Cellular and Molecular Life Sciences最新文献

The selective elimination of inappropriate projections is essential for sculpting neural circuits during development. The class IV dendritic arborization (C4da) sensory neurons of Drosophila remodel the dendritic branches during metamorphosis. Glial cells in the central nervous system (CNS), are required for programmed axonal pruning of mushroom body (MB) γ neurons during metamorphosis in Drosophila. However, it is entirely unknown whether the glial cells are involved in controlling the neurite pruning of C4da sensory neurons. Here, we show that glial deletion of Eiger (Egr), orthologous to mammalian tumor necrosis factor TNF superfamily ligand, results in dendrite remodeling deficiency of Drosophila C4da sensory neurons. Moreover, the attenuation of neuronal Wengen (Wgn) and Grindelwald (Grnd), the receptors for TNF ligands, is also examined for defects in dendrite remodeling. We further discover that Wgn and Grnd facilitate dendrite elimination through the JNK Signaling. Overall, our findings demonstrate that glial-derived Egr signal links to the neuronal receptor Wgn/Grnd, activating the JNK signaling pathway and promoting developmental neuronal remodeling. Remarkably, our findings reveal a crucial role of peripheral glia in dendritic pruning of C4da neurons.

Cyclic GMP-AMP synthase (cGAS) is a DNA sensing cellular receptor that induces IFN-I transcription in response to pathogen and host derived cytosolic DNA and can limit the replication of some RNA viruses. Some viruses have nonetheless evolved mechanisms to antagonize cGAS sensing. In this study, we evaluated the interaction between Bluetongue virus (BTV), the prototypical dsRNA virus of the Orbivirus genus and the Sedoreoviridae family, and cGAS. We found mitochondrial damage and DNA accumulation in the cytoplasm of infected cells. In addition, we show that BTV infection blocks DNA-induced IFN-I transcription and that virus infection prevents DNA sensing by inducing cGAS and STING degradation. We identify BTV-NS3 as the viral protein responsible for cGAS degradation, showing that NS3 physically interacts with cGAS and induces its degradation through an autophagy-dependent mechanism. Taken together, these findings identify for the first time a mechanism by which a dsRNA virus interferes with a DNA sensing pathway to evade the innate immune response.

Metabolism is a fundamental characteristic of life. In 2010, we discovered that the metabolic enzyme CTP synthase (CTPS) can assemble a snake like structure inside cells, which we call the cytoophidium. Including CTPS, an increasing number of metabolic enzymes have been found to form cytoophidia in cells. However, the distribution and relationship among cytoophidia formed by different metabolic enzymes remain elusive. Here we investigate five metabolic enzymes that can form cytoophidia, namely Asn1, Bna5, CTPS (i.e. Ura7), Glt1, and Prs5 in Saccharomyces cerevisiae. We find that multiple cytoophidia can be assembled into cytoophidium complexes by docking one after another. Glt1 cytoophidia tend to assemble in non-quiescent cells, while CTPS cytoophidia are more abundant in quiescent cells and form complexes with Prs5 and Asn1 cytoophidia. Blocking CTPS cytoophidium assembly can lead to a non-quiescent phenotype and increase the assembly of Glt1 cytoophidia, Bna5 cytoophidia, and a cytoophidium complex of them. Blocking CTPS cytoophidium assembly also inhibits the NAD biosynthesis pathway, which includes Bna5 and Sir2. Consistent with this result, the non-quiescent phenotype caused by blocking CTPS cytoophidium assembly can be rescued by blocking Glt1 cytoophidium assembly, supplementing nicotinic acid, or overexpressing Sir2. Our results indicate that the assembly of cytoophidium complexes with different compositions resonates with distinct cell fates.

Dynamic changes in DNA methylation are prevalent during the progression of breast cancer. However, critical alterations in aberrant methylation and gene expression patterns have not been thoroughly characterized. Here, we utilized guide positioning sequencing (GPS) to conduct whole-genome DNA methylation analysis in a unique human breast cancer progression model: MCF10 series of cell lines (representing benign/normal, atypical hyperplasia, and metastatic carcinoma). By integrating with mRNA-seq and matched clinical expression data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO), six representative methylation-related differentially expressed genes (mrDEGs) were identified, including CAVIN2, ARL4D, DUSP1, TENT5B, P3H2, and MMP28. To validate our findings, we independently developed and optimized the dCas9-DNMT3L-DNMT3A system, achieving a high efficiency with a 98% increase in methylation at specific sites. DNA methylation levels significantly increased for the six genes, with CAVIN2 at 67.75 ± 1.05%, ARL4D at 53.29 ± 6.32%, DUSP1 at 57.63 ± 8.46%, TENT5B at 44.00 ± 5.09%, P3H2 at 58.50 ± 3.90%, and MMP28 at 49.60 ± 5.84%. RT-qPCR confirmed an inverse correlation between increased DNA methylation and gene expression. Most importantly, we mimicked tumor progression in vitro, demonstrating that transcriptional silencing of the TENT5B promotes cell proliferation in MCF10A cells owing to the crosstalk between hypermethylation and histone deacetylation. This study unveils the practical implications of DNA methylation dynamics of mrDEGs in reshaping epigenomic features during breast cancer malignant progression through integrated data analysis of the methylome and transcriptome. The application of the CRISPR/dCas9-based methylation editing technique elucidates the regulatory mechanisms and functional roles of individual genes within the DNA methylation signature, providing valuable insights for understanding breast cancer pathogenesis and facilitating potential therapeutic approaches in epigenome editing for patients with breast cancer.

