Host cell glutamine metabolism as a potential antiviral target.

A virus minimally contains a nucleic acid genome packaged by a protein coat. The genome and capsid together are known as the nucleocapsid, which has an envelope containing a lipid bilayer (mainly phospholipids) originating from host cell membranes. The viral envelope has transmembrane proteins that are usually glycoproteins. The proteins in the envelope bind to host cell receptors, promoting membrane fusion and viral entry into the cell. Virus-infected host cells exhibit marked increases in glutamine utilization and metabolism. Glutamine metabolism generates ATP and precursors for the synthesis of macromolecules to assemble progeny viruses. Some compounds derived from glutamine are used in the synthesis of purines and pyrimidines. These latter compounds are precursors for the synthesis of nucleotides. Inhibitors of glutamine transport and metabolism are potential candidate antiviral drugs. Glutamine is also an essential nutrient for the functions of leukocytes (lymphocyte, macrophage, and neutrophil), including those in virus-infected patients. The increased glutamine requirement for immune cell functions occurs concomitantly with the high glutamine utilization by host cells in virus-infected patients. The development of antiviral drugs that target glutamine metabolism must then be specifically directed at virus-infected host cells to avoid negative effects on immune functions. Therefore, the aim of this review was to describe the landscape of cellular glutamine metabolism to search for potential candidates to inhibit glutamine transport or glutamine metabolism.

The Critical Role of Cell Metabolism for Essential Neutrophil Functions.

Neutrophils were traditionally considered as short-lived cells with abundant secretory and protein synthetic activity. Recent studies, however, indicate neutrophils are in reality a heterogeneous population of cells. Neutrophils differentiate from pluripotent stem cells in the bone marrow, and can further mature in the blood stream and can have different phenotypes in health and disease conditions. Neutrophils undergo primary functions such as phagocytosis, production of reactive oxygen species (ROS), release of lipid mediators and inflammatory proteins (mainly cytokines), and apoptosis. Neutrophils stimulate other neutrophils and trigger a cascade of immune and inflammatory responses. The underpinning intracellular metabolisms that support these neutrophil functions are herein reported. It has been known for many decades that neutrophils utilize glucose as a primary fuel and produce lactate as an end product of glycolysis. Neutrophils metabolize glucose through glycolysis and the pentose- phosphate pathway (PPP). Mitochondrial glucose oxidation is very low. The PPP provides the reduced nicotinamide adenine dinucleotide phosphate (NADPH) for the NADPH-oxidase (NOX) complex activity to produce superoxide from oxygen. These cells also utilize glutamine and fatty acids to produce the required adenosine triphosphate (ATP) and precursors for the synthesis of molecules that trigger functional outcomes. Neutrophils obtained from rat intraperitoneal cavity and incubate for 1 hour at 37°C metabolize glutamine at higher rate than that of glucose. Glutamine delays neutrophil apoptosis and maintains optimal NOX activity for superoxide production. Under limited glucose provision, neutrophils move to fatty acid oxidation (FAO) to obtain the required energy for the cell function. FAO is mainly associated with neutrophil differentiation and maturation. Hypoxia, hormonal dysfunction, and physical exercise markedly change neutrophil metabolism. It is now become clear that neutrophil metabolism underlies the heterogeneity of neutrophil phenotypes and should be intense focus of investigation.

Proteomic profiling of the extracellular matrix in the human adrenal cortex.

The extracellular matrix (ECM) comprises macromolecules that shape a complex three-dimensional network. Filling the intercellular space and playing a crucial role in the structure and function of tissues, ECM regulates essential cellular processes such as adhesion, differentiation, and cell signaling. In the human adrenal gland, composed of cortex and medulla surrounded by a capsule, the ECM has not yet been directly described, although its impact on the processes of proliferation and steroidogenesis of the adrenal cortex is recognized. This study analyzes the ECM of the adult human adrenal cortex, which was separated into outer fraction (OF) and inner fraction (IF), by comparing their proteomic profiles. The study discusses the composition, spatial distribution, and relevance of differentially expressed ECM signatures of the adrenal cortex matrisome on adrenal structure and function. The findings were validated through database analysis (cross-validation), histochemical, and immunohistochemical approaches. A total of 121 ECM proteins were identified and categorized into glycoproteins, collagens, ECM regulators, proteoglycans, ECM-affiliated proteins, and secreted factors. Thirty-one ECM proteins were identified only in OF, nine only in IF, and 81 were identified in common with both fractions. Additionally, 106 ECM proteins were reported in the Human matrisome DB 2.0, and the proteins differentially expressed in OF and IF, were identified. This study provides significant insights into the composition and regulation of the ECM in the human adrenal cortex, shedding light on the adrenal microenvironment and its role in the functioning, maintenance, and renewal of the adrenal gland.

Evidence for Monocyte Reprogramming in a Long-Term Postsepsis Study.

