School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, China.
School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, China; Central Laboratory, the First Affiliated Hospital of Henan University of Science and Technology, Luoyang 471003, China.
Chin J Nat Med. 2021 Oct;19(10):732-740. doi: 10.1016/S1875-5364(21)60090-0.
Physalin B (PB), one of the major active steroidal constituents of Solanaceae Physalis plants, has a wide variety of biological activities. We found that PB significantly down-regulated β-amyloid (Aβ) secretion in N2a/APPsw cells. However, the underlying mechanisms are not well understood. In the current study, we investigated the changes in key enzymes involved in β-amyloid precursor protein (APP) metabolism and other APP metabolites by treating N2a/APPsw cells with PB at different concentrations. The results indicated that PB reduced Aβ secretion, which was caused by down-regulation of β-secretase (BACE1) expression, as indicated at both the protein and mRNA levels. Further research revealed that PB regulated BACE1 expression by inducing the activation of forkhead box O1 (FoxO1) and inhibiting the phosphorylation of signal transducer and activator of transcription 3 (STAT3). In addition, the effect of PB on BACE1 expression and Aβ secretion was reversed by treatment with FoxO1 siRNA and STAT3 antagonist S3I-201. In conclusion, these data demonstrated that PB can effectively down-regulate the expression of BACE1 to reduce Aβsecretion by activating the expression of FoxO1 and inhibiting the phosphorylation of STAT3.
白果内酯（PB）是茄科酸浆属植物的主要活性甾体成分之一，具有广泛的生物活性。我们发现 PB 可显著下调 N2a/APPsw 细胞中β-淀粉样蛋白（Aβ）的分泌。然而，其潜在的机制尚不清楚。在本研究中，我们用不同浓度的 PB 处理 N2a/APPsw 细胞，研究了参与β-淀粉样前体蛋白（APP）代谢的关键酶和其他 APP 代谢物的变化。结果表明，PB 通过下调β-分泌酶（BACE1）的表达降低了 Aβ的分泌，这在蛋白和 mRNA 水平上均有体现。进一步的研究表明，PB 通过诱导叉头框 O1（FoxO1）的激活和抑制信号转导和转录激活因子 3（STAT3）的磷酸化来调节 BACE1 的表达。此外，用 FoxO1 siRNA 和 STAT3 拮抗剂 S3I-201 处理可逆转 PB 对 BACE1 表达和 Aβ分泌的影响。总之，这些数据表明，PB 可以通过激活 FoxO1 的表达和抑制 STAT3 的磷酸化来有效地下调 BACE1 的表达，从而减少 Aβ的分泌。
