Experimental Therapeutics of Nrf2 as a Target for Prevention of Bacterial Exacerbations in COPD

Biswal, Shyam; Thimmulappa, Rajesh K.; Harvey, Christopher J.

doi:10.1513/pats.201201-009ms

Cited by 42 publications

(31 citation statements)

References 51 publications

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“…It has also been reported that carbocisteine harbors other anti-inflammatory targets, such as nuclear factor-erythroid 2-related factor (Nrf2), which is a redox-sensitive transcription factor in COPD [37,38] that can be activated by TNF-α in certain cell lines [39] . Via the activation of Nrf2, carbocisteine attenuated inflammation in vivo after exposure to cigarette smoke following influenza virus infection [40] and alleviated cigarette smoke extract (CSE)-induced oxidative stress in vitro [5] .…”

Section: Discussionmentioning

confidence: 99%

Carbocisteine attenuates TNF-α-induced inflammation in human alveolar epithelial cells in vitro through suppressing NF-κB and ERK1/2 MAPK signaling pathways

et al. 2016

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Aim: We previously proven that carbocisteine, a conventional mucolytic drug, remarkably reduced the rate of acute exacerbations and improved the quality of life in the patients with chronic obstructive pulmonary disease. In this study we investigated the mechanisms underlying the anti-inflammatory effects of carbocisteine in human alveolar epithelial cells in vitro. Methods: Human lung adenocarcinoma cell line A549 was treated with TNF-α (10 ng/mL). Carbocisteine was administered either 24 h prior to or after TNF-α exposure. The cytokine release and expression were measured using ELISA and qRT-PCR. Activation of NF-κB was analyzed with Western blotting, immunofluorescence assay and luciferase reporter gene assay. The expression of ERK1/2 MAPK signaling proteins was assessed with Western blotting. Results: Carbocisteine (10, 100, 1000 µmol/L), administered either before or after TNF-α exposure, dose-dependently suppressed TNF-α-induced inflammation in A549 cells, as evidenced by diminished release of IL-6 and IL-8, and diminished mRNA expression of IL-6, IL-8, TNF-α, MCP-1 and MIP-1β. Furthermore, pretreatment with carbocisteine significantly decreased TNF-α-induced phosphorylation of NF-κB p65 and ERK1/2 MAPK, and inhibited the nuclear translocation of p65 subunit in A549 cells. In an NF-κB luciferase reporter system, pretreatment with carbocisteine dose-dependently inhibited TNF-α-induced transcriptional activity of NF-κB. Conclusion: Carbocisteine effectively suppresses TNF-α-induced inflammation in A549 cells via suppressing NF-κB and ERK1/2 MAPK signaling pathways.

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Section: Discussionmentioning

confidence: 99%

Carbocisteine attenuates TNF-α-induced inflammation in human alveolar epithelial cells in vitro through suppressing NF-κB and ERK1/2 MAPK signaling pathways

et al. 2016

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“…This view is supported by a number of studies demonstrating that Nrf2 is essential for chemopreventive agents, such as sulforaphane and oltipraz, to block carcinogenesis and that Nrf2-deficient mice are more prone to chemical-induced cancer development [3–5]. Recent studies have demonstrated that Nrf2 also protects against chronic diseases such as cardiovascular disease, neurodegenerative diseases, and pulmonary injury [6–8]. However, the role of Nrf2 in human diseases is more complicated than originally thought.…”

Section: Introductionmentioning

confidence: 98%

The complexity of the Nrf2 pathway: beyond the antioxidant response

Huang

et al. 2015

The Journal of Nutritional Biochemistry

351

293

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The NF-E2-related factor 2 (Nrf2)-mediated signaling pathway provides living organisms an efficient and pivotal line of defensive to counteract environmental insults and endogenous stressors. Nrf2 coordinates the basal and inducible expression of antioxidant and phase II detoxification enzymes to adapt to different stress conditions. The stability and cellular distribution of Nrf2 is tightly controlled by its inhibitory binding protein Kelch-like ECH-associated protein 1 (Keap1). Nrf2 signaling is also regulated by post-translational, transcriptional, translational and epigenetic mechanisms, as well as by other protein partners, including p62, p21 and IQ motif-containing GTPase activating protein 1 (IQGAP1). Many studies have demonstrated that Nrf2 is a promising target for preventing carcinogenesis and other chronic diseases, including cardiovascular diseases, neurodegenerative diseases, and pulmonary injury. However, constitutive activation of Nrf2 in advanced cancer cells may confer drug resistance. Here, we review the molecular mechanisms of Nrf2 signaling, the diverse classes of Nrf2 activators, including bioactive nutrients and other chemicals and the cellular functions and disease relevance of Nrf2 and discuss the dual role of Nrf2 in different contexts.

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“…Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a membrane of the cap ‘n' collar type of basic region leucine zipper factor family. Nrf2 is expressed broadly in tissue but is activated only in response to a range of oxidative stimuli [10]. Upon activation, Nrf2 translocates to the nucleus and binds to the antioxidant response element (ARE), which mediates the induction of a spectrum of cytoprotective proteins: the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH):quinone oxidoreductase, heme oxygenase [11], glutathione reductase, superoxide dismutase (SOD) and catalase (CAT) [12].…”

Section: Introductionmentioning

confidence: 99%

Activation of the Nrf2-ARE Pathway Attenuates Hyperglycemia-Mediated Injuries in Mouse Podocytes

Wang

Peng

et al. 2014

Cell Physiol Biochem

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Background: Damage to podocytes caused by excessive reactive oxygen species (ROS) contributes to onset and progression of diabetic kidney disease (DKD). Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a redox-sensing transcription factor that can induce the expression of antioxidant enzymes. We explored whether activation of Nrf2 pathway attenuated hyperglycemia-induced injuries in mouse podocytes. Methods: Tert-Butylhydroquinone (tBHQ) and small interfering RNAs (siRNAs) were used to regulate Nrf2 expression. Apoptosis and intracellular superoxide anion production were measured by flow cytometry. The activity of the Nrf2 antioxidant pathway was measured by an antioxidant response element (ARE)-driven luciferase reporter gene assay, and Nrf2 expression was assessed by real-time PCR and western blot analyses. Results: Podocytes incubated with high-glucose (HG) medium had higher intracellular superoxide anion and hydrogen peroxide production, higher apoptosis rate, higher bovine serum albumin (BSA) permeability and lower synaptopodin expression compared with podocytes exposed normal glucose (NG) (p<0.05). tBHQ increased the activity of the Nrf2 antioxidant pathway and enhanced nuclear Nrf2 expression, reduced intracellular superoxide anion and hydrogen peroxide production, apoptosis rate and BSA permeability, and restored synaptopodin expression in podocytes exposed to HG (p

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Experimental Therapeutics of Nrf2 as a Target for Prevention of Bacterial Exacerbations in COPD

Cited by 42 publications

References 51 publications

Carbocisteine attenuates TNF-α-induced inflammation in human alveolar epithelial cells in vitro through suppressing NF-κB and ERK1/2 MAPK signaling pathways

Carbocisteine attenuates TNF-α-induced inflammation in human alveolar epithelial cells in vitro through suppressing NF-κB and ERK1/2 MAPK signaling pathways

The complexity of the Nrf2 pathway: beyond the antioxidant response

Activation of the Nrf2-ARE Pathway Attenuates Hyperglycemia-Mediated Injuries in Mouse Podocytes

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