Drugs targeting CMPK2 inhibit pyroptosis to alleviate severe pneumonia caused by multiple respiratory viruses.

Severe pneumonia caused by respiratory viruses has become a major threat to humans, especially with the SARS-CoV-2 outbreak and epidemic. The aim of this study was to investigate the universal molecular mechanism of severe pneumonia induced by multiple respiratory viruses and to search for therapeutic strategies targeting this universal molecular mechanism. The common differential genes of four respiratory viruses, including respiratory syncytial virus (RSV), rhinovirus, influenza, and SARS-CoV-2, were screened by GEO database, and the hub gene was obtained by Sytohubba in Cytoscape. Then, the effect of hub genes on inflammasome and pyrodeath was investigated in the model of RSV infection in vitro and in vivo. Finally, through virtual screening, drugs targeting the hub gene were obtained, which could alleviate severe viral pneumonia in vitro and in vivo. The results showed that CMPK2 is one of the hub genes after infection by four respiratory viruses. CMPK2 activates the inflammasome by activating NLRP3, and promotes the releases of inflammatory factors interleukin (IL)-1ß and IL-18 to induce severe viral pneumonia. Z25 and Z08 can reduce the expression level of CMPK2 mRNA and protein, thereby inhibiting NLRP3 and alleviating the development of severe viral pneumonia. In conclusion, the inflammatory response mediated by CMPK2 is the common molecular mechanism of severe pneumonia induced by viral infection, and Z25 and Z08 can effectively alleviate viral infection and severe pneumonia through this mechanism.

Lactobacillus paracasei L9 affects disease progression in experimental autoimmune neuritis by regulating intestinal flora structure and arginine metabolism.

BACKGROUND: Autoimmune neuropathies are common peripheral nervous system (PNS) disorders. Environmental influences and dietary components are known to affect the course of autoimmune diseases. Intestinal microorganisms can be dynamically regulated through diet, and this study combines intestinal microorganisms with diseases to open up new therapeutic ideas. METHODS: In Lewis rats, a model of EAN was established with P0 peptide, Lactobacillus were used as treatment, serum T-cell ratio, inflammatory factors, sciatic neuropathological changes, and pathological inflammatory effects on intestinal mucosa were detected, and fecal metabolomics and 16 s microbiome analysis were performed to further explore the mechanism. RESULTS: In the EAN rat model, Lactobacillus paracasei L9 (LP) could dynamically regulate the CD4+/CD8+T balance in serum, reduce serum IL-1, IL-6 and TNF-α expression levels, improve sciatic nerve demyelination and inflammatory infiltration, and reduce nervous system score. In the rat model of EAN, intestinal mucosa was damaged. Occludin and ZO-1 were downregulated. IL-1, TNF-α and Reg3γ were upregulated. LP gavage induced intestinal mucosa recovery; occludin and ZO-1 upregulation; IL-1, TNF-α and Reg3γ downregulation. Finally, metabolomics and 16 s microbiome analysis were performed, and differential metabolites were enriched with an important metabolic pathway, arginine and proline metabolism. CONCLUSION: LP improved EAN in rats by influencing intestinal community and the lysine and proline metabolism.

Respiratory syncytial virus infection disrupts pulmonary microbiota to induce microglia phenotype shift.

