Influenza A virus causes annual epidemics and occasional pandemics in humans. Here, we investigated four members of the fibroblast growth factor receptor (FGFR) family; FGFR1 to 4, and examined their ...expression patterns in human lung epithelial cells A549 with influenza A virus infection. We identified a functional role of FGFR1 in influenza A/Puerto Rico/8/1934 (PR8) and A/Anhui/01/2005 (H5N1) virus replication. Our results showed that FGFR1 silencing by siRNA interference promoted influenza A/PR8 and H5N1 virus replication in A549 cells, while lentivirus-mediated exogenous FGFR1 expression significantly suppressed influenza A virus replication; however, FGFR4 did not have the same effects. Moreover, FGFR1 phosphorylation levels were downregulated in A549 cells by influenza A virus infection, while the repression of FGFR1 kinase using PD173074, a potent and selective FGFR1 inhibitor, could enhance virus replication. Furthermore, we found that FGFR1 inhibits influenza virus internalization, but not binding, during viral entry. These results suggested that FGFR1 specifically antagonizes influenza A virus replication, probably by blocking viral entry.
The 2009 influenza pandemic affected people in almost all countries in the world, especially in younger age groups. During this time, the debate over whether to use corticosteroid treatment in severe ...influenza H1N1 infections patients resurfaced and was disputed by clinicians. There is an urgent need for a susceptible animal model of 2009 H1N1 infection that can be used to evaluate the pathogenesis and the therapeutic effect of corticosteroid treatment during infection.
We intranasally inoculated two groups of C57BL/6 and BALB/c mice (using 4- or 6-to 8-week-old mice) to compare the pathogenesis of several different H1N1 strains in mice of different ages. Based on the results, a very susceptible 4-week-old C57BL/6 mouse model of Beijing 501 strain of 2009 H1N1 virus infection was established, showing significantly elevated lung edema and cytokine levels compared to controls. Using our established animal model, the cytokine production profile and lung histology were assessed at different times post-infection, revealing increased lung lesions in a time-dependent manner. In additional,the mice were also treated with dexamethasone, which significantly improved survival rate and lung lesions in infected mice compared to those in control mice. Our data showed that corticosteroid treatment ameliorated acute lung injury induced by the 2009 A/H1N1 virus in mice and suggested that corticosteroids are valid drugs for treating 2009 A/H1N1 infection.
Using the established, very susceptible 2009 Pandemic Influenza A (H1N1) mouse model, our studies indicate that corticosteroids are a potential therapeutic remedy that may address the increasing concerns over future 2009 A/H1N1 pandemics.
Liver transplantation (LT) is the standard therapy for individuals afflicted with end-stage liver disease. Despite notable advancements in LT technology, the incidence of early allograft dysfunction ...(EAD) remains a critical concern, exacerbating the current organ shortage and detrimentally affecting the prognosis of recipients. Unfortunately, the perplexing hepatic heterogeneity has impeded characterization of the cellular traits and molecular events that contribute to EAD. Herein, we constructed a pioneering single-cell transcriptomic landscape of human transplanted livers derived from non-EAD and EAD patients, with 12 liver samples collected from 7 donors during the cold perfusion and portal reperfusion stages. Comparison of the 75 231 cells of non-EAD and EAD patients revealed an EAD-associated immune niche comprising mucosal-associated invariant T cells, granzyme B+ (GZMB+) granzyme K+ (GZMK+) natural killer cells, and S100 calcium binding protein A12+ (S100A12+) neutrophils. Moreover, we verified this immune niche and its association with EAD occurrence in two independent cohorts. Our findings elucidate the cellular characteristics of transplanted livers and the EAD-associated pathogenic immune niche at the single-cell level, thus, offering valuable insights into EAD onset.
