TL1A/DR3 Axis, A Key Target of TNF-a, Augments the Epithelial-Mesenchymal Transformation of Epithelial Cells in OVA-Induced Asthma.

Tumor necrosis factor (TNF)-like cytokine 1A (TL1A), a member of the TNF family, exists in the form of membrane-bound (mTL1A) and soluble protein (sTL1A). TL1A binding its only known functional receptor death domain receptor 3 (DR3) affects the transmission of various signals. This study first proposed that the TL1A/DR3 axis was significantly upregulated in patients and mice with both asthma and high TNF-a expression and in TNF-a-stimulated epithelial Beas-2B cells. Two independent approaches were used to demonstrate that the TL1A/DR3 axis of mice was strongly correlated with TNF-a in terms of exacerbating asthmatic epithelial-mesenchymal transformation (EMT). First, high expression levels of EMT proteins (e.g., collagen I, fibronectin, N-cadherin, and vimentin) and TL1A/DR3 axis were observed when mice airways were stimulated by recombinant mouse TNF-a protein. Moreover, EMT protein and TL1A/DR3 axis expression synchronously decreased after mice with OVA-induced asthma were treated with infliximab by neutralizing TNF-a activity. Furthermore, the OVA-induced EMT of asthmatic mice was remarkably improved upon the deletion of the TL1A/DR3 axis by knocking out the TL1A gene. TL1A siRNA remarkably intervened EMT formation induced by TNF-a in the Beas-2B cells. In addition, EMT was induced by the addition of high concentrations of recombinant human sTL1A with the cell medium. The TL1A overexpression via pc-mTL1A in vitro remarkably increased the EMT formation induced by TNF-a. Overall, these findings indicate that the TL1A/DR3 axis may have a therapeutic role for asthmatic with high TNF-a level.

Simultaneous blockage of epidermal growth factor receptor and cyclooxygenase-2 in a human xenotransplanted lung cancer model.

The effects of erlotinib combined with celecoxib in a lung cancer xenograft model were here explored with a focus on possible mechanisms. A xenotransplanted lung cancer model was established in nude mice using the human lung cancer cell A549 cell line and animals demonstrating tumour growth were randomly divided into four groups: control, erlotinib, celecoxib and combined (erotinib and celecoxib). The tumor major axis and short diameter were measured twice a week and after 40 days tissues were collected for immunohistochemical analyses of Bcl-2 and Bax positive cells and Western-blotting analyses for the epidermal growth factor recepto (EGFR), P-EGFR, and cyclooxygenase-2 (COX-2). Tumor size in the combined group was smaller than in the others (p<0.01) and the percentage of Bcl-2 positive cells was fewer in most cases (p<0.01), while that of Bax positive cells was greater than in the erlotinib and celecoxib groups (P>0.05). Western blotting showed decreased expression of P-EGFR and COX-2 with both erlotinib and celecoxib treatments, but most pronouncedly in the combined group (P<0.05). Simultaneous blockage of the EGFR and COX-2 signal pathways exerted stronger growth effects in our human xenotransplanted lung cancer model than inhibition of either pathway alone. The anti-tumor effects were accompanied by synergetic inhibition of tumor cell apoptosis, activation of p-EGFR and expression of COX-2.

AGEs induce cell death via oxidative and endoplasmic reticulum stresses in both human SH-SY5Y neuroblastoma cells and rat cortical neurons.

Advanced glycation endproducts (AGEs) are elevated in aging and neurodegenerative diseases such as Alzheimer's disease (AD), and they can stimulate the generation of reactive oxygen species (ROSs) via NADPH oxidase, induce oxidative stress that lead to cell death. In the current study, we investigated the molecular events underlying the process that AGEs induce cell death in SH-SY5Y cells and rat cortical neurons. We found: (1) AGEs increase intracellular ROSs; (2) AGEs cause cell death after ROSs increase; (3) oxidative stress-induced cell death is inhibited via the blockage of AGEs receptor (RAGE), the down-regulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and the increase of scavenging by anti-oxidant alpha-lipoic acid (ALA); (4) endoplasmic reticulum (ER) stress was triggered by AGE-induced oxidative stress, resulting in the activation of C/EBP homologous protein (CHOP) and caspase-12 that consequently initiates cell death, taurine-conjugated ursodeoxycholic acid (TUDCA) inhibited AGE-induced ER stress and cell death. Blocking RAGE-NADPH oxidase, and RAGE-NADPH oxidase-ROSs and ER stress scavenging pathways could efficiently prevent the oxidative and ER stresses, and consequently inhibited cell death. Our results suggest a new prevention and or therapeutic approach in AGE-induced cell death.