Oxidative stress-dependent activation of the eIF2α–ATFr unfolded protein response branch by skin sensitizer 1-fluoro-2,4-dinitrobenzene modulates dendritic-like cell maturation and inflammatory status in a biphasic manner

Luís, Ana Teresa; Martins, José Luı́s; Silva, Ana; Ferreira, Isabel; Cruz, Maria Teresa; Neves, Bruno Miguel

doi:10.1016/j.freeradbiomed.2014.09.008

Cited by 53 publications

(30 citation statements)

References 65 publications

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“…IL-8 is also secreted by primary monocytes and macrophages but is not associated with autocrine effects on these cells [ 64 ], making a contribution of this molecule to other results of this study unlikely. Substantiating our results, antioxidants were found to decrease steady state ROS and IL-8 levels [ 65 ] while increased ROS trigger IL-8 expression in primary monocytes/macrophages [ 66 ].…”

Section: Resultssupporting

confidence: 68%

Redox Stimulation of Human THP‐1 Monocytes in Response to Cold Physical Plasma

Bekeschus

Schmidt

Bethge

et al. 2015

Oxidative Medicine and Cellular Longevity

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In plasma medicine, cold physical plasma delivers a delicate mixture of reactive components to cells and tissues. Recent studies suggested a beneficial role of cold plasma in wound healing. Yet, the biological processes related to the redox modulation via plasma are not fully understood. We here used the monocytic cell line THP-1 as a model to test their response to cold plasma in vitro. Intriguingly, short term plasma treatment stimulated cell growth. Longer exposure only modestly compromised cell viability but apparently supported the growth of cells that were enlarged in size and that showed enhanced metabolic activity. A significantly increased mitochondrial content in plasma treated cells supported this notion. On THP-1 cell proteome level, we identified an increase of protein translation with key regulatory proteins being involved in redox regulation (hypoxia inducible factor 2α), differentiation (retinoic acid signaling and interferon inducible factors), and cell growth (Yin Yang 1). Regulation of inflammation is a key element in many chronic diseases, and we found a significantly increased expression of the anti-inflammatory heme oxygenase 1 (HMOX1) and of the neutrophil attractant chemokine interleukin-8 (IL-8). Together, these results foster the view that cold physical plasma modulates the redox balance and inflammatory processes in wound related cells.

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Section: Resultssupporting

confidence: 68%

Redox Stimulation of Human THP‐1 Monocytes in Response to Cold Physical Plasma

Bekeschus

Schmidt

Bethge

et al. 2015

Oxidative Medicine and Cellular Longevity

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“…In addition to metals, the central nervous system stimulant methamphetamine and the skin sensitizer 1-fluoro-2,4-dinitrobenzene were reported to induce the Nrf2 signaling pathway through impaired autophagic flux and p62 accumulation in a mouse atrial cardiac cell line and in a human monocytic cell line, respectively [51,52]. These studies provide a critical link between autophagy dysregulation and prolonged Nrf2 signaling, which provides important environmental health implications.…”

