Enterotoxin-related genes PPFIA4 and SCN3B promote colorectal cancer development and progression.

To identify the role of enterotoxin-related genes in colorectal cancer (CRC) development and progression. Upregulated differentially expressed genes shared by three out of five Gene Expression Omnibus (GEO) data sets were included to screen the key enterotoxin-induced oncogenes (EIOGs) according to criteria oncogene definition, enrichment, and protein-protein interaction (PPI) network analysis, followed by prognosis survival, immune infiltration, and protential drugs analyses was performed via integration of RNA-sequencing data and The Cancer Genome Atlas-derived clinical profiles. We screened nine common key EIOGs from at least three GEO data sets. A Cox proportional hazards regression models verified that more alive cases, decreased overall survival, and highest 4-year survival prediction in CRC patients with high-risk score. Protein tyrosine phosphatase receptor type F polypeptide-interacting protein alpha-4 (PPFIA4), STY11, SCN3B, and SPTBN5 were shared in the same PPI network. Immune infiltration results showed that SCN3B and synaptotagmin 11 expression were obviously associated with B cell, macrophage, myeloid dendritic cell, neutrophils, and T cell CD4+ and CD8+ in both colon adenocarcinoma and rectal adenocarcinoma. CHIR-99021, MLN4924, and YK4-279 were identified as the potential drugs for treatment. Finally, upregulated EIOGs genes PPFIA4 and SCN3B were found in colon adenocarcinoma and PPFIA4 and SCN3B were proved to promote cell proliferation and migration in vitro. We demonstrated here that EIOGs promoting a malignancy phenotype was related with poor survival and prognosis in CRC, which might be served as novel therapeutic targets in CRC management.

Xuebijing improves inflammation and pyroptosis of acute lung injury by up-regulating miR-181d-5p-mediated SPP1 inactivation.

BACKGROUND: Xuebijing (XBJ) is widely applied in the treatment of Acute Lung Injury (ALI). This study focused on the potential mechanism of XBJ in Lipopolysaccharide (LPS)-induced ALI. METHODS: The rat ALI model was established by injection of LPS (10 mg/kg) and pretreated with XBJ (4 mL/kg) three days before LPS injection. BEAS-2B cell line was stimulated with LPS (1 µg/mL) and ATP (5 mM) to induce pyroptosis, and XBJ (2 g/L) was pretreated 24h before induction. The improvement effects of XBJ on pulmonary edema, morphological changes, and apoptosis in ALI lung tissue were evaluated by lung wet/dry weight ratio, HE-staining, and TUNEL staining. Inflammatory cytokines in lung tissue and cell supernatant were determined by ELISA. pyroptosis was detected by flow cytometry. Meanwhile, the expressions of miR-181d-5p, SPP1, p-p65, NLRP3, ASC, caspase-1, p20, and GSDMD-N in tissues and cells were assessed by RT-qPCR and immunoblotting. The relationship between miR-181d-5p and SPP1 in experimental inflammation was reported by dual luciferase assay. RESULTS: XBJ could improve inflammation and pyroptosis of ALI by inhibiting contents of inflammatory cytokines, and levels of inflammation- and pyroptosis-related proteins. Mechanistically, XBJ could up-regulate miR-181d-5p and inhibit SPP1 in ALI. miR-181d-5p can target the regulation of SPP1. Depressing miR-181d-5p compensated for the ameliorative effect of XBJ on ALI, and overexpressing SPP1 suppressed the attenuating effect of XBJ on LPS-induced inflammation and pyroptosis. CONCLUSION: XBJ can regulate the miR-181d-5p/SPP1 axis to improve inflammatory response and pyroptosis in ALI.

Enterotoxigenic Bacteroides fragilis (ETBF) Enhances Colorectal Cancer Cell Proliferation and Metastasis Through HDAC3/miR-139-3p Pathway.

Enterotoxigenic Bacteroides fragilis (ETBF) is believed to promote the malignant process of colorectal cancer (CRC), but the underlying molecular mechanism still needs to be revealed. CRC cells (SW480 and HCT-116) were treated with ETBF strain. Cell proliferation, invasion and, migration were evaluated by cell counting kit 8 assay, EdU assay, colony formation assay, transwell assay, and wound healing assay. Protein expression was analyzed by western blot. MicroRNA (miR)-139-3p and histone deacetylase 3 (HDAC3) expression levels in tissues and cells were determined by qRT-PCR. Xenograft tumor model was conducted to evaluate the effect of miR-139-3p on CRC tumor growth. ETBF treatment could promote CRC cell proliferation, invasion and migration. MiR-139-3p expression was decreased by ETBF, and its overexpression reversed the effect of ETBF on CRC cell progression. HDAC3 negatively regulated miR-139-3p expression, and its overexpression facilitated CRC cell behaviors via reducing miR-139-3p expression. Moreover, HDAC3 expression was increased by ETBF, and its knockdown also abolished ETBF-mediated CRC cell progression. Additionally, miR-139-3p overexpression could reduce CRC tumor growth in vivo. ETBF aggravated CRC proliferation and metastasis via the regulation of HDAC3/miR-139-3p axis. The discovery of ETBF/HDAC3/miR-139-3p axis may provide a new direction for CRC treatment.