Panax ginseng (PG) and Panax notoginseng (PN) are highly valuable Chinese medicines (CM). Although both CMs have similar active constituents, their clinical applications are clearly different. Over ...the past decade, RNA sequencing (RNA-seq) analysis has been employed to investigate the molecular mechanisms of extracts or monomers. However, owing to the limited number of samples in standard RNA-seq, few studies have systematically compared the effects of PG and PN spanning multiple conditions at the transcriptomic level. Here, we developed an approach that simultaneously profiles transcriptome changes for multiplexed samples using RNA-seq (TCM-seq), a high-throughput, low-cost workflow to molecularly evaluate CM perturbations. A species-mixing experiment was conducted to illustrate the accuracy of sample multiplexing in TCM-seq. Transcriptomes from repeated samples were used to verify the robustness of TCM-seq. We then focused on the primary active components, Panax notoginseng saponins (PNS) and Panax ginseng saponins (PGS) extracted from PN and PG, respectively. We also characterized the transcriptome changes of 10 cell lines, treated with four different doses of PNS and PGS, using TCM-seq to compare the differences in their perturbing effects on genes, functional pathways, gene modules, and molecular networks. The results of transcriptional data analysis showed that the transcriptional patterns of various cell lines were significantly distinct. PGS exhibited a stronger regulatory effect on genes involved in cardiovascular disease, whereas PNS resulted in a greater coagulation effect on vascular endothelial cells. This study proposes a paradigm to comprehensively explore the differences in mechanisms of action between CMs based on transcriptome readouts.
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•A low-cost workflow of high-throughput transcriptional profiling was developed.•The atlas of signatures perturbed by PGS and PNS was established using TCM-seq.•The regulation of PGS and PNS was holistically compared with network analysis.•A paradigm of molecularly evaluating CMs with transcriptome readouts was proposed.
To evaluate the causes and risk factors of unplanned surgery after transcatheter closure of ventricular septal defect (VSD) in children.
A total of 773 patients with VSD who had the devices ...transcatheter released between January 2013 and December 2018 in our institution were retrospectively reviewed. Univariate and multivariate analyses were used to identify the risk factors for unplanned surgery.
Twenty four patients (3.1%) underwent unplanned surgery after transcatheter closure of VSD. The most common cause for unplanned surgery was new-onset or worsening aortic regurgitation (14/24; 58.3%), followed by occluder migration (4/24; 16.7%), complete atrioventricular block (2/24; 8.3%), severe hemolysis (2/24; 8.3%), residual shunt (1/24; 4.2%), and occluder edge near the tricuspid valve chordae (1/24; 4.2%). Logistic regression analysis revealed that primary aortic valve prolapse (OR: 5.507, 95%CI: 1.673-18.123,
= 0.005); intracristal VSD (OR: 8.731, 95%CI: 2.274-33.527,
= 0.002); eccentric occluder (OR: 4.191, 95%CI: 1.233-14.246,
= 0.022); larger occluder size (OR: 1.645, 95%CI: 1.331-2.033,
< 0.001); and pulmonary artery systolic pressure ≥45 mmHg (OR: 4.003, 95%CI: 1.073-14.941,
= 0.039) were risk factors for unplanned surgery.
New-onset or worsening aortic regurgitation was the primary cause for unplanned surgery after transcatheter closure of VSD in children. Primary aortic valve prolapse, intracristal VSD, eccentric occluder, larger occluder size, pulmonary artery systolic pressure ≥45 mmHg could increase the risk of unplanned surgery.
Acetylation and deacetylation of histones are important in regulating gene expression and play a key role in modification of gene transcription. Specific HDACs isoforms can be regarded as a target ...for cancer therapy avoiding side-effects, HDAC6 with a unique physiological function and structure has become a hot issue recently. The unique isoform HDAC6 is involved in tumorigenesis, development and metastasis through tubulin, HSP90, invasin and ubiquitin-protein. Here we review the structure elements, biological function, and recent selective inhibitors of HDAC6, and study the structure-activity and structureselectivity relationship.
Background:
Arrhythmia is the most common complication after transcatheter closure of a ventricular septal defect (VSD). However, the effects of postprocedural left anterior fascicular block are not ...clear. This study presents the clinical characteristics, prognosis, and related risk factors of left anterior fascicular block after transcatheter closure of a VSD in children.
Methods:
The clinical and follow-up data of the patients in the Heart Center of Children's Hospital of Chongqing Medical University from June 2009 to October 2018 were reviewed. And 30 cases were eligible out of all 1,371 cases.
