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The orphan nuclear receptor 4A1 (NR4A1) is highly expressed in human pancreatic cancer cells and exerts pro-oncogenic activity. In a previous study, we demonstrated that fangchinoline (FCN), a natural inhibitor of nuclear NR4A1, induces NR4A1-dependent apoptosis in human pancreatic cancer cells. In this study, we evaluated FCN and its structural analogs (berbamine, isotetrandrine, tetrandrine, and tubocurarine) for their inhibitory effects on NR4A1 transactivity, and confirmed that tetrandrine (TTD) showed the highest inhibitory effect in pancreatic cancer cells. Moreover, in a tryptophan fluorescence quenching assay, TTD directly bound to the ligand binding domain (LBD) of NR4A1 with a KD value of 10.60 μM. Treatment with TTD decreased proliferation and induced apoptosis in Panc-1 human pancreatic cancer cells in part through the reduced expression of the Sp1-dependent anti-apoptotic gene survivin and induction of ROS-mediated endoplasmic reticulum stress, which are the well-known NR4A1-dependent proapoptotic pathways. Furthermore, at a dose of 25 mg/kg/day, TTD reduced tumor growth in an athymic nude mouse xenograft model bearing Panc-1 cells. These data show that TTD is an NR4A1 antagonist and that modulation of the NR4A1-mediated pro-survival pathways is involved in the antitumor effects of TTD.

Aim: The mealworm (Tenebrio Molitor) and mealworm oil (MWO) have been reported to affect antioxidant, anticoagulation, antiadipogenic and anti-inflammatory activities. However, since the function of MWO in wound healing is unclear, we investigated the effects of MWO on the wound healing process. Method: Fibroblast cells and endothelial cells were analyzed after MWO treatment in vitro. The wound healing was investigated in vivo using five rats' wounded backs treated with MWO. We investigated the effects of MWO on the proliferation and migration of fibroblasts, the expressions of wound healing-related genes, and the activation of endothelial cells mediated by MWO-stimulated fibroblasts for angiogenesis. Results / Discussion: The mRNA expression levels of collagen-1, alpha-smooth muscle actin, and vascular endothelial growth factor related to wound healing were increased by MWO in fibroblasts. The wound gap of the fibroblasts narrowed by MWO treatment, which means the migration of fibroblast cells was induced by MWO. Migration and tube formation of the endothelial cell was enhanced in fibroblasts treated with MWO, suggesting that MWO induces angiogenesis for wound healing. The intensity and organization of collagen deposition, expression of CD31 as a marker of vascular endothelial cells for angiogenesis, and the length of regenerated epithelium in skin wounds of rats treated with MWO were increased. Conclusion: It confirmed that MWO promotes wound repair of skin in both in vitro and in vivo models. These results demonstrate that MWO might have the potential as a therapeutic agent for the treatment of skin wounds. [ABSTRACT FROM AUTHOR]