Xuebijing improves inflammation and pyroptosis of acute lung injury by up-regulating miR-181d-5p-mediated SPP1 inactivation

Abstract Background Xuebijing (XBJ) is widely applied in the treatment of Acute Lung Injury (ALI). This study focused on the potential mechanism of XBJ in Lipopolysaccharide (LPS)-induced ALI. Methods The rat ALI model was established by injection of LPS (10 mg/kg) and pretreated with XBJ (4 mL/kg) three days before LPS injection. BEAS-2B cell line was stimulated with LPS (1 μg/mL) and ATP (5 mM) to induce pyroptosis, and XBJ (2 g/L) was pretreated 24h before induction. The improvement effects of XBJ on pulmonary edema, morphological changes, and apoptosis in ALI lung tissue were evaluated by lung wet/dry weight ratio, HE-staining, and TUNEL staining. Inflammatory cytokines in lung tissue and cell supernatant were determined by ELISA. pyroptosis was detected by flow cytometry. Meanwhile, the expressions of miR-181d-5p, SPP1, p-p65, NLRP3, ASC, caspase-1, p20, and GSDMD-N in tissues and cells were assessed by RT-qPCR and immunoblotting. The relationship between miR-181d-5p and SPP1 in experimental inflammation was reported by dual luciferase assay. Results XBJ could improve inflammation and pyroptosis of ALI by inhibiting contents of inflammatory cytokines, and levels of inflammation- and pyroptosis-related proteins. Mechanistically, XBJ could up-regulate miR-181d-5p and inhibit SPP1 in ALI. miR-181d-5p can target the regulation of SPP1. Depressing miR-181d-5p compensated for the ameliorative effect of XBJ on ALI, and overexpressing SPP1 suppressed the attenuating effect of XBJ on LPS-induced inflammation and pyroptosis. Conclusion XBJ can regulate the miR-181d-5p/SPP1 axis to improve inflammatory response and pyroptosis in ALI.

Comparison of detection strategies for screening and confirming congenital cytomegalovirus infection in newborns in a highly seroprevalent population: a mother-child cohort study.

BACKGROUND: Universal screening of congenital cytomegalovirus (cCMV) infection is important for monitoring and intervention during critical stages of speech and language development. This study aimed to explore the optimal detection strategy for cCMV infection screening. METHODS: Serum samples from pregnant women and saliva and urine samples from their newborns were collected for the anti-CMV IgG and CMV DNA PCR tests, respectively. The sensitivity, specificity, and predictive values as well as the likelihood ratios of 12 potential screening strategies for cCMV infection, based on tests for saliva, urine, and their combination, were evaluated. FINDINGS: A total of 6729 pregnant women were enrolled, and the seroprevalence was 98.1%. Among 6350 newborns that were followed up, 49 were defined as having cCMV infection. In the screening test, the CMV DNA positivity rate remained similar from day 0 to day 5, increased slowly from day 6 to day 13, and became high in newborns beyond 13 days of birth. In the confirmatory testing, the positive rates increased significantly beyond day 21. For the 49 newborns with cCMV infection, the proportion of agreement between saliva and urine testing was poor. Upon evaluating alternative screening strategies, using saliva and urine screening with saliva and urine confirmation as the reference strategy, saliva screening with saliva and urine confirmation showed good diagnostic accuracy and feasibility, with sensitivity, specificity, positive predictive and negative predictive values of 85.7%, 100.0%, 100.0% and 99.9%, respectively. INTERPRETATION: In populations with high seroprevalence, saliva screening with saliva and urine confirmation might be an alternative strategy for screening cCMV infections. The suggested timeframes for screening and confirmation are within 13 (ideally 5) and 21 (ideally 13) days of birth, respectively. FUNDING: National Natural Science Foundation of China, National Science and Technology Major Project of China and Merck & Co., Inc., Kenilworth, New Jersey, U.S.A.

Effect of aspirin use on survival benefits of breast cancer patients: A meta-analysis.

