Otilonium bromide ameliorates pulmonary fibrosis in mice through activating phosphatase PPM1A.

Pulmonary fibrosis (PF) is a chronic, progressive and irreversible interstitial lung disease characterized by unremitting pulmonary myofibroblasts activation, extracellular matrix (ECM) deposition and inflammatory recruitment. PF has no curable medication yet. In this study we investigated the molecular pathogenesis and potential therapeutic targets of PF and discovered drug lead compounds for PF therapy. A murine PF model was established in mice by intratracheal instillation of bleomycin (BLM, 5 mg/kg). We showed that the protein level of pulmonary protein phosphatase magnesium-dependent 1A (PPM1A, also known as PP2Cα) was significantly downregulated in PF patients and BLM-induced PF mice. We demonstrated that TRIM47 promoted ubiquitination and decreased PPM1A protein in PF progression. By screening the lab in-house compound library, we discovered otilonium bromide (OB, clinically used for treating irritable bowel syndrome) as a PPM1A enzymatic activator with an EC50 value of 4.23 µM. Treatment with OB (2.5, 5 mg·kg-1·d-1, i.p., for 20 days) significantly ameliorated PF-like pathology in mice. We constructed PF mice with PPM1A-specific knockdown in the lung tissues, and determined that by targeting PPM1A, OB treatment suppressed ECM deposition through TGF-ß/SMAD3 pathway in fibroblasts, repressed inflammatory responses through NF-κB/NLRP3 pathway in alveolar epithelial cells, and blunted the crosstalk between inflammation in alveolar epithelial cells and ECM deposition in fibroblasts. Together, our results demonstrate that pulmonary PPM1A activation is a promising therapeutic strategy for PF and highlighted the potential of OB in the treatment of the disease.

Indoor Mapping with Entertainment Devices: Evaluating the Impact of Different Mapping Strategies for Microsoft HoloLens 2 and Apple iPhone 14 Pro.

Due to their low cost and portability, using entertainment devices for indoor mapping applications has become a hot research topic. However, the impact of user behavior on indoor mapping evaluation with entertainment devices is often overlooked in previous studies. This article aims to assess the indoor mapping performance of entertainment devices under different mapping strategies. We chose two entertainment devices, the HoloLens 2 and iPhone 14 Pro, for our evaluation work. Based on our previous mapping experience and user habits, we defined four simplified indoor mapping strategies: straight-forward mapping (SFM), left-right alternating mapping (LRAM), round-trip straight-forward mapping (RT-SFM), and round-trip left-right alternating mapping (RT-LRAM). First, we acquired triangle mesh data under each strategy with the HoloLens 2 and iPhone 14 Pro. Then, we compared the changes in data completeness and accuracy between the different devices and indoor mapping applications. Our findings show that compared to the iPhone 14 Pro, the triangle mesh accuracy acquired by the HoloLens 2 has more stable performance under different strategies. Notably, the triangle mesh data acquired by the HoloLens 2 under the RT-LRAM strategy can effectively compensate for missing wall and floor surfaces, mainly caused by furniture occlusion and the low frame rate of the depth-sensing camera. However, the iPhone 14 Pro is more efficient in terms of mapping completeness and can acquire a complete triangle mesh more quickly than the HoloLens 2. In summary, choosing an entertainment device for indoor mapping requires a combination of specific needs and scenes. If accuracy and stability are important, the HoloLens 2 is more suitable; if efficiency and completeness are important, the iPhone 14 Pro is better.

Novel AT2 Cell Subpopulations and Diagnostic Biomarkers in IPF: Integrating Machine Learning with Single-Cell Analysis.

