Computer Analysis of the Inhibition of ACE2 by Flavonoids and Identification of Their Potential Antiviral Pharmacophore Site.

In the present study, we investigated the antiviral activities of 17 flavonoids as natural products. These derivatives were evaluated for their in vitro antiviral activities against HIV and SARS-CoV-2. Their antiviral activity was evaluated for the first time based on POM (Petra/Osiris/Molispiration) theory and docking analysis. POM calculation was used to analyze the atomic charge and geometric characteristics. The side effects, drug similarities, and drug scores were also assumed for the stable structure of each compound. These results correlated with the experimental values. The bioinformatics POM analyses of the relative antiviral activities of these derivatives are reported for the first time.

Development of SARS-CoV-2 neutralizing antibody detection assay by using recombinant plant-produced proteins.

Detecting immunity against SARS-CoV-2 is vital for evaluating vaccine response and natural infection, but conventional virus neutralization test (cVNT) requires BSL3 and live viruses, and pseudo-virus neutralization test (pVNT) needs specialized equipment and trained professionals. The surrogate virus neutralization test (sVNT) was developed to overcome these limitations. This study explored the use of angiotensin converting enzyme 2 (ACE2) produced from Nicotiana benthamiana for the development of an affordable neutralizing antibodies detection assay. The results showed that the plant-produced ACE2 can bind to the receptor binding domain (RBD) of the SARS-CoV-2, and was used to develop sVNT with plant-produced RBD protein. The sVNT developed using plant-produced proteins showed high sensitivity and specificity when validated with a group of 30 RBD vaccinated mice sera and the results were correlated with cVNT titer. This preliminary finding suggests that the plants could offer a cost-effective platform for producing diagnostic reagents.

Study of frequency and inheritance model of ACE1 I/D and ACE2 rs2285666 polymorphisms in COVID-19 patients with varying severity of lung involvement and its effect on serum cytokines levels.

The angiotensin-converting enzyme (ACE) has been shown to play a role as a receptor for the COVID-19 virus. This virus usually gets into cells and infects them by attaching to their glycoprotein receptors, which are found on the ACE2 receptor. The aim of this study was to evaluate the frequency and inheritance of ACE1 I/D and ACE2 rs2285666 polymorphisms in COVID-19 patients with varying severity of lung involvement and its effect on serum cytokines levels of interleukin (IL)-1 and IL-6 and laboratory parameters. One hundred eighty-five COVID-19 patients were grouped according to the severity of lung involvement. (I/D) polymorphism of the ACE1 gene and rs2285666 polymorphism of the ACE2 gene were determined by single specific primer-polymerase chain reaction and restriction fragment length reaction-polymerase chain reaction methods, respectively. Serum levels of IL-1 and IL-6 were also measured by the enzyme linked immunosorbent assay technique. No statistically significant association of ACE2 rs2285666 polymorphism genotypes and ACE1 I/D with the severity of lung involvement was noted. However, there was a statistically significant association between I/D ACE1 polymorphism genotypes and IL-6, white blood cells (WBC), and neutrophil-to-lymphocyte ratio (NLR) levels. Also, there was no statistically significant association between rs2285666 polymorphism genotypes and patients' blood oxygen saturation level, IL-6, IL-1ß, lactate dehydrogenase activity, WBC count, and NLR. In patients with COVID-19, the rs2285666 polymorphism of the ACE2 gene and the I/D polymorphism of the ACE1 gene were not significantly associated with the severity of COVID-19 disease and serum IL-6 and IL-1 cytokine levels.

The Remarkable Roles of the Receptor for Advanced Glycation End Products (RAGE) and Its Soluble Isoforms in COVID-19: The Importance of RAGE Pathway in the Lung Injuries.

The respiratory symptoms of acute respiratory distress syndrome (ARDS) in the coronavirus disease 2019 (COVID-19) patients is associated with accumulation of pre-inflammatory molecules such as advanced glycation end-products (AGES), calprotectin, high mobility group box family-1 (HMGB1), cytokines, angiotensin converting enzyme 2 (ACE2), and other molecules in the alveolar space of lungs and plasma. The receptor for advanced glycation end products (RAGEs), which is mediated by the mitogen-activated protein kinase (MAPK), plays a critical role in the severity of chronic inflammatory diseases such as diabetes mellitus (DM) and ARDS. The RAGE gene is most expressed in the alveolar epithelial cells (AECs) of the pulmonary system. Several clinical trials are now being conducted to determine the possible association between the levels of soluble isoforms of RAGE (sRAGE and esRAGE) and the severity of the disease in patients with ARDS and acute lung injury (ALI). In the current article, we reviewed the most recent studies on the RAGE/ligands axis and sRAGE/esRAGE levels in acute respiratory illness, with a focus on COVID-19-associated ARDS (CARDS) patients. According to the research conducted so far, sRAGE/esRAGE measurements in patients with CARDS can be used as a powerful chemical indicator among other biomarkers for assessment of early pulmonary involvement. Furthermore, inhibiting RAGE/MAPK and Angiotensin II receptor type 1 (ATR1) in CARDS patients can be a powerful strategy for diminishing cytokine storm and severe respiratory symptoms.

Evaluation of Serum Levels of MicroRNA-200C and ACE2 Gene Expression in Severe and Mild Phases of Patients with COVID-19.

