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Reactive oxygen species (ROS) are byproducts of aerobic respiration and signaling molecules that control various cellular functions. Nrf2 governs the gene expression of endogenous antioxidant synthesis and ROS-eliminating enzymes in response to various electrophilic compounds that inactivate the negative regulator Keap1. Accumulating evidence has shown that mitochondrial ROS (mtROS) activate Nrf2, often mediated by certain protein kinases, and induce the expression of antioxidant genes and genes involved in mitochondrial quality/quantity control. Mild physiological stress, such as caloric restriction and exercise, elicits beneficial effects through a process known as “mitohormesis”. Exercise induces NOX4 expression in the heart, which activates Nrf2 and increases endurance capacity. Mice transiently depleted of SOD2 or overexpressing skeletal muscle-specific UCP1 exhibit Nrf2-mediated antioxidant gene expression and PGC1α-mediated mitochondrial biogenesis. ATF4 activation may induce a transcriptional program that enhances NADPH synthesis in the mitochondria and might cooperate with the Nrf2 antioxidant system. In response to severe oxidative stress, Nrf2 induces Klf9 expression, which represses mtROS-eliminating enzymes to enhance cell death. Nrf2 is inactivated in certain pathological conditions, such as diabetes, but Keap1 down-regulation or mtROS elimination rescues Nrf2 expression and improves the pathology. These reports aid us in understanding the roles of Nrf2 in pathophysiological alterations involving mtROS.

Reactive oxygen species (ROS) are produced mainly by mitochondrial respiration and function as signaling molecules in the physiological range. However, ROS production is also associated with the pathogenesis of various diseases, including insulin resistance (IR) and type 2 diabetes (T2D). This review focuses on the etiology of IR and early events, especially mitochondrial ROS (mtROS) production in insulin-sensitive tissues. Importantly, IR and/or defective adipogenesis in the white adipose tissues (WAT) is thought to increase free fatty acid and ectopic lipid deposition to develop into systemic IR. Fatty acid and ceramide accumulation mediate coenzyme Q reduction and mtROS production in IR in the skeletal muscle, while coenzyme Q synthesis downregulation is also involved in mtROS production in the WAT. Obesity-related IR is associated with the downregulation of mitochondrial catabolism of branched-chain amino acids (BCAAs) in the WAT, and the accumulation of BCAA and its metabolites as biomarkers in the blood could reliably indicate future T2D. Transcription factor NF-E2-related factor 2 (Nrf2), which regulates antioxidant enzyme expression in response to oxidative stress, is downregulated in insulin-resistant tissues. However, Nrf2 inducers, such as sulforaphane, could restore Nrf2 and target gene expression and attenuate IR in multiple tissues, including the WAT.

Background The Keap1-Nrf2 pathway has been reported to be impaired in several cancers. However, the status of Keap1-Nrf2 system in human colorectal cancer (CRC) has not been elucidated. Methods We used colorectal cancer (CRC) cell lines and surgical specimens to investigate the methylation status of the KEAP1 promoter region as well as expression of Nrf2 and its downstream antioxidative stress genes, NQO-1 and AKR1C1 . Results DNA sequencing analysis indicated that all mutations detected were synonymous, with no amino acid substitutions. We showed by bisulfite genomic sequencing and methylation-specific PCR that eight of 10 CRC cell lines had hypermethylated CpG islands in the KEAP1 promoter region. HT29 cells with a hypermethylated KEAP1 promoter resulted in decreased mRNA and protein expression but unmethylated Colo320DM cells showed higher expression levels. In addition, treatment with the DNA methyltransferase inhibitor 5-Aza-dC combined with the histone deacetylase inhibitor trichostatin A (TSA) increased KEAP1 mRNA expression. These result suggested that methylation of the KEAP1 promoter regulates its mRNA level. Time course analysis with the Nrf2-antioxidant response element (ARE) pathway activator t-BHQ treatment showed a rapid response within 24 h. HT29 cells had higher basal expression levels of NQO-1 and AKR1C1 mRNA than Colo320DM cells. Aberrant promoter methylation of KEAP1 was detected in 53% of tumor tissues and 25% of normal mucosae from 40 surgical CRC specimens, indicating that cancerous tissue showed increased methylation of the KEAP1 promoter region, conferring a protective effect against cytotoxic anticancer drugs. Conclusion Hypermethylation of the KEAP1 promoter region suppressed its mRNA expression and increased nuclear Nrf2 and downstream ARE gene expression in CRC cells and tissues.

