Curcumin (CUR), the main compound extracted from Curcuma longa , has various biological actions, including hepatoprotective, anti-infective, anti-inflammatory, antioxidant, and neurotrophic properties. But it has not yet been clarified how CUR affects the accumulation of fatty in hepatic cells. Our study uncovered that CUR decreased the lipid deposition in free fat acids (FFAs)-treated hepatocytes, which could be blocked by Compound C (an AMPK inhibitor). This result suggests that protective effect was associated with the AMPK pathway activation. MiR-3666 directly targets the AMPK gene, and overexpression of miR-3666 greatly weakens the hypolipidemic effect of CUR. Our results showed that CUR reduced FFAs-induced lipid deposition by targeting miR-3666. This boosted AMPK phosphorylation and inhibited its downstream targets, including ACC and SREBP1 . These findings together confirm that CUR-mediated inhibition of miR-3666 to activate the AMPK pathway is a potential alternative for alleviation of hepatic lipid deposition.
Introduction Cisplatin-based chemotherapy is one of the fundamental therapeutic modalities for gastric cancer (GC). Chemoresistance to cisplatin is a great clinical challenge, and its underlying mechanisms remain poorly understood. Circular RNAs (circRNAs) are involved in the pathophysiology of multiple human malignancies. Methods High-throughput sequencing was performed to determine the differentially expressed profile of circRNA in GC tissues and cisplatin-resistant GC cells. Quantitative real-time polymerase chain reaction and Fluorescence in situ hybridization was utilized to confirm the dysregulation of circ_0008315 in GC tissues. To evaluate the prognostic significance of circ_0008315 in GC, we used Kaplan-Meier plot. The self-renewal ability of drug-resistant GC cell was verified through tumor sphere formation assay. GC organoids were constructed to simulate the tumor microenvironment and verified the function of circ_0008315 in cisplatin resistance of gastric cancer. In vivo evaluation was conducted using patient-derived xenograft models. Dual-luciferase reporter gene, RNA immunoprecipitation and miRNA pull-down assays were employed to investigate the molecular mechanisms of circ_0008315 in GC. Results We revealed that a novel circRNA hsa_circ_0008315 was upregulated in GC and cisplatin-resistant GC cells. Elevated circ_0008315 was also observed in cisplatin-resistant GC organoid model. High circ_0008315 expression predicted unfavorable survival outcome in GC patients. Downregulation of circ_0008315 expression inhibited proliferation, mobility, and epithelial-mesenchymal transition of GC cells in vitro and in vivo. Reducing circ_0008315 expression in cisplatin-resistant GC organoid model reversed cisplatin resistance. Mechanistically, circ_0008315 modulated the stem cell properties of GC through the miR-3666/CPEB4 signaling pathway, thereby promoting cisplatin resistance and GC malignant progression. Furthermore, we developed PLGA-PEG nanoparticles targeting circ_0008315, and the nanoparticles could effectively inhibit GC proliferation and cisplatin resistance. Conclusion Circ_0008315 exacerbates GC progression and cisplatin resistance, and can be used as a prognostic predictor. Circ_0008315 may function as a promising nanotherapeutic target for GC treatment. Graphical Abstract
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