Endometrial cancer (EC) is a common form of cancer in women. Metastasis is the main cause of EC treatment failure. Eukaryotic translation initiation factor 4E (eIF4E) is an oncogene that is overexpressed in a variety of malignancies and their distant metastases. The present study analyzed microarray data from the Oncomine database and revealed that high eIF4E expression was associated with poor prognosis and high pathological grade of EC. The expression of eIF4E was higher in EC tissues compared with in adjacent normal tissues. In addition, microRNA (miR)-320a and miR-340-5p expression levels were downregulated in EC tissues compared with those in adjacent normal tissues, which suggested that these microRNAs may serve as EC tumor suppressor genes. miR-320a and miR-340-5p could bind to the 3'-UTR of eIF4E mRNA, thus downregulating the expression of eIF4E and phosphorylated (p)-eIF4E in EC cells. Overexpression of miR-320a or miR-340-5p effectively suppressed HEC-1A cell migration and invasion. The downregulation of eIF4E and p-eIF4E following miR-320a or miR-340-5p transfection reduced the invasiveness and metastatic capability of EC cells in a manner associated with decreased expression of matrix metallopeptidase (MMP)-3 and MMP-9. In addition, one of the effects of transforming growth factor β1 (TGF-β1), which is to induce the phosphorylation of eIF4E, was suppressed by miR-320a and miR-340-5p overexpression. These two microRNAs also attenuated the features of TGF-β1-induced epithelial-mesenchymal transition (EMT). In conclusion, the results of the present study demonstrated that eIF4E was upregulated in EC, whereas miR-320a and miR-340-5p were downregulated in EC compared with adjacent normal tissues. In vitro, miR-320a and miR-340-5p inhibited the migratory capability of EC cells by downregulating MMP-3 and MMP-9 and prevented TGF-β1-induced EMT through p-eIF4E.

Previous studies supported a role of hypothalamic inflammation in fine ambient particulate matter (PM2.5) exposure-mediated diabetes development. We therefore investigated the effects of PM2.5 exposure on insulin resistance and the disorders of hepatic glucose and lipid metabolism via hypothalamic inflammation. KKAy mice, a genetically susceptible model of type II diabetes mellitus, were administered intra-cerebroventricularly with IKK2 inhibitor (IMD-0354) and were exposed to either concentrated PM2.5 or filtered air (FA) for 4 weeks simultaneously via a versatile aerosol concentration exposure system. At the end of the exposure, fasting blood glucose and serum insulin were evaluated before epididymal adipose tissue and liver were collected, flow cytometry, quantitative PCR and Western blot were performed at euthanasia. We observed that intracerebroventricular administration of IMD-0354 attenuated insulin resistance, inhibited macrophage polarization to M1 phenotype in epididymal adipose tissue in response to PM2.5 exposure. Although the treatment did not affect hepatic inflammation or endoplasmic reticulum stress, it inhibited the expression of the enzymes for gluconeogenesis and lipogenesis in the liver. Therefore, our current finding indicates an important role of hypothalamic inflammation in PM2.5 exposure-mediated hepatic glucose and lipid metabolism disorder.

Background & aims: Emerging evidence supports ambient fine particulate matter (PM 2.5 ) exposure is associated with insulin resistance (IR) and hepatic lipid accumulation. In this study, we aimed to evaluate the sex-dependent vulnerability in response to PM 2.5 exposure and investigate the underlying mechanism by which PM 2.5 modulates hepatic lipid metabolism.Methods: Both male and female C57BL/6 mice were randomly assigned to ambient PM 2.5 or filtered air for 24 weeks via a whole body exposure system. High-coverage quantitative lipidomics approaches and liquid chromatographymass spectrometry techniques were performed to measure hepatic metabolites and hormones in plasma. Metabolic studies, histological analyses, as well as gene expression levels and molecular signal transduction analysis were applied to examine the effects and mechanisms by which PM 2.5 exposure-induced metabolic disorder.Results: Female mice were more susceptible than their male counterparts to ambient PM 2.5 exposure-induced IR and hepatic lipid accumulation. The hepatic lipid profile was changed in response to ambient PM 2.5 exposure. Levels of hepatic triacylglycerols (TAGs), free fatty acids (FFAs) and cholesterol were only increased in female mice from PM group compared to control group. Plasmalogens were dysregulated in the liver from PM 2.5 -exposed mice as well. In addition, exposure to PM 2.5 led to enhanced hepatic ApoB and microsomal triglyceride transport protein expression in female mice. Finally, PM 2.5 exposure inhibited hypothalamus-pituitary-adrenal (HPA) axis and decreased glucocorticoids levels, which may contribute to the vulnerability in PM 2.5 -induced metabolic dysfunction.Conclusions: Ambient PM 2.5 exposure inhibited HPA axis and demonstrated sex-associated differences in its effects on IR and disorder of hepatic lipid metabolism. These findings provide new mechanistic evidence of hormone regulation in air pollution-mediated metabolic abnormalities of lipids and more personalized care should be considered in terms of sex-specific risk factors.

Sepsis is a major cause of death for hospitalized patients and is characterized by massive overreaction of immune responses to invading pathogens which is mediated by cytokines. For decades, there has been no effective treatment for sepsis. Sialic acid-binding, Ig-like lectin-9 (Siglec-9), is an immunomodulatory receptor expressed primarily on hematopoietic cells which is involved in various aspects of inflammatory responses and is a potential target for treatment of sepsis. The aim of the present study was to develop a human anti-Siglec-9 Fab fragment, which was named hS9-Fab03 and investigate its immune activity in human macrophages. We began by constructing the hS9-Fab03 prokaryotic expression vector from human antibody library and phage display. Then, we utilized a multitude of assays, including SDS-PAGE, Western blotting, ELISA, affinity, and kinetics assay to evaluate the binding affinity and specificity of hS9-Fab03. Results demonstrated that hS9-Fab03 specifically bind to Siglec-9 antigen with high affinity, and pretreatment with hS9-Fab03 could attenuate lipopolysaccharide (LPS)-induced TNF-α, IL-6, IL-1β, IL-8, and IFN-β production in human PBMC-derived macrophages, but slightly increased IL-10 production in an early time point. We also observed similar results in human THP-1-differentiated macrophages. Collectively, we prepared the hS9-Fab03 with efficient activity for blocking LPS-induced pro-inflammatory cytokines production in human macrophages. These results indicated that ligation of Siglec-9 with hS9-Fab03 might be a novel anti-inflammatory therapeutic strategy for sepsis.