Results:
An electrocardiogram showed a left anterior fascicular block within 3 days, and most patients gradually returned to normal within 1–2 years, showing a dynamic change. Left ventricular end-diastolic dimension
Z
-score ranged from −2 to 2 in all children, and no decrease of left ventricular ejection fraction was found in all children. The high ratio between VSD size and body surface area
p
< 0.05, odds ratio (OR) 2.6, 95% CI: 1.136–6.113 and large diameter difference between the occluder size and VSD size (
p
< 0.05, OR 2.1, 95% CI: 1.036–4.609) were independent risk factors for postprocedural left anterior fascicular block.
Conclusions:
The incidence of postprocedural left anterior fascicular block is not that low, and the overall prognosis is quite good at the current follow-up stage. No progressive severity has been found, such as complete left bundle branch block, double (triple) bundle branch block, and atrioventricular block, to have an influence on cardiac systolic and diastolic function.
IntroductionIdiopathic pulmonary fibrosis is a progressive fibrotic lung disease with limited therapeutic options and high lethality, related to alveolar type II epithelial (ATII) cell dysregulation, ...the abnormal repair of alveolar epithelial cells and activation of fibroblasts promote the development of pulmonary fibrosis. Fatty acid binding protein 1 (FABP1) was significantly downregulated in the fibrotic state by proteomics screening in our previous date, and the ATII cell dysregulation can be mediated by FABP1 via regulating fatty acid metabolism and intracellular transport. The aim of this study was to evaluate the role and potential mechanism of FABP1 in the development of pulmonary fibrosis.MethodsProteomics screening was used to detect changes of the protein profiles in two different types (induced by bleomycin and silica, respectively) of pulmonary fibrosis models. The localisation of FABP1 in mouse lung was detected by Immunofluorescence and immunohistochemistry. Experimental methods such as lung pathology, micro-CT, western blotting, small animal imaging in vivo, EdU, etc were used to verify the role of FABP1 in pulmonary fibrosis.ResultsThe expression of FABP1 in the mouse lung was significantly reduced in the model of pulmonary fibrosis from our proteomic analysis and immunological methods, the double immunofluorescence staining showed that FABP1 was mainly localised in type II alveolar epithelial cells. Additionally, the expression of FABP1 was negatively correlated with the progression of pulmonary fibrosis. Further in vivo and in vitro experiments showed that overexpression of FABP1 alleviated pulmonary fibrosis by protecting alveolar epithelium from injury and promoting cell survival.ConclusionOur findings provide a proof-of-principle that FABP1 may represent an effective treatment for pulmonary fibrosis by regulating alveolar epithelial regeneration, which may be associated with the fatty acid metabolism in ATII cells.
Disabilities triggered by neurodegeneration mainly result in mortality in the elderly, and patients with neurodegenerative disease also display deficits in olfactory function. Therefore drug ...distribution to the brain through intranasal administration has become one of the most difficult challenges in the treatment of central nervous system (CNS) diseases. TAT-human acidic fibroblast growth factor (HaFGF) is a new fused protein retaining the neuroprotective activities of HaFGF, and is a promising prospect in the treatment of neurodegenerative diseases. TAT (a cell-penetrating peptide) contains a high relative abundance of positively charged amino acids such as lysine and arginine, which have a powerful attraction to the negatively charge on the nasal epithelial membrane. The present study focused on the evaluation of the safety and absorption characteristics of TAT-HaFGF following intranasal administration. After TAT-HaFGF intranasal administration (100, 300, 600 µg/kg) for 5 weeks, hematoxylin–eosin (HE) staining showed no pathology in any of the investigated tissues and organs. The expression of olfactory marker protein (OMP) was observed with immunohistochemical staining, which showed no altered expression in the sensory neurons of the nasal epithelium. Nasal ciliotoxicity studies carried out using an in situ palate model and optical microscope showed that TAT-HaFGF had no nasal ciliotoxicity. The distribution of the TAT-HaFGF following intranasal administration was assessed using a radioisotopic tracing method. Radioactivity was observed in the brain after 15 min. This became stronger at 30 min and weaker at 1 h. All of the results confirmed the in vivo safety of TAT-HaFGF via intranasal administration.
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