Explore the vast range of titles available.

Background Patients with chronic obstructive pulmonary disease (COPD) have high oxidative stress associated with the severity of the disease. Nuclear factor erythroid-2 related factor 2 (Nrf2)-directed stress response plays a critical role in the protection of lung cells to oxidative stress by upregulating antioxidant genes in response to tobacco smoke. There is a critical gap in our knowledge about Nrf-2 regulated genes in active smokers and former-smokers with COPD in different cell types from of lungs and surrogate peripheral tissues. Methods We compared the expression of Nrf2 and six of its target genes in alveolar macrophages, nasal, and bronchial epithelium and peripheral blood mononuclear cells (PBMCs) in current and former smokers with COPD. We compared cell-type specific of Nrf2 and its target genes as well as markers of oxidative and inflammatory stress. Results We enrolled 89 patients; expression all Nrf2 target gene measured were significantly higher in the bronchial epithelium from smokers compared to non-smokers. None were elevated in alveolar macrophages and only one was elevated in each of the other compartments. Conclusion Bronchial epithelium is the most responsive tissue for transcriptional activation of Nrf2 target genes in active smokers compared to former-smokers with COPD that correlated with oxidative stress and inflammatory markers. There were no consistent trends in gene expression in other cell types tested. Trial registration Clinicaltrials.gov : NCT01335971.

BACE1 is the rate-limiting enzyme for amyloid-β peptides (Aβ) generation, a key event in the pathogenesis of Alzheimer’s disease (AD). By an unknown mechanism, levels of BACE1 and a BACE1 mRNA-stabilizing antisense RNA (BACE1-AS) are elevated in the brains of AD patients, implicating that dysregulation of BACE1 expression plays an important role in AD pathogenesis. We found that nuclear factor erythroid-derived 2-related factor 2 (NRF2/NFE2L2) represses the expression of BACE1 and BACE1-AS through binding to antioxidant response elements (AREs) in their promoters of mouse and human. NRF2-mediated inhibition of BACE1 and BACE1-AS expression is independent of redox regulation. NRF2 activation decreases production of BACE1 and BACE1-AS transcripts and Aβ production and ameliorates cognitive deficits in animal models of AD. Depletion of NRF2 increases BACE1 and BACE1-AS expression and Aβ production and worsens cognitive deficits. Our findings suggest that activation of NRF2 can prevent a key early pathogenic process in AD.

s Background Many neurological diseases involve neuroinflammation, during which overproduction of cytokines by immune cells, especially microglia, can aggregate neuronal death. Ferroptosis is a recently discovered cell metabolism-related form of cell death and RSL3 is a well-known inducer of cell ferroptosis. Here, we aimed to investigate the effects of RSL3 in neuroinflammation and sensitivity of different type of microglia and macrophage to ferroptosis. Methods Here, we used quantitative RT-PCR analysis and ELISA analysis to analyze the production of proinflammatory cytokine production of microglia and macrophages after lipopolysaccharides (LPS) stimulation. We used CCK8, LDH, and flow cytometry analysis to evaluate the sensitivity of different microglia and macrophages to RSL3-induced ferroptosis. Western blot was used to test the activation of inflammatory signaling pathway and knockdown efficiency. SiRNA-mediated interference was conducted to knockdown GPX4 or Nrf2 in BV2 microglia. Intraperitoneal injection of LPS was performed to evaluate systemic inflammation and neuroinflammation severity in in vivo conditions. Results We found that ferroptosis inducer RSL3 inhibited lipopolysaccharides (LPS)-induced inflammation of microglia and peritoneal macrophages (PMs) in a cell ferroptosis-independent manner, whereas cell ferroptosis-conditioned medium significantly triggered inflammation of microglia and PMs. Different type of microglia and macrophages showed varied sensitivity to RSL3-induced ferroptosis. Mechanistically, RSL3 induced Nrf2 protein expression to inhibit RNA Polymerase II recruitment to transcription start site of proinflammatory cytokine genes to repress cytokine transcription, and protect cells from ferroptosis. Furthermore, simultaneously injection of RSL3 and Fer-1 ameliorated LPS-induced neuroinflammation in in vivo conditions. Conclusions These data revealed the proinflammatory role of ferroptosis in microglia and macrophages, identified RSL3 as a novel inhibitor of LPS-induced inflammation, and uncovered the molecular regulation of microglia and macrophage sensitivity to ferroptosis. Thus, targeting ferroptosis in diseases by using RSL3 should consider both the pro-ferroptosis effect and the anti-inflammation effect to achieve optimal outcome.

