A prognostic model of idiopathic pulmonary fibrosis constructed based on macrophage and mitochondria-related genes.

BACKGROUND: Studies have shown that mitochondrial function and macrophages may play a role in the development of idiopathic pulmonary fibrosis (IPF). However, the understanding of the interactions and specific mechanisms between mitochondrial function and macrophages in pulmonary fibrosis is still very limited. METHODS: To construct a prognostic model for IPF based on Macrophage- related genes (MaRGs) and Mitochondria-related genes (MitoRGs), differential analysis was performed to achieve differentially expressed genes (DEGs) between IPF and Control groups in the GSE28042 dataset. Then, MitoRGs, MaRGs and DEGs were overlapped to screen out the signature genes. The univariate Cox analysis and the least absolute shrinkage and selection operator (LASSO) algorithm were implemented to achieve key genes. Furthermore, the independent prognostic analysis was employed. The ingenuity pathway analysis (IPA) was employed to further understand the molecular mechanisms of key genes.Next, the immune infiltration analysis was implemented to identify differential immune cells between two risk subgroups. RESULTS: There were 4791 DEGs between IPF and Control groups. Furthermore, 26 signature genes were achieved by the intersection processing. Three key genes including ALDH2, MCL1, and BCL2A1 were achieved, and the risk model based on the key genes was created. In addition, a nomogram for survival forecasting of IPF patients was created based on riskScore, Age, and Gender, and we found that key genes were associated with classical pathways including 'Apoptosis Signaling', 'PI3K/AKT Signaling', and so on. Next, two differential immune cells including Monocytes and CD8 T cells were identified between two risk subgroups. Moreover, we found that MIR29B2CHG and hsa-mir-1-3p could regulate the expression of ALDH2. CONCLUSION: We achieved 3 key genes including ALDH2, MCL1,, and BCL2A1 associated with IPF, providing a new theoretical basis for clinical treatment of IPF.

Short-chain fatty acid-producing bacterial strains attenuate experimental ulcerative colitis by promoting M2 macrophage polarization via JAK/STAT3/FOXO3 axis inactivation.

BACKGROUND: Patients with inflammatory bowel disease (IBD), dysbiosis, and immunosuppression who receive fecal microbiota transplantation (FMT) from healthy donors are at an increased risk of developing bacteremia. This study investigates the efficacy of a mixture of seven short-chain fatty acid (SCFA)-producing bacterial strains (7-mix), the resulting culture supernatant mixture (mix-sup), and FMT for treating experimental ulcerative colitis (UC) and evaluates underlying mechanisms. METHODS: Utilizing culturomics, we isolated and cultured SCFA-producing bacteria from the stool of healthy donors. We used a mouse model of acute UC induced by dextran sulfate sodium (DSS) to assess the effects of 7-mix, mix-sup, and FMT on intestinal inflammation and barrier function, microbial abundance and diversity, and gut macrophage polarization by flow cytometry, immunohistochemistry, 16S rRNA gene sequencing, and transwell assays. RESULTS: The abundance of several SCFA-producing bacterial taxa decreased in patients with UC. Seven-mix and mix-sup suppressed the inflammatory response and enhanced intestinal mucosal barrier function in the mouse model of UC to an extent similar to or superior to that of FMT. Moreover, 7-mix and mix-sup increased the abundance of SCFA-producing bacteria and SCFA concentrations in colitic mice. The effects of these interventions on the inflammatory response and gut barrier function were mediated by JAK/STAT3/FOXO3 axis inactivation in macrophages by inducing M2 macrophage polarization in vivo and in vitro. CONCLUSIONS: Our approach provides new opportunities to rationally harness live gut probiotic strains and metabolites to reduce intestinal inflammation, restore gut microbial composition, and expedite the development of safe and effective treatments for IBD.

Genistein prevents the production of hypospadias induced by Di-(2-ethylhexyl) phthalate through androgen signaling and antioxidant response in rats.

