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IScience Jun 2024Aerobic exercise training (AET) has emerged as a strategy to reduce cancer mortality, however, the mechanisms explaining AET on tumor development remain unclear. Tumors...
Aerobic exercise training (AET) has emerged as a strategy to reduce cancer mortality, however, the mechanisms explaining AET on tumor development remain unclear. Tumors escape immune detection by generating immunosuppressive microenvironments and impaired T cell function, which is associated with T cell mitochondrial loss. AET improves mitochondrial content and function, thus we tested whether AET would modulate mitochondrial metabolism in tumor-infiltrating lymphocytes (TIL). Balb/c mice were subjected to a treadmill AET protocol prior to CT26 colon carcinoma cells injection and until tumor harvest. Tissue hypoxia, TIL infiltration and effector function, and mitochondrial content, morphology and function were evaluated. AET reduced tumor growth, improved survival, and decreased tumor hypoxia. An increased CD8 TIL infiltration, IFN-γ and ATP production promoted by AET was correlated with reduced mitochondrial loss in these cells. Collectively, AET decreases tumor growth partially by increasing CD8 TIL effector function through an improvement in their mitochondrial content and function.
PubMed: 38957793
DOI: 10.1016/j.isci.2024.110121 -
IScience Jun 2024The initiation of transcription in Escherichia coli () is facilitated by promoter specificity factors, also known as σ factors, which may bind a promoter only as part...
The initiation of transcription in Escherichia coli () is facilitated by promoter specificity factors, also known as σ factors, which may bind a promoter only as part of a complex with RNA polymerase (RNAP). By performing cross-linking mass spectrometry (CL-MS) of apo-σ, we reveal structural features suggesting a compact conformation compared to the known RNAP-bound extended conformation. Then, we validate the existence of the compact conformation using CL-MS by identifying cross-links similar to those found , which deviate from the extended conformation only during the stationary phase of bacterial growth. Conclusively, we provide information in support of a compact conformation of apo-σ that exists in live cells, which might represent a transcriptionally inactive form that can be activated upon binding to RNAP.
PubMed: 38957792
DOI: 10.1016/j.isci.2024.110140 -
IScience Jun 2024Recent developments in immunotherapy, including immune checkpoint blockade (ICB) and adoptive cell therapy (ACT), have encountered challenges such as immune-related...
Recent developments in immunotherapy, including immune checkpoint blockade (ICB) and adoptive cell therapy (ACT), have encountered challenges such as immune-related adverse events and resistance, especially in solid tumors. To advance the field, a deeper understanding of the molecular mechanisms behind treatment responses and resistance is essential. However, the lack of functionally characterized immune-related gene sets has limited data-driven immunological research. To address this gap, we adopted non-negative matrix factorization on 83 human bulk RNA sequencing (RNA-seq) datasets and constructed 28 immune-specific gene sets. After rigorous immunologist-led manual annotations and orthogonal validations across immunological contexts and functional omics data, we demonstrated that these gene sets can be applied to refine pan-cancer immune subtypes, improve ICB response prediction and functionally annotate spatial transcriptomic data. These functional gene sets, informing diverse immune states, will advance our understanding of immunology and cancer research.
PubMed: 38957791
DOI: 10.1016/j.isci.2024.110096 -
IScience Jun 2024HIV-1 hijacks host proteins involved in membrane trafficking, endocytosis, and autophagy that are critical for virus replication. Molecular details are lacking but are...
HIV-1 hijacks host proteins involved in membrane trafficking, endocytosis, and autophagy that are critical for virus replication. Molecular details are lacking but are essential to inform on the development of alternative antiviral strategies. Despite their potential as clinical targets, only a few membrane trafficking proteins have been functionally characterized in HIV-1 replication. To further elucidate roles in HIV-1 replication, we performed a CRISPR-Cas9 screen on 140 membrane trafficking proteins. We identified phosphatidylinositol-binding clathrin assembly protein (PICALM) that influences not only infection dynamics but also CD4 SupT1 biology. The knockout (KO) of PICALM inhibited viral entry. In CD4 SupT1 T cells, KO cells exhibited defects in intracellular trafficking and increased abundance of intracellular Gag and significant alterations in autophagy, immune checkpoint PD-1 levels, and differentiation markers. Thus, PICALM modulates a variety of pathways that ultimately affect HIV-1 replication, underscoring the potential of PICALM as a future target to control HIV-1.