The lung-brain axis is an emerging biological pathway that is being investigated in relation to microbiome medicine. Increasing evidence suggests that pulmonary viral infections can lead to distinct pathological imprints in the brain, so there is a need to explore and understand this mechanism and find possible interventions. This study used respiratory syncytial virus (RSV) infection in mice as a model to establish the potential lung-brain axis phenomenon. We hypothesized that RSV infection could disrupt the lung microbiota, compromise immune barriers, and induce a significant shift in microglia phenotype. One week old mice were randomized into the control, Ampicillin, RSV, and RSV+Ampicillin treated groups (n = 6 each). Seven days after the respective treatments, the mice were anaesthetized. Immunofluorescence and real-time qRT-PCR was used to detect virus. Hematoxylin-eosin staining was used to detect histopathology. Malondialdehyde and superoxide dismutase were used to determine oxidative stress and antioxidant capacity. Real-time qRT-PCR and enzyme-linked immunosorbent assay (ELISA) were used to measure Th differentiation in the lung. Real-time qRT-PCR, ELISA, and confocal immunofluorescence were used to determine the microglia phenotype. 16S DNA technology was used to detect lung microflora. RSV infection induces elevated oxidative stress, reduced antioxidant, and significant dysbacteriosis in the lungs of mice. Pulmonary microbes were found to enhance Th1-type immunoreactivity induced by RSV infection and eventually induced M1-type dominant microglia in the brains of mice. This study was able to establish a correlation between the pulmonary microbiome and brain function. Therefore, we recommend a large sample size study with robust data analysis for the long-term effects of antibiotics and RSV infection on brain physiology.

ADAM9: A regulator between HCMV infection and function of smooth muscle cells.

Lots of epidemiological and clinical studies have shown that human cytomegalovirus (HCMV) is related to the pathogenesis of atherosclerosis. Released by inflammatory cells and vascular smooth muscle cell (VSMCs), metalloproteinases are observed in many pathological vessel conditions, including atherosclerosis and restenosis. This study was designed to investigate the effect of HCMV infection on the expression of metalloproteinases and their involvements in the HCMV-induced functional changes of VSMCs. Differential metalloproteinase after HCMV infection was assayed using reverse transcription-polymerase chain reaction (RT-PCR) microarray. The most significant increased a disintegrin and metalloprotease 9 (ADAM9) was chosen to investigate the mechanism of its specific increase after infection using the treatment of UV-irradiated replication-deficient HCMV, HCMV-infected cell lysate filters or Foscarnet. The function of proliferation, migration, production of inflammatoty factors and phenotypic transformation were determined by using cell counting kit-8, transwell, Enzyme-linked immunosorbent assay, RT-quantitative PCR (qPCR) and Western blot, respectively. Moreover, the effect of ADAM9 deficiency on HCMV replication was also determined using RT-qPCR and immunofluorescence. The expression levels of 6 genes were upregulated and 14 genes were downregulated at different time points after HCMV infection. Among these, the expression level of ADAM9 increased most significantly at each time point and the abnormal expression of ADAM9 might be induced by the early gene products of HCMV. Further studies found that ADAM9 promoted the proliferation, the migration, the production of inflammatory factors and the transit from the contractile phenotype (decreased ACTA2 expression) to the synthetic phenotype (increased osteopontin [OPN] expression). Knockdown theADAM9 expression could rescue the decreased ACTA2 expression, but has no effect on OPN expression. ADAM-9 deficiency didn't affect the replication of HCMV. The findings of our study suggest that HCMV infection changed VSMC function through ADAM9 expression, which may contribute to the understanding of the underlying pathological mechanisms of HCMV-induced atherosclerosis.

Gimap5 promoted RSV degradation through interaction with M6PR.

Respiratory syncytial virus (RSV) is one of the main pathogens of viral pneumonia and bronchiolitis in infants and young children and life-threatening diseases among infants and young children. GTPases of the immune-associated protein family (GIMAP) are new family members of immune-associated GTPases. In recent years, much attention has been paid to the function of the GIMAP family in coping with infection and stress. Gimap5 is a member of the GIMAP family, which may be correlated with anti-infectious immunity. RT-qPCR, Western blot, and indirect immunofluorescence (IFA) were used to detect the expression of Gimap5, M6PR and IGF1R(the major RSV receptor). Transmission electron microscopy (TEM) was used to detect the degradation of RSV in Gimap5-overexpressed or -silent cell lines. Computer virtual screening was used to screen small molecule compounds targeting Gimap5 and the anti-RSV effects were explored through in vivo and in vitro experiments. GIMAP5 and M6PR were significantly downregulated after RSV infection. Gimap5 accelerated RSV degradation in lysosomes by interacting with M6PR, and further prevented RSV invasion by downregulating the expression of RSV surface receptor IGF1R. Three small molecule compounds targeting Gimap5 were confirmed to be the agonists of Gimap5. The three compounds effectively inhibited RSV infection and RSV-induced complications. Gimap5 promotes the degradation of RSV and its receptor through interacting with M6PR. Gimap5 agonists can effectively reduce RSV infection and RSV-induced complication in vivo and in vitro, which provides a new choice for the treatment of RSV.

