Sepsis is a systemic inflammatory response syndrome caused by infection, resulting in organ dysfunction. Sepsis‐induced acute kidney injury (AKI) is one of the most common potential complications. ...Increasing reports have shown that M1 and M2 macrophages both take part in the progress of AKI by influencing the level of inflammatory factors and the cell death, including pyroptosis. However, whether M1 and M2 macrophages regulate AKI by secreting exosome remains unknown. In the present study, we isolated the exosomes from M1 and M2 macrophages and used Western blot and enzyme‐linked immunosorbent assay (ELISA) to investigate the effect of M1 and M2 exosomes on cell pyroptosis. miRNA sequencing was used to identify the different miRNA in M1 and M2 exosomes. Luciferase reporter assay was used to verify the target gene of miRNA. We confirmed that exosomes excreted by macrophages regulated cell pyroptosis in vitro by using Western blot and ELISA. miRNA sequencing revealed the differentially expressed level of miRNAs in M1 and M2 exosomes, among which miR‐93‐5p was involved in the regulation of pyroptosis. By using bioinformatics predictions and luciferase reporter assay, we found that thioredoxin–interacting protein (TXNIP) was a direct target of miR‐93‐5p. Further in vitro and in vivo experiments indicated that exosomal miR‐93‐5p regulated the TXNIP directly to influence the pyroptosis in renal epithelial cells, which explained the functional difference between different phenotypes of macrophages. This study might provide new targets for the treatment of sepsis‐induced AKI.
Bronchopulmonary dysplasia (BPD) is a severe complication of preterm infants characterized by increased alveolarization and inflammation. Premature exposure to hyperoxia is believed to be a key ...contributor to the pathogenesis of BPD. No effective preventive or therapeutic agents have been created. Stimulator of interferon gene (STING) is associated with inflammation and apoptosis in various lung diseases. Long non‐coding RNA MALAT1 has been reported to be involved in BPD. However, how MALAT1 regulates STING expression remains unknown. In this study, we assessed that STING and MALAT1 were up‐regulated in the lung tissue from BPD neonates, hyperoxia‐based rat models and lung epithelial cell lines. Then, using the flow cytometry and cell proliferation assay, we found that down‐regulating of STING or MALAT1 inhibited the apoptosis and promoted the proliferation of hyperoxia‐treated cells. Subsequently, qRT‐PCR, Western blotting and dual‐luciferase reporter assays showed that suppressing MALAT1 decreased the expression and promoter activity of STING. Moreover, transcription factor CREB showed its regulatory role in the transcription of STING via a chromatin immunoprecipitation. In conclusion, MALAT1 interacts with CREB to regulate STING transcription in BPD neonates. STING, CREB and MALAT1 may be promising therapeutic targets in the prevention and treatment of BPD.
Septic acute kidney injury (AKI) is characterized by inflammation. Pyroptosis often occurs during AKI and is associated with the development of septic AKI. This study found that induction of ...insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1) to a higher level can induce pyroptosis in renal tubular cells. Meanwhile, macrophage migration inhibitory factor (MIF), a subunit of NLRP3 inflammasomes, was essential for IGF2BP1-induced pyroptosis. A putative m6A recognition site was identified at the 3'-UTR region of E2F transcription factor 1 (E2F1) mRNA via bioinformatics analyses and validated using mutation and luciferase experiments. Further actinomycin D (Act D) chase experiments showed that IGF2BP1 stabilized E2F1 mRNA dependent on m6A. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) indicated that E2F1 acted as a transcription factor to promote MIF expression. Thus, IGF2BP1 upregulated MIF through directly upregulating E2F1 expression via m6A modification. Experiments on mice with cecum ligation puncture (CLP) surgery verified the relationships between IGF2BP1, E2F1, and MIF and demonstrated the significance of IGF2BP1 in MIF-associated pyroptosis
. In conclusion, IGF2BP1 was a potent pyroptosis inducer in septic AKI through targeting the MIF component of NLRP3 inflammasomes. Inhibiting IGF2BP1 could be an alternate pyroptosis-based treatment for septic AKI.
