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Jiadifenolide has been reported to have neurotrophin-like activity in primary rat cortical neurons, and also possesses neurotrophic effects in neuronal precursor cells derived from human induced pluripotent stem cells (hiPSCs), as we have previously reported. However, the molecular mechanisms by which jiadifenolide exerts its neurotrophic effects in rat and human neurons are unknown. Thus, we aimed to investigate the molecular mechanisms and pathways by which jiadifenolide promotes neurotrophic effects. Here, we found that jiadifenolide activated cellular communication network factor (CCN) signaling pathways by up-regulating mRNA level expression of CCN genes in human neuronal cells. We also found that CCN2 (also known as connective tissue growth factor, CTGF) protein promotes neurotrophic effects through activation of the p44/42 mitogen-activated protein kinase signaling pathway. This is the first discovery which links neurotrophic activity with CCN signaling., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

EphA4 receptor tyrosine kinase has been shown to be critically involved in neural tissue development. Here, we found EphA4 was also distributed among hypertrophic chondrocytes and osteoblasts in the growth plate of developing mouse long bones. In vitro evaluation revealed that ephA4 expression was elevated upon hypertrophic differentiation of chondrocytes and that markedly stronger expression was observed in osteoblastic SaOS-2 than chondrocytic HCS-2/8 cells. Of note, RNAi-mediated silencing of ephA4 in SaOS-2 cells resulted in the repression of osteocalcin gene expression and alkaline phosphatase activity. Interestingly, confocal laser-scanning microscopic analysis revealed the presence of EphA4 molecules in the nucleus as well as on the surface of SaOS-2 cells. These findings are the first indication of a critical role of EphA4 in ossification, especially at the final stage in which osteoblasts and hypertrophic chondrocytes play major roles.

The occurrence of in vitro thiol exchange reactions involving selenotrisulfides has been documented by HPLC analyses of reaction solutions. Asymmetric selenotrisulfide (RSSeSR') (R,R' = penicillamine, cysteine, glutathione) was formed by the reactions between (i) a mixture of thiols and selenite, (ii) thiol (R'SH) and symmetric selenotrisulfide (RSSeSR), and (iii) symmetric selenotrisulfides (RSSeSR and R'SSeSR'). Further reaction of an asymmetric selenotrisulfide with thiol (R'SH) produced another symmetric selenotrisulfide (R'SSeSR'). These thiol exchange reactions may offer significant information to elucidate intake and metabolism of selenium in vivo.