Correction: Palmeira et al. Preliminary Virtual Screening Studies to Identify GRP78 Inhibitors Which May Interfere with SARS-CoV-2 Infection. Pharmaceuticals 2020, 13, 132.

There was an error in the original publication [...].

The methylome of buccal epithelial cells is influenced by age, sex, and physiological properties.

Epigenetic modifications, particularly DNA methylation, have emerged as regulators of gene expression and are implicated in various biological processes and disease states. Understanding the factors influencing the epigenome is essential for unraveling its complexity. In this study, we aimed to identify how the methylome of buccal epithelial cells, a noninvasive and easily accessible tissue, is associated with demographic and health-related variables commonly used in clinical settings, such as age, sex, blood immune composition, hemoglobin levels, and others. We developed a model to assess the association of multiple factors with the human methylome and identify the genomic loci significantly impacted by each trait. We demonstrated that DNA methylation variation is accurately modeled by several factors. We confirmed the well-known impact of age and sex and unveiled novel clinical factors associated with DNA methylation, such as blood neutrophils, hemoglobin, red blood cell distribution width, high-density lipoprotein cholesterol, and urea. Genomic regions significantly associated with these traits were enriched in relevant transcription factors, drugs, and diseases. Among our findings, we showed that neutrophil-impacted loci were involved in neutrophil functionality and maturation. Similarly, hemoglobin-influenced sites were associated with several diseases, including aplastic anemia, and the genomic loci affected by urea were related to congenital anomalies of the kidney and urinary tract. Our findings contribute to a better understanding of the human methylome plasticity and provide insights into novel factors shaping DNA methylation patterns, highlighting their potential clinical implications as biomarkers and the importance of considering these physiological traits in future medical epigenomic investigations.NEW & NOTEWORTHY We have developed a quantitative model to assess how the human methylome is associated with several factors and to identify the genomic loci significantly impacted by each trait. We reported novel health-related factors driving DNA methylation patterns and new site-specific regulations that further elucidate methylome dynamics. Our study contributes to a better understanding of the plasticity of the human methylome and unveils novel physiological traits with a potential role in future medical epigenomic investigations.

Investigation of Serum Angiotensin-Converting Enzyme (ACE) Concentration and ACE Gene Polymorphism in Patients With SARS-CoV-2 Pneumonia Admitted to the Emergency Department.

Background This study seeks to investigate the distribution of the angiotensin-converting enzyme (ACE) gene polymorphism and serum levels in patients with viral pneumonia and predict which polymorphism will lead to severe progression of the disease. Methodology The serum ACE levels and ACE gene polymorphisms were successfully evaluated with respect to subsequent viral pneumonia using records of 100 patients with viral pneumonia and 100 healthy controls. Results ACE serum concentration was statistically significantly elevated. ACE serum concentration with a cut-off value of ≥5,256.05 pg/mL had 85.3% sensitivity and 83.2% selectivity. In addition, patients with ACE genotype D/D were 0.08 times more likely to manifest severe lung involvement than those with I/I, and patients with the I/D genotype were 0.02 times more likely than their counterparts with I/I. The computed tomography findings of the patients revealed that ACE serum concentration was significantly effective in discriminating between mild and moderate-to-severe lung involvement. No significant difference was observed between the blood parameters and ACE genotype distributions. Conclusions I/D polymorphism likely affects the expression of the ACE gene and/or the function of the angiotensin I converting enzyme. The D/D genotype is associated with vessel wall thickness and higher blood pressure. Strong evidence was found between D/D and I/D genotypes in the patient cohort concerning genotypes and ACE serum concentration. Further analysis showed that ACE serum levels were more elevated in the D/D genotype compared to the I/D genotype in the patient cohort.

The Correlation Between Peroxisome Proliferator-Activated Receptor Alpha and Gamma Polymorphisms and Acute Coronary Syndrome.

OBJECTIVE: This study aims to evaluate the relationship between peroxisome proliferator-activated receptor (PPAR) alpha and gamma gene polymorphisms and acute coronary syndrome (ACS) clinically. SUBJECT AND METHODS: Peripheral blood samples were collected from a total of 200 people, including 100 acute coronary syndrome patients and 100 controls aged 19 to 93 years, admitted to the Pamukkale University Emergency Medicine Department. The healthy volunteers had no known chronic or acute diseases, no history of drug use, and no recent history of coronary artery disease (CAD). PPAR alpha L162V and PPAR gamma C161T gene polymorphic regions were detected using DNA sequencing analyses. In addition, data collected from the hemogram and biochemical parameters and comorbidities of the patients were statistically analyzed. RESULTS: PPAR gamma C161T polymorphisms were compared between groups. The CT heterozygous rate in the patient group (74%) was higher than in the control group (7%). The T allele was more common in the patient group (0.37) compared to the control group (0.03). When PPAR alpha L162V polymorphism was compared, VV homozygous individuals were %19 in the patient group and none in the control group. The V allele was found to be statistically higher in patients with ACS (p<0.01). CONCLUSION: The findings revealed that elevated PPAR alpha L162V and PPAR gamma C161T gene polymorphisms were associated with a progressive risk of ACS.