Idiopathic pulmonary fibrosis (IPF) is a long-term condition with an unidentified cause, and currently there are no specific treatment options available. Alveolar epithelial type II cells (AT2) constitute a heterogeneous population crucial for secreting and regenerative functions in the alveolus, essential for maintaining lung homeostasis. However, a comprehensive investigation into their cellular diversity, molecular features, and clinical implications is currently lacking. In this study, we conducted a comprehensive examination of single-cell RNA sequencing data from both normal and fibrotic lung tissues. We analyzed alterations in cellular composition between IPF and normal tissue and investigated differentially expressed genes across each cell population. This analysis revealed the presence of two distinct subpopulations of IPF-related alveolar epithelial type II cells (IR_AT2). Subsequently, three unique gene co-expression modules associated with the IR_AT2 subtype were identified through the use of hdWGCNA. Furthermore, we refined and identified IPF-related AT2-related gene (IARG) signatures using various machine learning algorithms. Our analysis demonstrated a significant association between high IARG scores in IPF patients and shorter survival times (p-value < 0.01). Additionally, we observed a negative correlation between the percent predicted diffusing capacity for lung carbon monoxide (% DLCO) and increased IARG scores (cor = -0.44, p-value < 0.05). The cross-validation findings demonstrated a high level of accuracy (AUC > 0.85, p-value < 0.01) in the prognostication of patients with IPF utilizing the identified IARG signatures. Our study has identified distinct molecular and biological features among AT2 subpopulations, specifically highlighting the unique characteristics of IPF-related AT2 cells. Importantly, our findings underscore the prognostic relevance of specific genes associated with IPF-related AT2 cells, offering valuable insights into the advancement of IPF.

Reduced Graphene Oxide-Supported SrV4O9 Microflowers with Enhanced Electrochemical Performance for Sodium-Ion Batteries.

Sodium-ion batteries (SIBs) have received considerable attention in recent years. Anode material is one of the key factors that determine SIBs' electrochemical performance. Current commercial hard carbon anode shows poor rate performance, which greatly limits applications of SIBs. In this study, a novel vanadium-based material, SrV4O9, was proposed as an anode for SIBs, and its Na+ storage properties were studied for the first time. To enhance the electrical conductivity of SrV4O9 material, a microflower structure was designed and reduced graphene oxide (rGO) was introduced as a host to support SrV4O9 microflowers. The microflower structure effectively reduced electron diffusion distance, thus enhancing the electrical conductivity of the SrV4O9 material. The rGO showed excellent flexibility and electrical conductivity, which effectively improved the cycling life and rate performance of the SrV4O9 composite material. As a result, the SrV4O9@rGO composite showed excellent electrochemical performance (a stable capacity of 273.4 mAh g-1 after 200 cycles at 0.2 A g-1 and a high capacity of 120.4 mAh g-1 at 10.0 A g-1), indicating that SrV4O9@rGO composite can be an ideal anode material for SIBs.

Cuproptosis-related gene CDKN2A as a molecular target for IPF diagnosis and therapeutics.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive chronic interstitial lung disease with limited therapeutic options. Cuproptosis is a recently proposed novel form of programmed cell death, which has been strongly implicated in the development of various human diseases. However, the prognostic and therapeutic value of cuproptosis-related genes (CRGs) in IPF remains to be elucidated. METHODS: In the present study, weighted gene co-expression network analysis (WGCNA) was employed to identify the key CRGs associated with the development of IPF. The subsequent GSEA, immune cell correlation analysis, and single-cell RNA-Seq analysis were conducted to explore the potential role of the identified CRGs in IPF. In addition, ROC curves and survival analysis were used to assess the prognostic value of the key CRGs in IPF. Moreover, we explored the molecular mechanisms of participation of identified key CRGs in the development of pulmonary fibrogenesis through in vivo and in vitro experiments. RESULTS: The expression level of cyclin-dependent kinase inhibitor 2A (CDKN2A) is upregulated in the lung tissues of IPF patients and associated with disease severity. Notably, CDKN2A was constitutively expressed by fibrosis-promoting M2 macrophages. Decreased CDKN2A expression sensitizes M2 macrophages to elesclomol-induced cuproptosis in vitro. Inhibition of CDKN2A decreases the number of viable macrophages and attenuates bleomycin-induced pulmonary fibrosis in mice. CONCLUSION: These findings indicate that CDKN2A mediates the resistance of fibrosis-promoting M2 macrophages to cuproptosis and promotes pulmonary fibrosis in mice. Our work provides fresh insights into CRGs in IPF with potential value for research in the pathogenesis, diagnosis, and a new therapy strategy for IPF.

