Glycation-Driven Inflammation: COVID-19 Severity in Pregnant Women and Perinatal Outcomes.

The link between being pregnant and overweight or obese and the infectivity and virulence of the SARS CoV-2 virus is likely to be caused by SARS-CoV-2 spike protein glycosylation, which may work as a glycan shield. Methylglyoxal (MGO), an important advanced glycation end-product (AGE), and glycated albumin (GA) are the results of poor subclinical glucose metabolism and are indices of oxidative stress. Forty-one consecutive cases of SARS-CoV-2-positive pregnant patients comprising 25% pre-pregnancy overweight women and 25% obese women were recruited. The aim of our study was to compare the blood levels of MGO and GA in pregnant women with asymptomatic and symptomatic SARS-CoV-2 infection with pregnant women without SARS-CoV-2 infection with low risk and uneventful pregnancies and to evaluate the relative perinatal outcomes. The MGO and GA values of the SARS-CoV-2 cases were statistically significantly higher than those of the negative control subjects. In addition, the SARS-CoV-2-positive pregnant patients who suffered of moderate to severe COVID-19 syndrome had higher values of GA than those infected and presenting with mild symptoms or those with asymptomatic infection. Premature delivery and infants of a small size for their gestational age were overrepresented in this cohort, even in mild-asymptomatic patients for whom delivery was not indicated by the COVID-19 syndrome. Moreover, ethnic minorities were overrepresented among the severe cases. The AGE-RAGE oxidative stress axis on the placenta and multiple organs caused by MGO and GA levels, associated with the biological mechanisms of the glycation of the SARS-CoV-2 spike protein, could help to explain the infectivity and virulence of this virus in pregnant patients affected by being overweight or obese or having gestational diabetes, and the increased risk of premature delivery and/or low newborn weight.

Qatar Health 2022 Conference

The proceedings contain 74 papers. The topics discussed include: Qatar Health 2022: preparing for the 2022 World Cup and the response to pandemics in Qatar - a multidisciplinary team approach;leveraging primary health care corporation partnerships in preparation for the 2022 FIFA World Cup Qatar: a position paper;medical resources deployed for the 2019 world athletics championships in Doha, Qatar;Qatar 2021 national guidelines on physical activity and sedentary behavior: a descriptive review;interprofessional education for safe patient handling during mobilization;antiviral activity of glucose-derived reactive metabolite, methylglyoxal against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2);and coping strategies adopted by Hamad Medical Corporation paramedics before and during the COVID-19 pandemic.

Emerging Glycation-Based Therapeutics-Glyoxalase 1 Inducers and Glyoxalase 1 Inhibitors.

The abnormal accumulation of methylglyoxal (MG) leading to increased glycation of protein and DNA has emerged as an important metabolic stress, dicarbonyl stress, linked to aging, and disease. Increased MG glycation produces inactivation and misfolding of proteins, cell dysfunction, activation of the unfolded protein response, and related low-grade inflammation. Glycation of DNA and the spliceosome contribute to an antiproliferative and apoptotic response of high, cytotoxic levels of MG. Glyoxalase 1 (Glo1) of the glyoxalase system has a major role in the metabolism of MG. Small molecule inducers of Glo1, Glo1 inducers, have been developed to alleviate dicarbonyl stress as a prospective treatment for the prevention and early-stage reversal of type 2 diabetes and prevention of vascular complications of diabetes. The first clinical trial with the Glo1 inducer, trans-resveratrol and hesperetin combination (tRES-HESP)-a randomized, double-blind, placebo-controlled crossover phase 2A study for correction of insulin resistance in overweight and obese subjects, was completed successfully. tRES-HESP corrected insulin resistance, improved dysglycemia, and low-grade inflammation. Cell permeable Glo1 inhibitor prodrugs have been developed to induce severe dicarbonyl stress as a prospective treatment for cancer-particularly for high Glo1 expressing-related multidrug-resistant tumors. The prototype Glo1 inhibitor is prodrug S-p-bromobenzylglutathione cyclopentyl diester (BBGD). It has antitumor activity in vitro and in tumor-bearing mice in vivo. In the National Cancer Institute human tumor cell line screen, BBGD was most active against the glioblastoma SNB-19 cell line. Recently, potent antitumor activity was found in glioblastoma multiforme tumor-bearing mice. High Glo1 expression is a negative survival factor in chemotherapy of breast cancer where adjunct therapy with a Glo1 inhibitor may improve treatment outcomes. BBGD has not yet been evaluated clinically. Glycation by MG now appears to be a pathogenic process that may be pharmacologically manipulated for therapeutic outcomes of potentially important clinical impact.

Vulnerabilities of the SARS-CoV-2 Virus to Proteotoxicity-Opportunity for Repurposed Chemotherapy of COVID-19 Infection.

The global pandemic of COVID-19 disease caused by infection with the SARS-CoV-2 coronavirus, has produced an urgent requirement and search for improved treatments while effective vaccines are developed. A strategy for improved drug therapy is to increase levels of endogenous reactive metabolites for selective toxicity to SARS-CoV-2 by preferential damage to the viral proteome. Key reactive metabolites producing major quantitative damage to the proteome in physiological systems are: reactive oxygen species (ROS) and the reactive glycating agent methylglyoxal (MG); cysteine residues and arginine residues are their most susceptible targets, respectively. From sequenced-based prediction of the SARS-CoV-2 proteome, we found 0.8-fold enrichment or depletion of cysteine residues in functional domains of the viral proteome; whereas there was a 4.6-fold enrichment of arginine residues, suggesting SARS-CoV-2 is resistant to oxidative agents and sensitive to MG. For arginine residues of the SARS-CoV-2 coronavirus predicted to be in functional domains, we examined which are activated toward modification by MG - residues with predicted or expected low pKa by neighboring group in interactions. We found 25 such arginine residues, including 2 in the spike protein and 10 in the nucleoprotein. These sites were partially conserved in related coronaviridae: SARS-CoV and MERS. Finally, we identified drugs which increase cellular MG concentration to virucidal levels: antitumor drugs with historical antiviral activity, doxorubicin and paclitaxel. Our findings provide evidence of potential vulnerability of SARS-CoV-2 to inactivation by MG and a scientific rationale for repurposing of doxorubicin and paclitaxel for treatment of COVID-19 disease, providing efficacy and adequate therapeutic index may be established.