Crosstalk between the lung microbiome and lung cancer.

The human microbiome is a complex ecosystem that mediates interaction between the human host and the environment. All of the human body is colonized by microorganisms. The lung as an organ used to be considered sterile. Recently, however, there has been a growing number of reports with evidence that the lungs are also in a state of carrying bacteria. The pulmonary microbiome is associated with many lung diseases and is increasingly reported in current studies. These include; chronic obstructive pulmonary disease (COPD), asthma, acute chronic respiratory infections, and cancers. These lung diseases are associated with reduced diversity and dysbiosis. It directly or indirectly affects the occurrence and development of lung cancer. Very few microbes directly cause cancer, while many are complicit in cancer growth, usually working through the host's immune system. This review focuses on the correlation between lung microbiota and lung cancer, and investigates the mechanism of action of lung microorganisms on lung cancer, which will provide new and reliable treatments and diagnosis of lung cancer in the future.

The antiviral efficacies of small-molecule inhibitors against respiratory syncytial virus based on the F protein.

OBJECTIVES: Respiratory syncytial virus (RSV) infection is one of the three most common causes of death in the infants, pre-schoolers, immunocompromised patients and elderly individuals due to many complications and lack of specific treatment. During RSV infection, the fusion protein (F protein) mediates the fusion of the virus envelope with the host cell membrane. Therefore, the F protein is an effective target for viral inhibition. METHODS: We identified potential small-molecule inhibitors against RSV-F protein for the treatment of RSV infection using virtual screening and molecular dynamics (MD) simulations. The CCK8 assay was used to determine the cytotoxicity and quantitative RT-PCR and indirect fluorescence assay (IFA) were used to determine the viral replication and RSV-induced inflammation in vitro. An RSV-infected mouse model was established, and viral replication was assayed using real-time quantitative PCR and IFA. Virus-induced complications were also examined using histopathological analysis, airway resistance and the levels of IL-1ß, IL-6 and TNF-α. RESULTS: The top three potential inhibitors against the RSV-F protein were screened from the FDA-approved drug database. Z65, Z85 and Z74 significantly inhibited viral replication and RSV-induced inflammation. They also significantly alleviated RSV infection and RSV-induced complications in vivo. Z65 and Z85 had no cytotoxicity and better anti-RSV effects than Z74. CONCLUSIONS: Z65 and Z85 may be suitable candidates for the treatment of RSV and serve as the basis for the development of new drugs.

Lung-brain axis: Metabolomics and pathological changes in lungs and brain of respiratory syncytial virus-infected mice.

The lung-brain axis is an emerging area of study that got its basis from the gut-brain axis biological pathway. Using Respiratory Synctial Virus (RSV) as the model of respiratory viral pathogen, this study aims to establish some biological pathways. After establishing the mice model, the inflammation in lung and brain were assayed using Hematoxylin-eosin staining, indirect immunofluorescence (IFA), and quantitative reverse-transcription polymerase chain reaction. The biological pathways between lung and brain were detected through metabolomics analysis. In lung, RSV infection promoted epithelial shedding and infiltration of inflammatory cells. Also, RSV immunofluorescence and titerss were significantly increased. Moreover, interleukin (IL)-1, IL-6 and tumor necrosis factor-α (TNF-α) were also significantly increased after RSV infection. In brain, the cell structure of hippocampal CA1 area was loose and disordered. Inflammatory cytokines IL-6 and IL-1ß expression in the brain also increased, however, TNF-α expression showed no differences among the control and RSV group. We observed an increased expression of microglia biomarker IBA-1 and decreased neuronal biomarker NeuN. In addition, RSV mRNA expression levels were also increased in the brains. 15 metabolites were found upregulated in the RSV group including nerve-injuring metabolite glutaric acid, hydroxyglutaric acid and Spermine. ɑ-Estradiol increased significantly while normorphine decreased significantly at Day 7 of infection among the RSV group. This study established a mouse model for exploring the pathological changes in lungs and brains. There are many biological pathways between lung and brain, including direct translocation of RSV and metabolite pathway.

