DeepLCRmiRNA: A Hybrid Neural Network Approach for Identifying Lung Cancer-Associated miRNAs.

INTRODUCTION: Lung cancer stands as one of the most prevalent malignant neoplasms, with microRNAs (miRNAs) playing a pivotal role in the modulation of gene expression, impacting cancer cell proliferation, invasion, metastasis, immune escape, and resistance to therapy. METHOD: The intricate role of miRNAs in lung cancer underscores their significance as biomarkers for early detection and as novel targets for therapeutic intervention. Traditional approaches for the identification of miRNAs related to lung cancer, however, are impeded by inefficiencies and complexities. RESULTS: In response to these challenges, this study introduced an innovative deep-learning strategy designed for the efficient and precise identification of lung cancer-associated miRNAs. Through comprehensive benchmark tests, our method exhibited superior performance relative to existing technologies. CONCLUSION: Further case studies have also confirmed the ability of our model to identify lung cancer-associated miRNAs that have undergone biological validation.

Advantages of robot-assisted resection of large mediastinal tumors: a single-center preliminary study.

Current study aims to assess the safety and efficacy of robot-assisted thoracoscopic surgery (RATS) for sizable mediastinal masses with a minimum diameter ≥6 cm, compared with video-assisted thoracoscopic surgery (VATS) and open surgery. This study enrolled 130 patients with mediastinal tumors with no less than 6 cm diameter in Zhongnan Hospital, Wuhan University, including 33 patients who underwent RATS, 52 patients who underwent VATS and 45 patients who underwent open surgery. After classifying based on mass size and whether it has invaded or not, we compared their clinical characteristics and perioperative outcomes. There was no significant difference in age, gender, mass size, myasthenia gravis, mass location, pathological types (p > 0.05) in three groups. Patients undergoing open surgery typically presenting at a more advanced stage (p < 0.05). No obvious difference was discovered in the average postoperative length of stay, operation duration, chest tube duration and average postoperative day 1 drainage output between RATS group and VATS group (p > 0.05), while intraoperative blood loss in RATS group was significantly lower than VATS group (p = 0.046). Moreover, the postoperative length of stay, operation duration, chest tube duration and intraoperative blood loss in RATS group were significantly lower than open surgery group (p < 0.001). RATS is a secure and efficient approach for removing large mediastinal masses at early postoperative period. In comparison with VATS, RATS is associated with lower intraoperative blood loss. Compared with open surgery, RATS is also associated with shorter postoperative length of stay, operation duration, chest tube duration and intraoperative blood loss.

Integrated lipid metabolomics and proteomics analysis reveal the pathogenesis of polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is an endocrinological and metabolic disorder that can lead to female infertility. Lipid metabolomics and proteomics are the new disciplines in systems biology aimed to discover metabolic pathway changes in diseases and diagnosis of biomarkers. This study aims to reveal the features of PCOS to explore its pathogenesis at the protein and metabolic level. METHODS: We collected follicular fluid samples and granulosa cells of women with PCOS and normal women who underwent in vitro fertilization(IVF) and embryo transfer were recruited. The samples were for the lipidomic study and the proteomic study based on the latest metabolomics and proteomics research platform. RESULTS: Lipid metabolomic analysis revealed abnormal metabolism of glycerides, glycerophospholipids, and sphingomyelin in the FF of PCOS. Differential lipids were strongly linked with the rate of high-quality embryos. In total, 144 differentially expressed proteins were screened in ovarian granulosa cells in women with PCOS compared to controls. Go functional enrichment analysis showed that differential proteins were associated with blood coagulation and lead to follicular development disorders. CONCLUSION: The results showed that the differential lipid metabolites and proteins in PCOS were closely related to follicle quality,which can be potential biomarkers for oocyte maturation and ART outcomes.

Deficiency of INPP4A promotes M2 macrophage polarization in eosinophilic chronic rhinosinusitis with nasal polyps.

