Transcriptome-Wide Profiling of Nascent RNA in Neurons with Enriched H3K27ac Signal Elevates eRNA Identification Efficiency.

Growing evidence suggests that activity-dependent gene expression is crucial for neuronal plasticity and behavioral experience. Enhancer RNAs (eRNAs), a class of long noncoding RNAs, play a key role in these processes. However, eRNAs are highly dynamic and are often present at lower levels than their corresponding mRNAs, making them difficult to detect using total RNA-seq techniques. Nascent RNA sequencing, which separates nascent RNAs from the steady-state RNA population, has been shown to increase the ability to detect activity-induced eRNAs with a higher signal-to-noise ratio. However, there is a lack of bioinformatic tools or pipelines for detecting eRNAs utilizing nascent RNA-seq and other multiomics data sets. In this study, we addressed this gap by developing a novel bioinformatic framework, e-finder, for finding eRNAs and have made it available to the scientific community. Additionally, we reanalyzed our previous nascent RNA sequencing data and compared them with total RNA-seq data to identify activity-regulated RNAs in neuronal cell populations. Using H3K27 acetylome data, we characterized activity-dependent eRNAs that drive the transcriptional activity of the target genes. Our analysis identified a subset of eRNAs involved in mediating synapse organization, which showed increased activity-dependent transcription after the potassium chloride stimulation. Notably, our data suggest that nascent RNA-seq with an enriched H3K27ac signal exhibits high resolution to identify potential eRNAs in response to membrane depolarization. Our findings uncover the role of the eRNA-mediated gene activation network in neuronal systems, providing new insights into the molecular processes characterizing neurological diseases.

CDK4/6 inhibitor PD-0332991 suppresses hepatocarcinogenesis by inducing senescence of hepatic tumor-initiating cells.

INTRODUCTION: Owing to the limited treatment options for hepatocellular carcinoma (HCC), interventions targeting pre-HCC stages have attracted increasing attention. In the pre-HCC stage, hepatic tumor-initiating cells (hTICs) proliferate abnormally and contribute to hepatocarcinogenesis. Numerous studies have investigated targeted senescence induction as an HCC intervention. However, it remains to be clarified whether senescence induction of hTICs could serve as a pre-HCC intervention. OBJECTIVES: This study was designed to investigate whether senescence induction of hTICs in the precancerous stage inhibit HCC initiation. METHODS AND RESULTS: HCC models developed from chronic liver injury (CLI) were established by using Fah-/- mice and N-Ras + AKT mice. PD-0332991, a selective CDK4/6 inhibitor that blocks the G1/S transition in proliferating cells, was used to induce senescence during the pre-HCC stage. Upon administration of PD-0332991, we observed a significant reduction in HCC incidence following selective senescence induction in hTICs, and an alleviation liver injury in the CLI-HCC models. PD-0332991 also induced senescence in vitro in cultured hTICs isolated from CLI-HCC models. Moreover, RNA sequencing (RNA-seq) analysis delineated that the "Cyclin D-CDK4/6-INK4-Rb" pathway was activated in both mouse and human liver samples during the pre-HCC stage, while PD-0332991 exhibited substantial inhibition of this pathway, thereby inducing cellular senescence in hTICs. Regarding the immune microenvironment, we demonstrated that senescent hTICs secrete key senescence-associated secretory phenotypic (SASP) factors, CXCL10 and CCL2, to activate and recruit macrophages, and contribute to immune surveillance. CONCLUSION: We found that hTICs can be targeted and induced into a senescent state during the pre-HCC stage. The SASP factors released by senescent hTICs further activate the immune response, facilitating the clearance of hTICs, and consequently suppressing HCC occurrence. We highlight the importance of pre-HCC interventions and propose that senescence-inducing drugs hold promise for preventing HCC initiation under CLI.

The relationship between tricuspid annular plane systolic excursion on transesophageal echocardiography and the incidence of postoperative acute kidney injury in patients undergoing coronary artery bypass grafting surgery: a multicenter prospective cohort study.

