Repurposing niclosamide as a novel anti-SARS-Cov-2 drug by restricting entry protein CD147.

Background The burst of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing the global COVID-19 pandemic. But until today only limited numbers of drugs are discovered to treat COVID-19 patients. Even worse, the rapid mutations of SARS-CoV-2 compromise the effectiveness of existing vaccines and neutralizing antibodies due to the increased viral transmissibility and immune escape. CD147-spike protein, one of the entries of SRAR-CoV-2 into host cells, has been reported as a promising therapeutic target for developing drugs against COVID-19. Methods CRISPR-Cas9 induced gene knockout, western blotting, tet-off protein overexpression, ribonucleoprotein IP and RNA-IP were used to confirm the regulation of HuR on mRNA of CD147. Regulation of niclosamide on HuR nucleo-translocation was assessed by immunofluorescence staining of cell lines, IHC staining of tissue of mouse model and western blotting. Finally, the suppression of niclosamide on SARS-CoV-2 infection induced CD147 was evaluated by ACE2-expressing A549 cells and western blotting. Results We first discovered a novel regulation mechanism of CD147 via the RNA-binding protein HuR. We found that HuR regulates CD147 post-transcription by directly bound to its 3'-UTR. The loss of HuR reduced CD147 in multiple cell lines. Niclosamide inhibited CD147 function by blocking HuR cytoplasmic translocation and diminishing CD147 glycosylation. SARS-CoV-2 infection induced CD147 in ACE2-expressing A549 cells, which could be neutralized by niclosamide in a dose-dependent manner. Conclusion Together, our study reveals a novel regulation mechanism of CD147 and niclosamide can be repurposed as an effective COVID-19 drug by targeting the virus entry, CD147-spike protein.

Network Pharmacology and Bioinformatics Analysis Identifies Potential Therapeutic Targets of Paxlovid Against LUAD/COVID-19.

Background: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a pandemic in many countries around the world. The virus is highly contagious and has a high fatality rate. Lung adenocarcinoma (LUAD) patients may have higher susceptibility and mortality to COVID-19. While Paxlovid is the first oral drug approved by the U.S. Food and Drug Administration (FDA) for COVID-19, its specific drug mechanism for lung cancer patients infected with COVID-19 remains to be further studied. Methods: COVID-19 related genes were obtained from NCBI, GeneCards, and KEGG, and then the transcriptome data for LUAD was downloaded from TCGA. The drug targets of Paxlovid were revealed through BATMAN-TCM, DrugBank, SwissTargetPrediction, and TargetNet. The genes related to susceptibility to COVID-19 in LUAD patients were obtained through differential analysis. The interaction of LUAD/COVID-19 related genes was evaluated and displayed by STRING, and a COX risk regression model was established to screen and evaluate the correlation between genes and clinical characteristics. The Venn diagram was drawn to select the candidate targets of Paxlovid against LUAD/COVID-19, and the functional analysis of the target genes was performed using KEGG and GO enrichment analysis. Finally, Cytoscape was used to screen and visualize the Hub Gene, and Autodock was used for molecular docking between the drug and the target. Result: Bioinformatics analysis was performed by combining COVID-19-related genes with the gene expression and clinical data of LUAD, including analysis of prognosis-related genes, survival rate, and hub genes screened out by the prognosis model. The key targets of Paxlovid against LUAD/COVID-19 were obtained through network pharmacology, the most important targets include IL6, IL12B, LBP. Furthermore, pathway analysis showed that Paxlovid modulates the IL-17 signaling pathway, the cytokine-cytokine receptor interaction, during LUAD/COVID-19 treatment. Conclusions: Based on bioinformatics and network pharmacology, the prognostic signature of LUAD/COVID-19 patients was screened. And identified the potential therapeutic targets and molecular pathways of Paxlovid Paxlovid in the treatment of LUAD/COVID. As promising features, prognostic signatures and therapeutic targets shed light on improving the personalized management of patients with LUAD.

Network Pharmacology and Bioinformatics Analysis Identifies Potential Therapeutic Targets of Paxlovid Against LUAD/COVID-19

