In-vivo correlations between skin metabolic oscillations and vasomotion in wild-type mice and in a model of oxidative stress
Arterioles in the cutaneous microcirculation frequently display an oscillatory phenomenon defined vasomotion, consistent with periodic diameter variations in the micro-vessels associated with particular physiological or abnormal conditions. The cellular mechanisms underlying vasomotion and its physiological role have not been completely elucidated. Various mechanisms were demonstrated, based on cell Ca oscillations determined by the activity of channels in the plasma membrane or sarcoplasmic reticulum of vascular cells. However, the possible engagement in vasomotion of cell metabolic oscillations of mitochondrial or glycolytic origin has been poorly explored. Metabolic oscillations associated with the production of ATP energy were previously described in cells, while limited studies have investigated these fluctuations in-vivo. Here, we characterised a low-frequency metabolic oscillator (MO-1) in skin from live wild-type and Nrf2 mice, by combination of fluorescence spectroscopy and wavelet transform processing technique. Furthermore, the relationships between metabolic and microvascular oscillators were examined during phenylephrine-induced vasoconstriction. We found a significant interaction between MO-1 and the endothelial EDHF vasomotor mechanism that was reduced in the presence of oxidative stress (Nrf2 mice). Our findings suggest indirectly that metabolic oscillations may be involved in the mechanisms underlying endothelium-mediated skin vasomotion, which might be altered in the presence of metabolic disturbance.
Redox Regulation by NRF2 in Aging and Disease
NRF2, a transcription factor that has been deemed the master regulator of cellular redox homeostasis, declines with age. NRF2 transcriptionally upregulates genes that combat oxidative stress; therefore, loss of NRF2 allows oxidative stress to go unmitigated and drive the aging phenotype. Oxidative stress is a common theme among the key features associated with the aging process, collectively referred to as the "Hallmarks of Aging", as it disrupts proteostasis, alters genomic stability, and leads to cell death. In this review, we outline the role that oxidative stress and the reduction of NRF2 play in each of the Hallmarks of Aging, including how they contribute to the onset of neurodegenerative disorders, cancer, and other age-related pathologies.
Corrigendum to "Polydatin prevents fructose-induced liver inflammation and lipid deposition through increasing miR-200a to regulate Keap1/Nrf2 pathway" [Redox Biol. 18 (2018) 124-137]
Effects of silver nanoparticles functionalized with Cornus mas L. extract on architecture and apoptosis in rat testicle
To assess ultrastructural changes, alterations in matrix metalloproteinase activity and apoptosis induced by silver nanoparticles (AgNPs) in the rat testicle.
Safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia
Previous studies have demonstrated that suppression of Nrf2 in Friedreich ataxia tissues contributes to excess oxidative stress, mitochondrial dysfunction, and reduced ATP production. Omaveloxolone, an Nrf2 activator and NF-kB suppressor, targets dysfunctional inflammatory, metabolic, and bioenergetic pathways. The dose-ranging portion of this Phase 2 study assessed the safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia patients (NCT02255435).
Neutrophil elastase inhibitor suppresses oxidative stress in obese asthmatic rats by activating Keap1/Nrf2 signaling pathway
The aim of this study was to detect the oxidative stress response in the rat model of obesity, asthma and obese asthma. Meanwhile, we aimed to investigate the inhibitory effect of neutrophil elastase inhibitor (NEI) on cellular oxidative stress in the body and whether it exerted an effect on the oxidative stress response in obese asthma through the Kelch-like ECH-associated protein 1/nuclear factor E2-related factor 2 (Keap1/Nrf2) pathway.
DCA can improve the ACI-induced neurological impairment through negative regulation of Nrf2 signaling pathway
To investigate the effect of tauroursodeoxycholic acid (TUDCA) on neurological impairment induced by acute cerebral infarction (ACI) and its relevant mechanism of action.
CKIP-1 alleviates oxygen-glucose deprivation/reoxygenation-induced apoptosis and oxidative stress in cultured hippocampal neurons by downregulating Keap1 and activating Nrf2/ARE signaling
Accumulating evidence has shown that casein kinase 2 interacting protein-1 (CKIP-1) is a pivotal regulator of apoptosis and oxidative stress. However, whether CKIP-1 is involved in regulating neuronal injury during the progression of cerebral ischemia/reperfusion injury remains unknown. In the present study, we aimed to investigate the potential role and underlying mechanism of CKIP-1 in regulating neuronal apoptosis and oxidative stress induced by oxygen-glucose deprivation/reoxygenation (OGD/R) treatment in vitro. Herein, we found that OGD/R treatment resulted in a significant increase in CKIP-1 expression in cultured hippocampal neurons. The silencing of CKIP-1 exacerbated OGD/R-induced neuronal apoptosis and production of reactive oxygen species. By contrast, CKIP-1 overexpression reduced the apoptosis and reactive oxygen species production induced by the OGD/R treatment. Mechanistically, CKIP-1 inhibited the expression of Kelch-like ECH-associated protein 1 (Keap1) and promoted the expression of nuclear factor E2-related factor 2 (Nrf2). In addition, CKIP-1 increased the activation of antioxidant response element and the expression of downstream antioxidant genes. However, Keap1 overexpression or Nrf2 knockdown partially reversed the neuroprotective effect of CKIP-1 overexpression. Taken together, our results demonstrate that CKIP-1 overexpression alleviates OGD/R-induced neuronal injury by enhancing the Nrf2-mediated anti-oxidative stress signaling pathway, revealing a neuroprotective role of CKIP-1. Our study suggests CKIP-1 as a potential therapeutic target for neuroprotection.
