No abstract

The pathophysiology of COVID-19 associated thrombosis seems to be multifactorial. We hypothesized that COVID-19 is accompanied by procoagulant platelets and platelet apoptosis with subsequent alteration of the coagulation system. We investigated depolarization of mitochondrial inner transmembrane potential (ΔΨm), cytosolic calcium (Ca2+) concentration, and phosphatidylserine (PS) externalization by flow cytometry. Platelets from intensive care unit (ICU) COVID-19 patients (n=21) showed higher ΔΨm depolarization, cytosolic Ca2+ concentration and PS externalization, compared to healthy controls (n=18) and COVID-19 non-ICU patients (n=4). Moreover significant higher cytosolic Ca2+ concentration and PS was observed compared to septic ICU control group (ICU control). In ICU control group (n=5; ICU non-COVID-19) cytosolic Ca2+ concentration and PS externalization was comparable to healthy control, with an increase in ΔΨm depolarization. Sera from ICU COVID-19 patients induced significant increase in apoptosis markers (ΔΨm depolarization, cytosolic Ca2+ concentration and PS externalization) compared to healthy volunteer and septic ICU control. Interestingly, immunoglobulin G (IgG) fractions from COVID-19 patients induced an Fc gamma receptor IIA dependent platelet apoptosis (ΔΨm depolarization, cytosolic Ca2+ concentration and PS externalization). Enhanced PS externalization in platelets from ICU COVID-19 patients was associated with increased sequential organ failure assessment (SOFA) score (r=0.5635) and D-Dimer (r=0.4473). Most importantly, patients with thrombosis had significantly higher PS externalization compared to those without. The strong correlations between procoagulant platelet and apoptosis markers and increased D-Dimer levels as well as the incidence of thrombosis may indicate that antibody-mediated platelet apoptosis potentially contributes to sustained increased thromboembolic risk in ICU COVID-19 patients.

Urolithin A (UA) is a natural compound produced by gut bacteria from ingested ellagitannins (ETs) and ellagic acid (EA), complex polyphenols abundant in foods such as pomegranate, berries, and nuts. UA was discovered 40 years ago, but only recently has its impact on aging and disease been explored. UA enhances cellular health by increasing mitophagy and mitochondrial function and reducing detrimental inflammation. Several preclinical studies show how UA protects against aging and age-related conditions affecting muscle, brain, joints, and other organs. In humans, benefits of UA supplementation in the muscle are supported by recent clinical trials in elderly people. Here, we review the state of the art of UA's biology and its translational potential as a nutritional intervention in humans. Urolithin A: A Natural Gut Microbiome-Derived Metabolite UA belongs to the family of urolithins, characterized by a chemical structure containing an α-benzo-coumarin scaffold (Figure 1). Urolithins are produced in the colon following the microbiome-mediated transformation of the natural polyphenols ETs and EA, which are contained in dietary products, such as pomegranates, strawberries, raspberries, and walnuts [1-3]. (Figure 1 and Box 1).First identified as an EA metabolite in rats in 1980 [4], similar gut microbiome (see Glossary) conversion of ETs to UA was later demonstrated across many species, including flies and mice [1] . A pioneering study also showed the production of UA from ETs by the human gut microbiota [5], making UA the most common urolithin species produced in nature. Two clinical studies then measured UA in human plasma after consumption of pomegranate [6], berries, and nuts [7]. Interestingly, the conversion of dietary precursors to UA does not occur in all individuals. The process is variable [8] and takes place in only approximately 40% of the human elderly population [9]. Being a 'UA producer' requires an appropriate gut microbiome and varies with age, health status, and dietary intake [10].Backed by growing interest in nutritional interventions to address the ever-increasing health problems of an aging population [11,12], several research groups started to study the role and relevance of direct supplementation with UA instead of with UA precursors. This review outlines the most relevant in vivo preclinical studies that show positive impacts of UA on health conditions due to natural aging and on progressive diseases linked to aging. It describes the molecular mechanisms that explain how UA can counter the hallmarks of aging. Finally, this review explores the translational relevance and potential applications of UA as a nutritional intervention in humans.