Emerging evidence has shown that the N⁶-methyladenosine (m⁶A) modification of RNA plays key roles in tumorigenesis and the progression of various cancers. However, the potential roles of the m⁶A modification of long noncoding RNAs (lncRNAs) in pancreatic cancer (PaCa) are still unknown. To analyze the prognostic value of m⁶A-related lncRNAs in PaCa, an m6A-related lncRNA signature was constructed as a risk model via Pearson's correlation and univariate Cox regression analyses in The Cancer Genome Atlas (TCGA) database. The tumor microenvironment (TME), tumor mutation burden, and drug sensitivity of PaCa were investigated by m⁶A-related lncRNA risk score analyses. We established an m⁶A-related risk prognostic model consisting of five lncRNAs, namely, LINC01091, AC096733.2, AC092171.5, AC015660.1, and AC005332.6, which not only revealed significant differences in immune cell infiltration associated with the TME between the high-risk and low-risk groups but also predicted the potential benefit of immunotherapy for patients with PaCa. Drugs such as WZ8040, selumetinib, and bortezomib were also identified as more effective for high-risk patients. Our results indicate that the m⁶A-related lncRNA risk model could be an independent prognostic indicator, which may provide valuable insights for identifying therapeutic approaches for PaCa.

Background: Prolonged spaceflight is known to cause vascular deconditioning and remodeling. Tail suspension, a widely used spaceflight analog, is reported to result in vascular remodeling of rats. However, little is known about the cellular atlas of the heterogeneous cells of CA and FA from hindlimb-unloaded rats.

Methods: Firstly, we leveraged scRNA-seq to perform clustering analysis to identify diverse cell populations and sub-clusters within CA and FA from rats subjected to 3 months of hindlimb unloading. The dysregulated genes specific for artery types and cell types in HU group compared to Con were unraveled. Then R package "Cellchat" was used to reveal ligand-receptor cellular communication. At last, the TF network analysis was performed using the SCENIC R package to predict the pivotal TFs in rat artery remodeling induced by hindlimb unloading.

Results: Clustering analysis identified ECs, SMCs, fibroblasts, and a spectrum of immune cells, as well as neuronal and stem cells. Notably, an increased percentage of ECs in the CA and a diminished proportion of SMCs in both CA and FA were observed following tail suspension. Intersection of dysregulated genes specific for artery type and cell type after tail suspension revealed several gene sets involved in ECM remodeling, inflammation, vasoconstriction, etc. Fibroblasts, in particular, exhibited the most significant gene expression variability, highlighting their plasticity. Subclustering within ECs, SMCs and fibroblasts revealed specialized subsets engaged in processes such as EndoMT and cell cycle checkpoint regulation. Additionally, enhanced intercellular interactions among major cell types, especially between SMC and fibroblast, underscored the importance of cell communication in vascular remodeling. Several TFs were identified as potentially influential in the vascular remodeling process under simulated microgravity conditions.

Conclusions: This study presents the first cellular atlas of the conductive arteries in hindlimb-unloaded rats, revealing a spectrum of dysregulated gene profiles. The identification of the subclusters of ECs, SMCs and fibroblasts, cellular communication analysis and transcription factors prediction are also included in this work. The findings provide a reference for future research on vascular deconditioning following long-duration spaceflight.

The current opioid crisis has had an unprecedented public health impact. Approved medications for opioid use disorder (OUD) exist, yet their limitations indicate a need for innovative treatments. Limited preliminary clinical studies suggest specific psychedelics might aid OUD treatment, though most clinical evidence remains observational, with few controlled trials. This review aims to bridge the gap between preclinical findings and potential clinical applications, following PRISMA-ScR guidelines. Searches included MEDLINE, Embase, Scopus, and Web of Science, focusing on preclinical in vivo studies involving opioids and psychedelics in animals, excluding pain studies and those lacking control groups. Forty studies met criteria, covering both classic and non-classic psychedelics. Most studies showed that 18-methoxycoronaridine (18-MC), ibogaine, noribogaine, and ketamine could reduce opioid self-administration, alleviate withdrawal symptoms, and change conditioned place preference. However, seven studies (two on 2,5-dimethoxy-4-methylamphetamine (DOM), three on ibogaine, one on 18-MC, and one on ketamine) showed no improvement over controls. A methodological quality assessment rated most of the studies as having unclear quality. Interestingly, most preclinical studies are limited to iboga derivatives, which were effective, but these agents may have higher cardiovascular risk than other psychedelics under-explored to date. This review strengthens support for translational studies testing psychedelics as potential innovative targets for OUD. It also suggests clinical studies need to include a broader range of agents beyond iboga derivatives but can also explore several ongoing questions in the field, such as the mechanism of action behind the potential therapeutic effect, safety profiles, doses, and frequency of administrations needed.

