Background Several studies have shown that the neutrophil to lymphocyte ratio (NLR) in peripheral blood is a prognostic factor of various cancers. However, there is limited information on the clinical and prognostic significance of NLR in patients with metastatic advanced gastric cancer (AGC). Therefore, we examined whether the NLR can be used as a prognostic marker for predicting chemotherapeutic response and survival outcomes in metastatic AGC patients who are receiving palliative chemotherapy. Method A total of 268 patients diagnosed with metastatic AGC were enrolled. NLR was calculated from complete blood cell count taken before the first chemotherapy treatment. Patients were divided into two groups according to the median value of NLR: a high NLR group and a low NLR group. Result The median follow-up period was 340 days (range 72-1796 days) and median NLR was 3.06 (range 0.18-18.16). The high NLR group (NLR [3.0) contained 138 patients and the low NLR group (NLR B3.0) contained 130 patients. Low NLR group patients had a significantly higher chemotherapeutic disease control rate (90.0 % vs. 80.4; P = 0.028), and longer progression-free survival (PFS) and overall survival (OS) than the high NLR group patients (186 vs. 146 days; P = 0.001; 414 vs. 280 days; P \ 0.001, respectively). In multivariate analysis, NLR showed a significant association with PFS (HR 1.478; 95 % CI 1.154-1.892; P = 0.002) and OS (HR 1.569; 95 % CI 1.227-2.006; P \ 0.001). Conclusion Pretreatment NLR is a useful prognostic marker in patients with metastatic AGC who are undergoing palliative chemotherapy.

Although mesenchymal stem cells (MSCs) are a promising cell source for regenerative medicine, ischemia-induced endoplasmic reticulum (ER) stress induces low MSC engraftment and limits their therapeutic efficacy. To overcome this, we investigated the protective effect of tauroursodeoxycholic acid (TUDCA), a bile acid, on ER stress in MSCs in vitro and in vivo. In ER stress conditions, TUDCA treatment of MSCs reduced the activation of ER stress-associated proteins, including GRP78, PERK, eIF2α, ATF4, IRE1α, JNK, p38, and CHOP. In particular, TUDCA inhibited the dissociation between GRP78 and PERK, resulting in reduced ER stress-mediated cell death. Next, to explore the ER stress protective mechanism induced by TUDCA treatment, TUDCA-mediated cellular prion protein (PrPC) activation was assessed. TUDCA treatment increased PrPC expression, which was regulated by Akt phosphorylation. Manganese-dependent superoxide dismutase (MnSOD) expression also increased significantly in response to signaling through the TUDCA-Akt axis. In a murine hindlimb ischemia model, TUDCA-treated MSC transplantation augmented the blood perfusion ratio, vessel formation, and transplanted cell survival more than untreated MSC transplantation did. Augmented functional recovery following MSC transplantation was blocked by PrPC downregulation. This study is the first to demonstrate that TUDCA protects MSCs against ER stress via Akt-dependent PrPC and Akt-MnSOD pathway.

No abstract

Stress-induced glucocorticoids disturb mitochondrial bioenergetics and dynamics; however, instead of being removed via mitophagy, the damaged mitochondria accumulate. Therefore, we investigate the role of glucocorticoids in mitophagy inhibition and subsequent synaptic defects in hippocampal neurons, SH-SY5Y cells, and ICR mice. First, we observe that glucocorticoids decrease both synaptic density and vesicle recycling due to suppressed mitophagy. Screening data reveal that glucocorticoids downregulate BNIP3-like (BNIP3L)/NIX, resulting in the reduced mitochondrial respiration function and synaptic density. Notably, we find that glucocorticoids direct the glucocorticoid receptor to bind directly to the PGC1α promoter, downregulating its expression and nuclear translocation. PGC1α downregulation selectively decreases NIX-dependent mitophagy. Consistent with these results, NIX enhancer pre-treatment of a corticosterone-exposed mouse elevates mitophagy and synaptic density in hippocampus, improving the outcome of a spatial memory task. In conclusion, glucocorticoids inhibit mitophagy via downregulating NIX and that NIX activation represents a potential target for restoring synapse function.