A large group of flavonoids found in fruits and vegetables have been suggested to elicit health benefits due mainly to their anti-oxidative and anti-inflammatory properties. Recent studies with immune cells have demonstrated inhibition of these inflammatory responses through down-regulation of the pro-inflammatory pathway involving NF-κB and up-regulation of the anti-oxidative pathway involving Nrf2. In the present study, the murine BV-2 microglial cells were used to compare anti-inflammatory activity of quercetin and cyanidin, two flavonoids differing by their alpha, beta keto carbonyl group. Quercetin was 10 folds more potent than cyanidin in inhibition of lipopolysaccharide (LPS)-induced NO production as well as stimulation of Nrf2-induced heme-oxygenase-1 (HO-1) protein expression. In addition, quercetin demonstrated enhanced ability to stimulate HO-1 protein expression when cells were treated with LPS. In an attempt to unveil mechanism(s) for quercetin to enhance Nrf2/HO-1 activity under endotoxic stress, results pointed to an increase in phospho-p38MAPK expression upon addition of quercetin to LPS. In addition, pharmacological inhibitors for phospho-p38MAPK and MEK1/2 for ERK1/2 further showed that these MAPKs target different sites of the Nrf2 pathway that regulates HO-1 expression. However, inhibition of LPS-induced NO by quercetin was not fully reversed by TinPPIX, a specific inhibitor for HO-1 activity. Taken together, results suggest an important role of quercetin to regulate inflammatory responses in microglial cells and its ability to upregulate HO-1 against endotoxic stress through involvement of MAPKs.

Mutations in leucine-rich repeat kinase 2 (LRRK2) and α-synuclein lead to Parkinson’s disease (PD). Disruption of protein homeostasis is an emerging theme in PD pathogenesis, making mechanisms to reduce the accumulation of misfolded proteins an attractive therapeutic strategy. We determined if activating nuclear factor erythroid 2-related factor (Nrf2), a potential therapeutic target for neurode-generation, could reduce PD-associated neuron toxicity by modulating the protein homeostasis network. Using a longitudinal imaging platform, we visualized the metabolism and location of mutant LRRK2 and α-synuclein in living neurons at the single-cell level. Nrf2 reduced PD-associated protein toxicity by a cell-autonomous mechanism that was time-dependent. Furthermore, Nrf2 activated distinct mechanisms to handle different misfolded proteins. Nrf2 decreased steady-state levels of α-synuclein in part by increasing α-synuclein degradation. In contrast, Nrf2 sequestered misfolded diffuse LRRK2 into more insoluble and homogeneous inclusion bodies. By identifying the stress response strategies activated by Nrf2, we also highlight endogenous coping responses that might be therapeutically bolstered to treat PD.

Objective This study aims to investigate whether REDD1 (Regulated in Development and DNA Damage Responses 1) mediates the nuclear-to-cytoplasmic translocation and release of IL-33 in airway epithelial cells induced by house dust mites (HDM). Methods REDD1 expression levels in bronchial asthma patients were validated using public databases, followed by immunohistochemical analysis of REDD1 protein in airway epithelial cells from these patients. An asthma model was then established using HDM-induced 16HBE cell lines, with REDD1 gene knockout performed. The relationship between varying levels of REDD1 expression, Nrf2, and related inflammatory factors was assessed using Western blot and qPCR. To further investigate the role of the REDD1-Nrf2-IL-33 axis in the development of asthma, we employed Nrf2 activators and inhibitors to reassess the impact of REDD1 on IL-33. Results At both mRNA and protein levels, we found that REDD1 was significantly overexpressed in samples from asthma patients ( P  < 0.05). In vitro, 24-hour exposure to HDM induced a notable nuclear-to-cytoplasmic translocation of IL-33 and increased its levels in the culture medium of 16HBE cells. In addition, HDM treatment significantly upregulated the expression of both REDD1 and Nrf2. Knockdown of REDD1 markedly suppressed HDM-induced IL-33 release and the expression of TNF-α, IL-6, and IL-1β, while enhancing Nrf2 expression. Moreover, treatment with the Nrf2 agonist curcumin inhibited HDM-induced nuclear-to-cytoplasmic translocation and extracellular secretion of IL-33, whereas the opposite effect was observed when using the Nrf2 antagonist ML385. Conclusion This study reveals the crucial regulatory role of the REDD1-Nrf2-IL-33 axis in the pathological process of bronchial asthma. REDD1 modulates the expression of IL-33 and other inflammatory factors through the Nrf2 signaling pathway, thereby influencing the onset and progression of asthma. Clinical trial number Not applicable.

Oxidative stress is one of the earliest defects involved in the development of diabetes-induced cognitive impairment. Nrf2 is the master regulator of the cellular antioxidant system can be regulated by some microRNAs. The study aimed to evaluate the effects of quercetin (QC) and quercetin-conjugated superparamagnetic iron oxide nanoparticles (QCSPIONs) on Nrf2-controlled antioxidant genes through the redox-sensitive miR-27a. Expression levels of miR-27a, Nrf2, SOD1, GPX1, and CAT were measured by quantitative real-time PCR. Moreover, the oxidative stress parameters including total antioxidant capacity (TAC) and histological alterations were investigated. The expression level of miR-27a was significantly up-regulated in diabetic rats. While expression levels of Nrf2, SOD1, GPX1, and CAT were significantly down-regulated under diabetic condition. Interestingly, QCSPIONs decreased expression level of miR-27a and subsequently enhanced the expression levels of Nrf2, SOD1, and CAT to the control level. No significant difference was observed in the expression level of GPX1. Besides, QC in pure and especially conjugated form was able to normalize TAC and regenerate pathological lesions in STZ-diabetic rats. Our result demonstrates that QCSPIONs as an effective combined therapy can decrease miR-27a expression, which in turn increases the Nrf2 expression and responsive antioxidant genes, resulting in improvement of memory dysfunction in diabetic rats.

