Thioredoxin Reductase-1 Inhibition Augments Endogenous Glutathione-Dependent Antioxidant Responses in Experimental Bronchopulmonary Dysplasia

Wall, Stephanie; Wood, Rachael; Dunigan, Katelyn; Li, Qian; Li, Rui; Rogers, Lynette K.; Tipple, Trent E.

doi:10.1155/2019/7945983

Cited by 18 publications

(13 citation statements)

References 34 publications

(49 reference statements)

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“…For a comprehensive review, the reader is directed to a recent publication by Saha and colleagues, which extensively summarizes key relationships between NRF2/ARE, inflammatory mediator expression, canonical and non-canonical NFκB pathway activation, and macrophage metabolism [ 18 ]. We have extensively studied the effects of AFN and ATG in the setting of hyperoxia exposure and have consistently observed decreases in inflammation, tissue injury, and cell death [ 2 , 5 , 6 , 19 , 20 , 21 ]. Despite our robust experimental evidence of decreased inflammation in lung injury models, the mechanisms by which gold compounds attenuate pro-inflammatory responses have not been revealed in our studies of lung epithelia.…”

Section: Discussionmentioning

confidence: 99%

“…FDA-approved pharmaceutical gold compounds, such as aurothioglucose (ATG) and auranofin (AFN), decrease inflammation in the context of hyperoxic exposure and many other inflammatory diseases [ 3 ]. We and others have described a reduction in inflammatory cell numbers and cytokine expression in the lung following treatment with ATG or AFN [ 4 , 5 , 6 , 7 ]. Isakov et al reported that macrophages treated with AFN and subsequently induced by lipopolysaccharide (LPS) demonstrated selective repression of inflammatory genes such as interleukin (IL)-1 [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

“…Several studies have proposed that NRF2 activation increases antioxidant enzymes and, therefore, decreases oxidative burden by enhancing glutathione synthesis to relieve the oxidative effects of inflammation. Recent reports have identified a more direct role for NRF2 in the regulation of NFκB-dependent pathway activation [ 5 , 6 , 12 ]. Isakov et al indicated the effects of Txnrd1 inhibition on IL-1β activation were likely to be upstream of glutathione (GSH) synthesis and related to transcriptional regulation [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

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Auranofin-Mediated NRF2 Induction Attenuates Interleukin 1 Beta Expression in Alveolar Macrophages

Wall

Butler

et al. 2021

Antioxidants

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Background: Alveolar macrophages (AMs) are resident inflammatory cells in the lung that serve as early sentinels of infection or injury. We have identified thioredoxin reductase 1 inhibition by gold compounds increases activation of nuclear factor erythroid 2-related factor 2 (NRF2)-dependent pathways to attenuate inflammatory responses. The present studies utilized murine alveolar macrophages (MH-S) to test the hypothesis that the gold compound, auranofin (AFN), decreases interleukin (IL)-1β expression through NRF2-mediated interactions with nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway genes and/or increases in glutathione synthesis. Methods: MH-S cells were treated with AFN and lipopolysaccharide (LPS) and analyzed at 6 and 24 h. The Il1b promoter was analyzed by chromatin immunoprecipitation for direct interaction with NRF2. Results: Expression of IL-1β, p-IκBα, p-p65 NF-kB, and NOD-, LRR-, and pyrin domain-containing protein 3 were elevated by LPS exposure, but only IL-1β expression was suppressed by AFN treatment. Both AFN and LPS treatments increased cellular glutathione levels, but attenuation of glutathione synthesis by buthionine sulfoximine (BSO) did not alter expression of Il-1β. Analysis revealed direct NRF2 binding to the Il1b promoter which was enhanced by AFN and inhibited the transcriptional activity of DNA polymerase II. Conclusions: Our data demonstrate that AFN-induced NRF2 activation directly suppresses IL-1β synthesis independent of NFκB and glutathione-mediated antioxidant mechanisms. NRF2 binding to the promoter region of IL1β directly inhibits transcription of the IL1β gene. Collectively, our research suggests that gold compounds elicit NRF2-dependent pulmonary protection by suppressing macrophage-mediated inflammation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Auranofin-Mediated NRF2 Induction Attenuates Interleukin 1 Beta Expression in Alveolar Macrophages

Wall

Butler

et al. 2021

Antioxidants

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“…Auranofin can also inhibit phagocytosis by macrophages and can reduce proinflammatory cytokines through the inhibition of nuclear factor-kappa B activation [ 29 , 30 , 31 ]. In addition, auranofin has the antioxidant property of enhancing the activation of nuclear factor erythroid-2-related factor 2 [ 32 , 33 , 34 ]. However, to date, no research has been done on whether auranofin can improve NAFLD.…”

