The p62/SQSTM1 (sequestosome 1) protein, which acts as a cargo receptor for autophagic degradation of ubiquitinated targets, is up-regulated by various stressors. Induction the p62 gene oxidative stress mediated NF-E2-related factor 2 (NRF2) and, at same time, protein contributes to activation NRF2, but hitherto mechanisms involved were not known. Herein, we have mapped an antioxidant response element (ARE) in promoter that responsible its induction via NRF2. Chromatin immunoprecipitation...

Keap1 is a negative regulator of Nrf2, bZIP transcription factor that mediates adaptation to oxidative stress. Previous studies suggested this regulation consequence controlling the subcellular distribution Nrf2. We now report also controls total cellular level Nrf2 protein. In RL34 non-transformed rat liver cell line, was found accumulate rapidly in response stress caused by treatment with sulforaphane, and accumulation resulted from inhibition proteasomal-mediated degradation By...

In an attempt to reduce the rate of cesarean section, obstetricians now offer a trial labor pregnant women who have had previous section. Although is usually successful and relatively safe, few studies directly addressed maternal perinatal morbidity mortality associated with this method delivery.

Regulation of transcription factor Nrf2 (NF-E2-related 2) involves redox-sensitive proteasomal degradation via the E3 ubiquitin ligase Keap1/Cul3. However, is controlled by other mechanisms that have not yet been elucidated. We now show glycogen synthase kinase 3 (GSK-3) phosphorylates a group Ser residues in Neh6 domain mouse overlap with an SCF/β-TrCP destruction motif (DSGIS, 334 to 338) and promotes its Keap1-independent manner. was stabilized GSK-3 inhibitors Keap1-null embryo...

Identification of regulatable mechanisms by which transcription factor NF-E2 p45-related 2 (Nrf2) is repressed will allow strategies to be designed that counter drug resistance associated with its upregulation in tumours harbour somatic mutations Kelch-like ECH-associated protein-1 (Keap1), a gene encodes joint adaptor and substrate receptor for the Cul3-Rbx1/Roc1 ubiquitin ligase. We now show mouse Nrf2 contains two binding sites β-transducin repeat-containing protein (β-TrCP), acts as...

NQO1 [NAD(P)H:quinone oxidoreductase 1] has an integral role in cellular responses to oxidative stress. The expression of is up-regulated the mouse following challenge with electrophilic chemicals, Nrf2 (NF-E2 p45-related factor 2)-dependent fashion, but molecular basis for this observation remains unexplained. Through characterization murine nqo1 5'-upstream region, we now show that regulates gene directly via ARE (antioxidant response element) lies within a 24 bp region spanning nt -444...

The prevalence and mechanistic significance of self-association among substrate adaptors for the Cul-Rbx family ubiquitin ligases remain unclear. We now report that it is as a homodimer adaptor Keap1 interacts with Cul3. resulting complex facilitates ubiquitylation Nrf2 transcription factor but only when this possesses within its Neh2 domain second cryptic Keap1-binding site, DLG motif, in addition to previously described ETGE site. Both motifs recognize overlapping surfaces on Keap1, seven...

Mice that lack the Nrf2 basic-region leucine-zipper transcription factor are more sensitive than wild-type (WT) animals to cytotoxic and genotoxic effects of foreign chemicals oxidants. To determine basis for decrease in tolerance homozygous null mice xenobiotics, enzyme assay, Western blotting gene-specific real-time PCR (TaqMan®) have been used examine extent which hepatic expression GSH-dependent enzymes is influenced by factor. The amounts protein mRNA class Alpha, Mu Pi glutathione...

Recognition and repair of cellular damage is crucial if organisms are to survive harmful environmental conditions. In mammals, the Keap1 protein orchestrates this response, but how it perceives adverse circumstances not fully understood. Herein, we implicate NO, Zn 2+ , alkenals, endogenously occurring chemicals whose concentrations increase during stress, in process. By combining molecular modeling with phylogenetic, chemical, functional analyses, show that directly recognizes alkenals...

The Nrf2 transcription factor is more rapidly turned over in cells grown under homeostatic conditions than those experiencing oxidative stress. variable turnover of accomplished through the use at least two degrons and its redox-sensitive interaction with Kelch-repeat protein Keap1. In COS1 cells, Neh2 degron confers on a half-life less 10 min. Analyses deletion mutants Gal4(HA)mNeh2 fusion full-length mNrf2 indicate that full destabilizing activity depends upon separate sequences within...

To better understand the role of transcription factor NF-E2-related (NRF) 2 in human and its contribution to cancer chemoprevention, we have knocked down negative regulators, Kelch-like ECH-associated protein 1 (KEAP1) broad-complex, tramtrack bric à brac cap'n'collar homology (BACH1), HaCaT keratinocytes. Whole-genome microarray revealed that knockdown KEAP1 resulted 23 messenger RNAs (mRNAs) being up-regulated ≥2.0-fold. mRNA for aldo-keto reductase (AKR) 1B10, AKR1C1, AKR1C2 AKR1C3 were...

An overview is provided of the cancer chemo-prevention actions phenolic antioxidants and 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline (ethoxyquin). These agents principally appear to exert their beneficial effects through induction phase II drug-metabolizing enzymes such as glutathione S-transferase (GST). The requirement for oxidative metabolism synthetic carbonyl-containing compounds, including quinones, in order that they can induce gene expression discussed. Previous work has shown...

Trauma and/or accidental injury complicates 6-7% of all pregnancies. The management protocols for trauma in pregnancy are based largely on case reports and small series. purposes this study were to: describe the demographics pregnant patients at a tertiary care center large community hospital; identify variables predictive fetal outcome including an examination Kleihauer-Betke nonstress testing; recommend evaluation protocol after empirical data rather than anecdotal reports. Data from...

We performed a multicenter, randomized, controlled clinical trial of therapeutic peritoneal lavage (2 liters per hour for three days) in 91 patients with severe acute pancreatitis. Patients were entered into the study if pancreatitis was indicated by multiple laboratory criteria or diagnostic lavage. All received full supportive treatment. The median time between onset symptoms and randomization 38 hours. Forty-six assigned to control group 45 group. There 13 deaths (28 cent) 16 major...

Objectives. We assessed associations between psychosocial factors and preterm birth, stratified by race in a prospective cohort study. Methods. surveyed 1898 women who used university public health prenatal clinics regarding various factors. Results. African Americans were at higher risk of birth if they distancing from problems as coping mechanism or reported racial discrimination. Whites had high counts negative life events not living with partner. The association pregnancy-related anxiety...

The transcription factor NF-E2-related 2 (Nrf2) plays an essential role in the mammalian response to chemical and oxidative stress through induction of hepatic phase II detoxification enzymes regulation glutathione (GSH). Enhanced liver damage Nrf2-deficient mice treated with acetaminophen suggests a critical for Nrf2; however, direct evidence Nrf2 activation following exposure was previously lacking. We show that can initiate nuclear translocation vivo, maximum levels reached after 1 hour,...

Abstract Diagnostic peritoneal lavage was carried out in 79 patients with acute pancreatitis, at a mean time of 7 h after admission to hospital. The presence more than 10 ml free fluid, brown-coloured fluid or mid-straw-coloured the criterion used for prediction severe attack by lavage. Prior assessed as mild clinician and reassessed him 24 48 h. All attacks were finally classified means simple clinical grading scheme. There 61 18 (including 4 deaths). Initial assessment correctly predicted...