Urokinase System in Pathogenesis of Pulmonary Fibrosis: A Hidden Threat of COVID-19.

Pulmonary fibrosis is a common and threatening post-COVID-19 complication with poorly resolved molecular mechanisms and no established treatment. The plasminogen activator system, including urokinase (uPA) and urokinase receptor (uPAR), is involved in the pathogenesis of COVID-19 and contributes to the development of lung injury and post-COVID-19 pulmonary fibrosis, although their cellular and molecular underpinnings still remain obscure. The aim of the current study was to assess the role of uPA and uPAR in the pathogenesis of pulmonary fibrosis. We analyzed uPA and uPAR expression in human lung tissues from COVID-19 patients with pulmonary fibrosis using single-cell RNA-seq and immunohistochemistry. We modeled lung fibrosis in Plau-/- and Plaur-/- mice upon bleomycin instillation and explored the effect of uPAR downregulation in A549 and BEAS-2B lung epithelial cells. We found that uPAR expression drastically decreased in the epithelial airway basal cells and monocyte/macrophage cells, whereas uPA accumulation significantly increased in tissue samples of COVID-19 patients. Lung injury and fibrosis in Plaur-/- vs. WT mice upon bleomycin instillation revealed that uPAR deficiency resulted in pro-fibrogenic uPA accumulation, IL-6 and ACE2 upregulation in lung tissues and was associated with severe fibrosis, weight loss and poor survival. uPAR downregulation in A549 and BEAS-2B was linked to an increased N-cadherin expression, indicating the onset of epithelial-mesenchymal transition and potentially contributing to pulmonary fibrosis. Here for the first time, we demonstrate that plasminogen treatment reversed lung fibrosis in Plaur-/- mice: the intravenous injection of 1 mg of plasminogen on the 21st day of bleomycin-induced fibrosis resulted in a more than a two-fold decrease in the area of lung fibrosis as compared to non-treated mice as evaluated by the 42nd day. The expression and function of the plasminogen activator system are dysregulated upon COVID-19 infection, leading to excessive pulmonary fibrosis and worsening the prognosis. The potential of plasminogen as a life-saving treatment for non-resolving post-COVID-19 pulmonary fibrosis warrants further investigation.

The role of urban and periurban agriculture to build food secure cities and resilient food systems

The global population is estimated to reach 9.7 billion by 2050, 70% of which will be living in urban areas. This rapid process of urbanization and population growth can directly lead to increasing number of people to feed in cities, while indirectly relating to the rise of unhealthy diets and consequent health issues such as overweight, obesity and diet-related diseases. Meanwhile, the population suffering from food insecurity and malnutrition is on the rise. Currently, more than 700 million people experienced severe food insecurity with the majority located in sub-Saharan Africa and southern Asia. Urban and peri-urban agriculture (UPA) is increasingly recognized as a key component of the resilience of local food systems as it diversifies food value chains, improves the livelihood of city dwellers, and brings about multiple benefits to sustainable urban development through local food production and short supply chains. Growing research and awareness of the variety of production systems and practices in many cities and regions is bringing to light the significant contributions made by UPA, even more so during the COVID-19 pandemic. The keynote presentation describes the role of UPA in contributing to urban food security and to building resilient local food systems. In particular, the keynote presentation will be based on the findings of the upcoming FAO/Rikolto/RUAF publication "Urban and Peri-Urban Agriculture Sourcebook: from Production to Food Systems” (FAO, 2022) that catalogues, organizes and analyses various existing UPA typologies, cases and examples at the global level in order to set out the key lessons and provide guidance for a diverse range of actors involved in local food systems, particularly decision-makers, planners and practitioners responsible for planning and implementing UPA schemes. © 2022 International Society for Horticultural Science. All rights reserved.

The Association of uPA, uPAR, and suPAR System with Inflammation and Joint Damage in Rheumatoid Arthritis: suPAR as a Biomarker in the Light of a Personalized Medicine Perspective.

