COE targets EphA2 to inhibit vasculogenic mimicry formation induced by hypoxia in hepatocellular carcinoma.

Background: Vasculogenic Mimicry (VM) can reduce the efficacy of anti-angiogenesis and promote distant metastasis in hepatocellular carcinoma (HCC). Our previous studies have found that Celastrus orbiculatus extract (COE) can inhibit the VM formation in HCC by reducing EphA2 expression. However the underlying mechanism related to EphA2 in VM formation is unclear. Purpose: This study aimed to confirm that EphA2 is one of the potential targets of COE, and to explore the effect of EphA2 in VM formation in hypoxia context in HCC. Methods: TCM Systems Pharmacology database and proteomics analysis were used to explore the key targets of COE in HCC treatment. CD31-PAS double staining and VE-CAD staining were used to indicate vasculogenic mimicry. The localization of EphA2 and VE-CAD was examined through fluorescent microscopy. CCK8 assay, cell invasion assay, and tube formation assay were used to indicate the formation of VM under hypoxic conditions. The regulatory relationship of EphA2 upstream and downstream molecules were evaluated through COIP and Western Blot. The nude mouse xenograft tumor models were used to observe the VM formation after knocking down or overexpressing EphA2. Results: EphA2 is identified to the target of COE, and the driving gene of HCC. In HCC surgical specimens, EphA2 expression is closely associated with the VM formation of HCC. COE-regulated EphA2 is involved in hypoxia-induced VM formation in HCC cells in vitro. EphA2 is regulated by HIF directly or indirectly by C-MYC. Overexpression of EphA2 can promote the VM formation of HCC in nude mice, while knocking down EphA2 can inhibit the VM formation. Conclusion: EphA2, as a target of COE, plays a crucial regulatory role in the formation of vasculogenic mimicry in HCC, involving upstream HIF/MYC transcriptional promotion and downstream PI3K/FAK/VE-CAD expression regulation.

Synthesis of pterodontic acid derivatives and the study of their anti-influenza A virus (H1N1) activity.

Laggera pterodonta (DC.) Benth, a folk herb widely distributes in southwest China, especially in Yunnan Province, demonstrates anti-pathogenic microorganisms, anti-inflammatory, inhibition of Helicobacter pylori activities in vitro et al. Interestingly, previous studies have shown that pterodontic acid (1), a eudesmane-type sesquiterpene isolated from L. pterodonta (DC.), displays excellent selective antiviral activity to H1N1 subtype of influenza A virus. At the same time, our group also discovered that the antiviral activity of 1 was relatively close to that activity of post-marketed ribavirin. Therefore, we consider that the synthesis of pterodontic acid (1) derivatives and evaluation of their anti-influenza A virus (H1N1) activities is of potential clinical significance. In this manuscript, a series of pterodontic acid derivatives were prepared and demonstrated significantly improved anti-influenza A virus (H1N1) activities, providing more opportunities for the treatment of respiratory viral diseases.