Background Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a pandemic in many countries around the world. The virus is highly contagious and has a high fatality rate. Lung adenocarcinoma (LUAD) patients may have higher susceptibility and mortality to COVID-19. While Paxlovid is the first oral drug approved by the U.S. Food and Drug Administration (FDA) for COVID-19, its specific drug mechanism for lung cancer patients infected with COVID-19 remains to be further studied. Methods COVID-19 related genes were obtained from NCBI, GeneCards, and KEGG, and then the transcriptome data for LUAD was downloaded from TCGA. The drug targets of Paxlovid were revealed through BATMAN-TCM, DrugBank, SwissTargetPrediction, and TargetNet. The genes related to susceptibility to COVID-19 in LUAD patients were obtained through differential analysis. The interaction of LUAD/COVID-19 related genes was evaluated and displayed by STRING, and a COX risk regression model was established to screen and evaluate the correlation between genes and clinical characteristics. The Venn diagram was drawn to select the candidate targets of Paxlovid against LUAD/COVID-19, and the functional analysis of the target genes was performed using KEGG and GO enrichment analysis. Finally, Cytoscape was used to screen and visualize the Hub Gene, and Autodock was used for molecular docking between the drug and the target. Result Bioinformatics analysis was performed by combining COVID-19-related genes with the gene expression and clinical data of LUAD, including analysis of prognosis-related genes, survival rate, and hub genes screened out by the prognosis model. The key targets of Paxlovid against LUAD/COVID-19 were obtained through network pharmacology, the most important targets include IL6, IL12B, LBP. Furthermore, pathway analysis showed that Paxlovid modulates the IL-17 signaling pathway, the cytokine-cytokine receptor interaction, during LUAD/COVID-19 treatment. Conclusions Based on bioinformatics and network pharmacology, the prognostic signature of LUAD/COVID-19 patients was screened. And identified the potential therapeutic targets and molecular pathways of Paxlovid Paxlovid in the treatment of LUAD/COVID. As promising features, prognostic signatures and therapeutic targets shed light on improving the personalized management of patients with LUAD.

Vaccination and Government Stringent Control as Effective Strategies in Preventing SARS-CoV-2 Infections: A Global Perspective.

With the rapid implementation of global vaccination against the coronavirus disease 2019 (COVID-19), the threat posed by the disease has been mitigated, yet it remains a major global public health concern. Few studies have estimated the effects of vaccination and government stringent control measures on the disease transmission from a global perspective. To address this, we collected 216 countries' data on COVID-19 daily reported cases, daily vaccinations, daily government stringency indexes (GSIs), and the human development index (HDI) from the dataset of the World Health Organization (WHO) and the Our World in Data COVID-19 (OWID). We utilized the interrupted time series (ITS) model to examine how the incidence was affected by the vaccination and GSI at continental and country levels from 22 January 2020 to 13 February 2022. We found that the effectiveness of vaccination was better in Europe, North America, and Africa than in Asia, South America, and Oceania. The long-term effects outperformed the short-term effects in most cases. Countries with a high HDI usually had a high vaccination coverage, resulting in better vaccination effects. Nonetheless, some countries with high vaccination coverage did not receive a relatively low incidence due to the weaker GSI. The results suggest that in addition to increasing population vaccination coverage, it is crucial to maintain a certain level of government stringent measures to prevent and control the disease. The strategy is particularly appropriate for countries with low vaccination coverage at present.

Single-Layer-Graphene-Coated and Gold-Film-Based Surface Plasmon Resonance Prism Coupler Sensor for Immunoglobulin G Detection.

A graphene-based surface plasmon resonance (SPR) prism coupler sensor is proposed for the rapid detection of immunoglobulin G (IgG) antibodies. The feasibility of the proposed sensor is demonstrated by measuring the IgG concentration in phantom mouse and human serum solutions over the range of 0-250 ng/mL. The results show that the circular dichroism and principal fast axis angle of linear birefringence increase in line with increases in IgG concentration over the considered range. Moreover, the proposed device has a resolution of 5-10 ng/mL and a response time of less than three minutes. In general, the sensor provides a promising approach for IgG detection and has significant potential for rapid infectious viral disease testing applications.

Indicators and prediction models for the severity of Covid-19.

OBJECTIVES: Coronavirus disease 2019 (Covid-19) is outbreaking globally. We aimed to analyse the clinical characteristics, cardiac injury, electrocardiogram and computed tomography (CT) features of patients confirmed Covid-19 and explored the prediction models for the severity of Covid-19. METHODS: A retrospective and single-centre study enrolled 98 laboratory-confirmed Covid-19 patients. Clinical data, electrocardiogram and CT features were collected and analysed using Statistical Package for the Social Sciences software. RESULTS: There were 46 males and 52 females, with a median age of 44 years, categorised into three groups, including mild, moderate and severe/critical Covid-19. The rate of abnormal electrocardiograms in severe/critical group (79%) was significantly higher than that in the mild group (17%) (P = .027), which (r = 0.392, P = .005) positively related to the severity of Covid-19 (OR: 5.71, 95% CI: 0.45-3.04, P = .008). Age older than 60 years old, comorbidities, whether had symptoms on admission, fatigue, CT features, laboratory test results such as platelet count, lymphocyte cell count, eosinophil cell count, CD3+ cell count, CD4+ cell count, CD8+ cell count, the ratio of albumin/globulin decreased and D-dimer, C-reactive protein (CRP), B-type natriuretic peptide (BNP), cardiac troponin I (cTnI) elevated were the risk factors for the increased severity of Covid-19. The logistic model, adjusted by age, lobular involvement score and lymphocyte cell count, could be applied for assessing the severity of Covid-19 (AUC, 0.903; Sensitivity, 90.9%; Specificity, 78.1%). CONCLUSIONS: Age >60 years old, chronic comorbidities, lymphocytopoenia and lobular involvement score were associated with the Covid-19 severity. The inflammation induced by Covid-19 caused myocardial injury with elevated BNP and cTnI level and abnormal electrocardiograms.