Wnt8b regulates myofibroblast differentiation of lung-resident mesenchymal stem cells via the activation of Wnt/ß-catenin signaling in pulmonary fibrogenesis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal lung disease that is characterized by enhanced changes in stem cell differentiation and fibroblast proliferation. Lung resident mesenchymal stem cells (LR-MSCs) are important regulators of pathophysiological processes including tissue repair and inflammation, and evidence suggests that this cell population also plays an essential role in fibrosis. Our previous study demonstrated that Wnt/ß-catenin signaling is aberrantly activated in the lungs of bleomycin-treated mice and induces myofibroblast differentiation of LR-MSCs. However, the underlying correlation between LR-MSCs and the Wnt/ß-catenin signaling remains poorly understood. We found that Wnt8b was highly expressed by LR-MSCs undergoing myofibroblast differentiation. In vitro, Wnt8b promoted LR-MSCs differentiate into myofibroblasts via activating Wnt/ß-catenin signaling. Moreover, siRNA-mediated inhibition of Wnt8b prevented Transforming growth factor (TGF)-ß1-induced myofibroblast differentiation of LR-MSCs in vitro and ameliorated pulmonary fibrotic lesions. Our study identified Wnt proteins and Wnt/ß-catenin signaling in pulmonary fibrosis in vitro and in vivo, and highlighted Wnt8b as a potential therapeutic target in pulmonary fibrosis. Moreover, these finding might provide a new perspective in the development of treatment strategies for IPF.

Machine Learning and Single-Cell Analysis Identify Molecular Features of IPF-Associated Fibroblast Subtypes and Their Implications on IPF Prognosis.

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease of unknown cause, and the involvement of fibroblasts in its pathogenesis is well recognized. However, a comprehensive understanding of fibroblasts' heterogeneity, their molecular characteristics, and their clinical relevance in IPF is lacking. In this study, we aimed to systematically classify fibroblast populations, uncover the molecular and biological features of fibroblast subtypes in fibrotic lung tissue, and establish an IPF-associated, fibroblast-related predictive model for IPF. Herein, a meticulous analysis of scRNA-seq data obtained from lung tissues of both normal and IPF patients was conducted to identify fibroblast subpopulations in fibrotic lung tissues. In addition, hdWGCNA was utilized to identify co-expressed gene modules associated with IPF-related fibroblasts. Furthermore, we explored the prognostic utility of signature genes for these IPF-related fibroblast subtypes using a machine learning-based approach. Two predominant fibroblast subpopulations, termed IPF-related fibroblasts, were identified in fibrotic lung tissues. Additionally, we identified co-expressed gene modules that are closely associated with IPF-fibroblasts by utilizing hdWGCNA. We identified gene signatures that hold promise as prognostic markers in IPF. Moreover, we constructed a predictive model specifically focused on IPF-fibroblasts which can be utilized to assess disease prognosis in IPF patients. These findings have the potential to improve disease prediction and facilitate targeted interventions for patients with IPF.

Microcystin-leucine arginine induced the apoptosis of GnRH neurons by activating the endoplasmic reticulum stress resulting in a decrease of serum testosterone level in mice.