BACKGROUND: To date, the relationship between the Transesophageal Echocardiography (TEE) monitoring indicator tricuspid annular plane systolic excursion (TAPSE) and the incidence of postoperative acute kidney injury (AKI) in Coronary Artery Bypass Grafting(CABG) patients remains unknown. The main objective of this study was to explore the relationship between the TAPSE and the incidence of AKI in CABG patients. METHODS: This was a multicenter prospective cohort study was conducted between September 2021 and July 2022. Among 266 patients aged at least 18 years who underwent elective CABG, 140 were included. RESULTS: We measured TAPSE via M-mode TEE via the mid-esophageal (ME) right ventricle(RV) inflow-outflow view (60°). All echocardiographic measurements were performed three separate times at each time point: T0 (before the start of CABG), T2 (approximately 5 ∼ 10 min after neutralization of protamine) and T3 (before leaving the operating room), and then averaged. Serum creatinine was measured 1 day before and within 7 days after CABG. There was no statistically significant association between the TEE-monitoring indicator TAPSE and the incidence of postoperative AKI in patients who underwent CABG. CONCLUSIONS: The TAPSE was not significantly correlated with postoperative AKI incidence and could not predict the early occurrence of postoperative AKI in CABG patients. TEE needs more evaluation for clinical efficacy of predicting the early occurrence of postoperative AKI in isolated CABG.

An insight into G-quadruplexes: Identification and potential therapeutic targets in livestock viruses.

G-quadruplexes (G4s) are non-canonical nucleic acids secondary structures that involve in the regulation of some key biological processes, such as replication, transcription, and translation. G4s have been extensively described in the genomes of human and related diseases. In recent years, G4s were identified in several livestock viruses, including those of the emerging epidemics, like Nipah virus (NiV). Since their discovery, G4s have been developed as the potential antiviral targets, and the employment of G4 ligands or interacting proteins has helped to expound the viral infectivity and pathogenesis through G4-mediated mechanisms, and highlight the potential as therapeutic approaches. However, the comprehensively studies of G4s in livestock viruses have not been summarized. This review delves into the reported literatures of G4s in livestock viruses, particular focus on the presence, biophysical identification, and possible function of G4s in viral genome, summarizing the G4 ligands, interacted proteins and aptamers on antiviral applications. The strengths and the challenges of G4 targeting in this field are also discussed. Therefore, this review will shed new light on the future development of highly potent and targeting antiviral therapy.

TNC upregulation promotes glioma tumourigenesis through TDG-mediated active DNA demethylation.

Gliomas represent the most predominant primary malignant tumor in central nervous system. Thymine DNA glycosylase (TDG) is a central component in active DNA demethylation. However, the specific mechanisms of TDG-mediated active DNA demethylation in gliomas remain unclear. This research indicates TDG expression is overexpressed in gliomas and correlated with poor prognosis. TDG knockdown suppressed the malignant phenotype of gliomas both in vitro and vivo. Notably, RNA-seq analysis revealed a strong association between TDG and tenascin-C (TNC). ChIP-qPCR and MeDIP-qPCR assays were undertaken to confirm that TDG participates in TNC active DNA demethylation process, revealing decreased DNA methylation levels and elevated TNC expression as a result. Silencing TNC expression also suppressed the tumor malignant phenotype in both in vitro and in vivo experiments. Additionally, simultaneous silencing of TNC reduced or even reversed the glioma promotion caused by TDG overexpression. Based on our findings, we conclude that TDG exerts an indispensable role in TNC active DNA demethylation in gliomas. The DNA demethylation process leads to alternations in TNC methylation levels and promotes its expression, thereby contributing to the development of gliomas. These results suggest a novel epigenetic therapeutic strategy targeting active DNA demethylation in gliomas.

Solvent-Engineering-Assisted Ligand Exchange Strategy for High-Efficiency AgBiS2 Quantum Dot Solar Cells.

