BACKGROUNDLung cancer is the leading cause of cancer-related mortality. Cancer poses a significant challenge to human health and remains a persistent and pressing issue. Schisandrin C is one of the active ingredients of Schisandra chinensis and has various biological and pharmacological activities. This study aimed to investigate the effects of Schisandrin C on lung cancer and the underlying mechanism involved.METHODSA network pharmacology strategy was used to screen the target genes and pathways involved in the relationship between Schisandrin and lung cancer. Next, a single-cell RNA sequencing (scRNA-seq) assay revealed the expression of genes specifically expressed in lung cancer epithelial cells. A549 cells were subsequently treated with Schisandrin C for 24 h or 48 h, cell viability was assessed via MTT and EdU staining experiments, and target gene expression was measured via RT-qPCR and immunofluorescence assays. Moreover, lung cancer patient tissues were observed via multiplex immunofluroscence staining.RESULTSAKT1, CA9, BRAF, EGFR, ERBB2 and PIK3CA were overlapping target genes for network pharmacology and the scRNA-seq strategy. In vitro, the RT-qPCR results indicated that Schisandrin C inhibited the mRNA expression of the AKT1, CA9, FASN, MMP1, EGFR and BRAF genes. In clinical samples from patients with lung cancer, the expression levels of CA9 and AKT1 were found to be significantly higher in lung tumor tissues than in the adjacent normal (TAN) tissues. Moreover, the administration of an AKT kinase inhibitor reversed the inhibitory effect of Schisandrin C on A549 cells proliferation, whereas the administration of a CA9 inhibitor failed to have a similar effect.CONCLUSIONSSchisandrin C effectively suppressed the proliferation and viability of A549 cells. Its mechanism was related to the inhibition of the AKT1 signaling pathway.

02 Oct 2024·Journal of Agricultural and Food Chemistry

Astragaloside I Promotes Lipophagy and Mitochondrial Biogenesis to Improve Hyperlipidemia by Regulating Akt/mTOR/TFEB Pathway

Article

Author: Zhang, Xiaowei ; Wang, Tao ; Zhao, Liang ; Zhao, Jie ; Xu, Jiangyan ; Ding, Jing ; Gao, Gai ; Zhang, Zhenqiang ; Xie, Zhishen ; Liu, Wei

The simultaneous enhancement of lipophagy and mitochondrial biogenesis has emerged as a promising strategy for lipid lowering. The transcription factor EB (TFEB) exhibits a dual role, whereby it facilitates the degradation of lipid droplets (LDs) through the process of lipophagy while simultaneously stimulating mitochondrial biogenesis to support the utilization of lipophagy products. The purpose of this study was to explore the effect of astragaloside I (AS I) on hyperlipidemia and elucidate its underlying mechanism. AS I improved serum total cholesterol and triglyceride levels and reduced hepatic steatosis and lipid accumulation in db/db mice. AS I enhanced the fluorescence colocalization of LDs and autophagosomes and promoted the proteins and genes related to the autolysosome. Moreover, AS I increased the expression of mitochondrial biogenesis-related proteins and genes, indicating that AS I promoted lipophagy and mitochondrial biogenesis. Mechanistically, AS I inhibits the protein level of p-TFEB (ser211) expression and promotes TFEB nuclear translocation. The activation of TFEB by AS I was impeded upon the introduction of the mammalian target of rapamycin (mTOR) agonist MHY1485. The inhibition of p-mTOR by AS I and the activation of TFEB were no longer observed after administration of the Akt agonist SC-79, which indicated that AS I activated TFEB to promote lipophagy-dependent on the Akt/mTOR pathway and may be a potentially effective pharmaceutical and food additive for the treatment of hyperlipidemia.

01 Aug 2024·Naunyn-Schmiedeberg's Archives of Pharmacology

Molecular mechanism of Spatholobi Caulis treatment for cholangiocarcinoma based on network pharmacology, molecular docking, and molecular dynamics simulation

Article

Author: Peng, Chuang ; Tan, Zhiguo ; Sun, Bo ; Li, Yuhang ; Zeng, Jia ; Chen, Xu ; Yu, Zhangtao ; Liu, Jie

Cholangiocarcinoma (CCA) is a type of malignant tumor originating from the intrahepatic, periportal, or distal biliary system. The treatment means for CCA is limited, and its prognosis is poor. Spatholobi Caulis (SC) is reported to have effects on anti-inflammatory and anti-tumor, but its role in CCA is unclear. First, the potential molecular mechanism of SC for CCA treatment was explored based on network pharmacology, and the core targets were verified by molecular docking and molecular dynamics simulation. Then, we explored the inhibitory effect of SC on the malignant biological behavior of CCA in vitro and in vivo and also explored the related signaling pathways. The effect of combination therapy of SC and cisplatin (DDP) in CCA was also explored. Finally, we conducted a network pharmacological study and simple experimental verification on luteolin, one of the main components of SC. Network pharmacology analysis showed that the core targets of SC on CCA were AKT1, CASP3, MYC, TP53, and VEGFA. Molecular docking and molecular dynamics simulation indicated a good combination between the core target protein and the corresponding active ingredients. In vitro, SC inhibited proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of CCA cells. In vivo experiments, the results were consistent with in vitro experiments, and there was no significant hepatorenal toxicity of SC at our dosage. Based on KEGG enrichment analysis, we found PI3K/AKT signaling pathway might be the main signaling pathway of SC action on CCA by using AKT agonist SC79. To explore whether SC was related to the chemotherapy sensitivity of CCA, we found that SC combined with DDP could more effectively inhibit the progression of cholangiocarcinoma. Finally, we found luteolin may inhibit the proliferation and invasion of CCA cells. Our study demonstrates for the first time that SC inhibits the progression of CCA by suppressing EMT through the PI3K-AKT signaling pathway, and SC could enhance the effectiveness of cisplatin therapy for CCA.

100 Deals associated with Akt gene inhibitors(University of North Carolina)

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	FR	Pills	31 Jul 2009
Neoplasms	Preclinical	US	The University of North Carolina at Chapel Hill	31 Jul 2009
Neoplasms	Preclinical	TW	National Taiwan University Innovation & Incubation Co. Ltd.	31 Jul 2009

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