Dispersion and utilization of lipid droplets mediates respiratory syncytial virus-induced airway hyperresponsiveness.

BACKGROUND: Respiratory viral infections (RSV) can induce acute asthma attacks, thereby destroying lung function and accelerating the progression of the disease. However, medications in the stable phase of asthma are often not effective for acute attacks induced by viral infections. We aimed to clarify the possible mechanism of viral infection-induced asthma through fatty acid metabolism. METHODS AND RESULTS: The airway resistances, inflammatory injuries, and oxidative stress in the RSV-induced animal models were significantly higher than those in the control group at acute phase (7 days) and chronic phase (28 days). Moreover, the concentrations of the medium- and long-chain fatty acids in lung tissue at (28 days) were significantly increased, including 14:0 (myristic acid), 16:0 (palmitic acid, PA), 18:1 (oleic acid, OA), and 18:2 (linoleic acid, LA) using non-targeted metabonomics. Airway epithelial cells treated with RSV showed the reduced expression of FSP27, RAB8A, and PLIN5, which caused the fusion and growth of lipid droplet (LD), and increased expression of the LD dispersion gene perilipin 2. There was also a decrease in PPARγ expression and an increase in the fatty acid catabolism gene PPARα, causing lipid oxidation, free fatty acid releases, and an upsurge in IL-1, IL-2, IL-4, and IL-6 expression, which could be abrogated by GPR40 inhibitor. Treated mice or epithelial cells with C18 fatty acid exhibited inhibition of epithelial proliferation, increases of inflammation, and oxidative damage. CONCLUSIONS: RSV promoted lipid dispersion and utilization, causing enlarged oxidative injuries and an upsurge in the pro-inflammatory cytokines, leading to the progression of airway hyperresponsiveness (AHR).

Th17/IL-17 Axis Regulated by Airway Microbes Get Involved in the Development of Asthma.

PURPOSE OF REVIEW: Bronchial asthma is a common respiratory disease induced by immune imbalance, characterized by chronic non-specific airway inflammation and airway hyperresponsiveness (AHR). Many factors induce asthma, among which respiratory infection is the important cause. In this review, we discuss how respiratory microbes participate in the occurrence and progression of asthma via Th17/IL-17 axis. RECENT FINDINGS: Pathogenesis of asthma has been considered as closely related to the imbalance in number and function of Th1/Th2 in the CD4+ T lymphocyte subsets. Recent studies have shown that Th17 cell and its secretory IL-17 also play an important role in AHR. Respiratory virus, bacteria, fungi, and other respiratory microbial infections can directly or indirectly induce the differentiation of Th17 cell and the production of related cytokines to induce AHR. Respiratory microbial infection can affect the TH17/IL-17A axis through a variety of mechanisms, thereby promoting the occurrence and development of asthma, and these specific mechanisms may provide new effective therapeutic ideas for asthma.

Direct-acting Antiviral in the Treatment of Chronic Hepatitis C: Bonuses and Challenges.

Owing to the rapid development and wide clinical application of direct acting antiviral (DAA) drugs in the treatment of hepatitis C virus (HCV) infection, the era of interferon-based therapy has almost come to an end. Cumulative studies show that DAA therapy renders high cure efficiency (>90%) and good safety profile, and may even bring some unexpected benefits to the patients. However, some issues of concern arise, one of which is the resistance mutation of HCV genome leading to failure of treatment. With the aim of providing some meaningful references for the treatment of chronic hepatitis C (CHC), this article summarizes the research progress on benefits of DAA accompanied by viral clearance in the treatment of chronic hepatitis and the drug resistance.

