Local immune dysregulation and subsequent inflammatory response contribute to pulmonary edema caused by Enterovirus infection in mice.

Pulmonary edema that comes on suddenly is the leading cause of mortality in hand-foot-and-mouth disease (HFMD) patients; however, its pathogenesis is still largely unclear. A range of research suggest immunopathogenesis during the occurrence of pulmonary edema in severe HFMD patients. Herein, to investigate the potential mechanism of immune dysregulation in the development of pulmonary edema upon Enterovirus (EV) infection, we established mouse infection models for Enteroviruses (EVs) including Coxsackievirus (CV) A6, Enterovirus A71 (EVA71), and CVA2 exhibiting a high incidence of pulmonary edema. We found that EVs infection induced an immune system disorder by reducing the numbers of pulmonary and circulatory T cells, B cells, macrophages, and monocytes and increasing the numbers of lung neutrophils, myeloid-derived suppressor cells (MDSCs), and activated T cells. In addition, the concentrations of C-X-C motif chemokine ligand 1 (CXCL-1), tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and interleukin 6 were increased in EV-infected lungs. Moreover, we found that EVs replication in mice lungs lead to apoptosis of lung cells and degradation of tight junction proteins. In conclusion, EVs infection likely triggered a complexed immune defense mechanism and caused dysregulation of innate immune cells (MDSCs, neutrophils, monocytes, and macrophages) and adaptive cellular immunity (B cells, T cells). This dysregulation increased the release of cytokines and other inflammatory factors from activated immune-related cells and caused lung barrier damage and pulmonary edema.

Downregulation of SOCS gene expression can inhibit the formation of acute and persistent BDV infections.

High expression of suppressors of cytokine signalling (SOCS) has been detected during various viral infections. As a negative feedback regulator, SOCS participates in the regulation of multiple signalling pathways. In this study, to study the related mechanism between SOCS and BDV and to explore the effect of SOCS on IFN pathways in nerve cells, downregulated of SOCS1/3 in oligodendroglial (OL) cells and OL cells persistently infected with BDV (OL/BDV) were constructed with RNA interference technology. An interferon inducer (poly I:C, PIC) and an IFN-α/ß R1 antibody were used as stimulation in the SOCS1/3 low-expression cell models, qRT-PCR was used to detect type I IFN and BDV nucleic acid expression, Western blot was used to detect the expression of BDV P40 protein. After BDV acute infection with OL cells which with downregulated SOCS expression, the virus accounting was not detected, and the viral protein expression was lower than that of OL/BDV cells; the OL/BDV cells with downregulated SOCS expression had lower virus nucleic acid and protein expression than OL/BDV cells. Stimulated by IFN-α/ß R1 antibody, the expression of type I interferon in OL/BDV cells decreased, and the content of BDV nucleic acid and protein increased, which was higher than that of OL/BDV cells. From the results, it was concluded that downregulating SOCS1/3 can inhibit the formation of acute BDV infection and virus replication in persistent BDV infection by promoting the expression of IFN-α/ß and that SOCS can be used as a new target for antiviral therapy.

Photobiomodulation with 630-nm LED radiation inhibits the proliferation of human synoviocyte MH7A cells possibly via TRPV4/PI3K/AKT/mTOR signaling pathway.

Phototherapy has been used to treat postoperative pain and inflammatory response in rheumatoid arthritis. Confidence in this approach, however, is impaired by lack of understanding of the light-triggered cellular and molecular mechanisms. The purpose of this study was to characterize the response of human synoviocyte MH7A cells to visible LED red light in an attempt to elucidate the associated action mechanism. Human synoviocyte MH7A cells were treated with 630-nm LED light after stimulation of tumor necrosis factor-α (TNF-α). The effects of light radiation on cell proliferation and migration were detected by MTT assay and scratch test. The expressions of inflammatory cytokines were measured using RT-qPCR. This was followed by detection of the levels of extracellular proteins IL-6 and IL-8 after differential radiation. Furthermore, the expression levels and activation of proteins on PI3K/AKT/mTOR signaling pathway were examined with Western blot. In terms of the proliferation and migration, repeated radiation with LED red light (630 nm, 26 and 39 J/cm2) exerted an inhibitory effect on synoviocyte MH7A cells. Expression of inflammatory factors (IL-6, IL-1ß, IL-8, and MMP-3) was reduced; meanwhile, the expression of anti-inflammatory factor IL-10 was promoted. At the protein level, treatment with 39 J/cm2 of LED red light could decrease the level of extracellular protein (IL-6 and IL-8) and affect the expression and phosphorylation of proteins on TRPV4/PI3K/AKT/mTOR signaling pathway induced by TNF-α. These results demonstrated that LED red light (630 nm) inhibits proliferation and migration of MH7A cells. The growth-inhibiting effects of LED red light on human synoviocyte MH7A cells appear to be associated with regulation of the TRPV4/PI3K/AKT/mTOR signaling pathway.

Novel biomarkers containing citrullinated peptides for diagnosis of systemic lupus erythematosus using protein microarrays.