As the initial synthesized colloidal quantum dots (CQDs) are generally capped with insulating ligands, ligand exchange strategies are essential in the fabrication of CQD films for solar cells, which can regulate the surface chemical states of CQDs to make them more suitable for thin-film optoelectronic devices. However, uncontrollable surface adsorption of water molecules during the ligand exchange process introduces new defect sites, thereby impairing the resultant device performance, which attracts more efforts devoted to it but remains a puzzle. Here, we develop a solvent-engineering-assisted ligand exchange strategy to revamp the surface adsorption, improve the exchange efficiency, and modulate the surface chemistry for the environmentally friendly lead-free silver bismuth disulfide (AgBiS2) CQDs. The optimized AgBiS2 CQD solar cells deliver an outstanding champion power conversion efficiency (PCE) of up to 8.95 % and improved long-term stability. Our strategy is less environment-dependent and can produce solar cells with negligible performance variance for several batches across several months. Our work demonstrates the critical role of solvents for ligand exchange in the surface chemistry of CQDs and the realization of high-performance photovoltaic devices in a highly reproducible manner.

Impact of ß-blockers on in-hospital mortality in patients with heart failure: a retrospective propensity-score matched analysis based on MIMIC-IV database.

Introduction: This study assessed the relationship between ß-blockers treatment and in-hospital mortality among individuals diagnosed with heart failure (HF). Methods: A retrospective cohort study was carried out on 9,968 HF patients sourced from the Medical Information Mart for Intensive Care (MIMIC)-IV database. Propensity score matching (PSM) was employed to balance the baseline differences. A multivariate regression analysis was utilized to evaluate the impact of ß-blockers therapy on in-hospital mortality. Results: Among the 9,968 patients, 6,439 (64.6%) were ß-blockers users. Before matching, the overall in-hospital mortality rate was 12.2% (1,217/9,968). Following PSM, a total of 3,212 patient pairs were successfully matched. The analysis revealed a correlation between ß-blockers therapy and decreased in-hospital mortality (odds ratio 0.51 [0.43-0.60], P < 0.001), as well as shorter Los (length of stay) hospital (ß -1.43 [-1.96∼-0.09], P < 0.001). Notably, long-acting ß-blockers treatment was linked to a decreased risk of in-hospital mortality (odds ratio 0.55 [0.46-0.65], P < 0.001) and a shorter Los hospital (ß -1.21 [-1.80∼-0.63], P < 0.001). Conversely, the research results did not show a notable decrease in-hospital mortality (odds ratio 0.66 [0.44-1.01], P = 0.051) or Los hospital (ß -1.01 [-2.2∼-0.25], P = 0.117) associated with short-acting ß-blocker therapy. Discussion: ß-blockers therapy in the intensive care unit demonstrates potential benefits in lowering the risk of in-hospital mortality and reducing the duration of hospitalization among patients with HF. Specifically, long-acting ß-blockers exhibit a protective effect by significantly decreasing both in-hospital mortality and Los hospital. Conversely, the study did not observe a substantial impact on in-hospital mortality or Los hospital duration in this cohort of patients following the administration of short-acting ß-blockers.

Surface Engineering Enables Efficient AgBiS2 Quantum Dot Solar Cells.

Surface ligand chemistry is vital to control the synthesis, diminish surface defects, and improve the electronic coupling of quantum dots (QDs) toward emerging applications in optoelectronic devices. Here, we successfully develop highly homogeneous and dispersed AgBiS2 QDs, focus on the control of interdot spacing, and substitute the long-chain ligands with ammonium iodide in solution. This results in improved electronic coupling of AgBiS2 QDs with excellent surface passivation, which greatly facilitates carrier transport within the QD films. Based on the stable AgBiS2 QD dispersion with the optimal ligand state, a homogeneous and densely packed QD film is prepared by a facile one-step coating process, delivering a champion power conversion efficiency of approximately 8% in the QD solar cells with outstanding shelf life stability. The proposed surface engineering strategy holds the potential to become a universal preprocessing step in the realm of high-performance QD optoelectronic devices.

Bortezomib-encapsulated metal-phenolic nanoparticles for intracellular drug delivery.