Section: Prolonged Nrf2 Activation Results From the Noncanonical Mmentioning

confidence: 99%

p62 links autophagy and Nrf2 signaling

Jiang

Harder

Vega

et al. 2015

Free Radical Biology and Medicine

510

345

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The Nrf2-Keap1-ARE pathway is a redox and xenobiotic sensitive signaling axis that functions to protect cells against oxidative stress, environmental toxicants, and harmful chemicals through the induction of cytoprotective genes. To enforce strict regulation, cells invest a great deal of energy into the maintenance of the Nrf2 pathway to ensure rapid induction upon cellular insult and rapid return to basal levels once the insult is mitigated. Because of the protective role of Nrf2 transcriptional programs, controlled activation of the pathway has been recognized as a means for chemoprevention. On the other hand, constitutive activation of Nrf2, due to somatic mutations of genes that control Nrf2 degradation, promotes carcinogenesis and imparts chemoresistance to cancer cells. Autophagy, a bulk protein degradation process, is another tightly regulated complex cellular process that functions as a cellular quality control system to remove damaged proteins or organelles. Low cellular nutrient levels can also activate autophagy, which acts to restore metabolic homeostasis through the degradation of macromolecules to provide nutrients. Recently, these two cellular pathways were shown to intersect through the direct interaction between p62 (an autophagy adaptor protein) and Keap1 (the Nrf2 substrate adaptor for the Cul3 E3 ubiquitin ligase). Dysregulation of autophagy was shown to result in prolonged Nrf2 activation in a p62-dependent manner. In this review, we will discuss the progress that has been made in dissecting the intersection of these two pathways and the potential tumor-promoting role of prolonged Nrf2 activation.

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“…These studies set the basis for considering NRF2 as an attractive, druggable target to prevent VILI, ALI, and other airway diseases. Since MV is a procedure that can be anticipated, it may be possible to start preventive therapy that induces NRF2 before the procedure is initiated to decrease its negative side effects 4 . Although the use of direct antioxidants, like N-acetyl cysteine (NAC), has some degree of beneficial effects 16 we suggest that activating the body’s own defensive responses through upregulation of the NRF2 pathway in combination with low tidal ventilator strategies will result in greater benefits for the patients.…”

Section: Discussionmentioning

confidence: 99%

“…It is an intervention procedure for patients suffering from lung trauma, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), apnea, severe asthma, or for patients under general anesthesia 2 . Paradoxically, although MV is the only effective strategy to treat these conditions, it may also result in greater lung damage, referred to as ventilator-induced lung injury (VILI), and multi-organ failure that can compromise the patients’ lives 3 4 . VILI occurs as an effect of cyclic stretching and overdistension of the lung tissues, which cause severe inflammation and structural tissue damage ultimately leading to acute lung injury (ALI) 5 6 .…”

mentioning

confidence: 99%

Bixin protects mice against ventilation-induced lung injury in an NRF2-dependent manner

Tao

Vega

Quijada

et al. 2016

Sci Rep

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Mechanical ventilation (MV) is a therapeutic intervention widely used in the clinic to assist patients that have difficulty breathing due to lung edema, trauma, or general anesthesia. However, MV causes ventilator-induced lung injury (VILI), a condition characterized by increased permeability of the alveolar-capillary barrier that results in edema, hemorrhage, and neutrophil infiltration, leading to exacerbated lung inflammation and oxidative stress. This study explored the feasibility of using bixin, a canonical NRF2 inducer identified during the current study, to ameliorate lung damage in a murine VILI model. In vitro, bixin was found to activate the NRF2 signaling pathway through blockage of ubiquitylation and degradation of NRF2 in a KEAP1-C151 dependent manner; intraperitoneal (IP) injection of bixin led to pulmonary upregulation of the NRF2 response in vivo. Remarkably, IP administration of bixin restored normal lung morphology and attenuated inflammatory response and oxidative DNA damage following MV. This observed beneficial effect of bixin derived from induction of the NRF2 cytoprotective response since it was only observed in Nrf2+/+ but not in Nrf2−/− mice. This is the first study providing proof-of-concept that NRF2 activators can be developed into pharmacological agents for clinical use to prevent patients from lung injury during MV treatment.

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Oxidative stress-dependent activation of the eIF2α–ATFr unfolded protein response branch by skin sensitizer 1-fluoro-2,4-dinitrobenzene modulates dendritic-like cell maturation and inflammatory status in a biphasic manner

Cited by 53 publications

References 65 publications

Redox Stimulation of Human THP‐1 Monocytes in Response to Cold Physical Plasma

Redox Stimulation of Human THP‐1 Monocytes in Response to Cold Physical Plasma

p62 links autophagy and Nrf2 signaling

Bixin protects mice against ventilation-induced lung injury in an NRF2-dependent manner

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