Health-Related Quality of Life and Influencing Factors of Pediatric Medical Staff During the COVID-19 Outbreak.

Objective: To evaluate the health-related quality of life (HRQoL) status and explore its associated factors in pediatric medical staff during the COVID-19 epidemic so as to provide fundamental evidence for clinicians and administrators to formulate targeted intervention measures to improve the HRQoL and mental health status in pediatric medical staff during this, and future pandemics. Methods: A cross-sectional study was conducted to investigate the HRQoL of pediatric medical staff. Univariable and multivariable logistic regression were used to analyze the associated factors. Results: A total of 2,997 participants were recruited. Females scored worse than males in terms of emotional functioning (OR = 1.6, 95% CI: 1.2-2.1) and cognitive functioning (OR = 1.4, 95% CI: 1.1-1.8). The respondents aged 30-39 and 40-49 years scored worse in nearly all domains of HRQoL compared health care professionals under 30 years old. Respondents with high education had lower scores in physical functioning (OR = 1.3, 95% CI: 1.0-1.7) and emotional functioning (OR = 1.5, 95% CI: 1.2-1.9). Compared with doctors, nurses had higher scores in all domains except for summary score and worry. The respondents whose working places had not set up pediatric fever clinics and isolated observation areas independently had lower scores in all domains except for worry. The respondents who had ever treated patients with COVID-19 had lower scores in all domains. Conclusion: During the COVID-19 outbreak, the HRQoL of pediatric medical staff decreased. The factors associated with HRQoL can be used to develop intervention to improve HRQoL in pediatric medical staff.

An investigation for airflow and deposition of PM2.5 contaminated with SAR-CoV-2 virus in healthy and diseased human airway.

This study is motivated by the amplified transmission rates of the SAR-CoV-2 virus in areas with high concentrations of fine particulates (PM2.5) as reported in northern Italy and Mexico. To develop a deeper understanding of the contribution of PM2.5 in the propagation of the SAR-CoV-2 virus in the population, the deposition patterns and efficiencies (DEs) of PM2.5 laced with the virus in healthy and asthmatic airways are studied. Physiologically correct 3-D models for generations 10-12 of the human airways are applied to carry out a numerical analysis of two-phase flow for full breathing cycles. Two concentrations of PM2.5 are applied for the simulation, i.e., 30 µg⋅m-3 and 80 µg⋅m-3 for three breathing statuses, i.e., rest, light exercise, and moderate activity. All the PM2.5 injected into the control volume is assumed to be 100% contaminated with the SAR-CoV-2 virus. Skewed air-flow phenomena at the bifurcations are proportional to the Reynolds number at the inlet, and their intensity in the asthmatic airway exceeded that of the healthy one. Upon exhalation, two peak air-flow vectors from daughter branches combine to form one big vector in the parent generation. Asthmatic airway models has higher deposition efficiencies (DEs) for contaminated PM2.5 as compared to the healthy one. Higher DEs arise in the asthmatic airway model due to complex secondary flows which increase the impaction of contaminated PM2.5 on airways' walls.

Structural analysis, virtual screening and molecular simulation to identify potential inhibitors targeting 2'-O-ribose methyltransferase of SARS-CoV-2 coronavirus.

SARS-CoV-2, an emerging coronavirus, has spread rapidly around the world, resulting in over ten million cases and more than half a million deaths as of July 1, 2020. Effective treatments and vaccines for SARS-CoV-2 infection do not currently exist. Previous studies demonstrated that nonstructural protein 16 (nsp16) of coronavirus is an S-adenosyl methionine (SAM)-dependent 2'-O-methyltransferase (2'-O-MTase) that has an important role in viral replication and prevents recognition by the host innate immune system. In the present study, we employed structural analysis, virtual screening, and molecular simulation approaches to identify clinically investigated and approved drugs which can act as promising inhibitors against nsp16 2'-O-MTase of SARS-CoV-2. Comparative analysis of primary amino acid sequences and crystal structures of seven human CoVs defined the key residues for nsp16 2-O'-MTase functions. Virtual screening and docking analysis ranked the potential inhibitors of nsp16 from more than 4,500 clinically investigated and approved drugs. Furthermore, molecular dynamics simulations were carried out on eight top candidates, including Hesperidin, Rimegepant, Gs-9667, and Sonedenoson, to calculate various structural parameters and understand the dynamic behavior of the drug-protein complexes. Our studies provided the foundation to further test and repurpose these candidate drugs experimentally and/or clinically for COVID-19 treatment.Communicated by Ramaswamy H. Sarma.