Bortezomib (BTZ) is an important boronate proteasome inhibitor that is widely used in cancer therapy. However, the clinical application of BTZ suffers from poor stability and serious adverse effects. Herein, we fabricated metal-polyphenol nanoparticles for the covalent encapsulation of BTZ. BTZ-encapsulated tannic acid (TA)-Fe3+ nanoparticles can be prepared by mixing BTZ, TA, and ferric chloride owing to the formation of metal-polyphenol coordination interaction and dynamic boronate ester bonds. The BTZ-encapsulated TA-Fe3+ nanoparticles (BTZ NPs) are stable in physiological environment (pH 7.4) with minimal drug leakage. However, BTZ NPs can be disassembled in an acidic environment. Therefore, BTZ can be rapidly released from BTZ NPs in an acidic environment (pH 5.0). More than 50% BTZ can be released from BTZ NPs after 8 h incubation at pH 5.0. BTZ NPs exhibited high cytotoxicity against human osteosarcoma Saos-2 cells and human multiple myeloma OPM-2 cells. The metal-polyphenol nanoparticles can be a promising nanoplatform for the delivery of BTZ with simultaneously enhanced therapeutic efficacy and reduced side effects.

Experience With Immediate Internal Fixation Combined With Primary Wound Closure in Gustilo-Anderson Type IIIA Open Ankle Fractures.

Open ankle fractures, especially Gustilo-Anderson type III fractures are challenging to manage with controversy over the "best" or "superior" treatment strategy. This study aimed to evaluate the treatment outcome of immediate internal fixation combined with primary wound closure in the management of Gustilo-Anderson type IIIA open ankle fractures. We retrospectively assessed the outcomes of thirty-two patients treated using immediate internal fixation combined with primary wound closure with a minimum follow-up of twenty-four months. At the median follow-up of 38 months, the mean American Orthopaedic Foot and Ankle Society scale score was 87.22 ± 4.05. The physical component summary score of Short-Form 36 Health Status Survey was 66.63 ± 11.42 and the mental component summary score was 67.31 ± 7.20. Range of motion of Ankle/Foot injured side was 64.56 ± 4.30 degrees, and range of motion of Ankle/Foot uninjured side was 72.31 ± 3.12 degrees. Visual analog pain scale score was 1.5 ± 0.88 at rest and 3.09 ± 1.17 during activity. According to American Orthopaedic Foot and Ankle Society scale score, the rate of excellent and good outcomes was 90.6%. Postoperative complications were documented, comprising 2 (6.4%) cases of infection, 5 (15.6%) cases of wound skin necrosis, 1 (3.2%) case of postoperative ankle traumatic arthritis, and 1 (3.2%) case requiring reoperation due to suboptimal fibula fracture reduction. The study results demonstrated that immediate internal fixation combined with primary wound closure for Gustilo-Anderson type IIIA open ankle fractures achieve good functional outcomes and lower complication rates.

Exploring the Potential of Cyclic Peptidyl Antitumor Agents Derived from Natural Macrocyclic Peptide Phakellistatin 13.

The exploration of novel anticancer compounds based on natural cyclopeptides has emerged as a pivotal paradigm in the contemporary advancement of macrocyclic pharmaceuticals. Phakellistatin 13 is a cycloheptapeptide derived from the brown snubby sponge and exhibits remarkable antitumor activity. In this study, we have designed and synthesized a series of chiral cyclopeptides incorporating the rigid isoindolinone moiety at various sites within the natural cycloheptapeptide Phakellistatin 13, with the aim of investigating conformationally constrained cyclopeptides as potential antitumor agents. Cyclopeptide 3, comprising alternating l-/d-amino acid residues, exhibited promising antihepatocellular carcinoma effects. Detailed biological experiments have revealed that Phakellistatin 13 analogs effectively inhibit the proliferation of tumor cells and induce apoptosis and autophagy, while also causing cell cycle arrest through the modulation of the p53 and mitogen-activated protein kinase (MAPK) signaling pathway. This study not only provides valuable insights into chemical structural modifications but also contributes to a deeper understanding of the biological mechanisms underlying the development of natural cyclopeptide-based drugs.

Artemisinins ameliorate polycystic ovarian syndrome by mediating LONP1-CYP11A1 interaction.

