mtDNA-cGAS-STING axis-dependent NLRP3 inflammasome activation contributes to postoperative cognitive dysfunction induced by sevoflurane in mice DOI Creative Commons

Nan‐Shi‐Yu Yang,

Wenjing Zhong,

Han-Xi Sha

et al.

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 3, 2023

Abstract Background NLRP3 inflammasome activation is critical for neuroinflammation in microglia during postoperative cognitive dysfunction (POCD) induced by sevoflurane. However, the molecular mechanism which sevoflurane activates remains unclear. The cGAS- STING pathway an evolutionarily conserved inflammatory defense mechanism. role of cGAS-STING sevoflurane-induced inflammasome-dependent and underlying mechanisms require further investigation. Methods Prolonged anesthesia with was used to induce mice. passive avoidance test Y-maze were assess function. We then cGAS inhibitor RU.521 investigate whether involved mice microglia. To sevoflurane-treated microglia, we pre-treated Mdivi-1 (a DRP1 inhibitor), CsA mPTP inhibitor) or VBIT-4 VDAC inhibitor). Results found that prolonged triggered characterized inflammasome. Interestingly, activated hippocampus receiving While blockade attenuated In vitro , treatment significantly while pre-treatment robustly inhibited activation. Mechanistically, mitochondrial fission released DNA (mtDNA) into cytoplasm, could be abolished Mdivi-1. Blocking mtDNA release via mPTP-VDAC channel cytosolic escape reduced finally inhibiting Conclusion this study, reported a novel POCD. Therefore, regulating targeting may provide therapeutic target

Language: Английский

mtDNA-cGAS-STING axis-dependent NLRP3 inflammasome activation contributes to postoperative cognitive dysfunction induced by sevoflurane in mice DOI Creative Commons

Nan‐Shi‐Yu Yang,

Wenjing Zhong,

Han-Xi Sha

et al.

International Journal of Biological Sciences, Journal Year: 2024, Volume and Issue: 20(5), P. 1927 - 1946

Published: Jan. 1, 2024

The activation of NLRP3 inflammasome in microglia is critical for neuroinflammation during postoperative cognitive dysfunction (POCD) induced by sevoflurane.However, the molecular mechanism which sevoflurane activates remains unclear.The cGAS-STING pathway an evolutionarily conserved inflammatory defense mechanism.The role sevoflurane-induced inflammasome-dependent and underlying mechanisms require further investigation.We found that prolonged anesthesia with triggered characterized vivo.Interestingly, was activated hippocampus mice receiving sevoflurane.While blockade cGAS RU.521 attenuated mice.In vitro, we treatment significantly microglia, while pre-treatment robustly inhibited activation.Mechanistically, mitochondrial fission released DNA (mtDNA) into cytoplasm, could be abolished Mdivi-1.Blocking mtDNA release via mPTP-VDAC channel inhibitor cytosolic escape reduced finally inhibiting activation.Therefore, regulating targeting may provide a novel therapeutic target POCD.

Language: Английский

Citations

20
C3/C3aR Bridges Spinal Astrocyte‐Microglia Crosstalk and Accelerates Neuroinflammation in Morphine‐Tolerant Rats DOI Creative Commons
Xiangmin Peng, Jie Ju, Zheng Li

et al.

CNS Neuroscience & Therapeutics, Journal Year: 2025, Volume and Issue: 31(1)

Published: Jan. 1, 2025

Communication within glial cells acts as a pivotal intermediary factor in modulating neuroimmune pathology. Meanwhile, an increasing awareness has emerged regarding the detrimental role of and neuroinflammation morphine tolerance (MT). This study investigated influence crosstalk between astrocyte microglia on evolution tolerance. Sprague-Dawley rats were intrathecally treated with twice daily for 9 days to establish morphine-tolerant rat model. Tail-flick latency test was performed identify analgesic effect morphine. The microglia, C3-C3aR axis elucidated by real-time quantitative polymerase chain reaction, Western blot, immunofluorescence. Chronic treatment notably promoted activation upregulated production proinflammatory mediators (interleukin-1 alpha (IL-1α), tumor necrosis (TNFα), complement component 1q (C1q)). Simultaneously, it programed astrocytes pro-inflammatory phenotype (A1), which mainly expresses 3 (C3) serping1. PLX3397 (a colony-stimulating 1 receptor (CSF1R) inhibitor), Compstain C3 inhibitor) SB290157(a C3aR antagonist) could reverse above pathological process alleviate different extents. Our findings amplifier microglia-astrocyte crosstalk, node therapeutic intervention

Language: Английский

Citations

2
TL1A promotes the postoperative cognitive dysfunction in mice through NLRP3‐mediated A1 differentiation of astrocytes DOI Creative Commons
Genghuan Wang, Jian Shen, Liping Zhai

et al.

