Objective. To investigate the protective effect and mechanism of liquiritin (LIQ) on cardiomyocyte hypertrophy induced by angiotensin II (Ang II). Methods. H9c2 cells were pretreated with LIQ before and after Ang II treatment. CCK8 assay was performed to evaluate cell viability. The cell surface area was measured by phalloidin staining. The mRNA expression of atrial and B-type natriuretic peptides (ANP and BNP, respectively) and β-myosin heavy chain (β-MHC) was determined by quantitative reverse transcription-polymerase chain reaction (RT-qPCR); the protein levels of arginyltransferase 1 (ATE1), transforming growth factor beta-activated kinase 1 (TAK1), phos-TAK1, c-Jun N-terminal kinases1/2 (JNK1/2), and phos-JNK1/2 were determined by Western blotting. After constructing the ATE1 overexpression cell models with the pcDNA3.1/ATE1, the abovementioned indicators were tested using the introduced methods. Results. LIQ at a concentration of ≤30 μM was not cytotoxic to H9c2 cells before exposure to Ang II. The protective effect of LIQ was best observed at 30 μM after Ang II treatment. Phalloidin staining and RT-qPCR results indicated that the deposition of Ang II increased the cell surface area and levels of ANP, BNP, and β-MHC. On the other hand, Western blotting results showed that Ang II increased the ATE1 protein levels and TAK1 and JNK1/2 phosphorylation, which were significantly alleviated after LIQ treatment. LIQ also directly inhibited the ATE1 overexpression in H9c2 cells transfected with pcDNA3.1/ATE1 and further inhibited TAK1 and JNK1/2 phosphorylation. Conclusion. LIQ can attenuate Ang II-induced cardiomyocyte hypertrophy by regulating the ATE1/TAK1-JNK1/2 pathway.

Background:: The increasing prevalence of depression has become a global health issue. Currently approved anti-depressive including 5-hydroxytryptamine (5-HT), dopamine (DA), norepinephrine (NE), triple reuptake inhibitors (TRIs) and glutamate N-methyl-D-aspartate (NMDA) receptor antagonists have limited effects because of their insufficient efficacy and/or slow onset of action. Developing multifunctional antidepressants that can modulate 5-HT, DA, NE, and NMDA simultaneously can potentially overcome the current drug defects. Objective:: This study aimed to explore leads for the development of multi-functional anti-depressive agents that simultaneous triple reuptake inhibitory and NMDA-GluN2B receptor antagonistic activities objective: This study aimed to explore leads for the development of multi-functional anti-depressive agents that simultaneous triple reuptake inhibitory and NMDA-GluN2B receptor antagonistic activities. Methods:: Potential leads were screened virtually from the TCMSP database based on the 3D-Pharmacophore model of TRIs followed by the molecular docking into NMDA-GluN2B receptor, BBB score, and the in-silico toxicity evaluation. The biological activities of discovered leads on 5-HT, NE, and DA reuptake and their effect on the NMDA-GluN2B receptor were evaluated via radio-labeled neurotransmitters and competition radio-ligand binding experiment with [3H] ifenprodil, respectively. Lastly, the antidepressant effect of these potential leads was determined in vivo through the forced swim test in mice Results:: Two compounds were attained as potential leads after the aforementioned experiments. Further in vitro biological evaluation identified Hit-2 as a promising lead that exerted favorable triple 5-HT/DA/NE reuptake inhibitory activity (66.98% inhibition rate at 10μM against hNET, 73.01% inhibition rate at 1μM against hDAT and 86.27% inhibition rate at 1μM against hSERT), as well as potent NMDA-GluN2B receptor antagonistic activity (Ki=115.73±3.54nM). The antidepressant activity of Hit-2 was confirmed through in vivo experiments Conclusion:: Hit-2 not only simultaneously inhibited the reuptake of 5-HT, DA, and NE, and acted as an NMDA-GluN2B receptor antagonist in vitro but also showed in vivo antidepressant activity. These findings may serve as a structural basis for the further development of multi-functional anti-depressive agents. other: none