Polycystic ovary syndrome (PCOS), a prevalent reproductive disorder in women of reproductive age, features androgen excess, ovulatory dysfunction, and polycystic ovaries. Despite its high prevalence, specific pharmacologic intervention for PCOS is challenging. In this study, we identified artemisinins as anti-PCOS agents. Our finding demonstrated the efficacy of artemisinin derivatives in alleviating PCOS symptoms in both rodent models and human patients, curbing hyperandrogenemia through suppression of ovarian androgen synthesis. Artemisinins promoted cytochrome P450 family 11 subfamily A member 1 (CYP11A1) protein degradation to block androgen overproduction. Mechanistically, artemisinins directly targeted lon peptidase 1 (LONP1), enhanced LONP1-CYP11A1 interaction, and facilitated LONP1-catalyzed CYP11A1 degradation. Overexpression of LONP1 replicated the androgen-lowering effect of artemisinins. Our data suggest that artemisinin application is a promising approach for treating PCOS and highlight the crucial role of the LONP1-CYP11A1 interaction in controlling hyperandrogenism and PCOS occurrence.

Immunotherapy for patients with advanced non-small cell lung cancer harboring oncogenic driver alterations other than EGFR: a multicenter real-world analysis.

Background: The administration of immune checkpoint inhibitors (ICIs) in advanced non-small cell lung cancer (NSCLC) with oncogenic driver alterations other than epidermal growth factor receptor (EGFR) aroused a heated discussion. We thus aimed to evaluate ICI treatment in these patients in real-world routine clinical practice. Methods: A multicenter, retrospective study was conducted for NSCLC patients with at least one gene alteration (KRAS, HER2, BRAF, MET, RET, ALK, ROS1) receiving ICI monotherapy or combination treatment. The data regarding clinicopathologic characteristics, clinical efficacy, and safety were investigated. Results: A total of 216 patients were included, the median age was 60 years, 72.7% of patients were male, and 46.8% had a smoking history. The molecular alterations involved KRAS (n=95), HER2 (n=42), BRAF (n=22), MET (n=21), RET (n=14), ALK (n=14), and ROS1 (n=8); 56.5% of patients received immunotherapy in the first-line, and the rest 43.5% were treated as a second-line and above. For the entire cohort who received immunotherapy-based regimens in the first-line, the median progression-free survival (PFS) was 7.5 months and the median overall survival (OS) was 24.8 months. For the entire cohort who received immunotherapy-based regimens in the second-line and above, the median PFS was 4.7 months and median OS was 17.1 months. KRAS mutated NSCLC treated with immunotherapy-based regimens in the first-line setting had a median PFS and OS were 7.8 and 26.1 months, respectively. Moreover, the median PFS and OS of immunotherapy-based regimens for KRAS-mutant NSCLC that progressed after chemotherapy were 5.9 and 17.1 months. Programmed death ligand 1 (PD-L1) expression level was not consistently associated with response to immunotherapy across different gene alteration subsets. In the KRAS group, PD-L1 positivity [tumor proportion score (TPS) ≥1%] was associated with better PFS and OS according to the multivariate Cox analysis. No statistically significant association was found for smoking status, age, or gender with clinical efficacy in any gene group analyses. Conclusions: KRAS-mutant NSCLC could obtain clinical benefits from ICIs either for treatment-naive patients or those who have experienced progression after chemotherapy, and PD-L1 positive expression (TPS >1%) may be a potential positive predictor. For NSCLC with ALK, RET and ROS1 rearrangement, MET exon 14 skipping mutation, or BRAF V600E mutation, effectiveness of single or combined ICI therapy remains limited, therefore, targeted therapies should be considered prior to immunotherapy regimens. Future studies should address the investigation of better predictive biomarkers for immunotherapy response in oncogene-driven NSCLC.

A p21-ATD mouse model for monitoring and eliminating senescent cells and its application in liver regeneration post injury.

