Regulation of cGAS and STING signaling during inflammation and infection

Journal of Biological Chemistry, Год журнала: 2023, Номер 299(7), С. 104866 - 104866

Опубликована: Май 27, 2023

Stimulator of interferon genes (STING) is a sensor cyclic dinucleotides including GMP-AMP, which produced by GMP-AMP synthase (cGAS) in response to cytosolic DNA. The cGAS-STING signaling pathway regulates both innate and adaptive immune responses, as well fundamental cellular functions such autophagy, senescence, apoptosis. Mutations leading constitutive activation STING cause devastating human diseases. Thus, the great interest because its role diverse processes potential therapeutic implications targeting cGAS STING. Here, we review molecular mechanisms signaling, propose framework for understanding immunological other context disease.

Язык: Английский

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Emerging mechanisms and implications of cGAS-STING signaling in cancer immunotherapy strategies

Cancer Biology and Medicine, Год журнала: 2024, Номер unknown, С. 1 - 20

Опубликована: Янв. 3, 2024

The intricate interplay between the human immune system and cancer development underscores central role of immunotherapy in treatment. Within this landscape, innate system, a critical sentinel protecting against tumor incursion, is key player. cyclic GMP-AMP synthase (cGAS) stimulator interferon genes (STING) pathway has been found to be linchpin immunity: activation signaling orchestrates production type I (IFN-α/β), thus fostering maturation, differentiation, mobilization effectors microenvironment. Furthermore, STING facilitates release presentation antigens, therefore an attractive target for immunotherapy. Current strategies activate pathway, including use pharmacological agonists, have made substantial advancements, particularly when combined with checkpoint inhibitors. These approaches shown promise preclinical clinical settings, by enhancing patient survival rates. This review describes evolving understanding cGAS-STING pathway’s involvement biology therapy. Moreover, explores classical non-classical providing insights into their mechanisms action potential optimizing strategies. Despite challenges complexities, promising avenue treatment efficacy, revolutionize outcomes.

Язык: Английский

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Role of STING in the treatment of non-small cell lung cancer

Cell Communication and Signaling, Год журнала: 2024, Номер 22(1)

Опубликована: Апрель 2, 2024

Abstract Non-small cell lung cancer (NSCLC) is a prevalent form of cancer. Patients with advanced NSCLC are currently being treated various therapies, including traditional radiotherapy, chemotherapy, molecular targeted therapies and immunotherapy. However, considerable proportion advance patients who cannot benefit from them. Consequently, it essential to identify novel research target that offers an encouraging perspective. The stimulator interferon genes (STING) has emerged as such target. At present, confirmed activating STING in tumor cells can impede the proliferation metastasis dormant cells. This review focuses on role treatment factors influencing its activation. Additionally, explores correlation between activation diverse therapy modalities for NSCLC, Furthermore, proposes prospect innovative methods involving nanoparticles, aim using features develop more strategies therapy.

Язык: Английский

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Prediction of cell migration potential on human breast cancer cells treated with Albizia lebbeck ethanolic extract using extreme machine learning

Scientific Reports, Год журнала: 2023, Номер 13(1)

Опубликована: Дек. 14, 2023

Cancer is one of the major causes death in modern world, and incidence varies considerably based on race, ethnicity, region. Novel cancer treatments, such as surgery immunotherapy, are ineffective expensive. In this situation, ion channels responsible for cell migration have appeared to be most promising targets treatment. This research presents findings organic compounds present Albizia lebbeck ethanolic extracts (ALEE), well their impact anti-migratory, anti-proliferative cytotoxic potentials MDA-MB 231 MCF-7 human breast lines. addition, artificial intelligence (AI) models, multilayer perceptron (MLP), extreme gradient boosting (XGB), learning machine (ELM) were performed predict vitro both lines, our experimental data. The composition ALEE was studied using gas chromatography-mass spectrometry (GC-MS) analysis. Cytotoxicity, anti-proliferations, anti-migratory activity extract Tryphan Blue, MTT, Wound Heal assay, respectively. Among various concentrations (2.5-200 μg/mL) that used study, 2.5-10 μg/mL revealed potential with increased concentrations, they did not show any effect proliferation cells (P < 0.05; n ≥ 3). Furthermore, three data-driven Multi-layer Extreme (ELM), ability treated Overall, plant do affect type demonstrated effects reducing migration. XGB outperformed MLP ELM models performance efficiency by up 3% 1% MCF 2% MDA-MB231, respectively, testing phase.

