Intravenous Arginine Administration Downregulates NLRP3 Inflammasome Activity and Attenuates Acute Kidney Injury in Mice with Polymicrobial Sepsis

Tanuseputero, Sharon Angela; Lin, Ming Tsan; Yeh, Sung Ling; Yeh, Chiu Li

doi:10.1155/2020/3201635

Cited by 20 publications

(8 citation statements)

References 51 publications

(54 reference statements)

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“…Moreover, the inactivated NLRP3 inflammasome due to melatonin could ameliorate sepsis-induced heart injury [ 21 ]. Downregulated activity of NLRP3 inflammasome in response to intravenous arginine administration alleviated acute kidney injury in a mouse model of polymicrobial sepsis [ 22 ]. Additionally, repression of the NLRP3/IL-1β axis may exert protection against endothelial relaxation dysfunction induced by sepsis [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

YTHDF1 alleviates sepsis by upregulating WWP1 to induce NLRP3 ubiquitination and inhibit caspase-1-dependent pyroptosis

et al. 2022

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Pyroptosis is inflammation-associated caspase-1-dependent programmed cell death, which confers a crucial role in sepsis. The present study intends to investigate the regulatory network and function of the microarray-predicted YTHDF1 in caspase-1-dependent pyroptosis of sepsis. Peripheral blood of patients with sepsis was collected to determine WWP1 and YTHDF1 expression. An in vitro sepsis cell model was induced in RAW264.7 cells using lipopolysaccharide (LPS) and ATP and an in vivo septic mouse model by cecal ligation and perforation (CLP). After gain- and loss-of-function assays in vitro and in vivo, TNF-α and IL-1β levels and the cleavage of gasdermin-D (GSDMD) were detected by ELISA and Western blot assay, followed by determination of lactate dehydrogenase (LDH) activity. Immunoprecipitation and meRIP assay were performed to detect the ubiquitination of NLRP3 and the m6A modification of WWP1 mRNA. The binding of WWP1 to YTHDF1 was explored using RIP-RT-qPCR and dual luciferase gene reporter assay. It was noted that WWP1 and YTHDF1 were downregulated in clinical sepsis samples, LPS + ATP-treated RAW264.7 cells, and CLP-induced mice. The ubiquitination of NLRP3 was promoted after overexpression of WWP1. WWP1 translation could be promoted by YTHDF1. Then, WWP1 or YTHDF1 overexpression diminished LDH activity, NLRP3 inflammasomes and caspase-1-mediated cleavage of GSDMD in LPS + ATP-induced RAW264.7 cells. Overexpressed YTHDF1 restrained inflammatory response in CLP-induced mice. Collectively, the alleviatory effect of m6A reader protein YTHDF1 may be achieved through promotion of NLRP3 ubiquitination and inhibition of caspase-1-dependent pyroptosis by upregulating WWP1.

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Section: Discussionmentioning

confidence: 99%

YTHDF1 alleviates sepsis by upregulating WWP1 to induce NLRP3 ubiquitination and inhibit caspase-1-dependent pyroptosis

et al. 2022

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“…Circulating arginine is reduced in response to infections [13,56] as a result of reduced de novo synthesis and increased catabolism by arginase [57]. Arginine administration has shown benefit in preclinical [58,59] and some clinical [60][61][62] studies. Direct administration of NO via an inhaled route has recently been tested in patients with sepsis [63].…”

Section: Benefits Of Increased No Bioavailability In Sepsismentioning

confidence: 99%

A new perspective on NO pathway in sepsis and ADMA lowering as a potential therapeutic approach

