ABBV-744 alleviates LPS-induced neuroinflammation via regulation of BATF2-IRF4-STAT1/3/5 axis.

Suppression of neuroinflammation using small molecule compounds targeting the key pathways in microglial inflammation has attracted great interest. Recently, increasing attention has been gained to the role of the second bromodomain (BD2) of the bromodomain and extra-terminal (BET) proteins, while its effect and molecular mechanism on microglial inflammation has not yet been explored. In this study, we evaluated the therapeutic effects of ABBV-744, a BD2 high selective BET inhibitor, on lipopolysaccharide (LPS)-induced microglial inflammation in vitro and in vivo, and explored the key pathways by which ABBV-744 regulated microglia-mediated neuroinflammation. We found that pretreatment of ABBV-744 concentration-dependently inhibited the expression of LPS-induced inflammatory mediators/enzymes including NO, TNF-α, IL-1ß, IL-6, iNOS, and COX-2 in BV-2 microglial cells. These effects were validated in LPS-treated primary microglial cells. Furthermore, we observed that administration of ABBV-744 significantly alleviated LPS-induced activation of microglia and transcriptional levels of pro-inflammatory factors TNF-α and IL-1ß in mouse hippocampus and cortex. RNA-Sequencing (RNA-seq) analysis revealed that ABBV-744 induced 508 differentially expressed genes (DEGs) in LPS-stimulated BV-2 cells, and gene enrichment and gene expression network analysis verified its regulation on activated microglial genes and inflammatory pathways. We demonstrated that pretreatment of ABBV-744 significantly reduced the expression levels of basic leucine zipper ATF-like transcription factor 2 (BATF2) and interferon regulatory factor 4 (IRF4), and suppressed JAK-STAT signaling pathway in LPS-stimulated BV-2 cells and mice, suggesting that the anti-neuroinflammatory effect of ABBV-744 might be associated with regulation of BATF2-IRF4-STAT1/3/5 pathway, which was confirmed by gene knockdown experiments. This study demonstrates the effect of a BD2 high selective BET inhibitor, ABBV-744, against microglial inflammation, and reveals a BATF2-IRF4-STAT1/3/5 pathway in regulation of microglial inflammation, which might provide new clues for discovery of effective therapeutic strategy against neuroinflammation.

A novel AIE material for sensing of Erythromycin in pure water by hydrogen bond in portable test strips and cellular imaging applications.

Erythromycin could be used to treat various bacterial infection, but it was harmful to the colonic microflora. Therefore, it is highly desirable to develop a fluorescence probe that could selectively and sensitively detect Erythromycin in pure water. In this work, a fluorescent probe named EHMC, which exhibited aggregation-induced emission (AIE) characteristic in solid state and water/EtOH binary solvent was developed for "turn on" sensing Erythromycin in pure water with high selectivity and sensitivity (detection limit: 1.78 × 10-8 M). Also, there are fewer interference from other antibiotics in the detection process of probe EHMC for Erythromycin. Moreover, probe EHMC could as a portable test strips for highly selective detection of Erythromycin and identification of different concentrations of Erythromycin. In addition, living cells imaging experiments displayed that probe EHMC could detect Erythromycin in A549 cells and BEAS-2B cells successfully. Combined with the theoretical calculation results The sensing mechanisms that the CO in Erythromycin and OH in EHMC formed intermolecular hydrogen bond and further formed new aggregates were confirmed by job' plot, 1H NMR, FT-IR, ESI-MS, DLS and TEM and DFT calculation.

Associations between PBDEs exposure from house dust and human semen quality at an e-waste areas in South China-A pilot study.

