The role of cGAS-STING signaling pathway in ferroptosis DOI Creative Commons
Lina Ding, R Zhang,

Wenqi Du

et al.

Journal of Advanced Research, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 1, 2024

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway has been identified as a crucial mechanism in antiviral defense and innate immunity pathway. Ferroptosis, characterized by iron dependence lipid peroxidation, represents specialized form cell death. A burgeoning collection studies demonstrated that the cGAS-STING participates homeostatic regulation organism modulating ferroptosis-associated enzyme activity or gene expression. Consequently, elucidating specific roles STING ferroptosis vivo is vital for targeted disease intervention. This review systematically examines interactions between ferroptosis, highlighting their influence on progression contexts inflammation, injury, cancerous dynamics. Understanding these may provide novel therapeutic strategies. implicated various death mechanisms, including apoptosis, pyroptosis, necroptosis, autophagy, ferroptosis. Our focus primarily addresses role diseases, limiting discussion other modalities precluding comprehensive overview pathway's additional functions.

Language: Английский

Role of microglia in stroke DOI Creative Commons
Anna M. Planas

Glia, Journal Year: 2024, Volume and Issue: 72(6), P. 1016 - 1053

Published: Jan. 4, 2024

Abstract Microglia play key roles in the post‐ischemic inflammatory response and damaged tissue removal reacting rapidly to disturbances caused by ischemia working restore lost homeostasis. However, modified environment, encompassing ionic imbalances, disruption of crucial neuron–microglia interactions, spreading depolarization, generation danger signals from necrotic neurons, induce morphological phenotypic shifts microglia. This leads them adopt a proinflammatory profile heighten their phagocytic activity. From day three post‐ischemia, macrophages infiltrate core while microglia amass at periphery. Further, inflammation prompts metabolic shift favoring glycolysis, pentose‐phosphate shunt, lipid synthesis. These shifts, combined with intake, drive droplet biogenesis, fuel anabolism, enable proliferation. Proliferating release trophic factors contributing protection repair. some accumulate lipids persistently transform into dysfunctional potentially harmful foam cells. Studies also showed that either display impaired apoptotic cell clearance, or eliminate synapses, viable endothelial Yet, it will be essential elucidate viability engulfed cells, features local extent damage, temporal sequence. Ischemia provides rich variety region‐ injury‐dependent stimuli for microglia, evolving time generating distinct phenotypes including those exhibiting traits others showing pro‐repair features. Accurate profiling phenotypes, alongside more precise understanding associated conditions, is necessary step serve as potential foundation focused interventions human stroke.

Language: Английский

Citations

30
The neuroimmune nexus: unraveling the role of the mtDNA-cGAS-STING signal pathway in Alzheimer’s disease DOI Creative Commons

Shuiyue Quan,

Xiaofeng Fu,

Huimin Cai

et al.

Molecular Neurodegeneration, Journal Year: 2025, Volume and Issue: 20(1)

Published: March 4, 2025

The relationship between Alzheimer's disease (AD) and neuroimmunity has gradually begun to be unveiled. Emerging evidence indicates that cyclic GMP-AMP synthase (cGAS) acts as a cytosolic DNA sensor, recognizing damage-associated molecular patterns (DAMPs), inducing the innate immune response by activating stimulator of interferon genes (STING). Dysregulation this pathway culminates in AD-related neuroinflammation neurodegeneration. A substantial body mitochondria are involved critical pathogenic mechanisms AD, whose damage leads release mitochondrial (mtDNA) into extramitochondrial space. This leaked mtDNA serves DAMP, various pattern recognition receptors defense networks brain, including cGAS-STING pathway, ultimately leading an imbalance homeostasis. Therefore, modulation mtDNA-cGAS-STING restore neuroimmune homeostasis may offer promising prospects for improving AD treatment outcomes. In review, we focus on during stress activation pathway. Additionally, delve research progress further discuss primary directions potential hurdles developing targeted therapeutic drugs, gain deeper understanding pathogenesis provide new approaches its therapy.

