GlcNAc is a mast-cell chromatin-remodeling oncometabolite that promotes systemic mastocytosis aggressiveness.

Systemic mastocytosis (SM) is a KIT-driven hematopoietic neoplasm characterized by the excessive accumulation of neoplastic mast cells (MCs) in various organs and, mainly, the bone marrow (BM). Multiple genetic and epigenetic mechanisms contribute to the onset and severity of SM. However, little is known to date about the metabolic underpinnings underlying SM aggressiveness, which has thus far impeded the development of strategies to leverage metabolic dependencies when existing KIT-targeted treatments fail. Here, we show that plasma metabolomic profiles were able to discriminate indolent from advanced forms of the disease. We identified N-acetyl-d-glucosamine (GlcNAc) as the most predictive metabolite of SM severity. High plasma levels of GlcNAc in patients with advanced SM correlated with the activation of the GlcNAc-fed hexosamine biosynthesis pathway in patients BM aspirates and purified BM MCs. At the functional level, GlcNAc enhanced human neoplastic MCs proliferation and promoted rapid health deterioration in a humanized mouse model of SM. In addition, in the presence of GlcNAc, immunoglobulin E-stimulated MCs triggered enhanced release of proinflammatory cytokines and a stronger acute response in a mouse model of passive cutaneous anaphylaxis. Mechanistically, elevated GlcNAc levels promoted the transcriptional accessibility of chromatin regions that contain genes encoding mediators of receptor tyrosine kinases cascades and inflammatory responses, thus leading to a more aggressive phenotype. Therefore, GlcNAc is an oncometabolite driver of SM aggressiveness. This study suggests the therapeutic potential for targeting metabolic pathways in MC-related diseases to manipulate MCs effector functions.

Role of Probiotics in the Management of COVID-19: A Computational Perspective.

Coronavirus disease 2019 (COVID-19) was declared a pandemic at the beginning of 2020, causing millions of deaths worldwide. Millions of vaccine doses have been administered worldwide; however, outbreaks continue. Probiotics are known to restore a stable gut microbiota by regulating innate and adaptive immunity within the gut, demonstrating the possibility that they may be used to combat COVID-19 because of several pieces of evidence suggesting that COVID-19 has an adverse impact on gut microbiota dysbiosis. Thus, probiotics and their metabolites with known antiviral properties may be used as an adjunctive treatment to combat COVID-19. Several clinical trials have revealed the efficacy of probiotics and their metabolites in treating patients with SARS-CoV-2. However, its molecular mechanism has not been unraveled. The availability of abundant data resources and computational methods has significantly changed research finding molecular insights between probiotics and COVID-19. This review highlights computational approaches involving microbiome-based approaches and ensemble-driven docking approaches, as well as a case study proving the effects of probiotic metabolites on SARS-CoV-2.