Cellular senescence associates with pathological aging and tissue dysfunctions. Studies utilizing mouse models for cell lineage tracings have emphasized the importance of senescence heterogeneity in different organs and cell types. Here, we constructed a p21- (Akaluc - tdTomato - Diphtheria Toxin Receptor [DTR]) (ATD) mouse model to specifically study the undefined mechanism for p21-expressing senescent cells in the aged and liver injury animals. The successful expressions of these genes enabled in vitro flow cytometric sorting, in vivo tracing, and elimination of p21-expressing senescent cells. During the natural aging process, p21-expressing cells were found in various tissues of p21-ATD mice. Eliminating p21-expressing cells in the aged p21-ATD mice recovered their multiple biological functions. p21-ATD/Fah-/- mice, bred from p21-ATD mice and fumarylacetoacetate hydrolase (Fah)-/- mice of liver injury, showed that the majority of their senescent hepatocytes were the phenotype of p21+ rather than p16+. Furthermore, eliminating the p21-expressing hepatocytes significantly promoted the engraftment of grafted hepatocytes and facilitated liver repopulation, resulting in significant recovery from liver injury. Our p21-ATD mouse model serves as an optimal model for studying the pattern and function of p21-expressing senescent cells under the physical and pathological conditions during aging.

Methylation changes of liver DNA during the formation of gallstones.

Aim: To explore the overall methylation changes in liver tissues during the formation of gallstones, as well as the key pathways and genes involved in the process. Methods: Reduced-representation bisulfite sequencing and RNA sequencing were conducted on the liver tissues of mice with gallstones and control normal mice. Results: A total of 8705 differentially methylated regions in CpG and 1410 differentially expressed genes were identified. The joint analysis indicated that aberrant DNA methylation may be associated with dysregulated gene expression in key pathways such as cholesterol metabolism and bile secretion. Conclusion: We propose for the first time that methylation changes in some key pathway genes in liver tissue may be involved in the formation of gallstones.

Amphoteric Chelating Ultrasmall Colloids for FAPbI3 Nanodomains Enable Efficient Near-Infrared Light-Emitting Diodes.

Perovskite light-emitting diodes (PeLEDs) are the next promising display technologies because of their high color purity and wide color gamut, while two classical emitter forms, i.e., polycrystalline domains and quantum dots, are encountering bottlenecks. Weak carrier confinement of large polycrystalline domains leads to inadequate radiative recombination, and surface ligands on quantum dots are the main annihilation sites for injected carriers. Here, pinpointing these issues, we screened out an amphoteric agent, namely, 2-(2-aminobenzoyl)benzoic acid (2-BA), to precisely control the in situ growth of FAPbI3 (FA: formamidine) nanodomains with enhanced space confinement, preferred crystal orientation, and passivated trap states on the transport-layer substrate. The amphoteric 2-BA performs bidentate chelating functions on the formation of ultrasmall perovskite colloids (<1 nm) in the precursor, resulting in a smoother FAPbI3 emitting layer. Based on monodispersed and homogeneous nanodomain films, a near-infrared PeLED device with a champion efficiency of >22% plus enhanced T80 operational stability was achieved. The proposed perovskite nanodomain film tends to be a mainstream emitter toward the performance breakthrough of PeLED devices covering visible wavelengths beyond infrared.

A single 24 h maternal separation at PND 9 promotes behavioral resilience of female C57BL/6J mice and the possible role of hippocampal Homer1a.

Early life stress (ELS) has been thought to increase vulnerability to developing psychiatric disorders later in life, while some researchers have found that adversity early in life may promote stress resilience. Studies investigating the resilient effect of maternal separation (MS) are still relatively few, and the underlying mechanisms remain unknown. In the current study, the effect of a single 24 h MS paradigm at postnatal day 9 (PND 9) in female C57BL/6J mice was investigated by assessing behavioral performance in middle adolescence. We demonstrated that, mice in MS group displayed decreased anxiety-like behavior and increased exploratory behavior than controls in the open field test and elevated plus maze test. Furthermore, MS mice exhibited improved hippocampal-dependent spatial learning in the Morris water maze test. This performance indicated behavioral resilience to early life stress. The protein expression levels of Homer1 isoforms, which are implicated in a variety of neuropsychiatric disorders, were evaluated using Western blot analysis. A significant increase in hippocampal Homer1a protein expression was observed immediately after MS, which subsequently decreased until adolescence (PND 27-42), when a significant increase was observed again. This distinctive change of hippocampal Homer1a protein expression pattern indicated that hippocampal Homer1a might play a role in behavioral resilience to MS in female C57BL/6J mice. In conclusion, this study demonstrated that exposure to a single 24 h MS at PND 9 promoted behavioral resilience of female C57BL/6J mice in middle adolescence. This behavioral resilience might be related to increased expression of hippocampal Homer1a.