OBJECTIVE: The purpose of this study is to investigate whether aspirin improves the prognosis of breast cancer patients by meta analysis. METHODS: Searched PubMed, EMBASE, and other databases for literature on the relationship between aspirin use and breast cancer prognosis, with the deadline of October 2019. The related results of all-cause death, breast cancer-specific death, and breast cancer recurrence/metastasis were extracted to combine the effect amount. The sensitivity analysis and published bias analysis were carried out for the included data. Stata12.0 software was used to complete all statistical analysis. RESULTS: A total of 13 papers were included in the study, including 142,644 breast cancer patients. The results of meta-analysis showed that patients who took aspirin were associated with lower breast cancer-specific death (HR = 0.69, 95% CI = 0.61-0.76), all-cause death (HR = 0.78, 95% CI = 0.71-0.84), and risk of recurrence/metastasis (HR = 0.91, 95% CI: 0.82-1.00). CONCLUSIONS: Aspirin use may improve all-cause mortality, specific mortality, and risk of recurrence/metastasis in patients with breast cancer.

Efficacy, Safety, and Immunogenicity of an Escherichia coli-Produced Bivalent Human Papillomavirus Vaccine: An Interim Analysis of a Randomized Clinical Trial.

BACKGROUND: The high cost and insufficient supply of human papillomavirus (HPV) vaccines have slowed the pace of controlling cervical cancer. A phase III clinical trial was conducted to evaluate the efficacy, safety, and immunogenicity of a novel Escherichia coli-produced bivalent HPV-16/18 vaccine. METHODS: A multicenter, randomized, double-blind trial started on November 22, 2012 in China. In total, 7372 eligible women aged 18-45 years were age-stratified and randomly assigned to receive three doses of the test or control (hepatitis E) vaccine at months 0, 1, and 6. Co-primary endpoints included high-grade genital lesions and persistent infection (over 6 months) associated with HPV-16/18. The primary analysis was performed on a per-protocol susceptible population of individuals who were negative for relevant HPV type-specific neutralizing antibodies (at day 0) and DNA (at day 0 through month 7) and who received three doses of the vaccine. This report presents data from a prespecified interim analysis used for regulatory submission. RESULTS: In the per-protocol cohort, the efficacies against high-grade genital lesions and persistent infection were 100.0% (95% confidence interval = 55.6% to 100.0%, 0 of 3306 in the vaccine group vs 10 of 3296 in the control group) and 97.8% (95% confidence interval = 87.1% to 99.9%, 1 of 3240 vs 45 of 3246), respectively. The side effects were mild. No vaccine-related serious adverse events were noted. Robust antibody responses for both types were induced and persisted for at least 42 months. CONCLUSIONS: The E coli-produced HPV-16/18 vaccine is well tolerated and highly efficacious against HPV-16/18-associated high-grade genital lesions and persistent infection in women.

[Association between life style, diet intake and high risk-human papillomavirus persistent infection among rural women in Xinmi City, Henan Province].

OBJECTIVE: To explore the association between life style, diet intake and high risk human papillomavirus (HR-HPV) persistent infection among Chinese rural women living in Xinmi City, Henan Province. METHODS: In 2010, a 3-year prospective study in which 2500 women were enrolled and screened by different HR-HPV DNA tests was conducted, part of women among them was followed and tested for HR-HPV DNA in 2012 and 2014. Furthermore, socio demographic factors, gynecological information and diet intake in the past 12 months were collected by self-designed questionnaire in 2014. A total of 721 women with complete test results were eligible for the final analysis. Study participants were divided into 3 groups (persistent infection group, transient infection group, and negative group) by HR-HPV status, and the association between life style, diet intake and HR-HPV persistence was evaluated using ordinal logistic regression model. RESULTS: The average age of 721 women included in the analysis was 50 years old. 141 women had HR-HPV persistent infection, 180 women had HR-HPV transient infection, and 400 women were negative for HR-HPV in 3 years. Age (Χ2 = 58.449, P < 0.001, P(trend) < 0.001), smoking (Χ2 = 6.981, P = 0.021), contraception method (Χ2 = 8.448, P = 0.015) , menopause (Χ2 = 35.712, P < 0.001), number of live births (Χ2 = 16.340, P < 0.001, P(trend) < 0.001), and the intake frequency of cereals (Χ2 = 17.937, P = 0.001) or others (Χ2 = 12.107, P = 0.017) varied significantly between women grouped by different HR-HPV status. Compared to women who were older than 59 years, women in the younger groups had a much lower risk of HR-HPV persistence (adjusted OR1 = 0.39, 95% CI 0.26 - 0.59, OR2 = 0.40, 95% CI 0.23 - 0.69, and OR3 = 0.28, 95% CI 0.12 - 0.68). CONCLUSION: Age is the main risk factor of HR-HPV persistent infection. Lifestyle, diet intake do not associate with HR-HPV persistence after adjustment by age.

Simulation study on gold nanoparticle-cellular membrane complex in endocytosis process.