This study sought to identify monocyte alterations from septic patients after hospital discharge by evaluating gene expression of inflammatory mediators and monocyte polarization markers. It was hypothesized that sepsis reprograms the inflammatory state of monocytes, causing effects that persist after hospital discharge and influencing patient outcomes. DESIGN: The gene expression patterns of inflammatory receptors, M1 and M2 macrophage polarization markers, NLRP3 inflammasome components, and pro- and anti-inflammatory cytokines in monocytes were assessed. PATIENTS: Thirty-four patients from the University of São Paulo Hospital, during the acute sepsis phase (phase A), immediately after ICU discharge (phase B), and 3 months (phase C), 6 months (phase D), 1 year (phase E), and 3 years (phase F) after discharge, were included. Patients that died during phases A and B were grouped separately, and the remaining patients were collectively termed the survivor group. MEASUREMENTS AND MAIN RESULTS: The gene expression of toll-like receptor (TLR)2 and TLR4 (inflammatory receptors), NLRP3, NFκB1, adaptor molecule apoptosis-associated speck-like protein containing a CARD, caspase 1, caspase 11, and caspase 12 (NLRP3 inflammasome components), interleukin-1α, interleukin-1ß, interleukin-18, and high-mobility group box 1 protein (proinflammatory cytokines), interleukin-10 (anti-inflammatory cytokine), C-X-C motif chemokine ligand 10, C-X-C motif chemokine ligand 11, and interleukin-12p35 (M1 inflammatory polarization markers), and C-C motif chemokine ligand 14, C-C motif chemokine ligand 22, transforming growth factor-beta (TGF-ß), SR-B1, and peroxisome proliferator-activated receptor γ (M2 anti-inflammatory polarization and tissue repair markers) was upregulated in monocytes from phase A until phase E compared with the control group. CONCLUSIONS: Sepsis reprograms the inflammatory state of monocytes, probably contributing to postsepsis syndrome development and mortality.

4-Aminoquinoline compounds from the Spanish flu to COVID-19.

In 1918, quinine was used as one of the unscientifically based treatments against the H1N1 virus during the Spanish flu pandemic. Originally, quinine was extracted from the bark of Chinchona trees by South American natives of the Amazon forest, and it has been used to treat fever since the seventeenth century. The recent COVID-19 pandemic caused by Sars-Cov-2 infection has forced researchers to search for ways to prevent and treat this disease. Based on the antiviral potential of two 4-aminoquinoline compounds derived from quinine, known as chloroquine (CQ) and hydroxychloroquine (HCQ), clinical investigations for treating COVID-19 are being conducted worldwide. However, there are some discrepancies among the clinical trial outcomes.Thus, even after one hundred years of quinine use during the Spanish flu pandemic, the antiviral properties promoted by 4-aminoquinoline compounds remain unclear. The underlying molecular mechanisms by which CQ and HCQ inhibit viral replication open up the possibility of developing novel analogs of these drugs to combat COVID-19 and other viruses.

Profiling plasma-extracellular vesicle proteins and microRNAs in diabetes onset in middle-aged male participants in the ELSA-Brasil study.

We measured plasma-derived extracellular vesicle (EV) proteins and their microRNA (miRNA) cargos in normoglycemic (NG), glucose intolerant (GI), and newly diagnosed diabetes mellitus (DM) in middle-aged male participants of the Brazilian Longitudinal Study of Adult Health (ELSA-Brazil). Mass spectrometry revealed decreased IGHG-1 and increased ITIH2 protein levels in the GI group compared with that in the NG group and higher serotransferrin in EVs in the DM group than in those in the NG and GI groups. The GI group also showed increased serum ferritin levels, as evaluated by biochemical analysis, compared with those in both groups. Seventeen miRNAs were differentially expressed (DEMiRs) in the plasma EVs of the three groups. DM patients showed upregulation of miR-141-3p and downregulation of miR-324-5p and -376c-3p compared with the NG and GI groups. The DM and GI groups showed increased miR-26b-5p expression compared with that in the NG group. The DM group showed decreased miR-374b-5p levels compared with those in the GI group and higher concentrations than those in the NG group. Thus, three EV proteins and five DEMiR cargos have potential prognostic importance for diabetic complications mainly associated with the immune function and iron status of GI and DM patients.

Why Septic Patients Remain Sick After Hospital Discharge?

Sepsis is well known to cause a high patient death rate (up to 50%) during the intensive care unit (ICU) stay. In addition, sepsis survival patients also exhibit a very high death rate after hospital discharge compared to patients with any other disease. The addressed question is then: why septic patients remain ill after hospital discharge? The cellular and molecular mechanisms involved in the high rate of septic patient deaths are still unknown. We described herein the studies that investigated the percentage of septic patients that died after hospital discharge ranging from 90 days up to 5 years. We also reported the symptoms of septic patients after hospital discharge and the development of the recently called post-sepsis syndrome (PSS). The most common symptoms of the PSS are cognitive disabilities, physical functioning decline, difficulties in performing routine daily activities, and poor life quality. The PSS also associates with quite often reinfection and re-hospitalization. This condition is the cause of the high rate of death mentioned above. We reported the proportion of patients dying after hospital discharge up to 5 years of followed up and the PSS symptoms associated. The authors also discuss the possible cellular and metabolic reprogramming mechanisms related with the low survival of septic patients and the occurrence of PSS.