CNS Neuroscience & Therapeutics, Journal Year: 2023, Volume and Issue: 29(11), P. 3588 - 3597

Published: June 2, 2023

We investigated the mechanism, whereby tumor necrosis factor-like ligand 1A (TL1A) mediates A1 differentiation of astrocytes in postoperative cognitive dysfunction (POCD).The and behavioral abilities mice were assessed by Morris water maze open field tests, while levels key A2 astrocyte factors detected RT-qPCR. Immunohistochemical (IHC) staining was used to examine expression GFAP, western blot assay related proteins, enzyme-linked immunosorbent (ELISA) detect inflammatory cytokines.The results showed that TL1A could promote progression mice. Astrocytes differentiated into phenotype, unobvious changes noted biomarkers. Knockout NLRP3 or intervention with inhibitor inhibit effect TL1A, improving suppressing differentiation.Our demonstrate plays an important role POCD mice, which promotes through NLRP3, thereby exacerbating dysfunction.

Language: Английский

Citations

12
The Crosstalk Between Immune Cells After Intracerebral Hemorrhage DOI
Baiwen Zhang,

Ke-Han Sun,

Ting Liu

et al.

Neuroscience, Journal Year: 2023, Volume and Issue: 537, P. 93 - 104

Published: Dec. 5, 2023

Language: Английский

Citations

10
Actions of dexmedetomidine in regulating NLRP3 in postoperative cognitive dysfunction in aged mice via the autophagy–lysosome pathway DOI Open Access
Zhi Wang,

Li‐na Zhang,

Ting Wu

et al.

British Journal of Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 15, 2025

Autophagy-lysosomal pathway dysfunction leads to postoperative cognitive (POCD). Dexmedetomidine (Dex) improves POCD, and we probed the effects of Dex on autophagy-lysosomal in a POCD model. A mouse model was established intraperitoneally injected with Dex. Cognitive function evaluated by Morris water maze/open field test/novel object recognition assay. Levels neurotransmitters/inflammatory cytokines hippocampus, NLRP3/ASC/Cleaved Caspase-1 proteins were determined ELISA/Western blot. NLRP3 inflammasome-mediated microglial activation/astrocyte A1 differentiation hippocampal CA1 region assessed immunofluorescence BV-2 cells treated lipopolysaccharide (LPS) and/or inflammasome activator Nigericin, transfected si-TFEB for co-culture primary reactive astrocytes (RAs) verify vitro. alleviated mice repressed activation astrocyte differentiation. partially reversed protective effect condition. In vitro experiments verified inhibitory properties induces TFEB nuclear translocation, autophagy lysosomal biogenesis. By activating autophagy-lysosome pathway, regulated activation, inhibited vivo. regulates promoting translocation inhibits differentiation, thereby alleviating POCD.

Language: Английский

Citations

0
Inhibition of STAT3 phosphorylation attenuates perioperative neurocognitive disorders in mice with D-galactose-induced aging by regulating pro-inflammatory reactive astrocytes DOI

Ying Cao,

Xiaowan Lin, Danyang Gao

et al.

International Immunopharmacology, Journal Year: 2025, Volume and Issue: 148, P. 114095 - 114095

Published: Jan. 18, 2025

Language: Английский

Citations

0
Impaired hippocampal neurogenesis associated with regulatory ceRNA network in a mouse model of postoperative cognitive dysfunction DOI Creative Commons
Jingrun Lin,

Xiaoqiu Zhu,

Xuan Li

et al.

