Nafamostat mesilate (NM) is a serine protease inhibitor with anticoagulant and anti-inflammatory effects. NM has been used in Asia for anticoagulation during extracorporeal circulation in patients undergoing continuous renal replacement therapy and extra corporeal membrane oxygenation. Oxidative stress is an independent risk factor for atherosclerotic vascular disease and is associated with vascular endothelial function. We investigated whether NM could inhibit endothelial dysfunction induced by tumor necrosis factor-alpha (TNF-alpha). Human umbilical vein endothelial cells (HUVECs) were treated with TNF-alpha for 24 h. The effects of NM on monocyte adhesion, vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) protein expression, p38 mitogen-activated protein kinase (MAPK) activation, and intracellular superoxide production were then examined. NM (0.01~100 microg/mL) did not affect HUVEC viability; however, it inhibited the increases in reactive oxygen species (ROS) production and p66shc expression elicited by TNF-alpha (3 ng/mL), and it dose dependently prevented the TNF-alpha-induced upregulation of endothelial VCAM-1 and ICAM-1. In addition, it mitigated TNF-alpha-induced p38 MAPK phosphorylation and the adhesion of U937 monocytes. These data suggest that NM mitigates TNF-alpha-induced monocyte adhesion and the expression of endothelial cell adhesion molecules, and that the anti-adhesive effect of NM is mediated through the inhibition of p66shc, ROS production, and p38 MAPK activation.
Asia ; Endothelial Cells* ; Extracorporeal Circulation ; Human Umbilical Vein Endothelial Cells ; Humans ; Intercellular Adhesion Molecule-1 ; Membranes ; Mesylates* ; Monocytes ; Oxidative Stress ; Oxygen ; p38 Mitogen-Activated Protein Kinases ; Phosphorylation ; Protein Kinases ; Reactive Oxygen Species* ; Renal Replacement Therapy ; Risk Factors ; Serine Proteases ; Superoxides ; Tumor Necrosis Factor-alpha ; Up-Regulation ; Vascular Cell Adhesion Molecule-1 ; Vascular Diseases

Background: The nature and role of the mitochondrial stress response in adipose tissue in relation to obesity are not yet known. To determine whether the mitochondrial unfolded protein response (UPRmt) in adipose tissue is associated with obesity in humans and rodents. Methods: Visceral adipose tissue (VAT) was obtained from 48 normoglycemic women who underwent surgery. Expression levels of mRNA and proteins were measured for mitochondrial chaperones, intrinsic proteases, and components of electron-transport chains. Furthermore, we systematically analyzed metabolic phenotypes with a large panel of isogenic BXD inbred mouse strains and Genotype-Tissue Expression (GTEx) data. Results: In VAT, expression of mitochondrial chaperones and intrinsic proteases localized in inner and outer mitochondrial membranes was not associated with body mass index (BMI), except for the Lon protease homolog, mitochondrial, and the corresponding gene LONP1, which showed high-level expression in the VAT of overweight or obese individuals. Expression of LONP1 in VAT positively correlated with BMI. Analysis of the GTEx database revealed that elevation of LONP1 expression is associated with enhancement of genes involved in glucose and lipid metabolism in VAT. Mice with higher Lonp1 expression in adipose tissue had better systemic glucose metabolism than mice with lower Lonp1 expression. Conclusion Expression of mitochondrial LONP1, which is involved in the mitochondrial quality control stress response, was elevated in the VAT of obese individuals. In a bioinformatics analysis, high LONP1 expression in VAT was associated with enhanced glucose and lipid metabolism.

Background: The nature and role of the mitochondrial stress response in adipose tissue in relation to obesity are not yet known. To determine whether the mitochondrial unfolded protein response (UPRmt) in adipose tissue is associated with obesity in humans and rodents. Methods: Visceral adipose tissue (VAT) was obtained from 48 normoglycemic women who underwent surgery. Expression levels of mRNA and proteins were measured for mitochondrial chaperones, intrinsic proteases, and components of electron-transport chains. Furthermore, we systematically analyzed metabolic phenotypes with a large panel of isogenic BXD inbred mouse strains and Genotype-Tissue Expression (GTEx) data. Results: In VAT, expression of mitochondrial chaperones and intrinsic proteases localized in inner and outer mitochondrial membranes was not associated with body mass index (BMI), except for the Lon protease homolog, mitochondrial, and the corresponding gene LONP1, which showed high-level expression in the VAT of overweight or obese individuals. Expression of LONP1 in VAT positively correlated with BMI. Analysis of the GTEx database revealed that elevation of LONP1 expression is associated with enhancement of genes involved in glucose and lipid metabolism in VAT. Mice with higher Lonp1 expression in adipose tissue had better systemic glucose metabolism than mice with lower Lonp1 expression. Conclusion Expression of mitochondrial LONP1, which is involved in the mitochondrial quality control stress response, was elevated in the VAT of obese individuals. In a bioinformatics analysis, high LONP1 expression in VAT was associated with enhanced glucose and lipid metabolism.

Objective: This study examined the characteristics of patients visiting the emergency department (ED) with fever after the chronification of the coronavirus disease 2019 (COVID-19) pandemic. Methods: This retrospective observational study analyzed the medical records of patients who visited the ED with fever from May 1 to October 31, 2021, and the corresponding period in 2019. This study was conducted at a single center in Seoul, Korea. Results: There was no statistical difference in the comorbidities of the patients of the two groups: the AC (after the COVID-19 pandemic) group and the BC (before the COVID-19 pandemic) group. As for the level of consciousness at the time of ED arrival, there was a significantly larger decrease in consciousness (verbal response or less) in the AC group than in the BC group (P=0.002). In the case of the National Early Warning Score (NEWS), the proportion was higher in the AC group in the moderate-risk and high-risk groups (P=0.003). The median time from symptom onset to ED arrival was 15.7 hours in the BC group and 13.8 hours in the AC group, and there was no significant difference (P=0.137). When leaving the ED, the AC group had a higher admission rate to the ward and intensive care unit than the BC group. There was no statistical difference in the in-hospital mortality between the two groups (2.9% and 2.4%, respectively; P=0.62). Conclusion Patients who visited the emergency room with fever after one year of the COVID-19 pandemic showed a similar time from symptom onset to ED arrival compared to patients who visited before the COVID-19 pandemic. In addition, there was no difference in in-hospital mortality among these patients compared to those with fever before the COVID-19 pandemic.