DNA methylation profiles in pneumonia patients reflect changes in cell types and pneumonia severity.

Immune cell-type composition changes with age, potentially weakening the response to infectious diseases. Profiling epigenetics marks of immune cells can help us understand the relationship with disease severity. We therefore leveraged a targeted DNA methylation method to study the differences in a cohort of pneumonia patients (both COVID-19 positive and negative) and unaffected individuals from peripheral blood.This approach allowed us to predict the pneumonia diagnosis with high accuracy (AUC = 0.92), and the PCR positivity to the SARS-CoV-2 viral genome with moderate, albeit lower, accuracy (AUC = 0.77). We were also able to predict the severity of pneumonia (PORT score) with an R2 = 0.69. By estimating immune cellular frequency from DNA methylation data, patients under the age of 65 positive to the SARS-CoV-2 genome (as revealed by PCR) showed an increase in T cells, and specifically in CD8+ cells, compared to the negative control group. Conversely, we observed a decreased frequency of neutrophils in the positive compared to the negative group. No significant difference was found in patients over the age of 65. The results suggest that this DNA methylation-based approach can be used as a cost-effective and clinically useful biomarker platform for predicting pneumonias and their severity.

Association Between S100b Levels and COVID-19 Pneumonia: A Case Control Study.

BACKGROUND/AIM: Extracellular S100b effects are mediated by the receptor for advanced glycation end products (RAGE), which is the S100b membrane receptor. RAGE belongs to the immunoglobulin superfamily of cell surface molecules and serves as a multiligand receptor and is expressed in high abundance by alveolar type I (AT-I) cells in adult pulmonary tissue. This study aimed to provide an insight into the association between the severity of COVID-19 disease and serum S100b levels during admission to the emergency department (ED). PATIENTS AND METHODS: A total of 64 patients (34 mild cases; 30 severe cases) were diagnosed with COVID-19 pneumonia and 30 healthy volunteers were admitted to study. Serum S100b levels were measured by using enzymle linked immunoassay method from blood serum samples. RESULTS: Serum S100b levels showed a significantly higher mean value in mild and severe disease cohorts than in healthy controls (p=0.036 and p=0.028 respectively). Receiver operating characteristic (ROC) analysis indicated greater area under the curve (AUC) for serum S100b levels of the COVID-19 patients (AUC=0.663, 95% CI=0.541-0.785; p=0.014). In addition, serum S100b concentration was measured as 151.7 ng/ml at 79.3% sensitivity and 51.7% specificity (p=0.014). Serum S100b protein levels can serve as a valuable clinical marker in establishing diagnosis of patients. Though not useful in identifying different stages of COVID-19 infection, serum S100b concentration along with other known markers can be utilized to reliably predict clinical severity along with other clinical parameters.

Association between laboratory parameters and CT severity in patients infected with Covid-19: A retrospective, observational study.

INTRODUCTION: Patients diagnosed with COVID-19 have presented to emergency departments (EDs) worldwide with a wide range of symptoms. In this study we reported the clinical, laboratory and radiological features of the cases diagnosed with COVID-19. METHODS: This is a single-center, retrospective, descriptive, and observational study. The patients who have admitted to ED between March 11 and May 31, 2020 and diagnosed COVID-19 infection. RESULTS: 130 (73 male and 57 female) patients with COVID-19 polymerase chain reaction (PCR) positive test were included in the study. The average age of the study group was calculated as 52.63 ± 17.95 year. While 15.4% of the patients were asymptomatic, the most common symptom was identified as cough (46.2%), followed by dyspnea (23.1%), fever (17.7%). The computed tomography (CT) severity scores proved significantly higher in the patients with hypertension and coronary artery disease (CAD) than in those without these diseases (p = 0.010 and p = 0.042, respectively). The moderate positive correlation between serum ferritin level and CT severity score is another finding worth noting (rho = 0.530 and p = 0.0001). In a similar vein, the high level of D-dimer in the CT-positive group and its positive moderate correlation with CT severity (rho = 0.375 and p = 0.0001). CONCLUSION: In our study, serum ferritin and D-dimer levels were observed to be high in the CT-positive group and have moderate positive correlation with CT severity. We thus argue that D-dimer and ferritin levels measured at the time of admission to the ED can be taken into consideration to predict radiological severity.

