RU.521 mitigates subarachnoid hemorrhage-induced brain injury via regulating microglial polarization and neuroinflammation mediated by the cGAS/STING/NF-κB pathway

Shao, Jiang; Meng, Yuxiao; Yuan, Kaikun; Wu, Qiaowei; Zhu, Shiyi; Li, Yuchen; Wu, Pei; Zheng, Jiaolin; Shi, Huaizhang

doi:10.1186/s12964-023-01274-2

Cited by 13 publications

(2 citation statements)

References 57 publications

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“…Nissl staining was used to observe neuronal damage in the hippocampus of mice as previously described 26 . After the mice were intracardially perfused with PBS followed by 4% paraformaldehyde on the PND37, their brain tissues were removed for immersion in 4% paraformaldehyde, dehydrated with sucrose solution in PBS, and then embedded in optimal cutting temperature (O.C.T.)…”

Section: Methodsmentioning

confidence: 99%

Identification of differential m6A RNA methylomes and ALKBH5 as a potential prevention target in the developmental neurotoxicity induced by multiple sevoflurane exposures

Meng,

Wang,

Zhao

et al. 2024

The FASEB Journal

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Sevoflurane, as a commonly used inhaled anesthetic for pediatric patients, has been reported that multiple sevoflurane exposures are associated with a greater risk of developing neurocognitive disorder. N6‐Methyladenosine (m6A), as the most common mRNA modification in eukaryotes, has emerged as a crucial regulator of brain function in processes involving synaptic plasticity, learning and memory, and neurodevelopment. Nevertheless, the relevance of m6A RNA methylation in the multiple sevoflurane exposure‐induced developmental neurotoxicity remains mostly elusive. Herein, we evaluated the genome‐wide m6A RNA modification and gene expression in hippocampus of mice that received with multiple sevoflurane exposures using m6A‐sequencing (m6A‐seq) and RNA‐sequencing (RNA‐seq). We discovered 19 genes with differences in the m6A methylated modification and differential expression in the hippocampus. Among these genes, we determined that a total of nine differential expressed genes may be closely associated with the occurrence of developmental neurotoxicity induced by multiple sevoflurane exposures. We further found that the alkB homolog 5 (ALKBH5), but not methyltransferase‐like 3 (METTL3) and Wilms tumor 1‐associated protein (WTAP), were increased in the hippocampus of mice that received with multiple sevoflurane exposures. And the IOX1, as an inhibitor of ALKBH5, significantly improved the learning and memory defects and reduced neuronal damage in the hippocampus of mice induced by multiple sevoflurane exposures. The current study revealed the role of m6A methylated modification and m6A‐related regulators in sevoflurane‐induced cognitive impairment, which might provide a novel insight into identifying biomarkers and therapeutic strategies for inhaled anesthetic‐induced developmental neurotoxicity.

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Section: Methodsmentioning

confidence: 99%

Identification of differential m6A RNA methylomes and ALKBH5 as a potential prevention target in the developmental neurotoxicity induced by multiple sevoflurane exposures

Meng,

Wang,

Zhao

et al. 2024

The FASEB Journal

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“…Both of these inhibitors have improved outcomes in an expanding diversity of preclinical rodent models of diseases. RU.521 has been used to improve disease outcomes in rodent models of neuroinflammation caused by subarachnoid hemorrhage and cerebral venous sinus thrombosis, colitis, sepsis-induced organ injury, , acetaminophen-induced liver injury, acute lung injury, hypertensive heart injury, ischemic injury in the lung and neonatal brain, femoral fracture healing, and aging-related endothelial dysfunction . Additionally, administration of H-151 has improved outcomes in rodent models of acute kidney injury (AKI), renal fibrosis, amyotrophic lateral sclerosis (ALS), sepsis-induced organ injury, , psoriasis, ischemia-reperfusion injury in the intestine, myocardial infarction, LPS-induced acute lung injury, , Alzheimer’s, and neuropathic pain resulting from chronic constriction injury .…”

Section: Introductionmentioning

confidence: 99%

STING-Pathway Inhibiting Nanoparticles (SPINs) as a Platform for Treatment of Inflammatory Diseases

Pastora,

Namburu,

Arora

et al. 2024

ACS Appl. Bio Mater.