The in vitro and in vivo antiviral effects of IGF1R inhibitors against respiratory syncytial virus infection.

The insulin-like growth factor 1 receptor (IGF1R) was recognized as a pivotal receptor that facilitated the cellular entry of RSV. Small molecule inhibitors designed to target IGF1R exhibited potential as potent antiviral agents. Through virtual screening, we conducted a screening process involving small molecule compounds derived from natural products, aiming to target the IGF1R protein against respiratory syncytial virus infection. The molecular dynamics simulation analysis showed that tannic acid and daptomycin interacted with the IGF1R. The experimental results in vivo and in vitro showed that tannic acid and daptomycin had anti-RSV infection potential through reducing viral loads, inflammation, airway resistance and protecting alveolar integrity. The CC50 values of tannic acid and daptomycin were 6 nM and 0.45 µM, respectively. Novel small-molecule inhibitors targeting the IGF1R, tannic acid and daptomycin, may be effective anti-RSV therapy agents. This study may in future broaden the arsenal of therapeutics for use against RSV infection and lead to more effective care against the virus.Communicated by Ramaswamy H. Sarma.

A bioinformatics approach to systematically analyze the molecular patterns of monkeypox virus-host cell interactions.

Monkeypox has been spreading worldwide since May 2022, when the World Health Organization (WHO) declared the outbreak a "public health emergency of international concern." The spread of monkeypox has posed a serious threat to the health of people around the world, but few studies have been conducted, and the molecular mechanism of monkeypox after infection remains unclear. We therefore implemented a transcriptome analysis to identify signaling pathways and biomarkers in monkeypox-infected cells to help understand monkeypox-host cell interactions. In this study, datasets GSE36854 and GSE11234 were obtained from GEO. Of these, 84 significantly different genes were identified in the dataset GSE36854, followed by KEGG, GO analysis protein-protein interaction (PPI) construction, and Hub gene extraction. We also analyzed the expression regulation of hub genes and screened for drugs targeting hub genes. The results showed that monkeypox-infected cells significantly activated the cellular immune response. The top 10 hub genes are IER3, IFIT2, IL11, ZC3H12A, EREG, IER2, NFKBIE, FST, IFIT1 and AREG. AP-26113 and itraconazole can be used to counteract the inhibitory effect of monkeypox on IFIT1 and IFIT2 and serve as candidate drugs for the treatment of monkeypox virus infection. IRF1 may also be a transcription factor of IFIT. Our results provide a new entry point for understanding how monkeypox virus interacts with its host.

Diagnostic, clustering, and immune cell infiltration analysis of m6A regulators in patients with sepsis.

RNA N6-methladenosine (m6A) regulators are required for a variety of biological processes, including immune responses, and increasing evidence indicates that their dysregulation is closely associated with many diseases. However, the potential roles of m6A regulators in sepsis remain unknown. We comprehensively analyzed the transcriptional variations in and interactions of 26 m6A regulators in sepsis based on the Gene Expression Omnibus (GEO) database. A random forest (RF) model and nomogram were established to predict the occurrence and risk of sepsis in patients. Then, two different m6A subtypes were defined by consensus clustering analysis, and we explored the correlation between the subtypes and immune cells. We found that 17 of the 26 m6A regulators were significantly differentially expressed between patients with and without sepsis, and strong correlations among these 17 m6A regulators were revealed. Compared with the support vector machine (SVM) model, the RF model had better predictive ability, and therefore was used to construct a reliable nomogram containing 10 candidate m6A regulators to predict the risk of sepsis in patients. In addition, a consensus clustering algorithm was used to identify two different subtypes of m6A, which helped us distinguish different levels of immune cell infiltration and inflammation in patients with sepsis. Comprehensive analysis of m6A regulators in sepsis revealed their potential roles in sepsis occurrence, immune cell infiltration and inflammation in patients with sepsis. This study may contribute to the development of follow-up treatment strategies for sepsis.

miR-34b/c-5p/CXCL10 Axis Induced by RSV Infection Mediates a Mechanism of Airway Hyperresponsive Diseases.