Evidence has been emerging of the importance of long non‐coding RNAs (lncRNAs) in genome instability. However, no study has established how to classify such lncRNAs linked to genomic instability, and ...whether that connection poses a therapeutic significance. Here, we established a computational frame derived from mutator hypothesis by combining profiles of lncRNA expression and those of somatic mutations in a tumor genome, and identified 185 candidate lncRNAs associated with genomic instability in lung adenocarcinoma (LUAD). Through further studies, we established a six lncRNA‐based signature, which assigned patients to the high‐ and low‐risk groups with different prognosis. Further validation of this signature was performed in a number of separate cohorts of LUAD patients. In addition, the signature was found closely linked to genomic mutation rates in patients, indicating it could be a useful way to quantify genomic instability. In summary, this research offered a novel method by through which more studies may explore the function of lncRNAs and presented a possible new way for detecting biomarkers associated with genomic instability in cancers.
The emerging proof of long non‐coding RNAs (lncRNAs) as important components of genome instability have been revealed. Here, we established a six lncRNA‐based signature, which was found closely linked to genomic mutation rates in patients, indicating it could be a powerful way to quantify genomic instability.
Orosomucoid like-3 (ORMDL3) has been identified to be associated with the development of asthma according to previous studies. However, the definite role of ORMDL3 in the pathogenesis of asthma ...remains unclear. In this study, we found ORMDL3 was highly expressed in PBMC specimens from childhood asthma patients. Cytokines production and p-ERK/MMP-9 pathway expression was also increased in childhood asthma patients compared with controls. In addition, ORMDL3 overexpression induced IL-6 and IL-8 release and activated p-ERK/MMP-9 pathway in vitro. Increased ORMDL3 expression was observed after treated with 5-Aza-CdR. 5-Aza-CdR decreased the percentage of the CpG island in the ORMDL3 promoter region and increased its promoter activity. In addition, 5-Aza-CdR significantly increased IL-6 and IL-8 levels in NHBE cells while there was no obvious alteration after knocking down ORMDL3. Knockdown of ORMDL3 also significantly decreased the expression of p-ERK/MMP-9 pathway in the presence or absence of 5-Aza-CdR. In conclusion, our study provided novel evidence for the association between ORMDL3 and asthma-associated cytokines. Moreover, DNA methylation plays an important role in ORMDL3-mediated increased IL-6 and IL-8 levels and p-ERK/MMP-9 pathway expression.
•Dynamic expression of SHANK3 in brain organoids at various stages.•Transcription regulation of SHANK3 during brain development.•EGR1 positively regulates SHANK3 in ASD.
The expression levels of ...SHANK3 are associated with autism spectrum disorder (ASD). The dynamic changes in SHANK3 expression during different stages of brain development may impact the progression of ASD. However, no studies or detailed analyses exploring the upstream mechanisms that regulate SHANK3 expression have been reported. In this study, we employed immunofluorescence to examine the expression of SHANK3 in brain organoids at various stages. Our results revealed elevated levels of SHANK3 expression in brain-like organoids at Day 60. Additionally, we utilized bioinformatics software to predict and analyze the SHANK3 gene’s transcription start site. Through the dual luciferase reporter gene technique, we identified core transcription elements within the SHANK3 promoter. Site-directed mutations were used to identify specific transcription sites of SHANK3. To determine the physical binding of potential transcription factors to the SHANK3 promoter, we employed electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP). Our findings demonstrated that the transcription factor EGR1 regulates SHANK3 expression by binding to the transcription site of the SHANK3 promoter. Although this study did not investigate the pathological phenotypes of human brain organoids or animal model brains with EGR1 deficiency, which could potentially substantiate the findings observed for SHANK3 mutants, our findings provide valuable insights into the relationship between the transcription factor, EGR1, and SHANK3. This study contributes to the molecular understanding of ASD and offers potential foundations for precise targeted therapy.
