Background: Sanghuangporus vaninii has antioxidant, anti-inflammatory, anti-tumor and other effects. However, the antitumor effects and mechanisms of S.vaninii gainst pancreatic cancer remain unclear. Methods: The antitumor activity of compounds isolated from S. vaninii was evaluated, and cell function experiments, such as wound healing, transwell and 3D culture assays, were conducted after the target cancer species was determined. Transcriptome analysis, Micro-Scale Thermophoresis and western blot were used to verify the targets and signaling pathways. Results: 13 compounds were isolated and identified from S.vanini. Among them, compound 1, the phenylpentane derivative compound, has the strongest inhibitory activity on the pancreatic cancer cells. In vitro, compound 1 inhibited the proliferation, migration, invasion, tube formation and colony formation of PANC-1 cells in a dose-dependent manner. Through transcriptome analysis, the signaling pathways compound 1 targeted were identified as MAPK/PI3K and HIPPO pathways. Western blot and immunofluorescence assay also showed that compound 1 can inhibit the EMT through inactivated HIPPO signaling pathway. By molecular docking and MST assay, we confirmed that compound 1 interacted with EGFR by binding with LYS745/PHE856 of EGFR. After knocking down EGFR, the effect of compound 1 on downstream signaling pathways was weakened, and the functions such as migration and invasion of cancer cells were also decreased. Conclusion: Compound 1, the phenylpentane derivative isolated from S. vaninii, inhibited the malignant process and EMT in PANC-1 cells via MAPK/PI3K and HIPPO signaling pathways by targeting EGFR. These data indicated that compound 1 might be a potential drug candidate for pancreatic cancer treatment.

Background and Purpose Hepatocellular carcinoma has high ability of vascular invasion and metastasis. Vasculogenic mimicry (VM) is closely related to the metastasis and recurrence of hepatocellular carcinoma (HCC). According to previous research, Chloranthus henryi has anti-tumor effect, but its molecular mechanism in the treatment of HCC has not yet been stated. In our study, we aimed to investigate the effect of the extract of Chloranthus henryi in HCC and its target and molecular mechanism. Experimental Approach In this study, we isolated a chalcone compound from Chloranthus henryi, compound 4, identified as flavokawain A (FKA). We determined the anti-HCC effect of FKA by MTT and identified the target of FKA by molecular docking and CETSA. Hepatoma cells proliferation, migration, invasion, and VM formation were examined using EDU, wound healing, transwell, vasculogenic mimicry, and IF. WB, RT-PCR, and cell transfection were used to explore the mechanism of FKA on hepatoma cells. Tissue section staining is mainly used to demonstrate the effect of FKA on HCC in vivo. Key Results We confirmed that FKA can directly interact with CXCL12 and HCC proliferation, migration, invasion, and VM formation were all inhibited through reversing the EMT progress in vitro and in vivo through the PI3K/Akt/NF-κB signaling pathway. Additionally, by overexpressing and knocking down CXCL12, we got the same results. Conclusion and Implications FKA attenuated proliferation, invasion and metastatic and reversed EMT in HCC via PI3K/Akt/HIF-1α/NF-κB/Twist1 pathway by targeting CXCL12. This study proposed that FKA may be a candidate drug and prospective strategy for HCC therapy.

BACKGROUND AND PURPOSE Diosmetin exhibits a series of therapeutic efficacy but little is known of its effects on colitis. EXPERIMENTAL APPROACH In this study, two mouse models of DSS (the concentration of 3% and 5%)-induced colitis and Caco2 and IEC-6 cells were employed. The 16S amplicon sequencing was used to assess Gut microbiota changes by diosmetin. Various physical signs of mice (body weight, colon length and DAI score), proinflammatory cytokines and antioxidant enzymes were tested. KEY RESULTS The results showed that diosmetin can markedly decrease the disease activity index and microscopic colon tissue damage, increase the expression of tight junction protein (Occludin, Claudin-1 and Zo-1) and reduce the secretion of proinflammatory cytokines. And diosmetin also significantly inhibited colon oxidative damage through adjusting the levels of intracellular ROS, mitochondrial ROS, GSH-Px, SOD, MDA and GSH in vitro and in vivo. Furthermore, it was found that diosmetin can modulate the abundance of Bacteroidetes, Actinobacteria, Cyanobacteria and Firmicutes, which were reported to be the crucial bacteria related to inflammatory bowel disease (IBD). Also, diosmetin significantly increased the expression of Nrf2 and HO-1 and reduced the ratio of acetylated NF-κB and NF-κB by activating the circ-Sirt1/Sirt1 axis, thereby inhibiting oxidative stress and inflammation. CONCLUSIONS AND IMPLICATIONS Our results have linked colitis to the circ-Sirt1/Sirt1 signaling pathway, which is regulated by diosmetin. It implies that diosmetin may be a novel candidate to alleviate DSS-induced colitis or a lead compound for future optimization and modification.

BACKGROUND AND PURPOSE Diosmetin exhibits a series of therapeutic efficacy but little is known of its effects on colitis. EXPERIMENTAL APPROACH In this study, two mouse models of DSS (the concentration of 3% and 5%)-induced colitis and Caco2 and IEC-6 cells were employed. The 16S amplicon sequencing was used to assess Gut microbiota changes by diosmetin. Various physical signs of mice (body weight, colon length and DAI score), proinflammatory cytokines and antioxidant enzymes were tested. KEY RESULTS The results showed that diosmetin can markedly decrease the disease activity index and microscopic colon tissue damage, increase the expression of tight junction protein (Occludin, Claudin-1 and Zo-1) and reduce the secretion of proinflammatory cytokines. And diosmetin also significantly inhibited colon oxidative damage through adjusting the levels of intracellular ROS, mitochondrial ROS, GSH-Px, SOD, MDA and GSH in vitro and in vivo. Furthermore, it was found that diosmetin can modulate the abundance of Bacteroidetes, Actinobacteria, Cyanobacteria and Firmicutes, which were reported to be the crucial bacteria related to inflammatory bowel disease (IBD). CONCLUSIONS AND IMPLICATIONS Our data suggested that diosmetin ameliorated the colitis in mice induced by DSS in the potential mechanism that it alleviates intestinal epithelial barrier damage, inhibits the secretion of proinflammatory cytokines, decreases oxidative stress and modulates gut microbiota. It implies that diosmetin may be a novel candidate to alleviate DSS-induced colitis or a lead compound for future optimization and modification.