BACKGROUND: In recent years, the involvement of the soluble urokinase Plasminogen Activator Receptor (suPAR) in the pathophysiological modulation of Rheumatoid Arthritis (RA) has been documented, resulting in the activation of several intracellular inflammatory pathways. METHODS: We investigated the correlation of urokinase Plasminogen Activator (uPA)/urokinase Plasminogen Activator Receptor (uPAR) expression and suPAR with inflammation and joint damage in RA, evaluating their potential role in a precision medicine context. RESULTS: Currently, suPAR has been shown to be a potential biomarker for the monitoring of Systemic Chronic Inflammation (SCI) and COVID-19. However, the effects due to suPAR interaction in immune cells are also involved in both RA onset and progression. To date, the literature data on suPAR in RA endorse its potential application as a biomarker of inflammation and subsequent joint damage. CONCLUSION: Available evidence about suPAR utility in the RA field is promising, and future research should further investigate its use in clinical practice, resulting in a big step forward for precision medicine. As it is elevated in different types of inflammation, suPAR could potentially work as an adjunctive tool for the screening of RA patients. In addition, a suPAR system has been shown to be involved in RA pathogenesis, so new data about the therapeutic response to Jak inhibitors can represent a possible way to develop further studies.

Prevention of Depression and Anxiety in Subclinical Adolescents: Effects of a Transdiagnostic Internet-Delivered CBT Program

Anxiety and depressive symptoms are common problems in adolescence that could be addressed by means of preventive interventions. Even though transdiagnostic cognitive behavior therapy (T-CBT) is potentially an ideal strategy to deal with anxiety and depression, it has rarely been used for preventive purposes. In addition, so far, no study has used internet-delivered T-CBT to prevent anxiety and depression in adolescents. This study aimed to examine the utility of AMTE, an internet-delivered T-CBT program, for the indicated prevention of anxiety and depression in adolescents. AMTE was applied to 30 adolescents (56.7% females, age range = 12–18 years, Mage = 14.00, SDage = 1.89) who showed subclinical symptoms of anxiety and/or depression. Participants were assessed at pre- and post-treatment and follow-up (3 months). We found that after the program, the symptoms of self-reported anxiety and depression, clinician-rated symptom severity, and self-reported and parent-reported severity of the main problems had significantly improved. In addition, there were significant improvements in anxiety sensitivity and emotional avoidance. Finally, we found high feasibility and acceptability of the program. AMTE is feasible and potentially effective for the indicated prevention of anxiety and depression as well as of clinical transdiagnostic factors, in adolescents.

Structural Basis of Covalent Inhibitory Mechanism of TMPRSS2-Related Serine Proteases by Camostat.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the viral pathogen causing the coronavirus disease 2019 (COVID-19) global pandemic. No effective treatment for COVID-19 has been established yet. The serine protease transmembrane protease serine 2 (TMPRSS2) is essential for viral spread and pathogenicity by facilitating the entry of SARS-CoV-2 into host cells. The protease inhibitor camostat, an anticoagulant used in the clinic, has potential anti-inflammatory and antiviral activities against COVID-19. However, the potential mechanisms of viral resistance and antiviral activity of camostat are unclear. Herein, we demonstrate high inhibitory potencies of camostat for a panel of serine proteases, indicating that camostat is a broad-spectrum inhibitor of serine proteases. In addition, we determined the crystal structure of camostat in complex with a serine protease (uPA [urokinase-type plasminogen activator]), which reveals that camostat is inserted in the S1 pocket of uPA but is hydrolyzed by uPA, and the cleaved camostat covalently binds to Ser195. We also generated a homology model of the structure of the TMPRSS2 serine protease domain. The model shows that camostat uses the same inhibitory mechanism to inhibit the activity of TMPRSS2, subsequently preventing SARS-CoV-2 spread. IMPORTANCE Serine proteases are a large family of enzymes critical for multiple physiological processes and proven diagnostic and therapeutic targets in several clinical indications. The serine protease transmembrane protease serine 2 (TMPRSS2) was recently found to mediate SARS-CoV-2 entry into the host. Camostat mesylate (FOY 305), a serine protease inhibitor active against TMPRSS2 and used for the treatment of oral squamous cell carcinoma and chronic pancreatitis, inhibits SARS-CoV-2 infection of human lung cells. However, the direct inhibition mechanism of camostat mesylate for TMPRSS2 is unclear. Herein, we demonstrate that camostat uses the same inhibitory mechanism to inhibit the activity of TMPRSS2 as uPA, subsequently preventing SARS-CoV-2 spread.