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Cardiac glycosides (CGs) are candidate anticancer agents that function by increasing [Ca 2+ ]i to induce apoptotic cell death in several types of cancer cells. However, new findings have shown that the anti-cancer effects of CGs involve complex cell-signal transduction mechanisms. Hence, exploring the potential mechanisms of action of CGs may provide insight into their anti-cancer effects and thus aid in the selection of the appropriate CG. Periplocymarin (PPM), which is a cardiac glycoside, is an active ingredient extracted from Cortex periplocae. The role of PPM was evaluated in HepG2 cells and xenografted nude mice. Cell proliferation, real-time ATP rate assays, western blotting, cell apoptosis assays, short interfering RNA transfection, the patch clamp technique, electron microscopy, JC-1 staining, immunofluorescence staining and autophagic flux assays were performed to evaluate the function and regulatory mechanisms of PPM in vitro . The in vivo activity of the PPM was assessed using a mouse xenograft model. The present study demonstrated that PPM synchronously activated lethal apoptosis and protective autophagy in liver cancer, and the initiation of autophagy counteracted the inherent pro-apoptotic capacity and impaired the anti-cancer effects. Specifically, PPM exerted a proapoptotic effect in HepG2 cells and activated macroautophagy by initiation of the AMPK/ULK1 and mTOR signaling pathways. Activation of macroautophagy counteracted the pro-apoptotic effects of PPM, but when it was combined with an autophagy inhibitor, the anti-cancer effects of PPM in mice bearing HepG2 xenografts were observed. Collectively, these results indicated that a self-limiting effect impaired the pro-apoptotic effects of PPM in liver cancer, but when combined with an autophagy inhibitor, it may serve as a novel therapeutic option for the management of liver cancer.

Context Xiaoer lianhuaqinqgan (XELH), developed based on Lianhua Qingwen (LHQW) prescription, contains 13 traditional Chinese medicines. It has completed the investigational new drug application to treat respiratory viral infections in children in China. Objective This study demonstrates the pharmacological effects of XELH against viral pneumonia. Materials and methods The antiviral and anti-inflammatory effects of XELH were investigated in vitro using H3N2-infected A549 and LPS-stimulated RAW264.7 cells and in vivo using BALB/c mice models of influenza A virus (H3N2) and respiratory syncytial virus (RSV)-infection. Mice were divided into 7 groups ( n = 20): Control, Model, LHQW (0.5 g/kg), XELH-low (2 g/kg), XELH-medium (4 g/kg), XELH-high (8 g/kg), and positive drug (20 mg/kg oseltamivir or 60 mg/kg ribavirin) groups. The anti-inflammatory effects of XELH were tested in a rat model of LPS-induced fever and a mouse model of xylene-induced ear edoema. Results In vitro, XELH inhibited the pro-inflammatory cytokines and replication of H1N1, H3N2, H1N1, FluB, H9N2, H6N2, H7N3, RSV, and HCoV-229E viruses, with (IC 50 47.4, 114, 79, 250, 99.2, 170, 79, 62.5, and 93 μg/mL, respectively). In vivo , XELH reduced weight loss and lung index, inhibited viral replication and macrophage M1 polarization, ameliorated lung damage, decreased inflammatory cell infiltration and pro-inflammatory cytokines expression in lung tissues, and increased the CD4 + /CD8 + ratio. XELH inhibited LPS-induced fever in rats and xylene-induced ear edoema in mice. Conclusion XELH efficacy partially depends on integrated immunoregulatory effects. XELH is a promising therapeutic option against childhood respiratory viral infections.