OBJECTIVE: The treatment of eosinophilic chronic rhinosinusitis with nasal polyps (E-CRSwNP) remains a challenge due to its complex pathogenesis. Inositol polyphosphate-4-phosphatase type IA (INPP4A), a lipid phosphatase, has been implicated in allergic asthma. However, the expression and function of INPP4A in E-CRSwNP remain unclear. This study aims to investigate the role of INPP4A in macrophages in E-CRSwNP. METHODS: We assessed the expression of INPP4A in human and mouse nasal mucosal tissues via immunofluorescence staining. THP-1 cells were cultured and exposed to various cytokines to investigate the regulation of INPP4A expression and its functional role. Additionally, we established a murine nasal polyp (NP) model and administrated an INPP4A-overexpressing lentivirus evaluate its impact on NP. RESULTS: The percentage of INPP4A + CD68 + macrophages among total macrophages decreased in the E-CRSwNP group compared to the control and the non-eosinophilic CRSwNP (NE-CRSwNP) groups, exhibiting an inverse correlation with an increased percentage of CD206 + CD68 + M2 macrophages among total macrophages. Overexpression of INPP4A led to a reduced percentage of THP-1 cells polarizing towards the M2 phenotype, accompanied by decreased levels of associated chemotactic factors including CCL18, CCL22, CCL24, and CCL26. We also validated the involvement of the PI3K-AKT pathway in the function of INPP4A in vitro. Furthermore, INPP4A overexpression in the murine NP model resulted in the attenuation of eosinophilic inflammation in the nasal mucosa. CONCLUSIONS: INPP4A deficiency promotes macrophage polarization towards the M2 phenotype, leading to the secretion of chemokines that recruit eosinophils and Th2 cells, thereby amplifying eosinophilic inflammation in E-CRSwNP. INPP4A may exert a suppressive role in eosinophilic inflammation and could potentially serve as a novel therapeutic strategy.

Differential expression of follicular fluid exosomal microRNA in women with diminished ovarian reserve.

PURPOSE: Decreased ovarian reserve function is mainly characterized by female endocrine disorders and fertility decline. Follicular fluid (FF) exosomal microRNAs (miRNAs) have been shown to regulate the function of granulosa cells (GCs). The present study explored differentially expressed miRNAs (DEmiRNAs) in patients with diminished ovarian reserve (DOR). METHODS: FF was collected from 12 DOR patients and 12 healthy controls. DEmiRNAs between the two groups were identified and analyzed using high-throughput sequencing technology and validated by real-time quantitative PCR (RT-qPCR). RESULTS: A total of 592 DEmiRNAs were identified using high-throughput miRNA sequencing, of which 213 were significantly upregulated and 379 were significantly downregulated. The sequencing results were further validated by RT-qPCR. These DEmiRNA target genes were mainly involved in the cancer pathway, phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, regulation of actin cytoskeleton signaling pathway, and biological processes related to protein binding, nucleoplasm, cytoplasm, and cell membrane. CONCLUSION: FF exosomal miRNAs are significantly differentially expressed in DOR patients versus non-DOR patients, underscoring their crucial role in regulating the pathogenesis of DOR.

Dust mite component Analysis: Identifying key allergens components for effective immunotherapy in allergic rhinitis.

BACKGROUND: The aim of this study was to examine the frequency of sensitization to house dust mite (HDM) components among allergic rhinitis patients receiving subcutaneous immunotherapy (SCIT), and to assess the correlation between SCIT efficacy and specific IgE (sIgE) levels for allergenic HDM components. METHODS: Serum samples and clinical data were collected from 38 allergic rhinitis patients receiving HDM-SCIT at baseline and after 1 year of treatment. Effective treatment was defined as a therapeutic index (TI) of at least 50% after 1 year. Cytokine levels were analyzed using commercial ELISA kits, while serum total and specific IgE levels were determined by the fluoroenzymeimmunoassay technique. The ALLEOS 2000 magnetic particle chemiluminescence system was used to measure sIgE levels for Der f, Der p 1, Der p 2, Der p 10, and Der p 23. RESULTS: Allergic rhinitis patients undergoing HDM-SCIT had a high rate of allergic sensitization to the HDM major allergens Der p (100%), Der f (100%), Der p 1 (94.74%), Der p 2 (94.74%), and Der p 23 (36.84%). Patients who responded to SCIT had higher levels of IgE for HDM components at baseline, while those with ineffective treatment showed an opposite performance, particularly for Der p 1 (P＜0.05). After 1 year of treatment, effective and ineffective patients showed opposite trends in sIgE for dust mite components (decreased in effective patients, increased in ineffective patients). HDM-SCIT led to a significant reduction in IL-2, IL-4, IL-6, and EOS% (P＜0.05). IgE for Der p, Der f, Der p 1, Der p 2, and HDM sIgE were significantly positively correlated (P < 0.001). The correlation heatmap analysis based on changes in values reveals a negative correlation between CSMS score changes and sIgE for Der f and Der p 1, and a positive correlation with IL-2, IL-10, and TNF (P < 0.05). CONCLUSIONS: The molecular sensitization profiles during HDM-SCIT are variable and relate to treatment efficacy. Molecular diagnosis can assist allergists in identifying patients eligible for HDM-SCIT, thereby enhancing the treatment's clinical efficacy. Serum cytokine levels of IL-2, IL-4, IL-6，and EOS% may serve as useful biomarkers for monitoring HDM-SCIT efficacy.

