Research exploring the development and outcome of COVID-19 infections has led to the need to find better diagnostic and prognostic biomarkers. This cross-sectional study used targeted metabolomics to ...identify potential COVID-19 biomarkers that predicted the course of the illness by assessing 110 endogenous plasma metabolites from individuals admitted to a local hospital for diagnosis/treatment. Patients were classified into four groups (≈ 40 each) according to standard polymerase chain reaction (PCR) COVID-19 testing and disease course: PCR-/controls (i.e., non-COVID controls), PCR+/not-hospitalized, PCR+/hospitalized, and PCR+/intubated. Blood samples were collected within 2 days of admission/PCR testing. Metabolite concentration data, demographic data and clinical data were used to propose biomarkers and develop optimal regression models for the diagnosis and prognosis of COVID-19. The area under the receiver operating characteristic curve (AUC; 95% CI) was used to assess each models' predictive value. A panel that included the kynurenine: tryptophan ratio, lysoPC a C26:0, and pyruvic acid discriminated non-COVID controls from PCR+/not-hospitalized (AUC = 0.947; 95% CI 0.931-0.962). A second panel consisting of C10:2, butyric acid, and pyruvic acid distinguished PCR+/not-hospitalized from PCR+/hospitalized and PCR+/intubated (AUC = 0.975; 95% CI 0.968-0.983). Only lysoPC a C28:0 differentiated PCR+/hospitalized from PCR+/intubated patients (AUC = 0.770; 95% CI 0.736-0.803). If additional studies with targeted metabolomics confirm the diagnostic value of these plasma biomarkers, such panels could eventually be of clinical use in medical practice.
Diabetes is a chronic disease characterized by marked alterations in the metabolism of glucose and by high concentrations of glucose in the blood due to a decreased insulin production or resistance ...to the action of this hormone in peripheral tissues. The International Diabetes Federation estimates a global incidence of diabetes of about 10% in the adult population (20 - 79 years old), some 430 million cases reported worldwide in 2018. It is well documented that people with diabetes have a higher susceptibility to infectious diseases and therefore show higher morbidity and mortality compared to the non-diabetic population. Given that the innate immune response plays a fundamental role in protecting against invading pathogens through a myriad of humoral and cellular mechanisms, the present work makes a comprehensive review of the innate immune alterations in patients with type 2 diabetes mellitus (T2D) as well as a brief description of the molecular events leading or associated to such conditions. We show that in these patients a compromised innate immune response increases susceptibility to infections.
The rheumatoid arthritis (RA) inflammatory process occurs in the joints where immune cells are attracted into the synovium to promote remodeling and tissue damage. GPR15 is a G protein‐coupled ...receptor (GPCR) located on chromosome 3 and has similarity in its sequence with chemokine receptors. Recent evidence indicates that GPR15 may be associated with modulation of the chronic inflammatory response. We evaluated the expression of GPR15 and GPR15L in blood and synovial tissue samples from RA patients, as well as to perform a functional migration assay in response to GPR15L. The expression of GPR15 and c10orf99/gpr15l mRNA was analyzed by RT‐qPCR. Samples of synovial fluid and peripheral blood were analyzed for CD45+CD3+CD4+GPR15+ and CD45+CD3+CD8+GPR15+ T cell frequency comparing RA patients versus control subjects by flow cytometry. Migration assays were performed using PBMCs isolated from these individuals in response to the synthetic GPR15 ligand. Statistical analysis included Kruskal–Wallis test, T‐test, or Mann–Whitney U test, according to data distribution. A higher expression in the mRNA for GPR15 was identified in early RA subjects. The frequencies of CD4+/CD8+ GPR15+ T lymphocytes are higher in RA patients comparing with healthy subjects. Also, the frequency CD4+/CD8+ GPR15+ T lymphocytes are higher in synovial fluid of established RA patients comparing with OA patients. GPR15 and GPR15L are present in the synovial tissue of RA patients and GPR15L promotes migration of PBMCs from RA patients and healthy subjects. Our results suggest that GPR15/GPR15L have a pathogenic role in RA and their antagonizing could be a therapeutic approach in RA.
Graphical
: GPR15/GPR15L interaction promotes leukocyte chemotaxis to synovium in patients with RA, this interaction might be a therapeutic target.
Peptidyl arginine deiminases (PAD) are proteins that modify arginine residues to citrulline. In humans there are five isoforms PAD1-4 and PAD6. PAD4 is involved in several human diseases such as ...Alzheimer, breast cancer, rheumatoid arthritis and therefore has been recognized as a potential pharmacological target.
In this work, 3175 molecules retrieved from ZINC12 Food and Drug Administration (FDA) catalog database were assayed through a structure-based virtual screening to identify potential PAD4 binders. Three were confirmed through enzyme inhibition studies. Flow cytometry analysis were used to check for drug cytotoxic effects on blood cells from three healthy donors.
Molecular docking in a wild-type PAD4 structure showed the top 20 FDA molecules with the best binding energies. Those molecules were distributed in clusters of mixed binding energies but with similar chemical structures. These patterns along with the FDA information were used to aid in the rational selection of methotrexate, testosterone and leucovorin compounds for in vitro evaluations. Time course fluorescent enzyme kinetics confirmed that methotrexate (0.01–1 mmol) and testosterone enanthate (49.9–12.5 mmol) inhibit PAD4 at similar levels to the known inhibitor BB-Cl-amidine (8.8 mmol), except leucovorin. The chosen concentrations lack cytotoxic effects on blood cells.
These findings encourage repositioning campaigns in the quest of PAD4 inhibitors.
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