Language: Английский

Citations

5
Mitophagy and cGAS–STING crosstalk in neuroinflammation DOI Creative Commons
Xiaogang Zhou, Jing Wang, Lu Yu

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(8), P. 3327 - 3361

Published: May 13, 2024

Mitophagy, essential for mitochondrial health, selectively degrades damaged mitochondria. It is intricately linked to the cGAS–STING pathway, crucial innate immunity. This pathway responds DNA and associated with cellular stress. Our review explores molecular details regulatory mechanisms of mitophagy pathway. We critically evaluated literature demonstrating how dysfunctional leads neuroinflammatory conditions, primarily through accumulation mitochondria, activating activation prompts production proinflammatory cytokines, exacerbating neuroinflammation. emphasizes interaction between Effective might suppress offering protection against Conversely, impaired may activate potentially leading chronic Additionally, we explored this influences neurodegenerative disorders, suggesting a common mechanism in such diseases. In conclusion, there need additional targeted research unravel complexities mitophagy–cGAS–STING interactions their role neurodegeneration. highlights potential therapies targeting these pathways, which could lead new treatments conditions. synthesis enhances our understanding foundations neuroinflammation opens therapeutic avenues disease research.

Language: Английский

Citations

16
mtDNA regulates cGAS-STING signaling pathway in adenomyosis DOI
Kun Wang,

Yi Wen,

Xianyun Fu

et al.

Free Radical Biology and Medicine, Journal Year: 2024, Volume and Issue: 216, P. 80 - 88

Published: March 15, 2024

Language: Английский

Citations

5
DNA fragments detected in monovalent and bivalent Pfizer/BioNTech and Moderna modRNA COVID-19 vaccines from Ontario, Canada: Exploratory dose response relationship with serious adverse events. DOI Open Access
David J. Speicher, Jessica Rose,

L. Maria Gutschi

et al.

Published: Oct. 19, 2023

Background: In vitro transcription (IVT) reactions used to generate nucleoside modified RNA (modRNA) for SARS-CoV-2 vaccines currently rely on an polymerase transcribing from a DNA template. Production of modRNA in the original Pfizer randomized clinical trial (RCT) utilized PCR-generated template (Process 1). To billions vaccine doses, this was cloned into bacterial plasmid vector amplification Escherichia coli before linearization 2), expanding size and complexity potential residual introducing sequences not present Process 1 It appears that Moderna similar plasmid-based process both post-trial use vaccines. Recently, sequencing studies have revealed at significant levels Pfizer-BioNTech These surveyed limited number lots questions remain regarding variance observed internationally.Methods: Using previously published primer probe sequences, quantitative chain reaction (qPCR) Qubit® fluorometry performed additional 27 mRNA vials obtained Canada drawn 12 unique (5 child/adult monovalent, lot adult bivalent BA.4/5, BA.1, XBB.1.5 3 BA.4/5). The Vaccine Adverse Events Reporting System (VAERS) database queried categorization adverse events (AEs) reported each tested. content one studied vial COVID-19 examined by Oxford Nanopore determine distribution fragments. This sample also if is packaged lipid nanoparticles (LNPs) thus resistant DNaseI or resides outside LNP labile. Results: Quantification cycle (Cq) values (1:10 dilution) origin replication (ori) spike ranged 18.44 - 24.87 18.03 23.83 Pfizer, 22.52 – 24.53 25.24 30.10 Moderna, respectively. correspond 0.28 4.27 ng/dose 0.22 2.43 (Pfizer), 0.01 -0.34 0.25 0.78 (Moderna), ori respectively measured qPCR, 1,896 3,720 3,270 5,100 respectfully. SV40 promoter-enhancer-ori only detected with Cq scores ranging 16.64 22.59. exploratory analysis, we found preliminary evidence dose response relationship amount per frequency serious (SAEs). different products. Size analysis mean maximum fragment lengths 214 base pairs (bp) 3.5 kb, likely inside LNPs protected nucleases.Conclusion: data demonstrate presence hundreds molecules these fluorometry, all exceed guidelines set FDA WHO 10 188 509-fold. However, qPCR were below emphasizing importance methodological clarity consistency when interpreting guidelines. dose-response effect SAEs warrant confirmation further investigation. Our findings extend existing concerns about safety call question relevance conceived introduction efficient transfection using LNPs. With several obvious limitations, urge our work replicated under forensic conditions be revised account highly cumulative dosing.

Language: Английский

Citations

12
The cGAS−STING-mediated ROS and ferroptosis are involved in manganese neurotoxicity DOI
Zhimin Zhang, Jirui Yang,

Qiongli Zhou

et al.

Journal of Environmental Sciences, Journal Year: 2024, Volume and Issue: 152, P. 71 - 86

Published: May 9, 2024

Language: Английский

Citations

4
PANoptosis‐Related Optimal Model (PROM): A Novel Prognostic Tool Unveiling Immune Dynamics in Lung Adenocarcinoma DOI Creative Commons

Jianming Peng,

Liquan Tong,

Rui Liang

et al.