PubMed: 38957789
DOI: 10.1016/j.isci.2024.110131 -
IScience Jun 2024Alpine lakes play pivotal roles in plateau hydrological processes but are highly sensitive to climate change, yet we lack comprehensive knowledge of their multitrophic...
Alpine lakes play pivotal roles in plateau hydrological processes but are highly sensitive to climate change, yet we lack comprehensive knowledge of their multitrophic biodiversity patterns. Here, we compared the biodiversity characteristics of diverse taxonomic groups across water depths and in surface sediments from a freshwater lake and a hypersaline lake on the northwestern Tibetan Plateau. Using multi-marker environmental DNA metabarcoding, we detected 134 cyanobacteria, 443 diatom, 1,519 invertebrate, and 28 vertebrate taxa. Each group had a substantially different community composition in the two lakes, and differences were also found between water and sediments within each lake. Cooccurrence network analysis revealed higher network complexity, lower modularity, and fewer negative cohesions in the hypersaline lake, suggesting that high salinity may destabilize ecological networks. Our results provide the first holistic view of Tibetan lake biodiversity under contrasting salinity levels and reveal structural differences in the ecological networks that may impact ecosystem resilience.
PubMed: 38957787
DOI: 10.1016/j.isci.2024.110124 -
Cell Insight Aug 2024
PubMed: 38957574
DOI: 10.1016/j.cellin.2024.100177 -
Frontiers in Immunology 2024Enteric glial cells (EGCs) are an essential component of the enteric nervous system (ENS) and play key roles in gastrointestinal development, homeostasis, and disease.... (Review)
Review
Enteric glial cells (EGCs) are an essential component of the enteric nervous system (ENS) and play key roles in gastrointestinal development, homeostasis, and disease. Derived from neural crest cells, EGCs undergo complex differentiation processes regulated by various signalling pathways. Being among the most dynamic cells of the digestive system, EGCs react to cues in their surrounding microenvironment and communicate with various cell types and systems within the gut. Morphological studies and recent single cell RNA sequencing studies have unveiled heterogeneity among EGC populations with implications for regional functions and roles in diseases. In gastrointestinal disorders, including inflammatory bowel disease (IBD), infections and cancer, EGCs modulate neuroplasticity, immune responses and tumorigenesis. Recent evidence suggests that EGCs respond plastically to the microenvironmental cues, adapting their phenotype and functions in disease states and taking on a crucial role. They exhibit molecular abnormalities and alter communication with other intestinal cell types, underscoring their therapeutic potential as targets. This review delves into the multifaceted roles of EGCs, particularly emphasizing their interactions with various cell types in the gut and their significant contributions to gastrointestinal disorders. Understanding the complex roles of EGCs in gastrointestinal physiology and pathology will be crucial for the development of novel therapeutic strategies for gastrointestinal disorders.
Topics: Humans; Neuroglia; Enteric Nervous System; Animals; Gastrointestinal Diseases
PubMed: 38957473
DOI: 10.3389/fimmu.2024.1408744 -
Frontiers in Immunology 2024
Topics: Animals; Immunity, Humoral; Immunity, Innate; Drosophila; Immunity, Cellular
PubMed: 38957463
DOI: 10.3389/fimmu.2024.1416296 -
PNAS Nexus Jul 2024The Fanconi anemia (FA) repair pathway governs repair of highly genotoxic DNA interstrand crosslinks (ICLs) and relies on translesion synthesis (TLS). TLS is facilitated...
