and Chemical, Environment and Systems Toxicology Division, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, Uttar Pradesh, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
Front Pharmacol. 2025 Feb 25;16:1510337. doi: 10.3389/fphar.2025.1510337. eCollection 2025.
Soybean-based foods enhance cognitive functions by influencing hippocampal mechanisms. These salutary effects have so far been attributed to isoflavones present in soybeans. Considering cellular senescence contributes to cognitive decline and that no specific soy-derived peptides are known for their potential to mitigate senescence, we examined the efficacy of a thirteen amino acid soy-derived peptide, Soymetide, on a doxorubicin-induced senescence mice model. Soymetide pretreatment lowered the senescence markers p53, p21 and p16, pro-inflammatory cytokines, and Senescence β-Galactosidase staining while enhancing the mature neuronal marker NeuN in the hippocampus. This anti-senescent effect was comparable with that of a well-known senolytic combination (dasatinib and quercetin). Research indicates that Wnt signaling influences cellular senescence, and our findings here demonstrate that doxorubicin decreased hippocampal Wnt3a, p-LRP6, Frizzled, Dishevelled, Axin1, and β-catenin levels and increased GSK-3β, while Soymetide mitigated these effects. Additionally, upon inhibition of the Wnt/β-catenin pathway, Soymetide's ability to reduce senescence markers and restore NeuN expression was reduced. We validated the anti-senescence impact on hippocampal neurons by co-immunostaining Wnt/β-catenin and senescence indicators alongside NeuN in mice and assessed it in primary hippocampal neurons. Further examining the neuronal survival and functions revealed that Soymetide blocked the doxorubicin-induced loss in Nissl-stained surviving neurons and learning-memory performances, measured by Y-Maze and Passive Avoidance tests, which Wnt/β-catenin inhibitors could counteract. In conclusion, our study identifies a novel Wnt/β-catenin-linked mechanism of doxorubicin-induced senescence in the hippocampal neurons and demonstrates Soymetide's effectiveness in reversing this process. Hence, this suggests Soymetide's potential therapeutic application in addressing cognitive decline associated with cellular aging.
大豆类食品通过影响海马体机制来增强认知功能。迄今为止，这些有益作用一直归因于大豆中含有的异黄酮。考虑到细胞衰老会导致认知能力下降，且目前尚无特定的大豆衍生肽具有减轻衰老的潜力，我们研究了一种由13个氨基酸组成的大豆衍生肽Soymetide对阿霉素诱导的衰老小鼠模型的功效。Soymetide预处理降低了衰老标志物p53、p21和p16、促炎细胞因子以及衰老β-半乳糖苷酶染色，同时增强了海马体中成熟神经元标志物NeuN。这种抗衰老作用与一种著名的衰老溶解组合（达沙替尼和槲皮素）相当。研究表明，Wnt信号传导会影响细胞衰老，我们在此的研究结果表明，阿霉素会降低海马体中Wnt3a、p-LRP6、卷曲蛋白、散乱蛋白、轴蛋白1和β-连环蛋白的水平，并增加GSK-3β，而Soymetide可减轻这些影响。此外，在抑制Wnt/β-连环蛋白通路后，Soymetide降低衰老标志物和恢复NeuN表达的能力降低。我们通过在小鼠中对Wnt/β-连环蛋白和衰老指标与NeuN进行共免疫染色，验证了其对海马体神经元的抗衰老作用，并在原代海马体神经元中进行了评估。进一步研究神经元的存活和功能发现，Soymetide可阻止阿霉素诱导的尼氏染色存活神经元的损失以及学习记忆能力，这通过Y迷宫和被动回避试验来测量，而Wnt/β-连环蛋白抑制剂可以抵消这种作用。总之，我们的研究确定了阿霉素诱导海马体神经元衰老的一种新的Wnt/β-连环蛋白相关机制，并证明了Soymetide在逆转这一过程中的有效性。因此，这表明Soymetide在解决与细胞衰老相关的认知能力下降方面具有潜在的治疗应用价值。