International Journal of Genomics, Journal Year: 2025, Volume and Issue: 2025(1)

Published: Jan. 1, 2025

Background: PANoptosis, a recently characterized inflammatory programmed cell death modality orchestrated by the PANoptosome complex, integrates molecular mechanisms of pyroptosis, apoptosis, and necroptosis. Although this pathway potentially mediates tumor progression, its role in lung adenocarcinoma (LUAD) remains largely unexplored. Methods: Through comprehensive single-cell transcriptomic profiling, we systematically identified critical PANoptosis-associated gene signatures. Prognostic determinants were subsequently delineated via univariate Cox proportional hazards regression analysis. We constructed PANoptosis-related optimal model (PROM) through integration 10 machine learning algorithms. The was initially developed using Cancer Genome Atlas (TCGA)-LUAD cohort validated across six independent LUAD cohorts. Model performance evaluated mean concordance index. Furthermore, conducted extensive multiomics analyses to delineate differential activation patterns immune infiltration profiles between PROM-stratified risk subgroups. Results: Cellular populations exhibiting elevated PANoptosis signatures demonstrated enhanced intercellular signaling networks. PROM superior prognostic capability multiple validation Receiver operating characteristic curve revealed area under values exceeding 0.7 all seven cohorts, with several achieving above 0.8, indicating robust discriminative performance. score exhibited significant correlation immunological parameters. Notably, high scores associated attenuated responses, suggesting an immunosuppressive microenvironment. Multiomics investigations alterations oncogenic pathways landscape Conclusion: This investigation establishes as clinically applicable tool for stratification. Beyond predictive utility, elucidates biological underlying progression. These findings provide novel mechanistic insights into pathogenesis may inform development targeted therapeutic interventions personalized treatment strategies optimize patient outcomes.

Language: Английский

Citations

0
The critical role of Sirt1 in ischemic stroke DOI Creative Commons
Ziyi Jia, Ke Xu, Ruobing Li

et al.

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: March 14, 2025

Ischemic stroke, the most prevalent form of is responsible for highest disability rates globally and ranks as primary cause mortality worldwide. Sirt1, extensively investigated in neurodegenerative disorders, well-known earliest member sirtuins family. However, its mechanism action during ischemic stroke remains ambiguous. The literature examination revealed intricate involvement Sirt1 regulating both physiological pathological mechanisms stroke. demonstrates deacetylation effects on PGC-1α, HMGB1, FOXOs, p53. It hinders activation NLRP3 inflammasome NF-κB while also engaging with AMPK. regulates inflammatory response, oxidative stress, mitochondrial dysfunction, autophagy, pro-death, necrotic apoptosis. Therefore, potential a therapeutic target management promising.

Language: Английский

Citations

0
Neuroprotective mechanisms of microglia in ischemic stroke: a review focused on mitochondria DOI
Jianhua Gan, Xinyi Yang, Jianan Wu

et al.

Molecular Biology Reports, Journal Year: 2025, Volume and Issue: 52(1)

Published: April 1, 2025

Language: Английский

Citations

0
Mitochondria: the hidden engines of traumatic brain injury-driven neurodegeneration DOI Creative Commons

Olusola A. Olatona,

Sydney P Sterben,

Sahan BS Kansakar

et al.

Frontiers in Cellular Neuroscience, Journal Year: 2025, Volume and Issue: 19

Published: May 9, 2025

Mitochondria play a critical role in brain energy metabolism, cellular signaling, and homeostasis, making their dysfunction key driver of secondary injury progression traumatic (TBI). This review explores the relationship between mitochondrial bioenergetics, oxidative stress, neuroinflammation post-TBI brain. Mitochondrial disrupts adenosine triphosphate (ATP) production, exacerbates calcium dysregulation, generates reactive oxygen species, triggering cascade neuronal damage neurodegenerative processes. Moreover, damaged mitochondria release damage-associated molecular patterns (DAMPs) such as DNA (mtDNA), Cytochrome C, ATP, inflammatory pathways that amplify tissue injury. We discuss metabolic shifts occur post-TBI, including transition from phosphorylation to glycolysis consequences inflexibility. Potential therapeutic interventions targeting dynamics, bioenergetic support, inflammation modulation are explored, highlighting emerging strategies mitochondrial-targeted antioxidants, substrate supplementation, pharmacological regulators permeability pores. Understanding these mechanisms is crucial for developing novel approaches mitigate neurodegeneration enhance recovery following trauma.

Language: Английский

Citations

0