Inhibition of STAT3 alleviates LPS-induced apoptosis and inflammation in renal tubular epithelial cells by transcriptionally down-regulating TASL.

BACKGROUND: Systemic lupus erythematosus (SLE) is a common autoimmune disease that impacts various organs. Lupus nephritis (LN) significantly contributes to death in children with SLE. Toll-like receptor (TLR) adaptor interacting with SLC15A4 on the lysosome (TASL) acts as an innate immune adaptor for TLR and is implicated in the pathogenesis of SLE. A transcription factor known as signal transducer and activator of transcription 3 (STAT3), which is known to be linked to autoimmune diseases, is also involved in the development of SLE. METHODS: Bioinformatics and real-time quantitative PCR (qRT-PCR) was used to detect the expression of STAT3 and TASL in peripheral blood of SLE patients and their correlation. Bioinformatics analysis, qRT-PCR, luciferase assay and chromatin immunoprecipitation (ChIP) were used to verify the regulation of transcription factor STAT3 on TASL. The expression levels of STAT3, TASL and apoptosis-related genes in LPS-induced HK2 cells were detected by qRT-PCR and Western blot. TUNEL staining were used to detect the apoptosis of HK2 cells after LPS stimulation. ELISA and qRT-PCR were used to detect the levels of inflammatory cytokines in the cell culture supernatant. TASL knockdown in HK2 cells was used to detect the changes in apoptosis-related genes and inflammatory factors. The expression level of TASL in LPS-stimulated HK2 cells and its effect on cell apoptosis and inflammatory factors were observed by knocking down and overexpressing STAT3, respectively. It was also verified in a rescue experiment. RESULTS: The expressions of STAT3 and TASL were higher in SLE than in healthy children, and the expression of STAT3 was positively correlated with TASL. Transcription factor STAT3 can directly and positively regulate the expression of TASL through the promoter region binding site. The expression of STAT3, TASL and inflammatory cytokines was elevated, and the change of apoptosis was up-regulated in LPS-stimulated HK2 cells. Inhibition of STAT3 alleviates LPS-stimulated apoptosis and inflammatory response in HK2 cells through transcriptional regulation of TASL. CONCLUSIONS: These findings provide new insights into the transcriptional regulation of TASL and provide new evidence of a direct regulatory relationship between signaling nodes in the lupus signaling network.

Integration of transcriptomics reveals ferroptosis-related signatures and immune cell infiltration in bronchopulmonary dysplasia.

Ferroptosis has emerged as a significant factor in the development of bronchopulmonary dysplasia (BPD). Nevertheless, our understanding of the potential involvement of ferroptosis-related genes (FRGs) in BPD remains incomplete. In this study, we leveraged the Gene Expression Omnibus (GEO) database to investigate this aspect. We identified 20 differentially expressed FRGs that are associated with BPD, shedding light on their potential role in the condition.LASSO along with SVM-RFE algorithms found that 12 genes: MEG3, ACSL1, DPP4, GALNT14, MAPK14, CD82, SMPD1, NR1D1, PARP3, ACVR1B, H19, and SLC7A11 were closely related to ferroptosis modulation and immunological response. These genes were used to create a nomogram with good predictive power and were found to be involved in BPD-linked pathways. In addition, the marker genes-based prediction model performed well in external validation data sets. The study also showed a significance between BPD and control samples in terms of immune cell infiltration. These findings may help improve our understanding of FRGs in BPD and lead to the development of more effective immunotherapies.

Comprehensive analysis for cellular senescence-related immunogenic characteristics and immunotherapy prediction of acute myeloid leukemia.

