Bayer AG.

Abstract. Phospholipase D4 (PLD4) is a newly identified protein expressed in microglia. However, the function of PLD4 in tumor-associated macrophages (TAMs) is unknown. In the present study, we revealed that the expression of PLD4 was located in macrophages in the colon cancer mesenchymal and lymph nodes as shown by immunohistochemical analysis. furthermore, its expression was associated with clinical staging of colon cancer. Then, THP-1 as a cell model induced into TAMs. Western blot and RT-PCR analysis showed that PLD4 was mainly presented in M1 phenotype TAMs. The secretion of pro-inflammatory cytokines in M1 macrophages was significantly reduced after the expression of PLD4 inhibited by PLD4-siRNA. furthermore, co-cultured with condition-medium from control or PLD4-siRNA M1 macrophages for 24 h, cell apoptosis, cycle and proliferation of cancer cells improved compared to control. These results indicated that PLD4 could be involved in the activation process of M1 phenotype macrophages.

Background: To evaluate the association between heart rate (HR) fluctuation and mortality in critically ill patients in the intensive care unit (ICU). Methods: A total of 27,814 patients were enrolled from the Medical Information Mart for Intensive Care database and were divided into 3 groups: low HR fluctuation [<25 beats per minute (bpm)], control (25-34 bpm), and high HR fluctuation (≥35 bpm), based on the initial 24-hour HR fluctuation (calculated as the maximum HR minus minimum HR). Multivariate Cox regression and restricted cubic spline models were used.Results: Compared to the control group, higher risk of 28-day and 1-year mortality remained significant in an adjusted model, with hazard ratios of 1.210 [95% confidence interval (CI), 1.103-1.327] and 1.150 (95% CI, 1.078-1.227), respectively, in the high HR fluctuation group, as well as hazard ratios of 1.130 (95% CI, 1.035-1.232) and 1.087 (95% CI, 1.022-1.157), respectively, in the low HR fluctuation group. Restricted cubic splines showed a U-type curve, with the lowest risk of mortality at an HR fluctuation of 30 bpm.Conclusions: This retrospective cohort study revealed that both high and low HR fluctuation correlated with increased mortality in critically ill ICU patients, providing new insights for optimizing HR control strategies.

High density lipoprotein (HDL) has been proposed to be internalized and to promote reverse cholesterol transport in endothelial cells (ECs). However, the mechanism underlying these processes has not been studied. In this study, we aim to characterize HDL internalization and cholesterol efflux in ECs and regulatory mechanisms. We found mature HDL particles were reduced in patients with coronary artery disease (CAD), which was associated with an increase in CC-chemokine ligand 2 (CCL2). In cultured primary human coronary artery endothelial cells and human umbilical vein endothelial cells, we determined that CCL2 suppressed the binding (4 °C) and association (37 °C) of HDL to/with ECs and HDL cellular internalization. Furthermore, CCL2 inhibited [3H]cholesterol efflux to HDL/apoA1 in ECs. We further found that CCL2 induced CC-chemokine receptor 2 (CCR2) expression and siRNA-CCR2 reversed CCL2 suppression on HDL binding, association, internalization, and on cholesterol efflux in ECs. Moreover, CCL2 induced p42/44 mitogen-activated protein kinase (MAPK) phosphorylation via CCR2, and p42/44 MAPK inhibition reversed the suppression of CCL2 on HDL metabolism in ECs. Our study suggests that CCL2 was elevated in CAD patients. CCL2 suppressed HDL internalization and cholesterol efflux via CCR2 induction and p42/44 MAPK activation in ECs. CCL2 induction may contribute to impair HDL function and form atherosclerosis in CAD.