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Aberrant activation of the cyclic GMP-AMP synthase (cGAS)/ Stimulator of Interferon Genes (STING) pathway has been implicated in the development and progression of a myriad of inflammatory diseases including colitis, nonalcoholic steatohepatitis, amyotrophic lateral sclerosis (ALS), and age-related macular degeneration. Thus, STING pathway inhibitors could have therapeutic application in many of these inflammatory conditions. The cGAS inhibitor RU.521 and the STING inhibitor H-151 have shown promise as therapeutics in mouse models of colitis, ALS, and more. However, these agents require frequent high-dose intraperitoneal injections, which may limit translatability. Furthermore, long-term use of systemically administered cGAS/STING inhibitors may leave patients vulnerable to viral infections and cancer. Thus, localized or targeted inhibition of the cGAS/STING pathway may be an attractive, broadly applicable treatment for a variety of STING pathway-driven ailments. Here we describe STING-Pathway Inhibiting Nanoparticles (SPINS)−poly(lacticco-glycolic acid) (PLGA) nanoparticles loaded with RU.521 and H-151−as a platform for enhanced and sustained inhibition of cGAS/STING signaling. We demonstrate that SPINs are equally or more effective at inhibiting type-I interferon responses induced by cytosolic DNA than free H-151 or RU.521. Additionally, we describe a SPIN formulation in which PLGA is coemulsified with poly(benzoyloxypropyl methacrylamide) (P(HPMA-Bz)), which significantly improves drug loading and allows for tunable release of H-151 over a period of days to over a week by varying P(HPMA-Bz) content. Finally, we find that all SPIN formulations were as potent or more potent in inhibiting cGAS/STING signaling in primary murine macrophages, resulting in decreased expression of inflammatory M1-like macrophage markers. Therefore, our study provides an in vitro proof-of-concept for nanoparticle delivery of STING pathway inhibitors and positions SPINs as a potential platform for slowing or reversing the onset or progression of cGAS/ STING-driven inflammatory conditions.

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Neutrophil Extracellular Traps Regulate Surgical Brain Injury by Activating the cGAS-STING Pathway

Li,

Xu,

Wang

et al. 2024

Cell Mol Neurobiol

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Surgical brain injury (SBI), induced by neurosurgical procedures or instruments, has not attracted adequate attention. The pathophysiological process of SBI remains sparse compared to that of other central nervous system diseases thus far. Therefore, novel and effective therapies for SBI are urgently needed. In this study, we found that neutrophil extracellular traps (NETs) were present in the circulation and brain tissues of rats after SBI, which promoted neuroinflammation, cerebral edema, neuronal cell death, and aggravated neurological dysfunction. Inhibition of NETs formation by peptidylarginine deiminase (PAD) inhibitor or disruption of NETs with deoxyribonuclease I (DNase I) attenuated SBI-induced damages and improved the recovery of neurological function. We show that SBI triggered the activation of cyclic guanosine monophosphate–adenosine monophosphate synthase stimulator of interferon genes (cGAS-STING), and that inhibition of the cGAS-STING pathway could be beneficial. It is worth noting that DNase I markedly suppressed the activation of cGAS-STING, which was reversed by the cGAS product cyclic guanosine monophosphate–adenosine monophosphate (cGMP-AMP, cGAMP). Furthermore, the neuroprotective effect of DNase I in SBI was also abolished by cGAMP. NETs may participate in the pathophysiological regulation of SBI by acting through the cGAS-STING pathway. We also found that high-dose vitamin C administration could effectively inhibit the formation of NETs post-SBI. Thus, targeting NETs may provide a novel therapeutic strategy for SBI treatment, and high-dose vitamin C intervention may be a promising translational therapy with an excellent safety profile and low cost. Graphical Abstract The schematic diagram shows the formation of NETs activated cGAS-STING pathway after SBI, leading to increased microglia activation, accompanied with elevation of inflammatory factors, which in turn aggravated brain injury.

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RU.521 mitigates subarachnoid hemorrhage-induced brain injury via regulating microglial polarization and neuroinflammation mediated by the cGAS/STING/NF-κB pathway

Cited by 13 publications

References 57 publications

Identification of differential m6A RNA methylomes and ALKBH5 as a potential prevention target in the developmental neurotoxicity induced by multiple sevoflurane exposures

Identification of differential m6A RNA methylomes and ALKBH5 as a potential prevention target in the developmental neurotoxicity induced by multiple sevoflurane exposures

STING-Pathway Inhibiting Nanoparticles (SPINs) as a Platform for Treatment of Inflammatory Diseases

Neutrophil Extracellular Traps Regulate Surgical Brain Injury by Activating the cGAS-STING Pathway

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