Environmental estrogen exposure has increased dramatically over the past 50 years. In particular, prenatal exposure to estrogen causes many congenital diseases, among which reproductive system development disorders are extremely serious. In this study, the molecular mechanism of hypospadias and the therapeutic effect of genistein (GEN) were investigated through in vivo models prepared by Di-(2-ethylhexyl) phthalate (DEHP) exposure between 12 and 19 days of gestation. With increased DEHP concentrations, the incidence of hypospadias increased gradually. DEHP inhibited the key enzymes involved in steroid synthesis, resulting in decreasing testosterone synthesis. At the same time, DEHP increased reactive oxygen species (ROS) and produced inflammatory factors via NADPH oxidase-1 (NOX1) and NADPH oxidase-4 (NOX4) pathways. It also inhibited Steroid 5 α Reductase 2 (Srd5α2) and decreased dihydrotestosterone (DHT) synthesis. Additionally, DEHP inhibited the androgen receptor (AR), resulting in reduced DHT binding to the AR that ultimately retarded the development of the external reproductive system. GEN, a phytoestrogen, competes with DEHP for binding to estrogen receptor ß (ERß). This competition, along with GEN's antiestrogen and antioxidant properties, could potentially reverse impairments. The findings of this study provide valuable insights into the role of phytoestrogens in alleviating environmental estrogen-induced congenital diseases.

Regulation of epithelial cell differentiation by the Ubiquitous expressed transcript isoform 1 in ulcerative colitis.

BACKGROUND AND AIM: Mucosal healing has emerged as a desirable treatment goal for patients with ulcerative colitis (UC). Healing of mucosal wounds involves epithelial cell proliferation and differentiation, and Y-box transcription factor ZONAB has recently been identified as the key modulator of intestinal epithelial restitution. METHODS: We studied the characteristics of UXT-V1 expression in UC patients using immunohistochemistry and qPCR. The functional role of UXT-V1 in the colonic epithelium was investigated using lentivirus-mediated shRNA in vitro and ex vivo. Through endogenous Co-immunoprecipitation and LC-MS/MS, we identified ZONAB as a UXT-V1-interactive protein. RESULTS: Herein, we report that UXT-V1 promotes differentiation of intestinal epithelial cells by regulating the nuclear translocation of ZONAB. UXT-V1 was upregulated in the intestinal epithelia of UC patients compared with that of healthy controls. Knocking down UXT-V1 in NCM-460 cells led to the enrichment of pathways associated with proliferation and differentiation. Furthermore, the absence of UXT-V1 in cultured intestinal epithelial cells and colonic organoids inhibited differentiation to the goblet cell phenotype. Mechanistically, the loss of UXT-V1 in the intestinal epithelial cells allowed nuclear translocation of ZONAB, wherein it regulated the transcription of differentiation-related genes, including AML1 and KLF4. CONCLUSION: Taken together, our study reveals a potential role of UXT-V1 in regulating epithelial cell differentiation, proving a molecular basis for mucosal healing in UC.

Identification of the molecular subtypes and construction of risk models in neuroblastoma.

The heterogeneity of neuroblastoma directly affects the prognosis of patients. Individualization of patient treatment to improve prognosis is a clinical challenge at this stage and the aim of this study is to characterize different patient populations. To achieve this, immune-related cell cycle genes, identified in the GSE45547 dataset using WGCNA, were used to classify cases from multiple datasets (GSE45547, GSE49710, GSE73517, GES120559, E-MTAB-8248, and TARGET) into subgroups by consensus clustering. ESTIMATES, CIBERSORT and ssGSEA were used to assess the immune status of the patients. And a 7-gene risk model was constructed based on differentially expressed genes between subtypes using randomForestSRC and LASSO. Enrichment analysis was used to demonstrate the biological characteristics between different groups. Key genes were screened using randomForest to construct neural network and validated. Finally, drug sensitivity was assessed in the GSCA and CellMiner databases. We classified the 1811 patients into two subtypes based on immune-related cell cycle genes. The two subtypes (Cluster1 and Cluster2) exhibited distinct clinical features, immune levels, chromosomal instability and prognosis. The same significant differences were demonstrated between the high-risk and low-risk groups. Through our analysis, we identified neuroblastoma subtypes with unique characteristics and established risk models which will improve our understanding of neuroblastoma heterogeneity.

