Inhibition of cGAS ameliorates acute lung injury triggered by zinc oxide nanoparticles

Jiang, Ziqi; Jiang, Yu; Fan, Jie; Zhang, Jun; Xu, Guohai; Fan, Yinzhen; Zhang, Liyu; Qin, Xia; Jiang, Xuejun; Mao, Lejiao; Liu, Gang; Chen, Chengzhi; Zou, Zhen

doi:10.1016/j.toxlet.2022.11.002

Cited by 12 publications

(5 citation statements)

References 66 publications

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“…Notably, a clinical trial of Dexmedetomidine for ARDS in critical care COVID-19 patients is under investigation (NCT04358627). The targeted inhibition of the cGAS-STING pathway is also a valuable idea, and several small-molecule inhibitors of cGAS-STING pathway, such as H-151 and RU.521 have been proven to alleviate lung injury in ALI models [ 237 , 238 ].…”

Section: Emerging Pharmacologic Therapies For Ardsmentioning

confidence: 99%

Signaling pathways and potential therapeutic targets in acute respiratory distress syndrome (ARDS)

Huang,

Le,

et al. 2024

Respir Res

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Acute respiratory distress syndrome (ARDS) is a common condition associated with critically ill patients, characterized by bilateral chest radiographical opacities with refractory hypoxemia due to noncardiogenic pulmonary edema. Despite significant advances, the mortality of ARDS remains unacceptably high, and there are still no effective targeted pharmacotherapeutic agents. With the outbreak of coronavirus disease 19 worldwide, the mortality of ARDS has increased correspondingly. Comprehending the pathophysiology and the underlying molecular mechanisms of ARDS may thus be essential to developing effective therapeutic strategies and reducing mortality. To facilitate further understanding of its pathogenesis and exploring novel therapeutics, this review provides comprehensive information of ARDS from pathophysiology to molecular mechanisms and presents targeted therapeutics. We first describe the pathogenesis and pathophysiology of ARDS that involve dysregulated inflammation, alveolar-capillary barrier dysfunction, impaired alveolar fluid clearance and oxidative stress. Next, we summarize the molecular mechanisms and signaling pathways related to the above four aspects of ARDS pathophysiology, along with the latest research progress. Finally, we discuss the emerging therapeutic strategies that show exciting promise in ARDS, including several pharmacologic therapies, microRNA-based therapies and mesenchymal stromal cell therapies, highlighting the pathophysiological basis and the influences on signal transduction pathways for their use.

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Section: Emerging Pharmacologic Therapies For Ardsmentioning

confidence: 99%

Signaling pathways and potential therapeutic targets in acute respiratory distress syndrome (ARDS)

Huang,

Le,

et al. 2024

Respir Res

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“…With a measured occurrence count (18, 19, 11, 13, and 13), this cluster zeroes in on the potential of ZnO NPs to ameliorate diabetes-related complications, especially addressing mitochondrial damage and the Nrf2 pathway's involvement. [113][114][115] Moreover, it explores the exciting prospects of synergistic inter-actions when these nanoparticles are combined with cisplatin, a prominent chemotherapy agent. [116,117] The mean publication years for these terms, spanning from 2020.2 to 2020.3, emphasize the currency of these explorations.…”

Section: Contemporary Topics Per Clustermentioning

confidence: 99%

A Data Mining Study of Zinc Oxide Nanostructures Utilization in Drug Delivery Nanosystems

Valladão,

da Silva,

Souza

2024

Macromolecular Symposia

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The present investigation offers a thorough bibliometric exploration spotlighting the pivotal utilization of zinc oxide nanostructures, encompassing both zero‐dimensional (0D) nanoparticles and one‐dimensional (1D) nanostructures, within the realm of nanotechnology‐driven drug delivery systems. This analysis particularly illuminates the distinctive potential of these nanostructures in the cancer therapy context, not merely as carriers and deliverers of pharmaceutical agents, but as entities capable of selectively inducing apoptosis in cancer cells through the orchestrated generation of reactive oxygen species (ROS). Recent research endeavors notably underscore the application prospects of ZnO nanostructures in domains like DNA cleavage, bioimaging, and agricultural defense mechanisms. Moreover, the study elucidates the pronounced enhancement in solubility and biocompatibility that these nanostructures bring about when harmoniously integrated into polymeric nanocomposites. Concomitantly, the involvement of polymers in this symbiotic system is unveiled, wherein they play a multifaceted role in dictating release selectivity, thereby facilitating targeted and efficacious interactions with tissues. Functionally engineered polymeric nanocomposites emerge as promising candidates for targeted delivery modalities in cancer treatment, demonstrating an affinity for specific cell receptors and exhibiting enhanced cellular uptake within the size range of 100–200 nm. The study unearths robust associations among pivotal research terminologies through an exhaustive analysis of Link Strength Between Items (LSBI), culminating in the presentation of a cogent map delineating the evolving trends and forthcoming trajectories in this dynamic domain. In summation, this all‐encompassing bibliometric inquiry serves as a poignant testament to the prodigious potential of zinc oxide nanostructures in the realm of forthcoming nanotechnology‐driven drug delivery paradigms.

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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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Inhibition of cGAS ameliorates acute lung injury triggered by zinc oxide nanoparticles

Cited by 12 publications

References 66 publications

Signaling pathways and potential therapeutic targets in acute respiratory distress syndrome (ARDS)

Signaling pathways and potential therapeutic targets in acute respiratory distress syndrome (ARDS)

A Data Mining Study of Zinc Oxide Nanostructures Utilization in Drug Delivery Nanosystems

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

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