Microcystin-leucine arginine (MC-LR) is a kind of toxin produced by cyanobacterial, resulting in decrease of testosterone levels in serum and leading to impaired spermatogenesis. Gonadotropin-releasing hormone (GnRH) neurons play crucial roles in the regulation of testosterone release. Meanwhile, it has been demonstrated that MC-LR is capable of entering the GnRH neurons and inducing apoptosis. Nevertheless, the molecular mechanism of MC-LR induced apoptosis of GnRH neurons remains elusive. In present study, we found that MC-LR inhibited the cell viability of GT1-7 cells. In addition, we discovered apoptosis of GnRH neurons and GT1-7 cells treated with MC-LR. And increased intracellular ROS production and the release of intracellular Ca2+ were all observed following exposure to MC-LR. Furthermore, we also found the endoplasmic reticulum stress (ERs) and autophagy were activated by MC-LR. Additionally, pretreatment of the ERs inhibitor (4-Phenyl butyric acid) reduced the apoptotic rate of GT1-7 cells comparing with MC-LR exposure alone. Comparing with MC-LR treatment alone, apoptotic cell death was increased by pretreatment of GT1-7 cells with an autophagy inhibitor (3-methyladenine). Together, our data implicated that the treatment of MC-LR induced the apoptosis of GnRH neurons by activating the ERs resulting in a decrease of serum testosterone level in mice. Autophagy is a protective cellular process which was activated by ER stress and thus protected cells from apoptosis upon MC-LR exposure.

Identification of Key Candidate Genes Involved in the Progression of Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a lethal, agnogenic interstitial lung disease with limited therapeutic options. To investigate vital genes involved in the development of IPF, we integrated and compared four expression profiles (GSE110147, GSE53845, GSE24206, and GSE10667), including 87 IPF samples and 40 normal samples. By reanalyzing these datasets, we managed to identify 62 upregulated genes and 20 downregulated genes in IPF samples compared with normal samples. Differentially expressed genes (DEGs) were analyzed by gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis to illustrate relevant pathways of IPF, biological processes, molecular function, and cell components. The DEGs were then subjected to protein-protein interaction (PPI) for network analysis, serving to find 11 key candidate genes (ANXA3, STX11, THBS2, MMP1, MMP9, MMP7, MMP10, SPP1, COL1A1, ITGB8, IGF1). The result of RT-qPCR and immunohistochemical staining verified our finding as well. In summary, we identified 11 key candidate genes related to the process of IPF, which may contribute to novel treatments of IPF.

The Shh/Gli signaling cascade regulates myofibroblastic activation of lung-resident mesenchymal stem cells via the modulation of Wnt10a expression during pulmonary fibrogenesis.

Lung-resident mesenchymal stem cells (LR-MSCs) are important regulators of lung repair and regeneration, and evidence suggests that this cell population also plays a vital role in fibrosis. Crosstalk between sonic hedgehog (Shh) signaling and wingless/integrated (Wnt) has been demonstrated in idiopathic pulmonary fibrosis (IPF). However, the underlying correlation between LR-MSCs and the Shh-Wnt signaling cascade remains poorly understood. Here, we identified Wnt10a as a key factor in pulmonary fibrosis. Using a bleomycin mouse model, we found that highly expressed Wnt10a was secreted by LR-MSCs undergoing myofibroblastic differentiation. LR-MSCs with myofibroblast characteristics isolated from fibrotic lungs exhibited increased Shh pathway activity, suggesting their role as Shh targets. In vitro, LR-MSCs responded to stimulation by recombinant Shh, acquiring a myofibroblast phenotype. We further demonstrated that the Shh/glioblastoma (Gli) system machinery regulated LR-MSC-to-myofibroblast transition and pulmonary fibrosis via manipulation of Wnt/ß-catenin signaling. Accordingly, inhibition of the Shh-Wnt signaling cascade prevented LR-MSC transformation into myofibroblasts and ameliorated pulmonary fibrotic lesions. Moreover, induction of Wnt10a expression and activation of Shh/Gli signaling were confirmed in human pulmonary fibrosis. In summary, this study linking the Shh-Wnt signaling cascade with LR-MSC fibrogenic activity furthered the current understanding of pulmonary fibrosis pathogenesis and might provide a new perspective in the development of treatment strategies for IPF.