2022

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The nitric oxide pathway plays a critical role in vascular homeostasis. Increased levels of systemic nitric oxide (NO) are observed in preclinical models of sepsis and endotoxemia. This has led to the postulation that vasodilation by inducible nitric oxide synthase (iNOS) generated NO may be a mechanism of hypotension in sepsis. However, contrary to the expected pharmacological action of a nitric oxide synthase (NOS) inhibitor, clinical studies with L-NAME produced adverse cardiac and pulmonary events, and higher mortality in sepsis patients. Thus, the potential adverse effects of NO in human sepsis and shock have not been fully established. In recent years, the emerging new understanding of the NO pathway has shown that an endogenously produced inhibitor of NOS, asymmetric dimethylarginine (ADMA), a host response to infection, may play an important role in the pathophysiology of sepsis as well as organ damage during ischemia–reperfusion. ADMA induces microvascular dysfunction, proinflammatory and prothrombotic state in endothelium, release of inflammatory cytokines, oxidative stress and mitochondrial dysfunction. High levels of ADMA exist in sepsis patients, which may produce adverse effects like those observed with L-NAME. Several studies have demonstrated the association of plasma ADMA levels with mortality in sepsis patients. Preclinical studies in sepsis and ischemia–reperfusion animal models have shown that lowering of ADMA reduced organ damage and improved survival. The clinical finding with L-NAME and the preclinical research on ADMA “bed to bench” suggest that ADMA lowering could be a potential therapeutic approach to attenuate progressive organ damage and mortality in sepsis. Testing of this approach is now feasible by using the pharmacological molecules that specifically lower ADMA.

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“…5B). Arginine is a semi-essential amino acid, which plays an indispensable role in the immune reaction of sepsis [34]. The primary mediator of in ammation is inducible nitric oxide synthase (iNOS), which could produce nitric oxide (NO) from arginine.…”

Section: Amino Acid Metabolismmentioning

confidence: 99%

Construction of the Metabolomics-Based Prognosis-Prediction Models for ICU Septic Patients

Ding

Tong²,

Song³

et al. 2022

SSRN Journal

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Background: Global mortality related to sepsis remains unacceptably high in intensive care units (ICUs). Accurate prognostic evaluation of sepsis could effectively reduce the mortality of septic patients. Our goal is to present an effective and rapid method to assess the prognosis of sepsis.Methods: We included 96 septic patients according to the sepsis 3.0 in ICU, who were grouped into survival and death groups according to 28-day, hospital, and 90-day prognosis. Liquid chromatography/mass spectrometry was performed to detect the metabolite changes in plasma. Multivariate logistic regression models, using differential metabolites and clinical indicators within 24 h after diagnosis of sepsis, were used to construct the prediction models for 28-day, hospital, and 90-day prognosis in sepsis.Results: Metabolic pro les related to 28-day, hospital, and 90-day prognosis were signi cantly different between the survival and the death group. Speci cally, 13, 4, and 29 primary differential metabolites related to amino acid metabolism and fatty acid metabolism were identi ed between the survival and death group at 28-day, hospital, and 90-day prognosis, respectively. Further, we found that model 1 including indoleacetic acid, 3-methylene-indolenine, heart rate, respiratory support, and application of pressure drugs; model 2 including lymphocyte count, alkaline phosphatase, SOFA, and L-alpha-amino-1H-pyrrole-1-hexanoic acid; model 3 including pyrrolidine, dopamine, heart rate, respiratory support, and application of pressure drugs, could predict 28-day, hospital, and 90-day prognosis of sepsis with a sensitivity of 75.51%, 73.58%, and 83.33%, speci city of 78.72%, 72.09%, and 76.19%, the area under the receiver operating characteristics curve of 0.881, 0.830, 0.892, respectively.Conclusions: This research could be used to predict the 28-day, hospital, and 90-day prognosis of septic patients based on differential metabolites and clinical parameters, and could also be used to develop novel sepsis-treatment methods.

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Intravenous Arginine Administration Downregulates NLRP3 Inflammasome Activity and Attenuates Acute Kidney Injury in Mice with Polymicrobial Sepsis

Cited by 20 publications

References 51 publications

YTHDF1 alleviates sepsis by upregulating WWP1 to induce NLRP3 ubiquitination and inhibit caspase-1-dependent pyroptosis

YTHDF1 alleviates sepsis by upregulating WWP1 to induce NLRP3 ubiquitination and inhibit caspase-1-dependent pyroptosis

A new perspective on NO pathway in sepsis and ADMA lowering as a potential therapeutic approach

Construction of the Metabolomics-Based Prognosis-Prediction Models for ICU Septic Patients

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