Gold nanoparticles (AuNPs) are of biomedical importance, such as delivery vectors. Therefore, we used all-atom molecular dynamic simulations to study the interaction of AuNPs with cell membrane (DMPC bilayer). We observed that the AuNPs adhered spontaneously on the surface of the cellular membrane from the bulk phase, largely as a result of the AuNP-DMPC headgroup attraction. We calculated the potential of mean force for transferring an AuNP through a DMPC bilayer. It was observed that a high energetic barrier to AuNP was inserted into the hydrophobic core of the bilayer. The inclusion of AuNP induced local bilayer deformation and slowed fluidity of the lipid molecules in the vicinity of it. As the size of the AuNP increased, the lipids in the vicinity of the AuNP had larger local deformation and slower fluidity. We found that a nanoparticle-membrane complex was formed by the AuNP and its neighbor lipids. These neighbor lipids moved laterally together with AuNP. On average, they moved significantly more slowly than the other lipids. The nanoparticle-membrane complex not only provided a clue for endocytosis mechanism regulating the translocation of AuNPs across the cellular membrane but also helped us to better understand the endocytosis process.

A Monte Carlo study of crowding effects on the self-assembly of amphiphilic molecules.

In this work, lattice Monte Carlo was used to study the effects of crowding on the self-assembly of surfactants. Simulation results show that crowding strongly shifts the critical micelle concentration (CMC) of surfactants from the bulk value. Two effects originated from crowding are found to govern the CMC shift: one is the depletion effect by crowding agents and the other is the available volume for micelle formation. The depletion effects inevitably result in the enrichment of surfactants in crowding-free regions and cause the decrease in CMC. On the other hand, the appearance of crowding agents decreases the available volume for micelle formation, which reduces the conformational entropy and impedes the micelle formation. Three factors, including the radius of crowding agents, the arrangement of crowding agents, and the volume fraction of crowding agents, are considered in this work to study the crowding effects. The trends of CMC shifts are interpreted from the competition between the depletion effects and the available volume for micelle formation.

Stability and rupture of archaebacterial cell membrane: a model study.

It is known that the thermoacidophilic archaebacterium Sulfolobus acidocaldarius can grow in hot springs at 65-80 degrees C and live in acidic environments (pH 2-3); however, the origin of its unusual thermal stability remains unclear. In this work, using a vesicle as a model, we study the thermal stability and rupture of archaebacterial cell membrane. We perform a simulation investigation of the structure-property relationship of monolayer membrane formed by bolaform lipids and compare it with that of bilayer membrane formed by monopolar lipids. The origin of the unusually thermal stability of archaebacterial cell and the mechanism for its rupture are presented in molecular details.

Macrophase and microphase separations for surfactants adsorbed on solid surfaces: a gauge cell monte carlo study in the lattice model.

By combining the gauge cell method and lattice model, we study the surface phase transition and adsorption behaviors of surfactants on a solid surface. Two different cases are considered in this work: macrophase transition and adsorption in a single-phase region. For the case of macrophase transition, where two phases coexist, we investigate the shape and size of the critical nuclei and determine the height of the nucleation barrier. It is found that the nucleation depends on the bulk surfactant concentration. Our simulations show that there exist a critical temperature and critical adsorption energy, below which the transition from low-affinity adsorption to the bilayer structure shows the characteristic of a typical first-order phase transition. Such a surface phase transition in the adsorption isotherm is featured by a hysteresis loop. The hysteresis loop becomes narrower at higher temperature and weaker adsorption energy and finally disappears at the critical value. For the case where no macrophase transition occurs, we study the adsorption isotherm and microphase separation in a single-phase region. The simulation results indicate that the adsorption isotherm in adsorption processes is divided into four regions in a log-log plot, being in agreement with experimental observations. In this work, the four regions are called the low-affinity adsorption region, the hemimicelle region, the morphological transition region, and the plateau region. Simulation results reveal that in the second region the adsorbed monomers aggregate and nucleate hemimicelles, while adsorption in the third region is accompanied by morphological transitions.

Adsorption and morphology transition of surfactants on hydrophobic surfaces: a lattice Monte Carlo study.

In this work, we first show that there are only five independent interchange parameters in the surfactant-solvent-interface system in Larson's model, and then adsorption and morphology transition of surfactants on hydrophobic surfaces are studied by extensive lattice Monte Carlo simulations. In our simulations, we found that there exist six adsorbed morphologies: (1) premature admicelle, (2) hemisphere, (3) hemisphere-hemicylinder mixture, (4) wormlike hemicylinder, (5) perforated monolayer, and (6) monolayer. The surface morphologies and the amount of adsorption on hydrophobic surfaces are found to be affected obviously by two interchange parameters. One is the attractive interaction between tail groups and surface (chiTS), and the other is the solubility of head groups in bulk (chiHW). Phase diagrams in chiHW versus chiTS planes for surfactants with different hydrophobicities (chiTW) and for surfactants with different molecular structures are determined in this work, from which the transitions of surface morphologies and adsorption behaviors are discussed.