Язык: Английский

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SAMHD1 enhances HIV-1-induced apoptosis in monocytic cells via the mitochondrial pathway

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 10, 2025

SUMMARY Sterile alpha motif (SAM) and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) inhibits HIV-1 replication in non-dividing cells by reducing the intracellular dNTP pool. SAMHD1 enhances spontaneous apoptosis cells, but its effects on HIV-1-induced underlying mechanisms remain unknown. Here we uncover a new mechanism which monocytic through mitochondrial pathway. We found that endogenous levels induced infection dividing THP-1 cells. Mechanistically, expression decreases membrane potential promotes cytochrome c release thereby enhancing apoptotic SAMHD1-enhanced is associated with increased of pro-apoptotic BCL-2-interacting killer (BIK) further demonstrated BIK contributes to during infection. Overall, our results reveal an unappreciated regulatory via pathway

Язык: Английский

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Potential role of lactylation in intrinsic immune pathways in lung cancer

Frontiers in Pharmacology, Год журнала: 2025, Номер 16

Опубликована: Март 17, 2025

Lung cancer, one of the most lethal malignancies, has seen its therapeutic strategies become a focal point significant scientific attention. Intrinsic immune signaling pathways play crucial roles in anti-tumor immunity but face clinical application challenges despite promising preclinical outcomes. Lactylation, an emerging research focus, may influences lung cancer progression by modulating functions histones and non-histone proteins. Recent findings have suggested that lactylation regulates key intrinsic molecules, including cGAS-STING, TLR, RIG-I, thereby impacting interferon expression. However, precise mechanisms which governs remain unclear. This review presents comprehensive systematic analysis relationship between emphasizes innovative perspective linking lactylation-mediated epigenetic modifications with regulation. By thoroughly examining current findings, this uncovers potential regulatory highlights implications targeting cancer. Future investigations into intricate interactions are anticipated to unveil novel targets strategies, potentially improving patient survival

Язык: Английский

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Harnessing single-cell and multi-omics insights: STING pathway-based predictive signature for immunotherapy response in lung adenocarcinoma

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Апрель 16, 2025

Background Lung adenocarcinoma is the most prevalent type of small-cell carcinoma, with a poor prognosis. For advanced-stage patients, efficacy immunotherapy suboptimal. The STING signaling pathway plays pivotal role in lung adenocarcinoma; therefore, further investigation into relationship between and warranted. Methods We conducted comprehensive analysis integrating single-cell RNA sequencing (scRNA-seq) data bulk transcriptomic profiles from public databases (GEO, TCGA). pathway-related genes were identified through Genecard database. Advanced bioinformatics analyses using R packages (Seurat, CellChat) revealed heterogeneity, intercellular communication networks, immune landscape characteristics. developed signature (STINGsig) 101 machine learning frameworks. functional significance ERRFI1, key component STINGsig, was validated mouse models multicolor flow cytometry, particularly examining its enhancing antitumor immunity potential synergy α-PD1 therapy. Results Our characterized 15 distinct cell populations, including epithelial cells, macrophages, fibroblasts, T B endothelial each unique marker gene profiles. activity scoring elevated activation neutrophils, contrasting lower inflammatory macrophages. Cell-cell demonstrated enhanced interaction networks high-STING-score evident fibroblasts cells. STINGsig showed robust prognostic value microenvironment characteristics risk groups. Notably, ERRFI1 knockdown experiments confirmed significant modulating therapy response. Conclusion STING-related exhibited expression levels across high-score cells showing tumor-promoting pathways, active interactions, enrichment IFI27+ In contrast, low-score associated phenotypes reduced activity. (STINGsig), which linked to microenvironment. Through vivo experiments, we that critical within significantly enhances synergizes cancer model, underscoring therapeutic responses.