Diagnostic value of neuronal pentraxin II methylation in patients with pancreatic cancer: Meta-analysis.

BACKGROUND: Pancreatic cancer (PC) is a devasting disease of which mortality almost parallels its incidence. PC tissue may express aberrantly methylated neuronal pentraxin II (NPTX2), but it is unclear what the consequences of this are. METHODS: We systematically searched PubMed, Web of Science, the Chinese National Knowledge Infrastructure (CNKI), from inception to July 15, 2020, to identify if the detection of methylated NPTX2 have sufficient sensitivity and specificity to identify PC from other benign pancreatic diseases. RESULTS: Majority of the studies obtained samples from pancreatic juice by endoscopy or surgery and composed of population with chronic pancreatitis, benign cystic lesion, intraductal papillary mucinous neoplasm, and healthy controls. Our results demonstrated that the diagnostic value of methylated NPTX2 is of widely various sensitivity and specificity and it shown higher specificity in differentiate PC from benign diseases. The lab method of quantitative real-time methylation-specific PCR (QMSP) has higher specificity than real-time methylation-specific PCR (MSP) in detecting the indicator. CONCLUSIONS: NPTX2 methylation could serve as a promising molecular biomarker for pancreatic cancer diagnosis, for its high diagnostic value in differentiating pancreatic cancer from benign pancreatic disease with the lab method. The variable sensitivity of methylated NPTX2 was multifactorial, and it must be promoted before applied as screening test in clinical practice. Furthermore, experiments on methylated NPTX2 were needed to expanded for lower the heterogeneity.

Systematic review and meta-analysis of the role of Faecalibacterium prausnitzii alteration in inflammatory bowel disease.

BACKGROUND AND AIM: We comprehensively carry out a systematic review and meta-analysis of previous studies to determine the association between intestinal Faecalibacterium prausnitzii (F. prausnitzii) and inflammatory bowel disease (IBD) in human studies. METHODS: A systematic literature search of PubMed, Embase, and the Cochrane Library database was conducted until April 1, 2020. Inclusion criteria were studies involving patients with Crohn's disease (CD) or ulcerative colitis (UC) with abundance of F. prausnitzii. The quality of the studies was assessed by the modified Newcastle-Ottawa scale. RESULTS: A total of 1669 subjects (427 CD patients, 560 UC patients, and 682 healthy controls) were enrolled from 16 studies. Both CD (standardized mean difference [SMD]: -1.36; 95% CI, -1.74 to -0.98; P < 0.00001) and UC patients (SMD: -0.81; 95% CI, -1.21 to -0.42; P < 0.0001) had a lower abundance of F. prausnitzii than the healthy controls. Compared with the IBD remission patients, the IBD active patients had lower levels of F. prausnitzii (SMD: -0.56; 95% CI, -0.91 to -0.21; P = 0.002). In the subgroup analyses, the abundance of F. prausnitzii was reduced in both active CD patients (SMD: -0.78; 95% CI, -1.51 to -0.04; P = 0.04) and active UC patients (SMD:-0.44; 95%CI, -0.81 to -0.07; P = 0.02) when compared with the patients with CD or UC in remission, respectively. CONCLUSION: A negative association between abundance of F. prausnitzii and IBD activity is observed, but a cut-off level of F. prausnitzii to diagnose and/or to start treating IBD is not determined.

Genipin protects against H2O2-induced oxidative damage in retinal pigment epithelial cells by promoting Nrf2 signaling.