Orosomucoid 1-like protein 3 (ORMDL3) is an asthma candidate gene associated with virus-triggered recurrent wheeze. Stimulator of interferon gene (STING) controls TLR-independent cytosolic responses ...to viruses. However, the association of STING with ORMDL3 is unclear. Here, we have shown that ORMDL3 expression shows a linear correlation with STING in recurrent wheeze patients. In elucidating the molecular mechanisms of the ORMDL3-STING relationship, we found that STING promoted the transcriptional activity of ORMDL3, which was significantly associated with increased levels of interferon regulatory factor 3 (IRF3) and signal transducer and activator of transcription 6 (STAT6). Further study showed that via activation of TANK binding kinase 1 (TBK1), STING enhanced the phosphorylation and binding of IRF3 and STAT6, which upregulated ORMDL3 by binding to the promoter. Our results showed that STING positively regulated ORMDL3 through the TBK1-IRF3-STAT6 complex.
•STING and ORMDL3 genes expression was increased in patients with recurrent wheeze.•STING upregulates ORMDL3 expression and promoter activity in cells.•ORMDL3 is positively associated with the STING-TBK1-IRF3/STAT6 signaling pathway.•STING increases the ORMDL3 expression in asthma and recurrent wheeze by promoting both the expression and activity of the TBK1-IRF3-STAT6 complex.
Two substituted 1,10-phenanthroline derivatives, i.e., 1,10-phenanthroline-4,7-diol (PHEN-OH) and 1,10-phenanthroline-5,6-diamine (PHEN-NH2), were investigated in terms of their anticorrosive ...performance for mild steel in HCl media with the use of gravimetric, electrochemical and theoretical calculation methods. PHEN-OH exhibited more efficient corrosion inhibition than PHEN-NH2. Essentially, both inhibitors, PHEN-OH and PHEN-NH2, were confirmed to be predominately cathodic. Thermodynamic study indicated that PHEN-OH and PHEN-NH2 spontaneously adsorbed on the surface of the test sample via two adsorption modes predominately by chemisorption, and the adsorption was consistent with the Langmuir adsorption isotherm. The inhibition mechanism was further verified via adsorption isotherms, UV-vis spectroscopy, and surface analysis (SEM-EDX). The relationship between the molecular structure of the inhibitors and the anticorrosive performance was determined by theoretical calculation, consistent with experimental data.
In order to improve the corrosion inhibition performance and the application scope of o - phenanthroline derivatives, a new type of 1,2 - diphenyl - 1H - imidazo 4,5 - f1,10 phenanthroline (HIP) ...corrosion inhibitor was synthesized by molecular design method. The corrosion inhibition effect on mild steel in hydrochloric acid medium and the adsorption behavior on the surface of mild steel were studied through weightlessness method, electrochemical method and scanning electron microscope. In addition, the adsorption thermodynamics of corrosion inhibitor molecules were analyzed, and the relationship between the molecular structure of HIP and corrosion inhibition performance was further studied by quantum chemical method. Results showed that HIP had good corrosion inhibition performance for mild steel in 1.0 mol/L HCl solution, and the corrosion inhibition efficiency was 97.0% under the temperature of 40 ℃ with the inhibitor concentration of 1.0 mmol/L. Moreover, the adsorption of HIP on the surface of mild s
Objective To investigate the correlation between Glasgow score and blood inflammatory markers before treatment with the efficacy of nasopharyngeal carcinoma. Methods Cases from the two clinical ...centers were divided into training set and validation set， and the clinical characteristics of the two groups were compared to be balanced. To search the independent prognostic risk factors of nasopharyngeal carcinoma and then the prognostic index of each patient was calculated， and the patients were divided into high-risk， intermediate-risk and low-risk groups. Further validation in the validation set. Results Cox multivariate analysis of the training set showed that age >50， T3-T4， N2-N3， GPS score of 1-2， NLR>2.5， and LMR≤2.35 before treatment were poor prognostic factors affecting the 5-year disease-specific survival rate of patients with nasopharyngeal carcinoma. Conclusion The combination of GPS， NLR， LMR and age， TNM staging may provide a new way for the prognosis evaluation of patients with nasopharyngeal carci
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