Omega 3 rich diet modulates energy metabolism via GPR120-Nrf2 crosstalk in a novel antioxidant mouse model
With obesity rates reaching epidemic proportions, more studies concentrated on reducing the risk and treating this epidemic are vital. Redox stress is an important metabolic regulator involved in the pathophysiology of cardiovascular disease, Type 2 diabetes, and obesity. Oxygen and nitrogen-derived free radicals alter glucose and lipid homeostasis in key metabolic tissues, leading to increases in risk of developing metabolic syndrome. Oxidants derived from dietary fat differ in their metabolic regulation, with numerous studies showing benefits from a high omega 3 rich diet compared to the frequently consumed "western diet" rich in saturated fat. Omega 3 (OM3) fatty acids improve lipid profile, lower inflammation, and ameliorate insulin resistance, possibly through maintaining redox homeostasis. This study is based on the hypothesis that altering endogenous antioxidant production and/or increasing OM3 rich diet consumption will improve energy metabolism and maintain insulin sensitivity. We tested the comparative metabolic effects of a diet rich in saturated fat (HFD) and an omega 3-enriched diet (OM3) in the newly developed 'stress-less' mice model that overexpresses the endogenous antioxidant catalase. Eight weeks of dietary intervention showed that mice overexpressing endogenous catalase compared to their wild-type controls when fed an OM3 enriched diet, in contrast to HFD, activated GPR120-Nrf2 cross-talk to maintain balanced energy metabolism, normal circadian rhythm, and insulin sensitivity. These findings suggest that redox regulation of GPR120/FFAR4 might be an important target in reducing risk of metabolic syndrome and associated diseases.
Chitosan oligosaccharides induce apoptosis in human renal carcinoma via ROS-dependent ER stress
In recent years, various studies have confirmed the role of natural products as effective cancer prevention and treatment drug. The present study demonstrated chitosan oligosaccharide (COS) from shells of shrimp and crab, caused an inhibitory effect on the proliferation of human renal carcinoma in vitro and in vivo. First, the in vivo biodistribution of COS was investigated by the synthesis of cyanine 7-labelled COS (COS-Cy7) following tail vein injection. The kidney was found to be major target organ. Then, the impacts on renal carcinoma cell proliferation, apoptosis and ROS production were observed in vitro, and an orthotopic xenograft tumour model was designed to evaluate the antitumour efficacy of COS in vivo. In renal carcinoma cells, COS induced G2/M phase arrest and apoptosis in a ROS-dependent fashion. COS significantly promoted mRNA expression of Nrf2 and Nrf2 target genes, such as HMOX1, GCLM, and SLC7A11. Additionally, COS significantly upregulated the protein expression of GRP78, PERK, eIF2α, ATF4, CHOP and Cyt c, which justified the activation of the ER stress signalling pathway. In vivo, COS repressed tumour growth and induced apoptosis and ROS accumulation, consistent with the in vitro results. Taken together, COS repressed human renal carcinoma growth and induced apoptosis both in vitro and in vivo, mainly via ROS-dependent ER stress pathways.
Commensal microbiota induced redox signaling activates proliferative signals in the intestinal stem cell microenvironment
A distinct taxon of the microbiota, , is capable of stimulating the generation of reactive oxygen species (ROS) within cells, and inducing epithelial cell proliferation. Here we show microbial-induced ROS generation within larval stem cell compartments exhibits a distinct spatial distribution. Lactobacilli-induced ROS is strictly excluded from defined midgut compartments that harbor adult midgut progenitor (AMP) cells, forming a functional "ROS sheltered zone" (RSZ). The RSZ is undiscernible in germ-free larvae, but forms following mono-colonization with is a strong activator of the ROS-sensitive CncC/Nrf2 signaling pathway within enterocytes. Enterocyte-specific activation of CncC stimulated the proliferation of AMPs, demonstrating that pro-proliferative signals are transduced from enterocytes to AMPs. Mechanistically, we show that the cytokine Upd2 is expressed in the gut following colonization in a CncC dependent fashion, and may function in lactobacilli-induced AMP proliferation and intestinal tissue growth and development.