Section: Introductionmentioning

confidence: 99%

Auranofin Attenuates Non-Alcoholic Fatty Liver Disease by Suppressing Lipid Accumulation and NLRP3 Inflammasome-Mediated Hepatic Inflammation In Vivo and In Vitro

Hwangbo

Kim

et al. 2020

Antioxidants

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Non-alcoholic fatty liver disease (NAFLD) causes liver dysfunction and is associated with obesity and type 2 diabetes. Chronic inflammation is associated not only with the development of NAFLD, but also with hepatic diseases, including steatohepatitis, cirrhosis, and hepatocellular carcinoma. Auranofin is a treatment for rheumatoid arthritis and has recently been reported to have potential effects against a variety of diseases, including inflammation, cancer, and viral infection. In this study, auranofin may be considered as a new treatment for the management of metabolic syndrome, as well as in the treatment of NAFLD through immunomodulation. To determine the effect of auranofin on NAFLD, C57BL/6 mice were randomly grouped, fed a regular diet or a high fat diet (HFD), and injected with normal saline or auranofin for 8 weeks. Auranofin significantly decreased the body weight, epididymal fat weight, serum aspartate aminotransferase (AST), and glucose, as well as the serum triglyceride, cholesterol, and low-density lipoprotein cholesterol levels as compared to the HFD group. We also observed that hepatic steatosis was increased in the HFD group and was suppressed by auranofin treatment. In addition, auranofin suppressed the expressions of interleukin (IL)-1β, IL-18, caspase-1, and the NOD-like receptor family pyrin domain containing 3 (NLRP3) in the liver tissue. Furthermore, the expression of NADPH oxidase 4 and peroxisome proliferator-activated receptor γ (PPARγ), which are a major source of oxidative stress and a regulator of adipogenesis, respectively, were also decreased by auranofin. In addition, primary mouse hepatocytes were incubated with lipopolysaccharide (LPS) and palmitic acid (PA) to induce lipid accumulation and hepatic inflammation for an in vitro model. Auranofin could significantly inhibit LPS- and PA-induced inflammatory activity including nitric oxide and NLRP3 inflammasome-mediated cytokines. The results of this study demonstrate that auranofin treatment inhibits the characteristics of NAFLD through the inhibition of NLRP3 inflammasome. Therefore, auranofin may have potential as a candidate for improving NAFLD symptoms.

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“…GPx and thioredoxin reductase, two selenoproteins, are important members of the body's antioxidant system ( 46 ). GPx-1 activity decreases dramatically in Se deficiency and increases during Se supplementation.…”

Section: Se Deficiencymentioning

confidence: 99%

Keshan Disease: A Potentially Fatal Endemic Cardiomyopathy in Remote Mountains of China

et al. 2021

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Keshan disease (KD) as an endemic, highly lethal cardiomyopathy, first reported in northeast China's Keshan County in 1935. The clinical manifestations of patients with KD include primarily congestive heart failure, acute heart failure, and cardiac arrhythmia. Even though some possible etiologies, such as viral infection, fungal infection, microelement deficiency, and malnutrition, have been reported, the exact causes of KD remain poorly known. The endemic areas where KD is found are remote and rural, and many are poor and mountainous places where people are the most socioeconomically disadvantaged in terms of housing, income, education, transportation, and utilization of health services. To date, KD is a huge burden to and severely restricts the economic development of the local residents and health systems of the endemic areas. Although efforts have been made by the government to control, treat, and interrupt disease transmission, the cure for or complete eradication of KD still requires global attention. For this reason, in this review, we systematically describe the etiological hypothesis, clinical manifestations, incidence characteristics, and treatment of KD, to facilitate the better understanding of and draw more attention to this non-representative cardiovascular disease, with the aim of accelerating its elimination.

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Thioredoxin Reductase-1 Inhibition Augments Endogenous Glutathione-Dependent Antioxidant Responses in Experimental Bronchopulmonary Dysplasia

Cited by 18 publications

References 34 publications

Auranofin-Mediated NRF2 Induction Attenuates Interleukin 1 Beta Expression in Alveolar Macrophages

Auranofin-Mediated NRF2 Induction Attenuates Interleukin 1 Beta Expression in Alveolar Macrophages

Auranofin Attenuates Non-Alcoholic Fatty Liver Disease by Suppressing Lipid Accumulation and NLRP3 Inflammasome-Mediated Hepatic Inflammation In Vivo and In Vitro

Keshan Disease: A Potentially Fatal Endemic Cardiomyopathy in Remote Mountains of China

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