BACKGROUNDReprogramming of host metabolism supports viral pathogenesis by fueling viral proliferation, by providing, for example, free amino acids and fatty acids as building blocksMETHODSTo investigate metabolic effects of SARS-CoV-2 infection, we evaluated serum metabolites of patients with COVID-19 (n = 33; diagnosed by nucleic acid testing), as compared with COVID-19-negative controls (n = 16)RESULTSTargeted and untargeted metabolomics analyses identified altered tryptophan metabolism into the kynurenine pathway, which regulates inflammation and immunity Indeed, these changes in tryptophan metabolism correlated with interleukin-6 (IL-6) levels Widespread dysregulation of nitrogen metabolism was also seen in infected patients, with altered levels of most amino acids, along with increased markers of oxidant stress (eg, methionine sulfoxide, cystine), proteolysis, and renal dysfunction (eg, creatine, creatinine, polyamines) Increased circulating levels of glucose and free fatty acids were also observed, consistent with altered carbon homeostasis Interestingly, metabolite levels in these pathways correlated with clinical laboratory markers of inflammation (ie, IL-6 and C-reactive protein) and renal function (ie, blood urea nitrogen)CONCLUSIONIn conclusion, this initial observational study identified amino acid and fatty acid metabolism as correlates of COVID-19, providing mechanistic insights, potential markers of clinical severity, and potential therapeutic targetsFUNDINGBoettcher Foundation Webb-Waring Biomedical Research Award; National Institute of General and Medical Sciences, NIH; and National Heart, Lung, and Blood Institute, NIH

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COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status.

Over 5 million people around the world have tested positive for the beta coronavirus SARS-CoV-2 as of May 29, 2020, a third of which are in the United States alone. These infections are associated with the development of a disease known as COVID-19, which is characterized by several symptoms, including persistent dry cough, shortness of breath, chills, muscle pain, headache, loss of taste or smell, and gastrointestinal distress. COVID-19 has been characterized by elevated mortality (over 100 thousand people have already died in the US alone), mostly due to thromboinflammatory complications that impair lung perfusion and systemic oxygenation in the most severe cases. While the levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) have been associated with the severity of the disease, little is known about the impact of IL-6 levels on the proteome of COVID-19 patients. The present study provides the first proteomics analysis of sera from COVID-19 patients, stratified by circulating levels of IL-6, and correlated to markers of inflammation and renal function. As a function of IL-6 levels, we identified significant dysregulation in serum levels of various coagulation factors, accompanied by increased levels of antifibrinolytic components, including several serine protease inhibitors (SERPINs). These were accompanied by up-regulation of the complement cascade and antimicrobial enzymes, especially in subjects with the highest levels of IL-6, which is consistent with an exacerbation of the acute phase response in these subjects. Although our results are observational, they highlight a clear increase in the levels of inhibitory components of the fibrinolytic cascade in severe COVID-19 disease, providing potential clues related to the etiology of coagulopathic complications in COVID-19 and paving the way for potential therapeutic interventions, such as the use of pro-fibrinolytic agents. Raw data for this study are available through ProteomeXchange with identifier PXD020601.

Serum Proteomics in COVID-19 Patients: Altered Coagulation and Complement Status as a Function of IL-6 Level.

Bone physiological microenvironment and healing mechanism: Basis for future bone-tissue engineering scaffolds.

Platelets are abundant, small, anucleate circulating cells, serving many emerging pathophysiological roles beyond hemostasis; including active critical roles in thrombosis, injury response, and immunoregulation. In the absence of genomic DNA transcriptional regulation (no nucleus), platelets require strategic prepackaging of all the needed RNA and organelles from megakaryocytes, to sense stress (e.g., hyperglycemia), to protect themselves from stress (e.g., mitophagy), and to communicate a stress response to other cells (e.g., granule and microparticle release). Distinct from avian thrombocytes that have a nucleus, the absence of a nucleus allows the mammalian platelet to maintain its small size, permits morphological flexibility, and may improve speed and efficiency of protein expression in response to stress. In the absence of a nucleus, platelet lifespan of 7-10 days, is largely determined by the mitochondria. The packaging of 5-8 mitochondria is critical in aerobic respiration and yielding metabolic substrates needed for function and survival. Mitochondria damage or dysfunction, as observed with several disease processes, results in greatly attenuated platelet survival and increased risk for thrombovascular events. Here we provide insights into the emerging roles of platelets despite the lack of a nucleus, and the key role played by mitochondria in platelet function and survival both in health and disease.

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Role of Platelet Mitochondria: Life in a Nucleus-Free Zone.

Background Hydrogen peroxide (H2O2)-induced mitochondrial oxidative damage is critical to intestinal ischemia/reperfusion (I/R) injury, and PRDX3 is an efficient H2O2 scavenger that protects cells from mitochondrial oxidative damage and apoptosis. However, the function of PRDX3 in intestinal I/R injury is unclear. The aim of this study was to investigate the precise mechanism underlying the involvement of PRDX3 in intestinal I/R injury. Methods An intestinal I/R model was established in mice with superior mesenteric artery occlusion, and Caco-2 cells were subjected to hypoxia/reoxygenation (H/R) for the in vivo simulation of I/R. Results PRDX3 expression was decreased during intestinal I/R injury, and PRDX3 overexpression significantly attenuated H/R-induced mitochondrial oxidative damage and apoptosis in Caco-2 cells. The level of acetylated PRDX3 was clearly increased both in vivo and in vitro. The inhibition of SIRTs by nicotinamide (NAM) increased the level of acetylated PRDX3 and impaired the antioxidative activity of PRDX3. Furthermore, NAM did not increase the acetylation of PRDX3 in sirtuin-3 (SIRT3)-knockdown Caco-2 cells. Importantly, PRDX3 acetylation was increased in mice lacking SIRT3, and this effect was accompanied by serious mitochondrial oxidative damage, apoptosis and remote organ damage after intestinal I/R injury. We screened potential sites of PRDX3 acetylation in the previously reported acetylproteome through immunoprecipitation (IP) experiments and found that SIRT3 deacetylates K253 on PRDX3 in Caco-2 cells. Furthermore, PRDX3 with the lysine residue K253 mutated to arginine (K253R) increased its dimerization in Caco-2 cells after subjected to 12 h hypoxia and followed 4 h reoxygenation. Caco-2 cells transfected with the K253R plasmid exhibited notably less mitochondrial damage and apoptosis, and transfection of the K253Q plasmid abolished the protective effect of PRDX3 overexpression. Analysis of ischemic intestines from clinical patients further verified the correlation between SIRT3 and PRDX3. Conclusions PRDX3 is a key protective factor for intestinal I/R injury, and SIRT3-mediated PRDX3 deacetylation can alleviate intestinal I/R-induced mitochondrial oxidative damage and apoptosis.

Lauren Shih

Papers

TNF-α–driven inflammation and mitochondrial dysfunction define the platelet hyperreactivity of aging