Oxidative stress serves a vital function in the pathogenesis of age­related macular degeneration (AMD); genipin (GP) possesses antioxidative properties. The present study aimed to investigate the effects of GP on retinal pigment epithelial (RPE) cells induced by H2O2 and the underlying mechanism. ARPE­19 cells were subjected to H2O2 treatment to induce oxidative damage. Cell viability was determined via an MTT assay. Reactive oxygen species (ROS) levels and cell apoptosis were detected by flow cytometry. Nuclear factor­erythroid 2­related factor­2 (Nrf2) signaling­associated and the expression of apoptosis­associated factors were measured using reverse transcription­quantitative polymerase chain reaction assay and western blotting. The results revealed that 200 µM H2O2 and 30 µM GP were determined to be the optimal concentrations for subsequent experimentation. GP reversed the inhibitory effects of H2O2 by promoting cell viability, attenuating ROS accumulation and cell apoptosis, and increased the expression of Nrf2, heme oxygenase­1 (HO­1) and NAD(P)H: Quinine oxidoreductase 1 (NQO1); Nrf2 silencing inhibited HO­1 and NQO1 expression. In addition, Nrf2 silencing enhanced the effects of H2O2 by promoting ROS production and cell apoptosis. Compared with H2O2, Nrf2 silencing further decreased the expression levels of B­cell lymphoma­2 (Bcl­2), but increased that of Bcl­2­associated X protein and cleaved­caspase­3. The results of the present study revealed that Nrf2 silencing attenuated the protective effects of GP on H2O2­induced injury in ARPE­19 cells by promoting apoptosis and oxidation. Collectively, GP attenuated oxidative damage induced by H2O2 in ARPE­19 cells. Furthermore, the molecular mechanism may be associated with the Nrf2 signaling pathway. The findings of the present study nay provide insight into a potential therapeutic agent for the treatment of AMD.

Tear Luminex Analysis in Dry Eye Patients.

BACKGROUND The purpose of this study was to analyze tear inflammatory cytokines of different subclasses of dry eye disease (DED) patients using Luminex technology. MATERIAL AND METHODS Forty-five DED patients including 20 Sjogren syndrome aqueous tear deficiency (SS-ATD) patients, 20 non-Sjogren syndrome aqueous tear deficiency (NSS-ATD) patients, 15 meibomian gland dysfunction (MGD) patients, and 15 normal participants were enrolled in this study. Concentrations of 11 inflammatory cytokines in tear samples of study participants were measured by Luminex assay; ELISA assay was further applied for validation. RESULTS The levels of cytokines were mostly increased (TNF-α, IL-1α, IL-1ß, IL-6, IL-8, IL-12 P70, IL-13, IFN-γ, and MIP-1α) in DED patients compared with normal participants. And the levels of TNF-α, IL-6, IL-8, and IL-12P70 were significantly elevated in tears of the patient groups compared to tears of participants in the normal group (P<0.05). Statistical differences were also observed among the patient groups (SS-ATD, NSS-ATD, and MGD) for the level of IL-8 and TNF-α. The results of ELISA assay demonstrated the consistence with Luminex assay, confirming the practicality of Luminex technology for the analysis of multiple cytokines in DED patient tears. CONCLUSIONS The levels of inflammatory cytokines were mostly elevated in DED patients, and statistical differences of some cytokines were also found between SS-ATD, NSS-ATD, and MGD groups, suggesting that inflammatory cytokines could be potential supplements for the diagnosis of DED subclasses and therapeutic targets for DED patients.

HOXB5 promotes retinoblastoma cell migration and invasion via ERK1/2 pathway-mediated MMPs production.

Homeobox genes (HOX genes) have been implicated in many tumors. As a member of HOX genes, HOXB5 is overexpressed in bladder cancer and contributes to the proliferation and invasion of breast cancer cells. However, functions of HOXB5 in retinoblastoma remain elusive. In this study, we found that HOXB5 expression is upregulated in retinoblastoma cell lines and tissues. Overexpression of HOXB5 promoted retinoblastoma cell migration and invasion, but knockdown of HOXB5 suppressed the migration and invasion. Moreover, HOXB5 induced the activation of ERK1/2 and upregulated the production of MMP-3 and MMP-13. In addition, ERK1/2 pathway was required for HOXB5-mediated retinoblastoma cell migration and invasion. Taken together, our study suggests that HOXB5 promotes the migration and invasion of retinoblastoma cells by inducing the activation of ERK1/2 and increasing the production of MMP-3 and MMP-13. Therefore, HOXB5 may represent an effective target for treatment of retinoblastoma.