Endothelial dysfunction is a major contributor to multi-organ failure and mortality in sepsis, with the lungs being particularly susceptible to vascular leakage. Previous studies have implicated matrix metalloproteinase 8 (MMP8) in sepsis pathogenesis. However, the role of MMP8 in maintaining endothelial barrier integrity during sepsis remains unclear. This study aimed to investigate the role of MMP8 in sepsis-induced vascular leakage and the underlying mechanisms. A significant increase in MMP8 expression was observed in lipopolysaccharide (LPS)-treated endothelial cells and lung tissues from mice with cecum ligation and puncture-induced sepsis. In vitro, loss- or gain-of-function of MMP8 in endothelial cells modulated LPS- or Cytomix (TNF-α, IL-1β and IFN-γ)-induced endothelial hyperpermeability, without inducing cell apoptosis or affecting cell viability. In vivo, pharmacologic inhibition of MMP8 alleviated pulmonary vascular leakage, multi-organ injury, and mortality in septic mice. Mechanistically, MMP8 interacted with ERK, promoting its phosphorylation, and consequently activated calpains, leading to membrane VE-cadherin proteolysis. This induced VE-cadherin internalisation through clathrin- and caveolin 1-mediated endocytosis. Clinically, serum MMP8 levels were elevated in patients with sepsis, with the highest levels observed in those with pleural effusion. A nomogram incorporating albumin, blood urea nitrogen, lactate, Acute Physiology and Chronic Health Evaluation II score, and serum MMP8 levels showed favourable prediction accuracy and clinical utility for pleural effusion risk. These findings suggest the critical role of MMP8 in sepsis and its potential as a promising biomarker of sepsis-induced pulmonary vascular leakage.
Yao-Jun Peng, Qiyan Wu, Yu-Yu Liu et al.· Molecular Biomedicine· 0 citations
Background Adolescents with depressive symptoms are at increased risk of social functional impairment and are more likely to develop major depressive disorder. Digital interventions offer advantages, such as high accessibility, especially for adolescents. However, evidence on the effectiveness of web-based psychological interventions in alleviating depressive symptoms among adolescents remains limited. Objective This study aims to develop a brief web-based psychological intervention tailored to the developmental and psychological characteristics of Chinese adolescents and to evaluate its effectiveness and influencing factors. Methods In a 2-arm randomized controlled trial, adolescents aged 12 to 18 years with depressive symptoms were recruited from high schools in China. Eligible participants were randomly assigned in a 1:1 ratio to the intervention group (n=212) or the control group (n=224). Participants in the intervention group received a 4-week brief web-based emotional cognitive training program, whereas those in the control group received a web-based psychoeducation program. Nonprofessional helpers provided minimal support through text messages or phone calls. The primary outcome was depressive symptom severity. Secondary outcomes included the depressive symptom remission rate, changes in anxiety symptoms, suicidal ideation, and resilience. Data were collected at baseline (T0), postintervention (T1), and at 1- and 3-month follow-ups (T2 and T3). Statistical analyses included analysis of covariance (ANCOVA), logistic regression analysis, and mediation analysis. Results Two-way repeated-measures ANCOVA revealed a significant time effect (F3,1461=82.515; P<.001; η2p=0.140) on depressive symptom severity, with significantly lower scores at T1, T2, and T3 than at T0. No significant group effect (F1,1461=1.039; P=.31; η2p=0.001) or time-by-group interaction (F3,1461=2.424; P=.06; η2p=0.005) for depressive symptom severity was observed. Post hoc exploratory analysis showed that among adolescents with anxiety symptoms, the intervention group exhibited a higher depressive symptom remission rate at T1 than the control group (adjusted odds ratio 1.39, 95% CI 1.05-1.85; P=.02; number needed to treat=7). Additionally, the intervention group showed significantly greater improvements in the interpersonal support dimension of resilience at T1 (least squares mean difference=1.79, 95% CI 0.53-3.06; Cohen d=0.37, 95% CI 0.11-0.63; P=.006; false discovery rate–adjusted P=.04). Exploratory mediation analysis identified a significant indirect effect between the intervention and depressive symptom remission via the interpersonal support dimension of resilience at T1 (indirect effect=0.08, 95% CI 0.02-0.14; P=.009). Conclusions The brief web-based psychological intervention showed no significant difference from web-based psychoeducation in reducing depressive symptoms across the 3-month follow-up period. Post hoc exploratory analyses detected a potential between-group difference in depressive symptom remission among adolescents with comorbid anxiety symptoms, with interpersonal support showing a significant mediating association. These exploratory findings may provide new insights into identifying the target population suitable for brief web-based psychological interventions and inform the development of tailored interventions in the future. Trial Registration Chinese Clinical Trial Registry ChiCTR2400090235; https://www.chictr.org.cn/showproj.html?proj=243991
Pei Liu, Xin-Wei Wang, Xiaoxia Duan et al.· JMIR mHealth and uHealth· 0 citations
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