The causal relationship between multiple autoimmune diseases and nasal polyps.

Background: Although previous sporadic studies have reported the associations between a few autoimmune diseases and nasal polyps, these studies have limitations such as conflicting results, small sample sizes, and low levels of evidence. Methods: Several autoimmune diseases were selected as exposures while the nasal polyps were selected as outcomes. Bidirectional univariable Mendelian randomization and multivariable Mendelian randomization analyses were performed after rigorous screening of instrumental variables. Then mediation analyses were conducted to further investigate the underlying mechanisms. Results: For the first time, we investigated the causal relationships between nine autoimmune diseases and nasal polyps in different genders and found: (1) there was a causal association between adult-onset Still's disease and nasal polyps; (2) sarcoidosis, ulcerative colitis, type 1 diabetes, and Crohn's disease had no significant associations with nasal polyps; (3) celiac disease showed a suggestive positive association with female nasal polyps, whereas juvenile arthritis and multiple sclerosis showed suggestive positive associations with male nasal polyps. By contrast, arthropathic psoriasis showed a suggestive negative association with nasal polyps. In addition to these nine diseases, previous controversial issues were further investigated: (1) there was a causal relationship between rheumatoid arthritis and nasal polyps, which was partially mediated by "BAFF-R for IgD+ B cells"; (2) ankylosing spondylitis showed suggestive positive associations with the female but not the male nasal polyps. Besides, we validated that there was no causal effect of autoimmune hyperthyroidism on nasal polyps. Conclusion: Specific conclusions regarding the causal effects of multiple autoimmune diseases on nasal polyps are the same as above. By comparing results between different genders, we have initially observed the sex bimodality in the causal effects between autoimmune diseases and nasal polyps, with those on male nasal polyps being stronger than those on female nasal polyps. Our study lays a solid foundation for further research in the future, not only helping identify individuals susceptible to nasal polyps early but also improving our understanding of the immunopathogenesis of these heterogeneous diseases.

Combined Administration of Escitalopram Oxalate and Nivolumab Exhibits Synergistic Growth-Inhibitory Effects on Liver Cancer Cells through Inducing Apoptosis.

Liver cancer is one of the most lethal malignant cancers worldwide. However, the therapeutic options for advanced liver cancers are limited and reveal scant efficacy. The current study investigated the effects of nivolumab (Niv) and escitalopram oxalate (Esc) in combination on proliferation of liver cancer cells both in vitro and in vivo. Significantly decreased viability of HepG2 cells that were treated with Esc or Niv was observed in a dose-dependent manner at 24 h, 48 h, and 72 h. Administration of Esc (50 µM) + Niv (20 µM), Esc (75 µM) + Niv (5 µM), and Esc (75 µM) + Niv (20 µM) over 24 h exhibited synergistic effects, inhibiting the survival of HepG2 cells. Additionally, treatment with Esc (50 µM) + Niv (1 µM), Esc (50 µM) + Niv (20 µM), and Esc (75 µM) + Niv (20 µM) over 48 h exhibited synergistic effects, inhibiting the survival of HepG2 cells. Finally, treatment with Esc (50 µM) + Niv (1 µM), Esc (50 µM) + Niv (20 µM), and Esc (75 µM) + Niv (20 µM) for 72 h exhibited synergistic effects, inhibiting HepG2 survival. Com-pared with controls, HepG2 cells treated with Esc (50 µM) + Niv (20 µM) exhibited significantly increased sub-G1 portion and annexin-V signals. In a xenograft animal study, Niv (6.66 mg/kg) + Esc (2.5 mg/kg) significantly suppressed the growth of xenograft HepG2 tumors in nude mice. This study reports for the first time the synergistic effects of combined administration of Niv and Esc for inhibiting HepG2 cell proliferation, which may provide an alternative option for liver cancer treatment.