NR2F6 is essential for brown adipocyte differentiation and systemic metabolic homeostasis.

OBJECTIVE: Brown adipose tissue (BAT) development and function are essential for maintaining energy balance. However, the key factors that specifically regulate brown adipogenesis require further identification. Here, we demonstrated that the nuclear receptor subfamily 2 group F member 6 (NR2F6) played a pivotal role in brown adipogenesis and energy homeostasis. METHODS: We examined the differentiation of immortalized brown adipocytes and primary brown adipocytes when NR2F6 were deleted, and explored the mechanism through which NR2F6 regulated adipogenesis using ChIP-qPCR in vitro. Male wild type (WT) and Pdgfra-Cre-mediated deletion of Nr2f6 in preadipocytes (NR2F6-PKO) mice were fed with high fat diet (HFD) for 12 weeks, and adiposity, glucose intolerance, insulin resistance and inflammation were assessed. RESULTS: NR2F6 exhibited abundant expression in BAT, while its expression was minimal in white adipose tissue (WAT). Within BAT, NR2F6 was highly expressed in preadipocytes, experienced a transient increase in the early stage of brown adipocyte differentiation, and significantly decreased in the mature adipocytes. Depletion of NR2F6 in preadipocytes inhibited brown adipogenesis, caused hypertrophy of brown adipocytes, and impaired thermogenic function of BAT, but without affecting WAT development. NR2F6 transcriptionally regulated PPARγ expression to promote adipogenic process in brown adipocytes. Loss of NR2F6 in preadipocytes led to increased susceptibility to diet-induced metabolic disorders. CONCLUSIONS: Our findings unveiled NR2F6 as a novel key regulator of brown adipogenesis, potentially opening up new avenues for maintaining metabolic homeostasis by targeting NR2F6.

MUC1-EGFR crosstalk with IL-6 by activating NF-κB and MAPK pathways to regulate the stemness and paclitaxel-resistance of lung adenocarcinoma.

BACKGROUND: The chemotherapy resistance often leads to chemotherapy failure. This study aims to explore the molecular mechanism by which MUC1 regulates paclitaxel resistance in lung adenocarcinoma (LUAD), providing scientific basis for future target selection. METHODS: The bioinformatics method was used to analyse the mRNA and protein expression characteristics of MUC1 in LUAD. RT-qPCR and ELISA were used to detect the mRNA and protein expression, flow cytometry was used to detect CD133+ cells, and cell viability was detected by CCK-8 assay. The mRNA-seq was performed to analyse the changes in expression profile, GO and KEGG analysis were used to explore the potential biological functions. RESULTS: MUC1 is highly expressed in LUAD patients and is associated with a higher tumour infiltration. In paclitaxel resistance LUAD cells (A549/TAX cells), the expression of MUC1, EGFR/p-EGFR and IL-6 were higher than that of A549 cells, the proportion of CD133+ cells was significantly increased, and the expression of cancer stem cell (CSCs) transcription factors (NANOG, OCT4 and SOX2) were significantly up-regulated. After knocking down MUC1 in A549/Tax cells, the activity of A549/Tax cells was significantly decreased. Correspondingly, the expression of EGFR, IL-6, OCT4, NANOG, and SOX2 were significantly down-regulated. The mRNA-seq showed that knocking down MUC1 affected the gene expression, DEGs mainly enriched in NF-κB and MAPK signalling pathway. CONCLUSION: MUC1 was highly expressed in A549/TAX cells, and MUC1-EGFR crosstalk with IL-6 may be due to the activation of NF-κB and MAPK pathways, which promote the enrichment of CSCs and lead to paclitaxel resistance.