Assessing the causal relationship between immune traits and systemic lupus erythematosus by bi-directional Mendelian randomization analysis.

Previous studies have observed relationships between immune cells and systemic lupus erythematosus (SLE), but their causal links remain undetermined. Based on the public available genome-wide association studies (GWAS) summary statistics, we conducted two-sample Mendelian randomization (MR) to evaluate the associations between 731 immune phenotypes and SLE pairs. Pairwise pleiotropy analysis was performed to identify pleiotropic genes for significant immunophenotype-SLE pairs. A comprehensive gene function analysis was undertaken to explore the mechanisms of immune cells in SLE. By using the instrumental variables extracted from GWAS data, we observed that increased levels of five immune phenotypes were causally associated with SLE risk (FDR < 0.05), that were CD20 on IgD+ CD38- naïve, BAFF-R on IgD+ CD38dim, CD39+ secreting Treg AC, CD14- CD16+ monocyte AC, and HLA DR on CD14+ monocyte. Pairwise gene-based analyses identified a total of 38 pleiotropic genes for 5 significant pairs identified and gene set enrichment analysis revealed the involvement of the identified pleiotropic genes in complex pathways (i.e., systemic lupus erythematosus, an integral component of luminal side of endoplasmic reticulum membrane, C-type lectin receptor signaling pathway and regulation of hormone secretion). This study demonstrates that the immune response influences the progression of SLE in a complex pattern. These findings greatly improve our understanding of the interaction between immune response and SLE risk and also aid in the design of therapeutic strategies from an immunological perspective.

A novel cell-wall polysaccharide derived from the stipe of Agaricus bisporus inhibits mouse melanoma proliferation and metastasis.

Malignant melanoma is an invasive and highly aggressive skin cancer that-if diagnosed-poses a serious threat to the patient's health and life. In this work, a novel purified cell-wall polysaccharide (termed Abwp) was obtained from the discarded stipe of Agaricus bisporus (A. bisporus) and characterized to be a novel homogeneous polysaccharide consisted of a ß-(1 â†’ 4)- glucosyl backbone with ß-(1 â†’ 2) and (1 â†’ 6)-d-glucosyl side-chains. The anti-melanoma effects of Abwp and its associated mechanisms in mice were then explored using in vitro and in vivo approaches. In vitro results showed that Abwp inhibited B16 melanoma cell proliferation and promoted their apoptosis in both time- and dose-dependent manners. In B16 cells induced with tumor necrosis factor (TNF-α), Abwp significantly decreased the protein expression of inflammatory-related signaling pathway (e.g., p38 MAPK and NF-κB) in time-, concentration-, and dose-dependent manners. Moreover, Abwp blocked nuclear entry of NF-κB-p65. In an in vivo mouse model featuring neoplasm transplantation with B16 melanoma cells, Abwp significantly inhibited the growth and proliferation of mouse melanoma. Hematoxylin staining showed that the invasion of melanoma cells into the lung tissue of the Abwp-treated group was significantly reduced. Immunohistochemical analysis showed that the expression of proliferation cell nuclear antigen (PCNA), N-cadherin, MMP-9, and Snail in the lung of mouse was significantly inhibited. Immunofluorescence showed that Abwp significantly interfered with the nuclear transcription of NF-κB-p65 in a dose-dependent manner. Collectively, these results showed that Abwp mediated p38 MAPK and NF-κB signaling pathways to inhibit the inflammatory response and malignant proliferation and metastasis of melanoma in mice.

pH triggered doxorubicin delivery of PEGylated glycolipid conjugate micelles for tumor targeting therapy.

The main objective of this study was aimed at tumor microenvironment-responsive vesicle for targeting delivery of the anticancer drug, doxorubicin (DOX). A glucolipid-like conjugate (CS) was synthesized by the chemical reaction between chitosan and stearic acid, and polyethylene glycol (PEG) was then conjugated with CS via a pH-responsive cis-aconityl linkage to produce acid-sensitive PEGylated CS conjugates (PCCS). The conjugates with a critical micelle concentration (CMC) of 181.8 µg/mL could form micelles in aqueous phase, and presented excellent DOX loading capacity with a drug encapsulation efficiency up to 87.6%. Moreover, the PCCS micelles showed a weakly acid-triggered PEG cleavage manner. In vitro drug release from DOX-loaded PCCS micelles indicated a relatively faster DOX release in weakly acidic environments (pH 5.0 and 6.5). The CS micelles had excellent cellular uptake ability, which could be significantly reduced by the PEGylation. However, the cellular uptake ability of PCCS was enhanced comparing with insensitive PEGylated CS (PCS) micelles in weakly acidic condition imitating tumor tissue. Taking PCS micelles as a comparative group, the PCCS drug delivery system was demonstrated to show much more accumulation in tumor tissue, followed by a relatively better performance in antitumor activity together with a security benefit on xenograft tumor model.