Efficiency of Chinese medicine Bushen Huatan formula for treatment of polycystic ovary syndrome in mice via regulating gut microbiota and PPARγ pathway. / è¡¥è‚¾åŒ–ç—°æ–¹é€šè¿‡è°ƒæŽ§è‚ é“èŒåŠPPARγ通路治疗多囊卵巢综合征的机制.

OBJECTIVES: To explore the effect and mechanism of Chinese medicine Bushen Huatan formula in treatment of polycystic ovary syndrome (PCOS). METHODS: Twenty-four SPF female C57BL/6J mice were randomly divided into 3 groups with 8 animals in each group. Control group was given drinking water ad libitum; PCOS was induced by giving letrozole gavage and high-fat diet in model group and treatment group; treatment group received Bushen Huatan formula suspension for 35 d. The sex hormone levels of mice were detected by enzyme-linked immunosorbent assay. Ovary morphology was observed under light microscope after hematoxylin and eosin staining. The feces in the colon of mice were collected, and the gut microbiota was detected by 16S rRNA sequencing. The short chain fatty acids were detected by gas chromatography-mas spectrometry. The expression of peroxisome proliferator activated receptor (PPARγ) was detected by immunohistochemistry. The mRNA expression of mucin-2, occludin-1, tight junction protein zonula occludens 1 (ZO-1) and PPARγ in intestinal epithelium were detected by realtime RT-PCR. The expression of inducible nitric oxide synthase (iNOS) and PPARγ was detected by Western blotting. RESULTS: Compared with the control group, the body weight, serum levels of follicle stimulating hormone, luteinizing hormone and testosterone in the model group were increased, and serum levels of estradiol were decreased (all P<0.01); the ovarian structure under light microscope was consistent with the characteristics of PCOS. Compared with the model group, the serum levels of sex hormone and ovarian structure in treatment group were improved. The overall structure of gut microbiota in PCOS model mice changed. Compared with control group, there were significantly reduced abundance of Firmicutes, and increased abundance of Verrucomicrobia, Proteobacteria and Actinobacteria inthe model group at phylum level (all P<0.05); there were significantly reduced abundance of Lactobacillus, and increased abundance of Akkermansia, Lachnoclostridium, Lactococcus and Eubacterium_coprostanoligenes at genus level (all P<0.05). The disordered condition of gut microbiota was significantly improved in treatment group. Compared with control group, the contents of acetic acid, propionic acid and butyric acid in feces of model group were significantly decreased (all P<0.05); while the contents of propionic acid and butyric acid in treatment group were significantly increased compared with model control group (both P<0.05). Compared with control group, the mRNA expression of ZO-1 and protein expression of iNOS in model group were significantly increased, and the protein expression of PPARγ and the mRNA expressions of mucin-2 and occludin-1 were significantly decreased (all P<0.05). Compared with model group, the mRNA expression of ZO-1 and protein expression of iNOS in treatment group were decreased, and the protein expression of PPARγ and the mRNA expressions of mucin-2 and occludin-1 were increased. CONCLUSIONS: PCOS induced by letrozole high-fat diet induces microflora imbalance in mice. Chinese medicine Bushen Huatan formula may increase the level of short chain fatty acid by regulating gut microbiota, thereby activating the intestinal PPARγ pathway and improving intestinal barrier function to act as a cure for PCOS.