High GRP78 levels in Covid-19 infection: A case-control study.

INTRODUCTION: Covid-19 infection was declared a global pandemic by WHO on March 11, 2020. GRP78 protein is known to be involved in the intrusion of numerous viruses. Our current study tries to provide some insight into the variation of GRP78 protein levels in patients with Covid-19 (-) pneumonia, Covid-19 (+) pneumonia, and CT negative Covid-19 infection in comparison to the normal population through a larger number of cases. MATERIALS AND METHODS: 42 patients who have Covid-19 (-) pneumonia; 72 patients who have Covid-19 infection (30 pneumonia,42 CT negative patients) and 30 patient who have no known diseases (control group) have included in the study after the clinical and radiological evaluation. Serum GRP78 levels of the subjects were measured through a commercially available enzyme-linked immunosorbent assay (ELISA) kit. RESULTS: The GRP78 level was found to be significantly higher in the Covid-19 infection group than both Covid-19 (-) pneumonia and control group (p = 0.031 and p = 0.0001, respectively).No significant difference was evident between Covid-19 (-) pneumonia, Covid-19 (+) pneumonia and CT negative Covid 19 infection groups with respect to GRP78 levels (p = 0.09). In addition, the GRP78 levels were significantly higher in the Covid-19 (-) pneumonia group than the control group (p = 0.0001). CONCLUSION: This prospective case-control study reveals that the serum GRP78 levels significantly increased during Covid-19 infection in comparison to both the Covid-19 (-) pneumonia and the control group. As the association between SARS-CoV-2 virus and GRP78 protein is revealed more clearly, this association may come to the fore as a therapeutic target.

Preliminary Virtual Screening Studies to Identify GRP78 Inhibitors Which May Interfere with SARS-CoV-2 Infection.

SARS-CoV-2 Spike protein was predicted by molecular docking to bind the host cell surface GRP78, which was suggested as a putative good molecular target to inhibit Covid-19. We aimed to confirm that GRP78 gene expression was increased in blood of SARS-CoV-2 (+) versus SARS-CoV-2 (-) pneumonia patients. In addition, we aimed to identify drugs that could be repurposed to inhibit GRP78, thus with potential anti-SARS-CoV-2 activity. Gene expression studies were performed in 10 SARS-CoV-2 (-) and 24 SARS-CoV-2 (+) pneumonia patients. A structure-based virtual screen was performed with 10,761 small molecules retrieved from DrugBank, using the GRP78 nucleotide binding domain and substrate binding domain as molecular targets. Results indicated that GRP78 mRNA levels were approximately four times higher in the blood of SARS-CoV-2 (+) versus SARS-CoV-2 (-) pneumonia patients, further suggesting that GRP78 might be a good molecular target to treat Covid-19. In addition, a total of 409 compounds were identified with potential as GRP78 inhibitors. In conclusion, we found preliminary evidence that further proposes GRP78 as a possible molecular target to treat Covid-19 and that many clinically approved drugs bind GRP78 as an off-target effect. We suggest that further work should be urgently carried out to confirm if GRP78 is indeed a good molecular target and if some of those drugs have potential to be repurposed for SARS-CoV-2 antiviral activity.

Endoplasmic Reticulum Stress Markers in SARS-COV-2 Infection and Pneumonia: Case-Control Study.

BACKGROUND/AIM: A novel human coronavirus, named SARS-COV-2, has recently caused thousands of deaths all around the world. Endoplasmic reticulum (ER) stress plays an important role in the development of diseases. PATIENTS AND METHODS: We aimed to to investigate the relationship between ER stress markers in patients infected with SARS-COV-2 and patients with pneumonia. A total of 9 patients (4 patients diagnosed with pneumonia and 5 patients diagnosed with SARS-COV-2 infection) who admitted to the emergency Department with symptoms of pneumonia and SARS-COV-2 were included in the study. A total of 18 healthy individuals without any known chronic or acute disease and drug use were included as the healthy control group. Serum human glucose regulated protein 78 (GRP78), serum human C/EBP homologous protein (CHOP) and serum human phospho extracellular signal regulated kinase (PERK) levels were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: GRP78 levels were found to be significantly higher in SARS-COV-2 positive cases compared to individuals in other groups. Serum GRP-78 level median value was statistically significantly higher in SARS-COV-2-positive group compared to the other groups (p=0.0003). Serum PERK level was statistically significantly higher in SARS-COV-2-positive pneumonia cases (p=0.046). CONCLUSION: An association was shown between GRP78 and SARS-COV-2 infection. Although a small number of patients was investigated, these results will be important and guide future treatments of SARS-COV-2.