Piper retrofractum extract and its component piperine promote lymphangiogenesis via an AKT ‐ and ERK ‐dependent mechanism

Abstract

Administration of Piper retrofractum extract (PRE) has been reported to alleviate edema, but the mechanism underlying this effect is unknown. Promotion of lymphangiogenesis is known to improve lymphedema, but the effect of PRE on lymphangiogenesis remains unclear. In the present study, we investigated whether PRE and specifically, piperine, the main component of PRE, can induce lymphangiogenesis. Treatments with PRE and piperine significantly promoted the proliferation, migration, and tube formation in human dermal lymphatic microvascular endothelial cells (HDLECs) but had no effect on the expression of lymphangiogenic factors. Furthermore, PRE and piperine significantly promoted the phosphorylation of the AKT and ERK proteins in HDLECs, and pretreatment with AKT and ERK inhibitors significantly attenuated the PRE-and piperine-induced lymphangiogenesis. These results indicate that PRE and piperine promote lymphangiogenesis via an AKT-and ERK-dependent mechanism. Practical applicationsThe lymphatic system plays various roles such as maintaining tissue fluid homeostasis, immune defense, and metabolism. Disruption of the lymphatic system results in insufficient fluid drainage, which causes edema. Currently, there are no effective treatments for lymphedema; therefore, the development of novel treatment strategies is desirable. In this study, we showed that PRE and its main component piperine promote lymphangiogenesis in lymphatic endothelial cells. Therefore, PRE has the potential to be used as a novel functional food for relieving lymphedema.

Lymphangiogenesis: A new strategy for heart disease treatment (Review)

“…Several studies highlight the efficacy of Chinese herbal extracts and monomers in alleviating lymphedema by promoting lymphangiogenesis. Ishii et al ( 88 ) reported that piper retrofractum extract and piperine, isolated from piper retrofractum, notably enhanced the proliferation, migration and tube formation in human dermal lymphatic microvascular endothelial cells, thereby promoting lymphangiogenesis through the AKT and ERK pathways and effectively alleviating lymphedema. T total saponin of Panax notoginseng (PNS) can markedly promote lymphangiogenesis, and its mechanism may be related to the activation of the ERK1/2, PI3K and P38-MAPK signaling pathways, which stimulate the release of VEGF-C. PNS is a promising therapeutic option for managing secondary lymphedema or other lymphatic system disorder ( 89 ).…”