Short-chain fatty acid-butyric acid ameliorates granulosa cells inflammation through regulating METTL3-mediated N6-methyladenosine modification of FOSL2 in polycystic ovarian syndrome.

Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder characterized by chronic low-grade inflammation. Previous studies have demonstrated that the gut microbiome can affect the host tissue cells' mRNA N6-methyladenosine (m6A) modifications. This study aimed to understand the role of intestinal flora in ovarian cells inflammation by regulating mRNA m6A modification particularly the inflammatory state in PCOS. The gut microbiome composition of PCOS and Control groups was analyzed by 16S rRNA sequencing, and the short chain fatty acids were detected in patients' serum by mass spectrometry methods. The level of butyric acid was found to be decreased in the serum of the obese PCOS group (FAT) compared to other groups, and this was correlated with increased Streptococcaceae and decreased Rikenellaceae based on the Spearman's rank test. Additionally, we identified FOSL2 as a potential METTL3 target using RNA-seq and MeRIP-seq methodologies. Cellular experiments demonstrated that the addition of butyric acid led to a decrease in FOSL2 m6A methylation levels and mRNA expression by suppressing the expression of METTL3, an m6A methyltransferase. Additionally, NLRP3 protein expression and the expression of inflammatory cytokines (IL-6 and TNF-α) were downregulated in KGN cells. Butyric acid supplementation in obese PCOS mice improved ovarian function and decreased the expression of local inflammatory factors in the ovary. Taken together, the correlation between the gut microbiome and PCOS may unveil crucial mechanisms for the role of specific gut microbiota in the pathogenesis of PCOS. Furthermore, butyric acid may present new prospects for future PCOS treatments.

Autoimmunity: A New Focus on Nasal Polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) has long been considered a benign, chronic inflammatory, and hyperplastic disease. Recent studies have shown that autoimmune-related mechanisms are involved in the pathology of nasal polyps. Activated plasma cells, eosinophils, basophils, innate type 2 lymphocytes, mast cells, and proinflammatory cytokine in polyp tissue indicate the mobilization of innate and adaptive immune pathways during polyp formation. The discovery of a series of autoantibodies further supports the autoimmune nature of nasal polyps. Local homeostasis dysregulation, infection, and chronic inflammation may trigger autoimmunity through several mechanisms, including autoantigens overproduction, microbial translocation, molecular mimicry, superantigens, activation or inhibition of receptors, bystander activation, dysregulation of Toll-Like Receptors (TLRs), epitope spreading, autoantigens complementarity. In this paper, we elaborated on the microbiome-mediated mechanism, abnormal host immunity, and genetic changes to update the role of autoimmunity in the pathogenesis of chronic rhinosinusitis with nasal polyps.

A Cross-Sectional Survey of Different Types of School Bullying before and during COVID-19 in Shantou City, China.

BACKGROUND: Since the end of 2019, the COVID-19 pandemic has had serious wide-ranging effects on academic, occupational and other daily activities. Like other types of institutions, schools are facing unprecedented challenges. Students may face a variety of adverse consequences, including sleep disturbances and school bullying, if they are unable to adjust to the current learning and living environment. This study explored the effects of the COVID-19 pandemic on school bullying. METHODS: A total of 5782 middle school students were enrolled in this multi-stage, cross-sectional study (3071 before and 2711 during the pandemic). The pre-pandemic group had a mean age of 14.9 ± 1.73, the pandemic group of 14.75 ± 1.47. Three models were set up using binary logistic regression to adjust for confounding variables (gender, school type, alcohol consumption, smoking, playing violent video games). RESULTS: All types of bullying victimization and perpetration (physical, verbal, social and property bullying) were more common during the pandemic than before the pandemic. In terms of bullying victimization, property bullying victimization (crude odds ratio [OR]: 2.398, 95% CI: 2.014-2.854, p < 0.001; model 2 adjusted OR: 2.344, 95% CI: 1.966-2.795, p < 0.001; model 3 adjusted OR: 2.818, 95% CI: 2.292-3.464, p < 0.001) increased the most. In terms of bullying perpetration, verbal bullying perpetration (crude OR: 3.007, 95% CI: 2.448-3.693, p <0.001; model 2 adjusted OR: 2.954, 95% CI: 2.399-3.637, p < 0.001; model 3 adjusted OR:3.345, 95% CI: 2.703-4.139, p < 0.001) increased the most. CONCLUSION: This study corroborate the significance of the pandemic on traditional school bullying and suggests that we should further consider other types of bullying and establish and improve the response and prevention mechanisms during public health emergencies such as the COVID-19 pandemic.