Язык: Английский

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The dual roles of human PYHIN family proteins in cancer: mechanisms and therapeutic implications

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Май 2, 2025

The human PYHIN family proteins, including AIM2, IFI16, IFIX, and MNDA, which are crucial cytosolic nucleic acid sensors. These proteins share a common structural feature, signature N-terminal PYD domain C-terminal HIN-200 domain, enable them to recognize intracellular acids assemble inflammasomes, triggering inflammatory responses programmed cell death. Over the last decade, it has emerged that play multifaceted roles in cancer biology, with dualistic due tumor heterogeneity microenvironment’s plasticity through dependent or independent of inflammasome mechanisms. Here, we discuss their ability function as both suppressor promoter progression emphasizes need for further research delineate precise mechanisms by these operate various contexts. Understanding dynamics could pave way novel therapeutic approaches harness dual nature members improve treatment outcomes.

Язык: Английский

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Identification of biomarkers and potential drug targets in DFU based on fundamental experiments and multi-omics joint analysis

Frontiers in Pharmacology, Год журнала: 2025, Номер 16

Опубликована: Май 23, 2025

Objective This study aims to investigate the molecular mechanisms by which quercetin facilitates treatment of diabetic foot ulcers (DFU). Methods Transcriptome sequencing datasets for DFU, specifically GSE80178, GSE134431, and GSE147890, along with single-cell dataset GSE165816, were retrieved from Gene Expression Omnibus (GEO) online database ( https://www.ncbi.nlm.nih.gov/geo/ ). The data subjected processing, annotation, differential gene expression analysis, staining. transcriptome analyzed using weighted co-expression network analysis (WGCNA), followed assessment immune infiltration. By integrating transcriptomic differentially expressed genes identified through WGCNA, co-expressed obtained, a protein-protein interaction (PPI) was constructed enrichment analysis. Core screened four machine learning models (Random Forest, Lasso, XGBoost, SVM). Drug prediction performed identify potential therapeutic agents, docking simulations conducted assess binding interactions between macromolecular proteins encoded core quercetin. A rat model ulcer (DFU) established randomly divided into three groups: control, model, groups. Tissue samples collected at 3, 7, 14 days post-intervention RT-qPCR, hematoxylin eosin (H&amp;E) staining, Masson’s trichrome immunofluorescence staining evaluate effects via modulation on DFU. Results 275 that are extensively involved in IL-17 signaling pathway, metabolic pathways, PI3K/Akt Staphylococcus aureus infection, complement coagulation cascades, among others. From these, (CIB2, SAMHD1, DPYSL2, IFI44) selected techniques. Immune infiltration demonstrated strong correlation IFI44, macrophages. Molecular studies revealed exhibits lower energy target protein site, forming stable structure. Single-cell indicated SAMHD1 is predominantly macrophages, whereas DPYSL2 not only macrophages but also significantly vascular endothelial cells other cell types. suggests may exert their modulating these cells, as corroborated basic experimental findings. improvement wound tissue morphology observed group more favorable compared group. In comparison acute group, profile aligned bioinformatics predictions. Furthermore, alterations following statistically significant. Conclusion Quercetin enhance healing macrophage activity regulation thereby contributing recovery process.

Язык: Английский

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SAMHD1 enhances HIV-1-induced apoptosis in monocytic cells via the mitochondrial pathway

mBio, Год журнала: 2025, Номер unknown

Опубликована: Май 28, 2025

ABSTRACT Sterile alpha motif (SAM) and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) inhibits HIV-1 replication in non-dividing cells by reducing the intracellular dNTP pool. While SAMHD1 is known to promote spontaneous apoptosis, its role HIV-1-induced apoptosis underlying mechanisms remain unclear. In this study, we identify a novel mechanism which enhances monocytic via mitochondrial pathway. We demonstrate that induced infection dividing THP-1 U937 cell lines, but not differentiated macrophage-like cells. Mechanistically, expression reduces membrane potential promotes cytochrome c release HIV-1-infected cells, thereby augmenting apoptotic Furthermore, SAMHD1-enhanced linked elevated levels of pro-apoptotic BCL-2-interacting killer (BIK) contributes enhanced during infection. These findings reveal previously unrecognized regulatory amplifying highlighting involvement IMPORTANCE (SAMHD1), triphosphohydrolase, lowers restricts induces death mainly through apoptosis. have shown endogenous unknown. aim bridge knowledge gap investigating functional significance regulating immune Our whereby This suggests modulating cellular responses

Язык: Английский

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