In malignancies, cellular senescence is critical for carcinogenesis, development, and immunological regulation. Patients with acute myeloid leukemia (AML) have not investigated a reliable cellular senescence-associated profile and its significance in outcomes and therapeutic response. Cellular senescence-related genes were acquired from the CellAge database, while AML data were obtained from the GEO and TCGA databases. The TCGA-AML group served as a training set to construct a prognostic risk score signature, while the GSE71014 set was used as a testing set to validate the accuracy of the signature. Through exploring the expression profiles of cellular senescence-related genes (SRGs) in AML patients, we used Lasso and Cox regression analysis to establish the SRG-based signature (SRGS), which was validated as an independent prognostic predictor for AML patients via clinical correlation. Survival analysis showed that AML patients in the low-risk score group had a longer survival time. Tumor immune infiltration and functional enrichment analysis demonstrated that AML patients with low-risk scores had higher immune infiltration and active immune-related pathways. Meanwhile, drug sensitivity analysis and the TIDE algorithm showed that the low-risk score group was more susceptible to chemotherapy and immunotherapy. Cell line analysis in vitro further confirmed that the SRGs in the proposed signature played roles in the susceptibility to cytarabine and YM155. Our results indicated that SRGS, which regulates the immunological microenvironment, is a reliable predictor of the clinical outcome and immunotherapeutic response in AML.

Identification of a prognostic model based on costimulatory molecule-related subtypes and characterization of tumor microenvironment infiltration in acute myeloid leukemia.

Costimulatory molecules have been found to play significant roles in anti-tumor immune responses, and are deemed to serve as promising targets for adjunctive cancer immunotherapies. However, the roles of costimulatory molecule-related genes (CMRGs) in the tumor microenvironment (TME) of acute myeloid leukemia (AML) remain unclear. In this study, we described the CMRG alterations in the genetic and transcriptional fields in AML samples chosen from two datasets. We next evaluated their expression and identified two distinct costimulatory molecule subtypes, which showed that the alterations of CMRGs related to clinical features, immune cell infiltration, and prognosis of patients with AML. Then, a costimulatory molecule-based signature for predicting the overall survival of AML patients was constructed, and the predictive capability of the proposed signature was validated in AML patients. Moreover, the constructed costimulatory molecule risk model was significantly associated with chemotherapeutic drug sensitivity of AML patients. In addition, the identified genes in the proposed prognostic signature might play roles in pediatric AML. CMRGs were found to be potentially important in the AML through our comprehensive analysis. These findings may contribute to improving our understanding of CMRGs in patients with AML, as well as provide new opportunities to assess prognosis and develop more effective immunotherapies.

CREB1 Transcriptionally Activates LTBR to Promote the NF-κB Pathway and Apoptosis in Lung Epithelial Cells.

Bronchopulmonary dysplasia (BPD) is a prevalent chronic pediatric lung disease. Aberrant proliferation and apoptosis of lung epithelial cells are important in the pathogenesis of BPD. Lymphotoxin beta receptor (LTBR) is expressed in lung epithelial cells. Blocking LTBR induces regeneration of lung tissue and reverts airway fibrosis in young and aged mice. This study is aimed at revealing the role of LTBR in BPD. A mouse model of BPD and two in vitro models of BPD using A549 cells and type II alveolar epithelial (ATII) cells were established by exposure to hyperoxia. We found that LTBR and CREB1 exhibited a significant upregulation in lungs of mouse model of BPD. LTBR and CREB1 expression were also increased by hyperoxia in A549 and ATII cells. According to results of cell counting kit-8 assay and flow cytometry analysis, silencing of LTBR rescued the suppressive effect of hyperoxia on cell viability and its promotive effect on cell apoptosis of A549 and ATII cells. Bioinformatics revealed CREB1 as a transcriptional factor for LTBR, and the luciferase reporter assay and ChIP assay subsequently confirmed it. The NF-κB pathway was regulated by LTBR. CREB1 induced LTBR expression at the transcriptional level to regulate NF-κB pathway and further modulate A549 and ATII cells viability and apoptosis. In conclusion, this study revealed the CREB1/LTBR/NF-κB pathway in BPD and supported the beneficial role of LTBR silence in BPD by promoting viability and decreasing apoptosis of lung epithelial cells.