No abstract

YTH Domain Containing 1 (YTHDC1) is one of the m6A readers that is essential for oocyte development and tumor progression. The role of YTHDC1 in neuronal survival and ischemic stroke is unknown. Here, we found that YTHDC1 was unregulated in the early phase of ischemic stroke. Knockdown of YTHDC1 exacerbated ischemic brain injury and overexpression of YTHDC1 protected rats against brain injury. Mechanistically, YTHDC1 promoted PTEN mRNA degradation to increase Akt phosphorylation, thus facilitating neuronal survival in particular after ischemia. These data identify YTHDC1 as a novel regulator of neuronal survival and modulating m6A reader YTHDC1 may provide a potential therapeutic target for ischemic stroke.

Acetylcholinesterase inhibitors (AChEIs) currently form the basis of the newest drugs available for the treatment of Alzheimer's disease. For the aim of screening effective AChEIs, the methanol extracts of the seeds of genus Peganum were found to show significant inhibitory activity of acetylcholinesterase enzyme (AChE) using an in vitro TLC-bioautographic assay. In further studies to seed of P. nigellastrum Bunge, activity-guided fractionation led to the isolation of two new alkaloids nigellastrine I (9) and nigellastrine II (10), and along with eight known alkaloids, vasicinone (1), vasicine (2), harmine (3), deoxyvasicinone (4), deoxyvasicine (5), harmaline (6), harmol (7), harman (8), in which harmol and harman were first isolated from species P. nigellastrum Bunge. As active constituents, all compounds showed good inhibitory activities against AChE. The results of in vitro semi-quality TLC-bioautographic assay showed that harmine, harmaline and harmol displayed a similar AChE inhibitive activities comparing to galanthamine. These results indicated that these alkaloids in P. nigellastrum Bunge could be a potent class of AChEIs.

p63 and c-Myc are key transcription factors controlling genes involved in the cell cycle and cellular senescence. We previously reported that p63α can destabilize MM1 protein to derepress c-Myc, resulting in cell cycle progress and tumorigenesis. However, how the proteasomal degradation of MM1 is facilitated remains unclear. In the present study, we identified a novel E3 ligase, HERC3, which can mediate ubiquitination of MM1 and promote its proteasome-dependent degradation. We found that ΔNp63α transcriptionally up-regulates HERC3 and knockdown of HERC3 abrogates ΔNp63α-induced down-regulation of MM1. Either overexpression of MM1 or ablation of HERC3 induces cell senescence, while knockdown of MM1 rescues cell senescence induced by deficiency of either ΔNp63α or HERC3, implicating the involvement of the ΔNp63α/HERC3/MM1/c-Myc axis in the modulation of cell senescence. Additionally, our Oncomine analysis indicates activation of the ΔNp63α/HERC3/MM1/c-Myc axis in invasive breast carcinoma. Together, our data illuminate a novel axis regulating cell senescence: ΔNp63α stimulates transcription of E3 ligase HERC3, which mediates ubiquitination of c-Myc modulator MM1 and targets it to proteasomal degradation; subsequently, c-Myc is derepressed by ΔNp63α, thereby cell senescence is modulated by this axis. Our work provides a new interpretation of crosstalk between p63 and c-Myc, and also sheds new light on ΔNp63α-controlled cell senescence and tumorigenesis.