Prediction of lung cancer metastasis by gene expression.

Tumor metastasis is the main cause of death in cancer patients. Early prediction of tumor metastasis can allow for timely intervention. At present, research on tumor metastasis mainly focuses on manual diagnosis by imaging or diagnosis by computational methods. With the deterioration of the tumor, gene expression levels in blood change greatly. It is feasible to measure the transcripts of key genes to predict whether cancer will metastasize. Therefore, in this paper, we obtained gene expression data from 226 patients from TCGA. These data included 239,322 transcripts. Background screening and LASSO analysis were used to select 31 transcripts as features. Finally, a deep neural network (DNN) was used to determine whether or not lung cancer would metastasize. We compared our methods with several other methods and found that our method achieved the best precision. In addition, in a previous study, we identified 7 genes that play a vital role in lung cancer. We added those gene transcripts into the DNN and found that the AUC and AUPR of the model were increased.

Genomic characterization of Bacillus cereus isolated from food poisoning cases revealed the mechanism of toxin production.

Introduction: Bacillus cereus is a ubiquitous opportunistic human pathogen that causes food intoxications worldwide. However, the genomic characteristics and pathogenic mechanisms of B. cereus are still unclear. Methods: Here, we isolated and purified nine strains of B. cereus (LY01-LY09) that caused vomiting, diarrhea and other symptoms from four foodborne outbreaks happened in Guizhou Province in southwest China from June to September 2021. After colony observation, Gram staining, microscopic examination and biochemical test, they were identified as B. cereus. The genomic characteristics, phylogenetic relationships and virulence factors of the isolated strains were analyzed at the genome level. Genome sequencing, comparative genomic analysis, secondary metabolite analysis and quantitative PCR were utilized to give a thorough exploration of the strains. Results: We obtained the genome maps of LY01-LY09 and found that LY01-LY09 had a complex interspecific relationship with B. anthracis and B. thuringiensis. We also observed a contraction of gene families in LY01-LY09, and the contracted families were mainly associated with prophage, which contributed to the species diversity of B. cereus. The Hsp20 gene family underwent a rapid evolution in LY01-LY09, which facilitated the adaptation of the strains to adverse environmental conditions. Moreover, the LY01-LY09 strains exhibited a higher copy number in the non-ribosomal polypeptide synthetase (NRPS) genes and carried the complete cereulide synthetase (ces) gene cluster sequences. Considering that the NRPS system is a classical regulatory mechanism for emetic toxin synthesis, we hypothesized that LY01-LY09 could synthesize emetic toxins through the regulation of ces gene clusters by the NRPS system. Discussion: These findings are important for further investigation into the evolutionary relationship between B. cereus and their related species, as well as the underlying mechanisms governing the synthesis and secretion of bacterial toxins.

Synergistic Effects of the Combinational Use of Escitalopram Oxalate and 5-Fluorouracil on the Inhibition of Gastric Cancer SNU-1 Cells.

