Rationale: In addition to the overwhelming lung inflammation that prevails in coronavirus disease 2019 (COVID-19), hypercoagulation and thrombosis contribute to the lethality of subjects infected with severe acute respiratory syndrome coronavirus 2. Platelets are chiefly implicated in thrombosis. Moreover, they can interact with viruses and are an important source of inflammatory mediators. While a lower platelet count is associated with severity and mortality, little is known about platelet function during COVID-19. Objective: To evaluate the contribution of platelets to inflammation and thrombosis in patients with COVID-19. Methods and Results: Blood was collected from 115 consecutive patients with COVID-19 presenting nonsevere (n=71) and severe (n=44) respiratory symptoms. We document the presence of severe acute respiratory syndrome coronavirus 2 RNA associated with platelets of patients with COVID-19. Exhaustive assessment of cytokines in plasma and in platelets revealed the modulation of platelet-associated cytokine levels in both patients with nonsevere and severe COVID-19, pointing to a direct contribution of platelets to the plasmatic cytokine load. Moreover, we demonstrate that platelets release their alpha- and dense-granule contents in both nonsevere and severe forms of COVID-19. In comparison to concentrations measured in healthy volunteers, phosphatidylserine-exposing platelet extracellular vesicles were increased in nonsevere, but not in severe cases of COVID-19. Levels of D-dimers, a marker of thrombosis, failed to correlate with any measured indicators of platelet activation. Functionally, platelets were hyperactivated in COVID-19 subjects presenting nonsevere and severe symptoms, with aggregation occurring at suboptimal thrombin concentrations. Furthermore, platelets adhered more efficiently onto collagen-coated surfaces under flow conditions. Conclusions: Taken together, the data suggest that platelets are at the frontline of COVID-19 pathogenesis, as they release various sets of molecules through the different stages of the disease. Platelets may thus have the potential to contribute to the overwhelming thrombo-inflammation in COVID-19, and the inhibition of pathways related to platelet activation may improve the outcomes during COVID-19.

Inflammatory bowel disease (IBD) is a group of chronic disorders that includes two main disease forms, Crohn’s disease, and ulcerative colitis. The understanding of the intestinal inflammation occurring in IBD has been immeasurably advanced by the development of the now numerous murine models of intestinal inflammation. The usefulness of this research tool in IBD arises from a convergence of underlying genetic susceptibility, immune system dysfunction, environmental factors, and shifts in gut microbiota. Due to the multifactorial feature of these diseases, different animal models have been used to investigate the underlying mechanisms and develop potential therapeutic strategies. The results of preclinical efficacy studies often inform the progression of therapeutic strategies. This review describes the distinct feature and limitations of each murine IBD model and discusses the previous and current lessons from the IBD models.

Rationale: In addition to the overwhelming lung inflammation that prevails in COVID-19, hypercoagulation and thrombosis contribute to the lethality of subjects infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Platelets are chiefly implicated in thrombosis. Moreover, they can interact with viruses and are an important source of inflammatory mediators. While a lower platelet count is associated with severity and mortality, little is known about platelet function during COVID-19. Objective: To evaluate the contribution of platelets to inflammation and thrombosis in COVID-19 patients. Methods and Results: We document the presence of SARS-CoV-2 RNA in platelets of COVID-19 patients. Exhaustive assessment of cytokines in plasma and in platelets revealed the modulation of platelet-associated cytokine levels in COVID-19, pointing to a direct contribution of platelets to the plasmatic cytokine load. Moreover, we demonstrate that platelets release their alpha- and dense-granule contents and phosphatidylserine-exposing extracellular vesicles. Functionally, platelets were hyperactivated in COVID-19 subjects, with aggregation occurring at suboptimal thrombin concentrations. Furthermore, platelets adhered more efficiently onto collagen-coated surfaces under flow conditions. Conclusions: These data suggest that platelets could participate in the dissemination of SARS-CoV-2 and in the overwhelming thrombo-inflammation observed in COVID-19. Thus, blockade of platelet activation pathways may improve outcomes in this disease. KEY POINTS: Platelets are a source of inflammatory cytokines and degranulate in COVID-19 Platelets contain SARS-CoV-2 RNA molecules and are prone to activation in COVID-19 Subject terms: Infectious diseases/Emerging infectious diseases, SARS-CoV-2, COVID-19, Hematology, Platelets

Benzodiazepines (BZDs) are widely used but are often associated with significant side effects such as amnesia, dependence, and withdrawal syndrome, prompting the search for safer alternatives. The current study aimed to assess the possible toxic effects of a novel 1,5-BZD derivative, which we named MAL. In silico analysis showed that MAL binds to the GABA-A receptor with a binding energy of -8.9 kcal/mol, and to its α1, β2, and γ2 subunits with binding energies of -7.6, -7.5, and -7.6 kcal/mol, respectively, indicating strong receptor affinity. To explore the safety of MAL, toxicological testing was conducted in laboratory animals in accordance with internationally accepted guidelines. Acute toxicity was evaluated by a single oral administration of 2 g/kg body weight to male mice, monitored over 14 days. Since BZDs are typically prescribed for up to two weeks in clinical practice, a 28-day repeated-dose toxicity study was also conducted. Mice received MAL (5, 25, 50, and 100 mg/kg) daily for 28 days to evaluate potential toxic effects. No adverse effects were observed on body weight gain, relative organ weights, or food and water consumption. Histological examination of major organs revealed no abnormalities, and biochemical analyses confirmed the absence of hepatotoxicity or nephrotoxicity. Additionally, we present ProTox, a comprehensive, open-source webserver designed for in silico toxicity prediction. In this study, ProTox predicted an oral LD50 of MAL at 3 g/kg. Based on the Globally Harmonized System (GHS) of classification, this places MAL in Category V. These findings support the potential safety of MAL for pharmaceutical formulations.