Graphical AbstractHighlights d HFS triggers synaptic plasticity of CGRP afferents and chronic pain d LTP-inducible HFS activates spinal microglia through CSF1 signaling d Microglial BDNF is essential for HFS-induced spinal LTP and chronic pain SUMMARY Spinal long-term potentiation (LTP) at C-fiber synapses is hypothesized to underlie chronic pain. However, a causal link between spinal LTP and chronic pain is still lacking. Here, we report that high-frequency stimulation (HFS; 100 Hz, 10 V) of the mouse sciatic nerve reliably induces spinal LTP without causing nerve injury. LTP-inducible stimulation triggers chronic pain lasting for more than 35 days and increases the number of calcitonin gene-related peptide (CGRP) terminals in the spinal dorsal horn. The behavioral and morphological changes can be prevented by blocking NMDA receptors, ablating spinal microglia, or conditionally deleting microglial brain-derived neurotrophic factor (BDNF). HFS-induced spinal LTP, microglial activation, and upregulation of BDNF are inhibited by antibodies against colony-stimulating factor 1 (CSF-1). Together, our results show that microglial CSF1 and BDNF signaling are indispensable for spinal LTP and chronic pain. The microglia-dependent transition of synaptic potentiation to structural alterations in pain pathways may underlie pain chronicity.

Sodium butyrate (NaBu) is reported to play important roles in a number of chronic diseases. The present work is aimed to investigate the effect of NaBu on angiotensin II (Ang II)‐induced cardiac hypertrophy and the underlying mechanism in in vivo and in vitro models. Sprague Dawley rats were infused with vehicle or Ang II (200 ng/kg/min) and orally administrated with or without NaBu (1 g/kg/d) for two weeks. Cardiac hypertrophy parameters and COX2/PGE2 pathway were analysed by real‐time PCR, ELISA, immunostaining and Western blot. The cardiomyocytes H9C2 cells were used as in vitro model to investigate the role of NaBu (2 mmol/L) in inhibition of Ang II‐induced cardiac hypertrophy. NaBu significantly attenuated Ang II‐induced increase in the mean arterial pressure. Ang II treatment remarkably increased cardiac hypertrophy as indicated by increased ratio of heart weight/body weight and enlarged cardiomyocyte size, extensive fibrosis and inflammation, as well as enhanced expression of hypertrophic markers, whereas hearts from NaBu‐treated rats exhibited a significant reduction in these hypertrophic responses. Mechanistically, NaBu inhibited the expression of COX2/PGE2 along with production of ANP and phosphorylated ERK (pERK) stimulated by Ang II in in vivo and in vitro, which was accompanied by the suppression of HDAC5 and HDAC6 activities. Additionally, knocking down the expression of HDAC5 and HDAC6 via gene‐editing strategy dramatically blocked Ang II‐induced hypertrophic responses through COX2/PGE2 pathway. These results provide solid evidence that NaBu attenuates Ang II‐induced cardiac hypertrophy by inhibiting the activation of COX2/PGE2 pathway in a HDAC5/HDAC6‐dependent manner.

Due to the presence of pores and low density, a high recoverable energy density (W rec) value is usually obtained at the cost of energy storage efficiency (η) in lead-free potassium sodium niobate [(K, Na)­NbO3, KNN] based ceramics, which also affects the hardness of ceramics, finally limiting the further development of practical applications. A high W rec (∼3.60 J/cm3 ) and a high η (∼74.2%) are obtained in 0.975K0.5Na0.5NbO3-0.025LaBiO3 (0.975KNN-0.025LB) ceramics simultaneously under a high dielectric breakdown strength (DBS) of 340 kV/cm, together with a fast discharge rate (t 0.9 ∼ 46 ns) and high power density (P D ∼ 49.4 MW/cm3). Further analysis of the intrinsic electronic structure is carried out via the first-principles calculation based on the density functional theory (DFT). An ultrahigh hardness (H) of 6.63 GPa can be accordingly obtained. This work combines excellent energy storage properties and ultrahigh hardness, which provides significant guidelines for applications in pulsed-power systems.

Estrogen promotes breast cancer metastasis. However, the detailed mechanism remains largely unknown. The actin binding protein ezrin is a key component in tumor metastasis and its over-expression is positively correlated to the poor outcome of breast cancer. In this study, we investigate the effects of 17β-estradiol (E2) on the activation of ezrin and its role in estrogen-dependent breast cancer cell movement. In T47-D breast cancer cells, E2 rapidly enhances ezrin phosphorylation at Thr567 in a time- and concentration-dependent manner. The signalling cascade implicated in this action involves estrogen receptor (ER) interaction with the non-receptor tyrosine kinase c-Src, which activates the phosphatidylinositol-3 kinase/Akt pathway and the small GTPase RhoA/Rho-associated kinase (ROCK-2) complex. E2 enhances the horizontal cell migration and invasion of T47-D breast cancer cells in three-dimensional matrices, which is reversed by transfection of cells with specific ezrin siRNAs. In conclusion, E2 promotes breast cancer cell movement and invasion by the activation of ezrin. These results provide novel insights into the effects of estrogen on breast cancer progression and highlight potential targets to treat endocrine-sensitive breast cancers.

Bmal1 is a transcription factor that plays a central role in the regulation of circadian rhythms. Recent study reported that Bmal1-/- mice displayed many known features of premature ageing, such as reduction of bone mass. Our previous study has found that both the proliferation of bone marrow mesenchymal stem cells (BMSCs) and Bmal1 expression decreased with advancing age. It seemed that a positive correlation existed between Bmal1 protein level and the proliferative activity of BMSCs. β-catenin, the core factor of the canonical Wnt pathway, also showed reduced expression in aged mice. In order to further confirm this, we constructed a lentiviral vector to over-express Bmal1 in NIH-3T3 cells; successful transfection was verified. The cell proliferation rate of infected cells was higher than the non-transfected NIH-3T3 cells, suggesting that circadian clock gene Bmal1 can promote proliferation. β-catenin showed an increased expression in NIH-3T3 cells after Bmal1 over-expression, indicating that activation of the canonical Wnt pathway might be the mechanism underlying the effect of circadian clock gene Bmal on promoting cell proliferation.