Owing to its high recurrence rate, gastric cancer (GC) is the leading cause of tumor-related deaths worldwide. Besides surgical treatment, chemotherapy is the most commonly used treatment against GC. However, the adverse events associated with chemotherapy use limit its effectiveness in GC treatment. In this study, we investigated the effects of using combinations of low-dose 5-fluorouracil (5-FU; 0.001 and 0.01 mM) with different concentrations of escitalopram oxalate (0.01, 0.02, 0.06, and 0.2 mM) to evaluate whether the assessed combination would have synergistic effects on SNU-1 cell survival. 5-FU (0.01 mM) + escitalopram oxalate (0.02 mM) and 5-FU (0.01 mM) + escitalopram oxalate (0.06 mM) administered over 24 h showed synergistic effects on the inhibition of SNU-1 cell proliferation. Moreover, 5-FU (0.001 mM) + escitalopram oxalate (0.02 or 0.06 mM) and 5-FU (0.01 mM) + escitalopram oxalate (0.02, 0.06, or 0.2 mM) administered over 48 h showed synergistic effects on the inhibition of SNU-1 cell proliferation. Compared with controls, SNU-1 cells treated with 5-FU (0.01 mM) + escitalopram oxalate (0.02 mM) exhibited significantly increased levels of annexin V staining, reactive oxygen species, cleaved poly (ADP-ribose) polymerase, and caspase-3 proteins. Furthermore, 5-FU (12 mg/kg) + escitalopram oxalate (12.5 mg/kg) significantly attenuated xenograft SNU-1 cell proliferation in nude mice. Our study is the first to report the synergistic effects of the combinational use of low-dose 5-FU and escitalopram oxalate on inhibiting SNU-1 cell proliferation. These findings may be indicative of an alternative option for GC treatment.

The mechanism and biomarker function of Cavin-2 in lung ischemia-reperfusion injury.

BACKGROUND: Lung Ischemia Reperfusion injury(LIRI) is one of the most predominant complications of ischemic lung disease. Cavin-2 emerged as a regulator of a variety of cellular processes, including endocytosis, lipid homeostasis, signal transduction and tumorigenesis, but the function of Cavin-2 in LIRI is unknown. The purpose of this study was to determine the predictive potential of Cavin-2 in protecting lung ischemia-reperfusion injury and its corresponding mechanisms. METHODS: We found the strong relationship between Cavin-2 and multiple immune-related genes by deep learning method. To reveal the mechanism of Cavin-2 in LIRI, the LIRI SD rat model was constructed to detect the expression of Cavin-2 in the lung tissue of SD rats after LIRI, and the expression of Cavin-2 in lung cell lines was also detected. The expression of IL-6, IL-10 and MDA in cells after Cavin-2 over-expression or knockdown was examined under hypoxic conditions. The expression levels of p-AKT, p-STAT3 and p-ERK1/2 were measured in over-expressing Cavin-2 cells under hypoxic-ischemia conditions, and then the corresponding blockers of AKT, STAT3 and ERK1/2 were given to verify, whether they play a protective role in LIRI. RESULTS: After hypoxia, the expression of Cavin-2 in rat lung tissues was significantly increased, and the cellular activity and IL-10 in Cavin-2 over-expressing cells were significantly higher than that of the control group, while IL-6 and MDA were significantly lower than that of the control group, while the above results were reversed in Cavin-2 knockdown cells; Meanwhile, the phosphorylation levels of AKT, STAT3, and ERK1/2 were significantly increased in Cavin-2 over-expression cells after hypoxia. When AKT, STAT3, and ERK1/2 specific blockers were given, they lost their protective effect against LIRI. CONCLUSIONS: Cavin-2 shows biomarker potential in protecting lung from ischemia-reperfusion injury through the survivor activating factor enhancement (SAFE) and reperfusion injury salvage kinase (RISK) pathway.

Blockade of interleukin-6 receptor attenuates apoptosis and modulates the inflammatory response in Mycoplasma pneumoniae infected A549 cells.

