Search

Abstract Repurposing existing drugs to inhibit SARS-CoV-2 infection in airway epithelial cells (AECs) is a quick way to find novel treatments for COVID-19. Computational screening has found dicoumarol (DCM), a natural anticoagulant, to be a potential SARS-CoV-2 inhibitor, but its inhibitory effects and possible working mechanisms remain unknown. Using air-liquid interface culture of primary human AECs, we demonstrated that DCM has potent antiviral activity against the infection of multiple Omicron variants (including BA.1, BQ.1 and XBB.1). Time-of-addition and drug withdrawal assays revealed that early treatment (continuously incubated after viral absorption) of DCM could markedly inhibit Omicron replication in AECs, but DCM did not affect the absorption, exocytosis and spread of viruses or directly eliminate viruses. Mechanistically, we performed single-cell sequencing analysis (a database of 77,969 cells from different airway locations from 10 healthy volunteers) and immunofluorescence staining, and showed that the expression of NAD(P)H quinone oxidoreductase 1 (NQO1), one of the known DCM targets, was predominantly localised in ciliated AECs. We further found that the NQO1 expression level was positively correlated with both the disease severity of COVID-19 patients and virus copy levels in cultured AECs. In addition, DCM treatment downregulated NQO1 expression and disrupted signalling pathways associated with SARS-CoV-2 disease outcomes (e.g., Endocytosis and COVID-19 signalling pathways) in cultured AECs. Collectively, we demonstrated that DCM is an effective post-exposure prophylactic for SARS-CoV-2 infection in the human AECs, and these findings could help physicians formulate novel treatment strategies for COVID-19.

ObjectiveTo investigate the prevalence and affecting factors of overweight/obesity among urban and rural residents aged 18 – 44 years in Fujian province and to provide evidences for developing relevant intervention strategies.Methods Using stratified random cluster sampling, we recruited 6 638 permanent residents at ages of 18 – 44 years in 25 urban communities and rural villages of 5 county/district-level regions located in coastal areas of Fujian province and conducted a questionnaire survey and physical examination among the residents from July 2018 through April 2019.ResultsOf the 6 150 residents with complete information, 1 317 (21.41%) and 455 (7.40%) were identified with overweight and obesity. Among the overweight/obesity sufferers, the prevalence rate of hypertension (5.64%), diabetes (1.91%) and hyperlipidemias (1.81%) were significantly higher than those among the residents without overweight/obesity (all P < 0.05). The results of unconditional logistic regression analysis revealed that significant risk factors of overweight/obesity included at an elder age (35 – 44 vs. 18 – 24: odds ratio [OR]=1.775, 95% confidence interval [CI]: 1.457 – 2.161), with lower education (junior high school vs. senior high school and above: OR = 1.468, 95% CI: 1.222 – 1.763; primary school or illiteracy vs. senior high school and above: OR = 1.228, 95% CI: 1.084 – 1.391), being married (OR = 1.479, 95% CI: 1.244 – 1.758), and frequent alcohol consumption (2 – 3 times/week vs. ≤ once/week: OR = 1.789, 95% CI: 1.547 – 2.068; 4 times and more/week vs. ≤ once/week: OR = 1.678, 95% CI: 1.336 – 2.108); while female gender (OR = 0.470, 95% CI: 0.416 – 0.531) was a protective factor against overweight/obesity.Conclusion The prevalence rate of overweight/obesity are relatively low and influenced significantly by gender, age, marital status, education and alcohol drinking among 18 to 44 years old permanent residents in coastal areas of Fujian province.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease attributed to the complex interplay of genetic and environmental risks. The muco-ciliary clearance (MCC) system plays a critical role in maintaining the conduit for air to and from the alveoli, but it remains poorly understood whether the MCC abnormalities in conducting airway are involved in IPF pathogenesis. In this study, we obtained the surgically resected bronchi and peripheral lung tissues from 31 IPF patients and 39 control subjects, and we sought to explore the morphologic characteristics of MCC in conducting airway by using immunostaining and scanning and transmission electron microscopy. In the submucosal regions of the bronchi, we found that the areas of mucus glands (MUC5B+) were significantly larger in IPF patients as compared with control subjects (p

After the first outbreak in China in 2006, human adenovirus type 55 (HAdV-B55) has become a common pathogen causing life threatening pneumonia in northern China. However, HAdV-B55 infection has been rarely reported in southern China. Here, we collected throat swabs from 3,192 hospitalized children with acute respiratory disease (ARD) from May 2017 to April 2019 in Guangzhou, southern China, tested them for HAdV-B55 infection. Only one of 1,399 patients from May 2017 to April 2018 was HAdV-B55 positive; HAdV-B55 infections significantly increased with 10 of 1,792 patients testing positive since May 2018. HAdV-B55-267, isolated from a case of death, was sequenced for whole genomic analysis. Three other strains, HAdV-B55-Y16, -TY12, and -TY26, isolated earlier in patients from Shanxi, northern China, were also sequenced and analyzed. The four HAdV-B55 strains formed similar plaques, grew to similar titers, and resulted in similar typical cell pathogenic effects. HAdV-B55-267 formed a subclade with the prototype strain QS-DLL; strains HAdV-B55-Y16, -TY12, and -TY26 were closely related to strain QZ01. HAdV-B55 could be divided into two subtypes (HAdV-B55-a and -b) according to the presence or absence of the insertion of “CCATATCCGTGTT”; all strains isolated from China except for strain BJ01 belong to subtype b. HAdV-B55-267 had only one non-synonymous substitution comparing with strain QS-DLL, and all HAdV-B55 strains had highly conserved capsid proteins and few non-synonymous substitutions. This study suggests that HAdV-B55 is an important pathogen associated with ARD in Guangzhou since 2018, exhibiting the relative genome stability across time and geographic space in China.

Dilation of bronchi and bronchioles caused by destruction and excessive epithelial remodeling is a characteristic feature of bronchiectasis. It is not known how epithelial progenitor cells contribute to these pathologic conditions in peripheral airways (bronchioles) in bronchiectasis. We aimed to explore the expression levels of signature airway progenitor cells in the dilated bronchioles in patients with bronchiectasis. We obtained the surgically resected peripheral lung tissues from 43 patients with bronchiectasis and 33 control subjects. Immunostaining was performed to determine the expression patterns of thyroid transcription factor-1 (TTF-1, for labeling progenitor cells in distal airways), P63 (basal cells), club cell 10 kDa protein (CC10, club cells), and surfactant protein C (SPC, alveolar type II epithelial cells) in epithelium or sub-epithelium. Here, we reported significantly lower percentage of TTF-1+ cells and CC10+ cells, and higher percentage of P63+ cells within the epithelium of dilated bronchioles compared with control bronchioles. In airway sub-epithelium of the dilated bronchioles, epithelial hyperplasia with disarrangement of TTF-1+ cells yielded cuboidal (100%) and columnar (93.0%) type among bronchiectasis patients. Most progenitor cell markers co-localized with TTF-1. The median (the 1st, 3rd quartile) percentage of P63+TTF-1+, CC10+TTF-1+, and SPC+TTF-1+ cells was 16.0% (8.9, 24.0%), 14.5% (7.1, 20.8%), and 52% (40.3, 64.4%), respectively. For cuboidal epithelial hyperplasia, 91.0% (86.5, 94.0%) of areas co-stained with SPC and TTF-1. Columnar epithelial hyperplasia was characterized by TTF-1 co-staining with P63+TTF-1+ and CC10+TTF-1+ cells. Taken together, aberrant proliferation of airway progenitor cells in both epithelium and sub-epithelium are implicated in bronchiectasis.