Background: RSV is closely correlated with post-infection airway hyperresponsive diseases (AHD), but the mechanism remains unclear. Objective: Due to the pivotal role of miRNAs in AHD, we analyzed the differentially expressed miRNAs (DEmiRs) in RSV-infected patients, asthma patients, and COPD patients from public datasets and explored the mechanisms of association between RSV and AHD. Methods: We obtained miRNA and mRNA databases of patients with RSV infection, as well as miRNA databases of asthma and COPD patients from the GEO database. Through integrated analysis, we screened DEmiRs and DEGs. Further analysis was carried out to obtain the hub genes through the analysis of biological pathways and enrichment pathways of DEGs targeted by DEmiRs and the construction of a protein-protein interaction (PPI) network. Results: The five differential molecules (miR-34b/c-5p, Cd14, Cxcl10, and Rhoh) were verified through in vivo experiments that had the same expression trend in the acute and chronic phases of RSV infection. Following infection of BEAS-2B cells with RSV, we confirmed that RSV infection down-regulated miR-34b/c-5p, and up-regulated the expression levels of CXCL10 and CD14. Furthermore, the results of the dual-luciferase reporter assay showed that CXCL10 was the target of hsa-miR-34c-5p. Conclusions: miR-34b/c-5p/CXCL10 axis mediates a mechanism of AHD.

The role of pyroptosis-related genes in the diagnosis and subclassification of sepsis.

Pyroptosis is a new form of programmed cell death recognized as crucial in developing sepsis. However, there is limited research on the mechanism of pyroptosis-related genes in sepsis-related from the Gene Expression Omnibus (GEO) database and standardized. The expression levels of pyroptosis-related genes were extracted, and differential expression analysis was conducted. A prediction model was constructed using random forest (RF), support vector machine (SVM), weighted gene co-expression new analysis (WGCNA), and nomogram techniques to assess the risk of sepsis. The relationship between pyroptosis-related subgroups and the immune microenvironment and inflammatory factors was studied using consistent clustering algorithms, principal component analysis (PCA), single-sample genomic enrichment analysis (ssGSEA), and immune infiltration. A risk prediction model based on 3 PRGs has been constructed and can effectively predict the risk of sepsis. Patients with sepsis can be divided into two completely different subtypes of pyroptosis-related clusters. Cluster B is highly correlated with the lower proportion of Th17 celld and has lower levels of expression of inflammatory factors. This study utilizes mechanical learning methods to further investigate the pathogenesis of sepsis, explore potential biomarkers, provide effective molecular targets for its diagnosis and treatment of sepsis.

Abnormal Gene Expression Regulation Mechanism of Myeloid Cell Nuclear Differentiation Antigen in Lung Adenocarcinoma.

Lung adenocarcinoma (LA) is the main pathological type of lung cancer with a very low 5-year survival rate. In the present study, after downloading the mRNA, miRNA, and DNA methylation sequencing data from TCGA, combined with the downloaded clinical data, comparative analysis, prognostic analysis, GO and KEGG analysis, GSEA analysis, methylation analysis, transcriptional regulation and post-transcriptional regulation were performed. We found that both methylation and gene expression of MNDA in LA were down-regulated, while high expression of MNDA was associated with good overall survival in LA. To probe the mechanism, further analysis showed that SPI1 was the main transcription factor of MNDA, but it was also down-regulated in LA. At the same time, the expression of eight target miRNAs of MNDA was significantly up-regulated, and the expression of hsa-miR-33a-5p and hsa-miR-33b-5p were verified to directly target MNDA. In conclusion, the abnormal expression of MNDA in LA is the result of the combined effects of transcriptional and post-transcriptional regulation.

Metagenomic next-generation sequencing in diagnosing Pneumocystis jirovecii pneumonia: A case report.