OBJECTIVES: Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterised by autoantibody production. This study aims to identify biomarkers involving citrullinated peptides that can be used for SLE diagnosis. METHODS: After a negative selection step with serum from healthy controls (HCs), a phage library of 12 peptides was used for three rounds of screening with sera from 30 SLE patients. After four rounds of biopanning, 21 positive peptides were sequenced. We produced 37-feature arrays containing 16 recombinant citrullinated peptides. The microarrays were tested with an independent validation set of serum samples from 50 HCs, 60 SLE patients, and 60 rheumatoid arthritis (RA) patients. RESULTS: Microarray analysis showed that the positive rates of 13S1212Cit3-IgM (60.0%), 13S1210-IgG (43.33%), and 13S1212Cit3-IgG (41.67%) were increased in SLE patients compared with HCs and RA patients. The area under the receiver operating characteristic curve (AUC) was 0.770, 0.687 and 0.698, respectively. The combination of 13S1212Cit3-IgM and 13S1210-IgG (termed COPSLE, for combination of peptides for SLE) was more efficient for SLE diagnosis, with a larger AUC (0.830) and a positive rate of 73.33%. COPSLE could be used to identify 80.0% of SLE patients who were negative for anti-Smith (Sm), anti-double-stranded DNA (ds-DNA), and anticardiolipin (ACA). The Spearman rank correlation indicated that COPSLE increased with albumin, serum level of C3 and platelet distribution width, but had negative correlations with decreased C3 and discoid lupus. CONCLUSIONS: A citrullinated/non-citrullinated peptide panel is a valuable diagnostic marker of SLE, even for patients who are negative for anti-Sm, anti-ds-DNA and ACA.

A rational design of manganese electrocatalysts for Lewis acid-assisted carbon dioxide reduction.

Herein, the mechanisms of Brønsted acid- and Lewis acid-assisted CO2 electroreduction by Mn(mesbpy)(CO)3Br (1) were investigated by density functional theory calculations. Our results indicate that for the Lewis acid-assisted cycle, an energy sink (13) is present owing to the interaction between Mg(OTf)2 and activated CO2, which is disadvantageous to the apparent activation energy (ΔG≠). Moreover, a series of substituted 13 counterparts were investigated to reduce the energy sink and decrease ΔG≠. Based on our study on the substituent effect, an excellent linear relationship was found between 2e reduction potentials and LUMO energies of substituted 1, and a moderate linear relationship was observed between ΔG of substituted 13 and the 2e reduction potential of substituted 1 counterparts. Moreover, for the CO2 reduction assisted by a Lewis acid, the formyl-substituted complex R8 has been predicted to be a more effective catalyst with lower overpotential and higher catalytic activity than its parent complex 1.

Web Crawling and mRNA Sequencing Analyze Mechanisms of Photobiomodulation.

Background: Photobiomodulation (PBM) is praised as a promising physical therapy, which has many advantages, such as being noninvasive and painless. However, the mechanisms are not fully elucidated. Methods: Using web crawling, mRNA sequence, and bioinformatics analysis, we selected genes, functional annotation, and mechanisms. The expressions of inflammatory cytokines were measured using quantitative real-time PCR (RT-qPCR). Results: A total of 146 human genes and 57 pathways were identified about PBM. The 630 nm light-emitting diode (LED)-stimulated-MH7A cells were sequenced to further analyze the mechanism of PBM. Two thousand nine hundred fifty differentially expressed genes were identified, and the gene ontology term enrichment analysis and Kyoto encyclopedia of genes and genomes pathway analysis were performed to better understand functions and pathways. The 12 pathways were matched with the KEGG results of PBM and MH7A cells. A protein-protein interaction network was performed among genes in 12 pathways, and 10 outstanding proteins were identified. Importantly, the 9 genes were predicted with potential research value. And we also demonstrated that expression of inflammatory factors [interleukin (IL)-6, IL-1ß, IL-8, and matrix metalloproteinase-3 (MMP-3)] was reduced; meanwhile, the expression of anti-inflammatory factor IL-10 was promoted after 630 nm LED. Conclusions: Using web crawling, bioinformatics analysis, and mRNA sequence, we obtained 9 key genes and 12 important pathways about PBM. Importantly, we demonstrated the anti-inflammatory effect of 630 nm LED red light by RT-qPCR.

Demethylation of SOCS1 mediates its abnormally high expression in ovarian cancer.

The present study aimed to investigate the association between methylation and the high expression of the suppressor of cytokine signaling 1 (SOCS1) in ovarian cancer by detecting the methylation rate and the degree of expression. The present study investigated the expression of SOCS1 mRNA and SOCS1 protein in ovarian cancer and normal ovary tissues using reverse transcription-quantitative polymerase chain reaction (PCR) and immunohistochemistry, and the methylation status of the CpG islands of SOCS1 mRNA in ovarian cancer tissue were examined using a methylation-specific PCR. The expression levels of SOCS1 mRNA in ovarian cancer specimens were significantly increased compared with that in the normal ovary tissues (P=0.0215). Consistent with this, the expression levels of SOCS1 protein in ovarian cancer specimens were significantly increased, while the methylation rate of SOCS1 mRNA was significantly decreased compared with that in the normal ovary tissues. Therefore, it may be concluded that the low methylation rate of SOCS1 mRNA in ovarian cancer increased the expression of SOCS1 mRNA, which may serve a role in the development of ovarian cancer.