Nuclear growth differentiation factor 15 (GDF15) reduces the binding of the mothers' against decapentaplegic homolog (SMAD) complex to its DNA-binding elements. However, the stimuli that control this process are unknown. Here, we examined whether saturated fatty acids (FA), particularly palmitate, regulate nuclear GDF15 levels and the activation of the SMAD3 pathway in human skeletal myotubes and mouse skeletal muscle, where most insulin-stimulated glucose use occurs in the whole organism. Human LHCN-M2 myotubes and skeletal muscle from wild-type and Gdf15^-/- mice fed a standard (STD) or a high-fat (HFD) diet were subjected to a series of studies to investigate the involvement of lipids in nuclear GDF15 levels and the activation of the SMAD3 pathway. The saturated FA palmitate, but not the monounsaturated FA oleate, increased the expression of GDF15 in human myotubes and, unexpectedly, decreased its nuclear levels. This reduction was prevented by the nuclear export inhibitor leptomycin B. The decrease in nuclear GDF15 levels caused by palmitate was accompanied by increases in SMAD3 protein levels and in the expression of its target gene SERPINE1, which encodes plasminogen activator inhibitor 1 (PAI-1). HFD-fed Gdf15^-/- mice displayed aggravated glucose intolerance compared to HFD-fed WT mice, with increased levels of SMAD3 and PAI-1 in the skeletal muscle. The increased PAI-1 levels in the skeletal muscle of HFD-fed Gdf15^-/- mice were accompanied by a reduction in one of its targets, hepatocyte growth factor (HGF)α, a cytokine involved in glucose metabolism. Interestingly, PAI-1 acts as a ligand of signal transducer and activator of transcription 3 (STAT3) and the phosphorylation of this transcription factor was exacerbated in HFD-fed Gdf15^-/- mice compared to HFD-fed WT mice. At the same time, the protein levels of insulin receptor substrate 1 (IRS-1) were reduced. These findings uncover a potential novel mechanism through which palmitate induces the SMAD3-PAI-1 pathway to promote insulin resistance in skeletal muscle by reducing nuclear GDF15 levels.

Hypoxia, or a state of low tissue oxygenation, has been characterized as an important feature of solid tumors that is related to aggressive phenotypes. The cellular response to hypoxia is controlled by Hypoxia-inducible factors (HIFs), a family of transcription factors. HIFs promote the transcription of gene products that play a role in tumor progression including proliferation, angiogenesis, metastasis, and drug resistance. HIF-1 and HIF-2 are well known and widely described. Although these proteins share a high degree of homology, HIF-1 and HIF-2 have non-redundant roles in cancer. In this review, we summarize the similarities and differences between HIF-1α and HIF-2α in their structure, expression, and DNA binding. We also discuss the canonical and non-canonical regulation of HIF-1α and HIF-2α under hypoxic and normal conditions. Finally, we outline recent strategies aimed at targeting HIF-1α and/or HIF-2α.

Uncontrollable cancer cell growth is characterized by the maintenance of cellular homeostasis through the continuous accumulation of misfolded proteins and damaged organelles. This review delineates the roles of two complementary and synergistic degradation systems, the ubiquitin-proteasome system (UPS) and the autophagy-lysosome system, in the degradation of misfolded proteins and damaged organelles for intracellular recycling. We emphasize the interconnected decision-making processes of degradation systems in maintaining cellular homeostasis, such as the biophysical state of substrates, receptor oligomerization potentials (e.g., p62), and compartmentalization capacities (e.g., membrane structures). Mitochondria, the cellular hubs for respiration and metabolism, are implicated in tumorigenesis. In the subsequent sections, we thoroughly examine the mechanisms of mitochondrial quality control (MQC) in preserving mitochondrial homeostasis in human cells. Notably, we explored the relationships between mitochondrial dynamics (fusion and fission) and various MQC processes-including the UPS, mitochondrial proteases, and mitophagy-in the context of mitochondrial repair and degradation pathways. Finally, we assessed the potential of targeting MQC (including UPS, mitochondrial molecular chaperones, mitochondrial proteases, mitochondrial dynamics, mitophagy and mitochondrial biogenesis) as cancer therapeutic strategies. Understanding the mechanisms underlying mitochondrial homeostasis may offer novel insights for future cancer therapies.