Tumor necrosis factor-inducible gene 6 protein and its derived peptide ameliorate liver fibrosis by repressing CD44 activation in mice with alcohol-related liver disease.

BACKGROUND: Alcohol-related liver disease (ALD) is a major health concern worldwide, but effective therapeutics for ALD are still lacking. Tumor necrosis factor-inducible gene 6 protein (TSG-6), a cytokine released from mesenchymal stem cells, was shown to reduce liver fibrosis and promote successful liver repair in mice with chronically damaged livers. However, the effect of TSG-6 and the mechanism underlying its activity in ALD remain poorly understood. METHODS: To investigate its function in ALD mice with fibrosis, male mice chronically fed an ethanol (EtOH)-containing diet for 9 weeks were treated with TSG-6 (EtOH + TSG-6) or PBS (EtOH + Veh) for an additional 3 weeks. RESULTS: Severe hepatic injury in EtOH-treated mice was markedly decreased in TSG-6-treated mice fed EtOH. The EtOH + TSG-6 group had less fibrosis than the EtOH + Veh group. Activation of cluster of differentiation 44 (CD44) was reported to promote HSC activation. CD44 and nuclear CD44 intracellular domain (ICD), a CD44 activator which were upregulated in activated HSCs and ALD mice were significantly downregulated in TSG-6-exposed mice fed EtOH. TSG-6 interacted directly with the catalytic site of MMP14, a proteolytic enzyme that cleaves CD44, inhibited CD44 cleavage to CD44ICD, and reduced HSC activation and liver fibrosis in ALD mice. In addition, a novel peptide designed to include a region that binds to the catalytic site of MMP14 suppressed CD44 activation and attenuated alcohol-induced liver injury, including fibrosis, in mice. CONCLUSIONS: These results demonstrate that TSG-6 attenuates alcohol-induced liver damage and fibrosis by blocking CD44 cleavage to CD44ICD and suggest that TSG-6 and TSG-6-mimicking peptide could be used as therapeutics for ALD with fibrosis.

The Risk of Retinal Vein Occlusion in Young Patients with Mental Disorders: A Nationwide Cohort Study.

We investigated the association between mental disorders and the incidence rate of retinal vein occlusion (RVO) in young Korean adults. This nationwide cohort study included subjects aged 20-40 years who underwent the Korean National Health Examination between 2009 and 2012. The diagnoses of RVO and mental disorders were based on the International Classification of Diseases Tenth Revision codes. Multivariate Cox proportional hazard regression models were used to evaluate the objective. In total, 6,891,399 subjects were included at baseline and 6,597,803 subjects (mean age, 30.86 ± 4.99) were finally analyzed for a mean follow-up duration of 7.36 ± 1.13 years, with the mental disorders group followed for 7.27 ± 1.15 years and the non-diagnosed group for 7.37 ± 1.12 years. Among a total of 10,145 subjects diagnosed with RVO, 1304 had been diagnosed with mental disorders, while 8841 had not. Cumulative incidence of RVO demonstrated a substantially higher incidence probability in subjects with mental disorders (log-rank p < 0.0001). Mental disorders were associated with an increased incidence rate of RVO (hazard ratio [HR]: 1.268; 95% confidence interval; [CI]: 1.196-1.344). In the subgroup analysis, subjects with depression, sleep disorder, and anxiety disorder exhibited an increased risk of incidence of RVO in all regression models (all p < 0.001). In conclusion, mental disorders and the incidence rate of RVO were significantly positively correlated in a Korean nationwide population-based cohort study. These findings suggest that mental disorders may also be associated with the pathophysiology of RVO in young adults.

The Effect of Selective Retina Therapy with Automatic Real-Time Feedback-Controlled Dosimetry for Chronic Central Serous Chorioretinopathy: A Randomized, Open-Label, Controlled Clinical Trial.

This prospective randomized controlled trial evaluated the safety and efficacy of real-time feedback-controlled dosimetry (RFD)-guided selective retina therapy (SRT) in chronic central serous chorioretinopathy (CSC). Forty-four participants with chronic CSC were included and randomly assigned to the control group or SRT group. The SRT laser system with RFD-guidance was applied to cover the entire leakage area. If SRF remained at the 6-week follow-up visit, re-treatment and rescue SRT was performed for the SRT group and crossover group, respectively. The rate of complete resolution of subretinal fluid (SRF), mean SRF height, and mean retinal sensitivity were compared between the two groups at 6-weeks post-treatment. The complete SRF resolution rate in all SRT-treated eyes was evaluated at 12-weeks post-treatment. The rate of complete SRF resolution was significantly higher in the SRT group (63.6%) than in the control group (23.8%) at 6-weeks post-treatment (p = 0.020). The mean SRF height at 6 weeks after SRT was significantly lower in the SRT group (p = 0.041). Overall, SRT-treated eyes showed complete SRF resolution in 70.3% of eyes at 12-weeks post-treatment. RFD-guided SRT was safe and effective to remove SRF in chronic CSC patients during the 3-month follow-up period.