m6A regulator-mediated RNA methylation modification patterns and immune microenvironment infiltration characterization in severe asthma.

N6-methyladenosine (m6A) modification is one of the most prevalent RNA modification forms of eukaryotic mRNA and is an important post-transcriptional mechanism for regulating genes. However, the role of m6A modification in the regulation of severe asthma has never been reported. Thus, we aimed to investigate the m6A regulator-mediated RNA methylation modification patterns and immune microenvironment infiltration characterization in severe asthma. In this study, 87 healthy controls and 344 severe asthma cases from the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes) programme were used to systematically evaluate the m6A modification patterns mediated by 27 m6A regulators and to investigate the effects of m6A modification on immune microenvironment characteristics. We found that 16 m6A regulators were abnormal and identified two key m6A regulators (YTHDF3 and YTHDC1) and three m6A modification patterns. The study of infiltration characteristics of immune microenvironment found that pattern 2 had more infiltrating immune cells and more active immune response. Besides, it was found that the eosinophils which are very important for severe asthma were affected by YTHDF3 and EIF3B. We also verified key m6A regulators with merip-seq and found that they were mainly distributed in exons and enriched in 3'UTR. In conclusion, our findings suggested that m6A modification plays a key role in severe asthma, and may be able to guide the future strategy of immunotherapy.

A Novel Compound YS-5-23 Exhibits Neuroprotective Effect by Reducing ß-Site Amyloid Precursor Protein Cleaving Enzyme 1's Expression and H2O2-Induced Cytotoxicity in SH-SY5Y Cells.

The abnormally accumulated amyloid-ß (Aß) and oxidative stress contribute to the initiation and progression of Alzheimer's disease (AD). ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate-limiting enzyme for the production of Aß. Furthermore, Aß was reported to increase oxidative stress; then the overproduced oxidative stress continues to increase the expression and activity of BACE1. Consequently, inhibition of both BACE1 and oxidative stress is a better strategy for AD therapy compared with those one-target treatment methods. In the present study, our novel small molecule YS-5-23 was proved to possess both of the activities. Specifically, we found that YS-5-23 reduces BACE1's expression in both SH-SY5Y and Swedish mutated amyloid precursor protein (APP) overexpressed HEK293 cells, and it can also suppress BACE1's expression induced by H2O2. Moreover, YS-5-23 decreases H2O2-induced cytotoxicity including alleviating H2O2-induced apoptosis and loss of mitochondria membrane potential (MMP) because it attenuates the reactive oxygen species (ROS) level elevated by H2O2. Meanwhile, PI3K/Akt signaling pathway is involved in the anti-H2O2 and BACE1 inhibition effect of YS-5-23. Our findings indicate that YS-5-23 may develop as a drug candidate in the prevention and treatment of AD.

A Series of Enthalpically Optimized Docetaxel Analogues Exhibiting Enhanced Antitumor Activity and Water Solubility.

A dual-purpose strategy aimed at enhancing the binding affinity for microtubules and improving the water solubility of docetaxel led to the design and synthesis of a series of C-2- and C-3'-modified analogues. Both aims were realized when the C-3' phenyl group present in docetaxel was replaced with a propargyl alcohol. The resulting compound, 3f, was able to overcome drug resistance in cultured P-gp-overexpressing tumor cells and showed greater activity than docetaxel against drug-resistant A2780/AD ovarian cancer xenografts in mice. In addition, the considerably lower hydrophobicity of 3f relative to both docetaxel and paclitaxel led to better aqueous solubility. A molecular model of tubulin-bound 3f revealed novel hydrogen-bonding interactions between the propargyl alcohol and the polar environment provided by the side chains of Ser236, Glu27, and Arg320.

Synthesis and biological evaluations of chalcones, flavones and chromenes as farnesoid x receptor (FXR) antagonists.

Farnesoid X receptor (FXR), a nuclear receptor mainly distributed in liver and intestine, has been regarded as a potential target for the treatment of various metabolic diseases, cancer and infectious diseases related to liver. Starting from two previously identified chalcone-based FXR antagonists, we tried to increase the activity through the design and synthesis of a library containing chalcones, flavones and chromenes, based on substitution manipulation and conformation (ring closure) restriction strategy. Many chalcones and four chromenes were identified as microM potent FXR antagonists, among which chromene 11c significantly decreased the plasma and hepatic triglyceride level in KKay mice.