The role of microRNA (miR)200c-3p in regulating ACE2 gene expression in viral and bacterial respiratory diseases has been established. Since ACE2 reduces the acute inflammatory effects in lung diseases and acts as a coronavirus receptor to invade the lung cells, this study investigates the relationship between miR-200c-3p and ACE2 expression in COVID -19 patients. In this study, COVID-19 patients were divided into two groups: mild phase (PCR-positive and mild symptoms) and severe phase (PCR-positive with acute pulmonary symptoms and inflammation). Then, the subjects' demographic, clinical, and paraclinical characteristics were recorded using a prepared checklist. Total RNA was isolated from all samples according to the Trizol kit protocol to evaluate gene expression. Subsequently, the extracted product was analysed for miR-200c expression and ACE2 target gene expression by real-time PCR. The results of the checklist data showed that smoking, cough, and the factors ESR and HCT were statistically significant between the two groups of patients in the mild and acute phases. Also, the mean expression of the miR-200c gene in the mild and acute patients was 1.87±0.70 and 1.87±0.62, respectively, which was not statistically significant. Still, the mean expression of the ACE2 gene, which was 3.96±0.76 and 3.28±0.52 in the mild and acute disease groups, respectively, showed a significant difference between the two groups. This study showed that the expression levels of ACE2 were significantly reduced in people with severe inflammation compared to people with mild inflammation.

Vitamin D association with the renin angiotensin system in polycystic ovary syndrome.

Vitamin D deficiency is a negative endocrine renin-angiotensin system (RAS) modulator and PCOS women are often vitamin D deficient, leading to RAS overactivation in PCOS. A cross-sectional study was performed in 99 PCOS and 68 control women who presented sequentially. Circulating plasma levels of RAS proteins (Angiotensin-converting enzyme 2 (ACE2), renin and angiotensinogen) were measured by Slow Off-rate Modified Aptamer (SOMA)-scan and 25-hydroxyvitamin D [25(OH)D] was measured by tandem mass spectroscopy. The RAS system was found to be overactivated in the PCOS women compared to non-PCOS control women with increased renin and decreased angiotensinogen (p < 0.05); 25-hydroxyvitamin D was also significantly lower in the PCOS group (p < 0.0001). In PCOS women, plasma renin was increased in vitamin D deficient and insufficient groups compared with the vitamin D sufficient group (p < 0.005), but did not differ across non-PCOS control subgroups. In non-PCOS controls, plasma ACE2 decreased from vitamin D insufficiency to deficiency (p < 0.05). Angiotensinogen was not different across the vitamin D sufficiency, insufficiency and deficiency strata for either PCOS or non-PCOS controls. These data show that RAS activation through increased plasma renin levels was seen in vitamin D insufficient and deficient PCOS subjects compared to non-PCOS control women. In addition, decreased plasma ACE2 levels were seen in vitamin D deficiency in non-PCOS controls, which may predispose these vitamin D deficient subjects to increased cardiovascular risk and susceptibility to infectious agents such as COVID-19 where this is a risk factor.

Inhibitory capacity of chloroquine against SARS-COV-2 by effective binding with angiotensin converting enzyme-2 receptor: An insight from molecular docking and MD-simulation studies.

The main binding site for SARS-COV-2 spike protein in human body is human Angiotensin converting enzyme 2 (ACE2) protein receptor. Herein we present the effect of chloroquine (CLQ) on human ACE2 receptor. Molecular docking studies showed that chloroquine have a docking score is quite high compare to other well known drugs. Furthermore, molecular dynamics (MD) studies with CLQ docked ACE2 results in large fluctuations on RMSD up to 2.3 ns, indicating conformational and rotational changes due to the presence of drug molecule in the ACE2 moiety. Analysis of results showed that CLQ can effect the conformation of human ACE2 receptor. We believed that this work will help researchers to understand better the effect of CLQ on ACE2.

Update and Supplementary Articles Proteins of SARS CoV-2, Which Causes COVID-19, and the Interacting Proteins.

Coronavirus disease 2019 (COVID-19), which is the pandemic caused by the virus, severe acute respiratory syndrome coronavirus-2 (SARS CoV-2), first appearing in December 2019, continues to confound the world. In this update we provide insights into how some of the new mutant variant strains of SARS CoV-2 have evolved to be more infective. We also introduce our supplement of the special issue on the topic of the proteins of SARS CoV-2 in the Protein Journal, which follows this introduction.

Renin-Angiotensin System overactivation in polycystic ovary syndrome, a risk for SARS-CoV-2 infection?

BACKGROUND: The SARS-CoV-2 coronavirus gains entry to target cells via the angiotensin-converting enzyme 2 (ACE2) receptor present on cells in blood vessels, lungs, heart, intestines, and kidneys. Renin-Angiotensin System (RAS) overactivity has also been described in metabolic syndrome, type 2 diabetes (T2D) and obesity, conditions shared by women with polycystic ovary syndrome (PCOS) We hypothesized that RAS overactivity may be present in PCOS. METHODS: We determined plasma levels of RAS-related proteins in a cohort of age matched control women (n = 97) and women with PCOS (n = 146). Plasma levels of RAS-related proteins (ACE2, Renin and Angiotensinogen (AGT)) were determined by Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement. RESULTS: PCOS women had a higher BMI (p < 0.001), systolic (p < 0.0001) and diastolic (p < 0.05) blood pressure, waist circumference (p < 0.0001), testosterone (p < 0.0001), free androgen index (p < 0.0001) and CRP (p < 0.0001). Renin was elevated in PCOS (p < 0.05) and angiotensinogen was lower in PCOS (p < 0.05), indicating overactivity of the RAS system in PCOS. ACE2 levels were lower in PCOS (p < 0.05), suggesting that PCOS women are at risk for development of hypertension. CONCLUSION: RAS proteins levels differed between PCOS and control women, suggesting that the insulin resistance inherent in PCOS may predispose these women to more severe COVID-19 infection.