It remains a huge challenge for clinicians to diagnose Pneumocystis jirovecii pneumonia (PJP) by a conventional method, which leads to delay in diagnosing PJP, accounting for higher mortality in patients with rheumatoid arthritis (RA). A 69-year-old woman, who suffered from RA for years, developed acute respiratory failure. The computed tomography scan showed diffused effusion and ground glass opacity in both lungs, which could not be differentiated from interstitial pneumonia. Metagenomic next-generation sequencing (mNGS) revealed P. jirovecii in both serum and bronchoalveolar lavage fluid with reads per million (RPM) of 17 and 437, while other diagnostic tests did not detect any pathogenic microorganism. The results were verified by quantitative polymerase chain reaction (mtSSU region) against the same samples. The DNA RPM of P. jirovecii declined notably after treatment with trimethoprim/sulfamethoxazole. The patient was discharged without treatment and finally passed away. This case fully highlights the sensitivity of mNGS in early diagnosis of PJP, which is of great significance for prognosis and treatment. Nonetheless, the clinical application of mNGS is worth further standardization and normalization.

RSV Promotes Epithelial Neuroendocrine Phenotype Differentiation through NODAL Signaling Pathway.

BACKGROUND: Respiratory syncytial virus (RSV) infects infants and children, predisposing them to development of asthma during adulthood. Epithelial neuroendocrine phenotypes may be associated with development of asthma. This study hopes to ascertain if RSV infection promotes epithelial neuroendocrine phenotypes through the NODAL signaling pathway. METHODS: The GSE6802 data set was obtained from the GEO database, and the differential genes were analyzed using the R language. An in vitro model was constructed with RSV infected human respiratory epithelial cells, and then real-time qPCR and immunofluorescence were used to detect the expression of different epithelial biomarkers and airway neuropeptides. The acute and chronic infection model of RSV infection was established by intranasal injection of RSV into guinea pigs. Immunohistochemistry and Western blot were used to detect the expression of pulmonary neuroendocrine cells markers ENO2 and neuropeptides. RESULTS: The expression levels of ENO2, SP, CGRP, and NODAL/ACTRII were significantly higher in the RSV infection group than those of the control group, which were abrogated by siRNA-NODAL. In vivo, we found that the expression levels of ENO2, SP, and CGRP were significantly higher than that of the control group. CONCLUSION: RSV promotes epithelial neuroendocrine phenotypes through the NODAL signaling pathway.

Gimap5 Inhibits Lung Cancer Growth by Interacting With M6PR.

OBJECTIVE: Several studies have demonstrated the impacts of GTPases of immunity-associated proteins (GIMAPs) on malignant cells. However, the mechanisms through which Gimap5 regulates lung cancer cells are yet to be thoroughly investigated in the literature. Our study aimed to investigate the function of Gimap5 in the development of lung cancer. METHODS: The expression levels of the GIMAP family were analyzed in lung cancer patients of various cancer databases and lung cancer cell lines. After the survival rates of the cells were analyzed, we constructed Gimap5 over-expressed lung cancer cell lines and assessed the effects of Gimap5 on cell migration, cell invasion, cell proliferation and the epithelial-mesenchymal transition (EMT). We later screened the interacting proteins of Gimap5 using Co-IP combined with mass spectrometry and then analyzed the expression and distribution of M6PR, including its impacts on protein-arginine deiminase type-4 (PADI4). RESULTS: Findings indicated that GIMAP family expression decreased significantly in lung cancer cell lines. We also noticed that the downregulation of the GIMAP family was related to the poor prognosis of lung cancer patients. Our experimental results showed that Gimap5 could inhibit the migration, invasion, proliferation and EMT of lung cancer cell lines. Moreover, we found that Gimap5 promoted the transport of M6PR from the cytoplasm to the cell membrane, thereby inhibiting the enhancement of EMT-related PADI4. CONCLUSION: Our research suggested that Gimap5 could inhibit the growth of lung cancer by interacting with M6PR and that it could be a potential biomarker for the diagnosis and prognosis of lung cancer.