The Fanconi anemia (FA) repair pathway governs repair of highly genotoxic DNA interstrand crosslinks (ICLs) and relies on translesion synthesis (TLS). TLS is facilitated by REV1 or site-specific monoubiquitination of proliferating cell nuclear antigen (PCNA) (PCNA-Ub) at lysine 164 (K164). A but not mutation renders mammals hypersensitive to ICLs. Besides the FA pathway, alternative pathways have been associated with ICL repair (1, 2), though the decision making between those remains elusive. To study the dependence and relevance of PCNA-Ub in FA repair, we intercrossed mice. A combined mutation ( ) was found embryonically lethal. RNA-seq of primary double-mutant (DM) mouse embryonic fibroblasts (MEFs) revealed elevated levels of replication stress-induced checkpoints. To exclude stress-induced confounders, we utilized a knock-down to obtain a model to study ICL repair in depth. Regarding ICL-induced cell toxicity, cell cycle arrest, and replication fork progression, single-mutant and DM MEFs were found equally sensitive, establishing PCNA-Ub to be critical for FA-ICL repair. Immunoprecipitation and spectrometry-based analysis revealed an unknown role of PCNA-Ub in excluding mismatch recognition complex MSH2/MSH6 from being recruited to ICLs. In conclusion, our results uncovered a dual function of PCNA-Ub in ICL repair, i.e. exclude MSH2/MSH6 recruitment to channel the ICL toward canonical FA repair, in addition to its established role in coordinating TLS opposite the unhooked ICL.
PubMed: 38957451
DOI: 10.1093/pnasnexus/pgae242 -
Frontiers in Endocrinology 2024Cannabidiol (CBD), a non-psychoactive phytocannabinoid of cannabis, is therapeutically used as an analgesic, anti-convulsant, anti-inflammatory, and anti-psychotic drug....
BACKGROUND
Cannabidiol (CBD), a non-psychoactive phytocannabinoid of cannabis, is therapeutically used as an analgesic, anti-convulsant, anti-inflammatory, and anti-psychotic drug. There is a growing concern about the adverse side effects posed by CBD usage. Pregnane X receptor (PXR) is a nuclear receptor activated by a variety of dietary steroids, pharmaceutical agents, and environmental chemicals. In addition to the role in xenobiotic metabolism, the atherogenic and dyslipidemic effects of PXR have been revealed in animal models. CBD has a low affinity for cannabinoid receptors, thus it is important to elucidate the molecular mechanisms by which CBD activates cellular signaling and to assess the possible adverse impacts of CBD on pro-atherosclerotic events in cardiovascular system, such as dyslipidemia.
OBJECTIVE
Our study aims to explore the cellular and molecular mechanisms by which exposure to CBD activates human PXR and increases the risk of dyslipidemia.
METHODS
Both human hepatic and intestinal cells were used to test if CBD was a PXR agonist via cell-based transfection assay. The key residues within PXR's ligand-binding pocket that CBD interacted with were investigated using computational docking study together with site-directed mutagenesis assay. The C57BL/6 wildtype mice were orally fed CBD in the presence of PXR antagonist resveratrol (RES) to determine how CBD exposure could change the plasma lipid profiles in a PXR-dependent manner. Human intestinal cells were treated with CBD and/or RES to estimate the functions of CBD in cholesterol uptake.
RESULTS
CBD was a selective agonist of PXR with higher activities on human PXR than rodents PXRs and promoted the dissociation of human PXR from nuclear co-repressors. The key amino acid residues Met246, Ser247, Phe251, Phe288, Trp299, and Tyr306 within PXR's ligand binding pocket were identified to be necessary for the agonistic effects of CBD. Exposure to CBD increased the circulating total cholesterol levels in mice which was partially caused by the induced expression levels of the key intestinal PXR-regulated lipogenic genes. Mechanistically, CBD induced the gene expression of key intestinal cholesterol transporters, which led to the increased cholesterol uptake by intestinal cells.
CONCLUSION
CBD was identified as a selective PXR agonist. Exposure to CBD activated PXR signaling and increased the atherogenic cholesterol levels in plasma, which partially resulted from the ascended cholesterol uptake by intestinal cells. Our study provides potential evidence for the future risk assessment of CBD on cardiovascular disease, such as dyslipidemia.
Topics: Pregnane X Receptor; Animals; Humans; Mice; Cannabidiol; Mice, Inbred C57BL; Cholesterol; Male; Intestinal Mucosa; Molecular Docking Simulation
PubMed: 38957441
DOI: 10.3389/fendo.2024.1398462