OBJECTIVE: To investigate the effect of silencing the interleukin (IL)-6 gene on the induction of inflammation, oxidative stress and apoptosis in Mycoplasma pneumoniae (MP) infected A549 cells and its mechanism of action. METHODS: IL-6 small interfering RNA (siRNA) was synthesized and transfected into A549 cells, which were divided into a blank control group, a negative control group, and an IL-6 siRNA group. The mRNA and protein expression of IL-6 and the protein expression of CyclinD1, Cleaved caspase-3, Bax, B-cell lymphoma 2 (Bcl-2), signal transducer and activator of transcription 3 (STAT3), phosphorylated STAT3 (p-STAT3), matrix metalloproteinase (MMP)-2 and MMP-9 were measured. Besides, cell viability and apoptosis were determined. Additionally, the levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), IL-1ß, IL-8 and tumor necrosis factor (TNF)-α were measured. RESULTS: The mRNA and protein levels of IL-6 in the IL-6 siRNA group were lower than those in the blank and negative control groups (P < 0.05). The IL-6 siRNA group had higher viability but lower apoptosis rate of A549 cells at 24 h, 48 h and 72 h than the blank and negative control groups (P < 0.05). The IL-6 siRNA group had lower protein expression levels of Cleaved caspase-3 and Bax, but higher protein expression levels of CyclinD1 and Bcl-2 than the blank and negative control groups (P < 0.05). The IL-6 siRNA group had lower levels of IL-6, IL-8, TNF-α and MDA, but higher levels of SOD and GSH-PX than the blank and negative control groups (P < 0.05). CONCLUSION: Silencing the IL-6 gene can reduce the MP-induced inflammatory response and oxidative stress of A549 cells, enhance cell viability and inhibit apoptosis. Meanwhile, it was also found that STAT3 expression was inhibited after silencing IL-6 gene expression. Therefore, it is speculated that IL-6 may play a role by regulating STAT3, but its exact molecular biological mechanism still needs to be further explored.

TIM-4 in macrophages contributes to nasal polyp formation through the TGF-ß1-mediated epithelial to mesenchymal transition in nasal epithelial cells.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is caused by prolonged inflammation of the paranasal sinus mucosa. The epithelial to mesenchymal transition (EMT) is involved in the occurrence and development of CRSwNP. The T-cell immunoglobulin domain and the mucin domain 4 (TIM-4) is closely related to chronic inflammation, but its mechanism in CRSwNP is poorly understood. In our study, we found that TIM-4 was increased in the sinonasal mucosa of CRSwNP patients and, especially, in macrophages. TIM-4 was positively correlated with α-SMA but negatively correlated with E-cadherin in CRS. Moreover, we confirmed that TIM-4 was positively correlated with the clinical parameters of the Lund-Mackay and Lund-Kennedy scores. In the NP mouse model, administration of TIM-4 neutralizing antibody significantly reduced the polypoid lesions and inhibited the EMT process. TIM-4 activation by stimulating with tissue extracts of CRSwNP led to a significant increase of TGF-ß1 expression in macrophages in vitro. Furthermore, coculture of macrophages and human nasal epithelial cells (hNECs) results suggested that the overexpression of TIM-4 in macrophages made a contribution to the EMT process in hNECs. Mechanistically, TIM-4 upregulated TGF-ß1 expression in macrophages via the ROS/p38 MAPK/Egr-1 pathway. In conclusion, TIM-4 contributes to the EMT process and aggravates the development of CRSwNP by facilitating the production of TGF-ß1 in macrophages. Inhibition of TIM-4 expression suppresses nasal polyp formation, which might provide a new therapeutic approach for CRSwNP.

Protective Effect of Escitalopram on Hepatocellular Carcinoma by Inducing Autophagy.

BACKGROUND: Hepatocellular carcinoma (HCC) is an aggressive cancer with poor prognosis. Although recent research has indicated that selective serotonin reuptake inhibitors (SSRIs), including escitalopram, have anticancer effects, little is known about the effects of escitalopram on HCC. METHODS: Both in vitro and in vivo studies were conducted to verify the potentials of escitalopram on HCC treatment. To explore whether the effects of escitalopram are clinically consistent with laboratory findings, a nationwide population-based cohort study was also adopted to examine the association between escitalopram and HCC risk. RESULTS: As compared with THLE-3 cells, escitalopram significantly inhibited the proliferation of HepG2 and Huh-7 cells. Specifically, escitalopram significantly induced autophagy in HepG2 and Huh-7 cells by increasing the LC3-II/LC3-I ratio and the expression of ATG-3, ATG-5, ATG-7, and Beclin-1 proteins. Moreover, escitalopram significantly inhibited the growth of xenografted Huh-7 cells in SCID mice that were treated with 12.5 mg/kg escitalopram. Accordingly, the risk of HCC was negatively correlated with escitalopram use. CONCLUSIONS: These findings provided evidence supporting the therapeutic potential of escitalopram for HCC. Both laboratory and nationwide population-based cohort evidence demonstrated the attenuated effects of escitalopram on HCC.