SIRT6 protects retinal ganglion cells against hydrogen peroxide-induced apoptosis and oxidative stress by promoting Nrf2/ARE signaling via inhibition of Bach1
Oxidative stress-induced damage of retinal ganglion cells (RGCs) is a major contributor to retinal degenerative diseases, such as glaucoma. Sirtuin 6 (SIRT6) has emerged as a cytoprotective protein against various insults. However, whether SIRT6 exerts a protective effect against oxidative stress-damaged RGCs remains unknown. In this study, we aimed to investigate the potential role and regulatory mechanism of SIRT6 in hydrogen peroxide (HO)-induced oxidative damage of RGCs in vitro. We found that SIRT6 expression was significantly downregulated in RGCs with HO treatment. Functional experiments showed that overexpression of SIRT6 improved survival and reduced apoptosis and the production of reactive oxygen species (ROS) in HO-treated RGCs. In contrast, SIRT6 knockdown had the opposite effect. Moreover, we found that SIRT6 overexpression promoted the nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and increased the activity of antioxidant response element (ARE). In addition, we found that the promotional effect of SIRT6 on Nrf2/ARE signaling was associated with inhibition of BTB and CNC homology 1 (Bach1), an inhibitor of Nrf2. However, overexpression of Bach1 or inhibition of Nrf2/ARE signaling partially reversed the SIRT6-mediated protective effect. Taken together, these results demonstrate that SIRT6 protects RGCs from oxidative stress-induced damage by promoting the activation of Nrf2/ARE signaling via inhibition of Bach1, suggesting a potential role of SIRT6 in retinal degenerative diseases.
N-Palmitoylethanolamine-oxazoline (PEA-OXA): A new therapeutic strategy to reduce neuroinflammation, oxidative stress associated to vascular dementia in an experimental model of repeated bilateral common carotid arteries occlusion
Recent studies revealed that pharmacological modulation of NAE-hydrolyzing acid amidase (NAAA) can be achieved with PEA oxazoline (PEA-OXA). Hence, the aim of the present work was to thoroughly evaluate the anti-inflammatory and neuroprotective effects of PEA-OXA in an experimental model of vascular dementia (VaD) induced by bilateral carotid arteries occlusion. At 24 h after VaD induction, animals were orally administered with 10 mg/kg of PEA-OXA daily for 15 days.
Hydrogen gas reduces HMGB1 release in lung tissues of septic mice in an Nrf2/HO-1-dependent pathway
Lung injury is a vital contributor of mortality in septic patients. Our previous studies have found that molecular hydrogen (H), which has anti-oxidant, anti-inflammatory, and anti-apoptosis effects, had a therapeutic effect on a septic animal model through increasing expression of nuclear factor-erythroid 2-related factor 2 (Nrf2). The aim of this research was to investigate the effects of 2% H gas inhalation on sepsis-induced lung injury and its underlying mechanisms.
Electrophiles modulate glutathione reductase activity via alkylation and upregulation of glutathione biosynthesis
Cells evolved robust homeostatic mechanisms to protect against oxidation or alkylation by electrophilic species. Glutathione (GSH) is the most abundant intracellular thiol, protects cellular components from oxidation and is maintained in a reduced state by glutathione reductase (GR). Nitro oleic acid (NO-OA) is an electrophilic fatty acid formed under digestive and inflammatory conditions that both reacts with GSH and induces its synthesis upon activation of Nrf2 signaling. The effects of NO-OA on intracellular GSH homeostasis were evaluated. In addition to upregulation of GSH biosynthesis, we observed that NO-OA increased intracellular GSSG in an oxidative stress-independent manner. NO-OA directly inhibited GR in vitro by covalent modification of the catalytic Cys61, with k of (3.45 ± 0.04) × 10 M s, k of (4.4 ± 0.4) × 10 s, and K of (1.3 ± 0.1) × 10 M. Akin to NO-OA, the electrophilic Nrf2 activators bardoxolone-imidazole (CDDO-Im), bardoxolone-methyl (CDDO-Me) and dimethyl fumarate (DMF) also upregulated GSH biosynthesis while promoting GSSG accumulation, but without directly inhibiting GR activity. In vitro assays in which GR was treated with increasing GSH concentrations and GSH depletion experiments in cells revealed that GR activity is finely regulated via product inhibition, an observation further supported by theoretical (kinetic modeling of cellular GSSG:GSH levels) approaches. Together, these results describe two independent mechanisms by which electrophiles modulate the GSH/GSSG couple, and provide a novel conceptual framework to interpret experimentally determined values of GSH and GSSG.