BMC Anesthesiology, Journal Year: 2025, Volume and Issue: 25(1)

Published: Feb. 6, 2025

Postoperative cognitive dysfunction (POCD) represents a post-surgical complication that features progressive impairment and memory loss, often occurring in elderly patients. This study aimed to investigate the potential biological mechanisms underlying POCD. Male C57BL/6 mice (2 17 months old) were randomly assigned surgery or control groups. The group underwent laparotomy under 1.5% isoflurane anesthesia, while controls received no intervention. Cognitive function was assessed 7–10 days post-surgery using open field, Y-maze, novel object recognition tests. Hippocampal mRNA expression analyzed Encyclopedia of Genes Genomes (KEGG) Gene Ontology (GO) enrichment. A competing endogenous RNA (ceRNA) network constructed microRNA (miRNA) target prediction databases (miRanda, miRTarbase, miRcode) sequencing results. Key findings validated by RT-qPCR immunofluorescence. Connectivity Map (CMap) database queried predict POCD treatments. Aging significantly affected mice's spontaneous activity field test (F1, 28 = 8.933, P < 0.01) proportion time spent center area 5.387, 0.05). Surgery reduced rate alternations Y-maze 16.94, 0.001) index 6.839, 0.05) aging mice, but had effect on young mice. Transcriptome analysis revealed downregulated multiple neurogenesis-related genes hippocampus. Doublecortin (DCX) immunofluorescence staining confirmed hippocampal neurogenesis which further decreased after surgery. We identified several key lncRNAs miRNAs implicated regulation. Additionally, drugs predicted as therapeutic candidates for treatment. Both have complex effects transcriptome significant decrease may be reason increased susceptibility regulatory lncRNAs, miRNAs, provide targets prevention

Language: Английский

Citations

0
Post-operative cognitive dysfunction is exacerbated by high-fat diet via TLR4 and prevented by dietary DHA supplementation DOI
Stephanie Muscat, Michael J. Butler,

Menaz N. Bettes

et al.

Brain Behavior and Immunity, Journal Year: 2023, Volume and Issue: 116, P. 385 - 401

Published: Dec. 23, 2023

Language: Английский

Citations

7
Curcumin activates the Wnt/β-catenin signaling pathway to alleviate hippocampal neurogenesis abnormalities caused by intermittent hypoxia: A study based on network pharmacology and experimental verification DOI
Yao He, Yan Zhao, Renjun Lv

et al.

International Immunopharmacology, Journal Year: 2024, Volume and Issue: 143, P. 113299 - 113299

Published: Oct. 2, 2024

Language: Английский

Citations

2
Inhibiting endoplasmic reticulum stress alleviates perioperative neurocognitive disorders by reducing neuroinflammation mediated by NLRP3 inflammasome activation DOI Creative Commons
Fanbing Meng, Jian Song, Xinwei Huang

et al.

CNS Neuroscience & Therapeutics, Journal Year: 2024, Volume and Issue: 30(10)

Published: Oct. 1, 2024

Abstract Aim The aim of this study is to explore the key mechanisms perioperative neurocognitive dysfunction (PND) after anesthesia/surgery (A/S) by screening hub genes. Methods Transcriptome sequencing was conducted on hippocampal samples obtained from 18‐month‐old C57BL/6 mice assigned control (Ctrl) and A/S groups. functionality differentially expressed genes (DEGs) investigated using Metascape. Hub associated with changes between two groups were screened combining weighted gene coexpression network analysis within CytoHubba. Reverse transcription PCR western blotting used validate in mRNA protein expression, respectively. NLRP3 inflammasome activation detected ELISA. Tauroursodeoxycholic acid (TUDCA), an inhibitor endoplasmic reticulum (ER) stress, administrated preoperatively its effects occurrence PND. Immunofluorescence performed evaluate astrocytes microglia hippocampus, hippocampus‐dependent learning memory assessed behavioral experiments. Results In total, 521 DEGs These significantly enriched biological processes related metabolic their regulation. Four ( Hspa5 , Igf1r Sfpq Xbp1 ) identified. Animal experiments have shown that group exhibited cognitive impairments accompanied increased ER inflammasome. Conclusions Inhibiting stress alleviated impairment mice; particularly, induced results neuroinflammation. Moreover, preoperative administration TUDCA inhibited activation,

Language: Английский

Citations

1