Oxidative stress is well known to play a pivotal role in cerebral ischemia–reperfusion injury. The nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway has been considered a potential target for neuroprotection in stroke. 11-Keto-β-boswellic acid (KBA) is a triterpenoid compound from extracts of Boswellia serrata . The aim of the present study was to determine whether KBA, a novel Nrf2 activator, can protect against cerebral ischemic injury. Middle cerebral artery occlusion (MCAO) was operated on male Sprague–Dawley rats. KBA (25 mg/kg) applied 1 h after reperfusion significantly reduced infarct volumes and apoptotic cells as well as increased neurologic scores at 48 h after reperfusion. Meanwhile, posttreatment with KBA significantly decreased malondialdehyde (MDA) levels, restored the superoxide dismutase (SOD) activity, and increased the protein Nrf2 and HO-1 expression in brain tissues. In primary cultured astrocytes, KBA increased the Nrf2 and HO-1 expression, which provided protection against oxygen and glucose deprivation (OGD)-induced oxidative insult. But knockdown of Nrf2 or HO-1 attenuated the protective effect of KBA. In conclusion, these findings provide evidence that the neuroprotection of KBA against oxidative stress-induced ischemic injury involves the Nrf2/HO-1 pathway.

This study investigated how non-hepatic surgery and subsequent acute stress affect iron distribution, redox state, antioxidant defence, and inflammation-related gene expressions and iron metabolism in the liver of borderline hypertensive rats. We used air-jet stress as a model of acute psychological stress (3 sessions of 5 sec. air-jet) applied approximately 22 hours post-surgery (carotid artery and jugular vein cannulation). Both the surgery (Su) and post-surgical stress (Su+Str) increased corticosterone and reduced iron concentrations in plasma, while increasing remanent magnetisation (Mr) and coercivity (Hc) in whole blood. In the liver, Su and Su+Str reduced mRNA expressions of genes encoding NFR2 and GPX4 proteins (Nfe2l2 and Gpx4, respectively), and induced a significant increase in hepatic conjugated dienes, proinflammatory factors (Il1b) and iron-regulating genes mRNA (Hmox1, Fpn1, Fth1, Hamp, Tfr1), despite elevated Hmox1 and Sod1 mRNA expressions. In addition, hepatic Mr and Hc after Su and Su+Str were elevated, suggesting a qualitative change of iron-containing substances in circulation and liver tissue. In addition, in the Su+Str group, the elevated saturation magnetisation (Ms) is indicative of elevated total iron content. These findings suggest that a mild non-hepatic surgery may reduce hepatic mRNA expression of NRF2 and GPX4, which was associated with oxidative tissue damage accompanied by qualitative alterations in cellular iron, indicating a pro-ferroptotic state that, together with enhanced inflammation, may contribute to post-surgical liver injury. Additionally, the combination of surgery and acute post-surgical stress led to tissue iron accumulation, which may contribute to liver damage.

Background: Resistance to chemotherapy is a major obstacle in the treatment of human hepatocellular carcinoma (HCC). Despite playing an important role in chemoprevention, nuclear factor erythroid 2-related factor 2 (NRF2) also contributes to chemo- and radio-resistance. The current study focusses on camptothecin as a novel NRF2 inhibitor to sensitise HCC to chemotherapy. Methods: The expression and transcriptional activity of NRF2 in human HCC biopsies and camptothecin-treated culture cells were determined using immunostaining, western blot, reverse-transcription quantitative real-time PCR (RT–qPCR) and luciferase reporter assay. The effect of camptothecin on chemosensitivity of cancer cells was assessed in vitro and in xenografts. Results: The expression and transcriptional activity of NRF2 were substantially elevated in HCC biopsies compared with corresponding adjacent tissues, and positively correlated with serum α -fetoprotein, a clinical indicator of pathological progression. In searching chemicals targeting NRF2 for chemotherapy, we discovered that camptothecin is a potent NRF2 inhibitor. Camptothecin markedly suppressed NRF2 expression and transcriptional activity in different types of cancer cells including HepG2, SMMC-7721 and A549. As a result, camptothecin sensitised these cells to chemotherapeutic drugs in vitro and in xenografts. Conclusions: Camptothecin is a novel NRF2 inhibitor that may be repurposed in combination with other chemotherapeutics to enhance their efficacy in treating high NRF2-expressing cancers.