Previous studies have confirmed that house dust is one of the main sources of polybrominated diphenyl ethers (PBDEs) exposure, and also indicated that PBDEs might affect human semen quality. The aim of this study was to explore the association between PBDEs concentration in house dust and the semen quality of male resident. Results showed that the semen qualities of the residents living around the e-waste dismantling workshops for a long time (3-17years) at the e-waste areas in South China significantly decreased, and the DNA damage of sperms were aggravated. The adjusted correlation analysed by multiple linear regression model showed that the sperm concentration and count both had negative correlation with BDE47 level in semen (ß = -0.295, 95%CI: -0.553∼-0.036; ß = -0.400, 95%CI: -0.708∼-0.092, respectively). In addition, the sperm progressive motility [(A+B)%] and sperm viability both had negative correlation with BDE100 level in dust (ß = -0.360, 95%CI: -0.680∼-0.040; ß = -0.114, 95% CI: -0.203∼-0.025, respectively). And there were significant linear positive correlation between PBDE congener (e.g. BDE28, 47, 153) concentrations in dust and in paired semen samples (rs = 0.367-0.547, p < 0.05). This study suggested that exposure to PBDEs from house dust might have adverse effects on human semen quality. But the results need to be confirmed in further studies with a large-scale sampling, and find out more direct and convincing evidence.

Phosphorylated Mammalian Target of Rapamycin p-mTOR Is a Favorable Prognostic Factor than mTOR in Gastric Cancer.

AIMS: The mammalian target of rapamycin (mTOR) and phosphorylated mTOR (p-mTOR) occurring downstream in the PI3K/Akt/mTOR pathway, are regarded as potential prognostic markers for gastric cancer (GC). However, the prognostic value of mTOR/p-mTOR expression remains controversial. In this study, we determined the expression of mTOR, p-mTOR, p70S6k, and p-p70S6K in GC, and investigated the correlation between their overexpression, clinicopathological parameters, and overall survival (OS). METHODS: The expression of mTOR, p-mTOR, p70S6k, and p-p70S6K was examined in 120 GC patients by immunohistochemistry (IHC). The association of protein expression with clinicopathological features and OS was explored. The p-mTOR expression was detected in normal, adjacent, and GC tissues using Western blot. Eligible studies retrieved from PubMed, Ovid, Web of Science and Cochrane databases, were reviewed in this meta-analysis. RESULTS: IHC showed that the rates of expression of the signal transduction molecules mTOR, p-mTOR, p70S6k and p-p70S6K in GC were 60.8%, 54.2%, 53.3% and 53.3%, respectively. Overexpression of mTOR and p70S6K showed no significant association with clinical variables. Expression of p-mTOR was significantly associated with differentiation (P < 0.01), depth of invasion (P < 0.01), lymph node metastasis (P = 0.04) and TNM stage (P = 0.02). Expression of p-p70S6K was associated with differentiation (P = 0.006), depth of invasion (P < 0.001), and TNM stage (P = 0.02). In survival analysis, differentiation, depth of invasion, lymph node metastasis and TNM stage were not related to OS (all P > 0.05). Furthermore, p-mTOR and p-p70S6K expression, but not mTOR and p70S6K, were tightly associated with OS of GC patients (P = 0.006 and P < 0.001, respectively). In Western blot, p-mTOR was significantly higher in GC tissues than in normal and adjacent tissues. In the present meta-analysis, mTOR overexpression showed no relationship with any clinicopathological variables. However, p-mTOR was correlated with depth of invasion, and TNM stage (all P < 0.05), and its overexpression was associated with a shorter survival time (P < 0.001). CONCLUSION: The results suggest that p-mTOR is a more valuable prognostic factor than mTOR in GC.

Cytotoxic sesquiterpene lactone dimers isolated from Inula japonica.

Two new sesquiterpene lactone dimers, neojaponicone B (1) and inulanolide E (2) along with five known sesquiterpene lactone dimers (3-7, resp.) were isolated from the aerial parts of Inula japonica Thunb. The chemical structures of 1 and 2 were elucidated by detailed spectroscopic analysis. The relative configuration of 2 was confirmed by biomimetic transformation from the known sesquiterpene lactone dimer inulanolide A (3). The cytotoxicities of the isolated sesquiterpene lactone dimers were evaluated against 6T-CEM and Jurkat cell lines. All compounds showed potent cytotoxicities with IC50 value of 2.2-5.9µm.