Extracellular ATP facilitates cell extrusion from epithelial layers mediated by cell competition or apoptosis

For the maintenance of epithelial homeostasis, various aberrant or dysfunctional cells are actively eliminated from epithelial layers. This cell extrusion process mainly falls into two modes: cell-competition-mediated extrusion and apoptotic extrusion. However, it is not clearly understood whether and how these processes are governed by common molecular mechanisms. In this study, we demonstrate that the reactive oxygen species (ROS) levels are elevated within a wide range of epithelial layers around extruding transformed or apoptotic cells. The downregulation of ROS suppresses the extrusion process. Furthermore, ATP is extracellularly secreted from extruding cells, which promotes the ROS level and cell extrusion. Moreover, the extracellular ATP and ROS pathways positively regulate the polarized movements of surrounding cells toward extruding cells in both cell-competition-mediated and apoptotic extrusion. Hence, extracellular ATP acts as an “extrude me” signal and plays a prevalent role in cell extrusion, thereby sustaining epithelial homeostasis and preventing pathological conditions or disorders

Improved Time in Range and Postprandial Hyperglycemia with Canagliflozin in Combination with Teneligliptin : Secondary Analyses of the CALMER study

Aims/Introduction We recently reported the beneficial effect of the combination of SGLT2 inhibitor and DPP‐4 inhibitor on daily glycemic variability in patients with type 2 diabetes mellitus (T2DM). Additional favorable effects of combination therapy were explored in this secondary analysis. Materials and Methods The CALMER study was a multicenter, open‐label, prospective, randomized, parallel‐group comparison trial for T2DM involving continuous glucose monitoring (CGM) under meal tolerance tests (MTTs). Patients were randomly assigned to switch from teneligliptin to canagliflozin (SWITCH group) or to add canagliflozin to teneligliptin (COMB group). The CGM metrics, including time in target range (TIR), were investigated. Results All 99 participants (mean age: 62.3 years; mean HbA1c: 7.4%) completed the trial. TIR was increased in the COMB group (71.2% to 82.7%, p<0.001). The extent of the reduction in time above target range (TAR) was significantly larger in the COMB group compared with the SWITCH group (?14.8% vs. ?7.5%, p<0.01). Area under the curve values for glucose at 120 min after all MTTs were significantly decreased in the COMB group compared with the SWITCH group (p<0.05). Conclusions SGLT2 inhibitor combined with DPP‐4 inhibitor improved the quality of glycemic variability and reduced postprandial hyperglycemia compared with each monotherapy

A role for IL-34 in osteolytic disease of multiple myeloma

Multiple myeloma (MM) is a hematological malignancy that grows in multiple sites of the axial skeleton and causes debilitating osteolytic disease. Interleukin-34 (IL-34) is a newly discovered cytokine that acts as a ligand of colony-stimulating factor-1 (CSF-1) receptor and can replace CSF-1 for osteoclast differentiation. In this study, we identify IL-34 as an osteoclastogenic cytokine that accelerates osteolytic disease in MM. IL-34 was found to be expressed in the murine MM cell line MOPC315.BM, and the expression of IL-34 was enhanced by stimulation with proinflammatory cytokines or by bone marrow (BM) stromal cells. MM-cell–derived IL-34 promoted osteoclast formation from mouse BM cells in vitro. Targeting Il34 by specific small interfering RNA impaired osteoclast formation in vitro and attenuated osteolytic disease in vivo. In BM aspirates from MM patients, the expression levels of IL-34 in CD138+ populations vary among patients from high to weak to absent. MM cell–derived IL-34 promoted osteoclast formation from human CD14+ monocytes, which was reduced by a neutralizing antibody against IL-34. Taken together, this study describes for the first time the expression of IL-34 in MM cells, indicating that it may enhance osteolysis and suggesting IL-34 as a potential therapeutic target to control pathological osteoclastogenesis in MM patients

Improved Time in Range and Postprandial Hyperglycemia with Canagliflozin in Combination with Teneligliptin: Secondary Analyses of the CALMER study

AIMS/INTRODUCTION: We recently reported the beneficial effect of the combination of sodium–glucose cotransporter 2 inhibitor and dipeptidyl peptidase‐4 inhibitor on daily glycemic variability in patients with type 2 diabetes mellitus. Additional favorable effects of combination therapy were explored in this secondary analysis. MATERIALS AND METHODS: The CALMER study was a multicenter, open‐label, prospective, randomized, parallel‐group comparison trial for type 2 diabetes mellitus involving continuous glucose monitoring under meal tolerance tests. Patients were randomly assigned to switch from teneligliptin to canagliflozin (SWITCH group) or to add canagliflozin to teneligliptin (COMB group). The continuous glucose monitoring metrics, including time in target range, were investigated. RESULTS: All 99 participants (mean age 62.3 years; mean glycated hemoglobin 7.4%) completed the trial. The time in target range was increased in the COMB group (71.2–82.7%, P < 0.001). The extent of the reduction in time above target range was significantly larger in the COMB group compared with the SWITCH group (−14.8% vs −7.5%, P < 0.01). Area under the curve values for glucose at 120 min after all meal tolerance tests were significantly decreased in the COMB group compared with the SWITCH group (P < 0.05). CONCLUSIONS: Sodium–glucose cotransporter 2 inhibitor combined with dipeptidyl peptidase‐4 inhibitor improved the quality of glycemic variability and reduced postprandial hyperglycemia compared with each monotherapy