Objective Various plants have been reported to contain compounds that promote the transcriptional activity of Nuclear factor erythroid 2-related factor 2 (Nrf2) to induce a set of xenobiotic detoxifying enzymes, such as NAD(P)H-quinone acceptor oxidoreductase 1 (NQO1), via the antioxidant response element (ARE). While conventional methods for evaluating Nrf2 induction potency include measurement of NQO1 activity, an ARE luciferase reporter assay was recently developed to specifically assess Nrf2 induction potency of compounds of interest. In this study, we compared the abilities of these two assays to evaluate and determine Nrf2 induction potency of plant-derived compounds. Results Although the compounds exhibited a high degree of consistency between assays, several compounds did not. These results suggest that although the NQO1 assay can be used as an evaluation method to estimate Nrf2 induction potency of a compound, an ARE luciferase reporter approach may offer greater precision. In summary, inconsistency in Nrf2 induction potency evaluated by the reporter and NQO1 assays of plant-derived compounds, including resveratrol, may be due to a variety of factors that may regulate NQO1 gene expression other than Nrf2 and/or directly modulate NQO1 enzymatic activity or protein levels, with each compound having a different degree of effect on these factors.

Lymph node metastasis (LNM) is a critical prognostic factor for patients with oral squamous cell carcinoma (OSCC). Previous research has implicated the partial epithelial-to-mesenchymal transition of tumor cells and myofibroblastic cancer-associated fibroblasts (myCAFs) in the LNM process. However, the underlying molecular mechanisms remain poorly understood. Here, we conducted a comprehensive molecular analysis integrating original and publicly available OSCC data from bulk genome and transcriptome, single-cell transcriptome, and spatial transcriptome analyses. We found that myCAFs were quantitatively and functionally activated in LNM-positive samples and spatially colocalized with OSCC cells within the invasive tumor front (ITF), providing a niche that may facilitate LNM. Immunohistochemical validation in 90 ITF samples confirmed significantly higher myCAF density in LNM-positive samples than in LNM-negative samples, and this density remained an independent predictor of LNM when adjusted for pathological grade and the pattern of invasion. In LNM-positive samples, myCAFs provided increased extracellular matrix (ECM) signals, upregulating stemness-related genes such as CD44 in OSCC cells. The functional importance of this myCAF-driven ECM-CD44 axis was further supported by our validation analysis of expanded, publicly available spatial transcriptome and experimental in vitro coculture data. We also extracted a spatially resolved, 23-gene signature from the metastatic ITF where OSCC and myCAFs colocalize. This signature predicted LNM status and poor overall survival in patients with OSCC. Our findings provide novel insight into the molecular myCAF/OSCC crosstalk that facilitates LNM and identify potential prognostic biomarkers and therapeutic targets for patients with OSCC.

Numerous small molecules (termed inducers), many of which are electrophiles, upregulate cytoprotective responses and inhibit pro-inflammatory pathways by activating nuclear factor-erythroid 2 p45-related factor 2 (NRF2). Key to NRF2 activation is the ability to chemically modifying critical sensor cysteines in the main negative regulator of NRF2, Kelch-like ECH-associated protein 1 (KEAP1), of which C151, C273 and C288 are best characterized. This study aimed to establish the requirement for these cysteine sensor(s) for the biological activities of the most potent NRF2 activators known to date, the cyclic cyanoenones, some of which are in clinical trials. It was found that C151 in KEAP1 is the main cysteine sensor for this class of inducers, irrespective of molecular size or shape. Furthermore, in primary macrophage cells expressing C151S mutant KEAP1, at low concentrations, the tricyclic cyanoenone TBE-31 is inactive as an activator of NRF2 as well as an inhibitor of lipopolysaccharide-stimulated gene expression of the pro-inflammatory cytokines IL6 and IL1β. However, at high inducer concentrations, NRF2 activation proceeds in the absence of C151, albeit at a lower magnitude. Our findings highlight the intrinsic flexibility of KEAP1 and emphasize the critical importance of establishing the precise dose of NRF2 activators for maintaining on-target selectivity.

In addition to testosterone, various endocrine hormones, such as dehydroepiandrosterone sulfate (DHEA-S) and estradiol, may be involved in erectile function. However, the role of these sex hormones in the erectile function of men without hypoandrogenism remains unclear. This cross-sectional study included 398 community-dwelling men without hypoandrogenism. The participants were categorized into the non-ED and ED groups. Multivariable logistic regression analyses were performed to investigate the relationship between ED and serum sex hormone levels, including total testosterone, DHEA-S, estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin. Among the 398 men, 66 (17%) and 332 (83%) were categorized into the non-ED and ED groups, respectively. In the multivariable analyses, serum DHEA-S and estradiol levels were significantly associated with ED (odds ratio [OR]: 0.996, P  = 0.030; OR: 1.082, P  = 0.002; respectively), whereas serum total testosterone, LH, FSH, and prolactin levels did not demonstrate significant association. After adjusting for age, none of neutrophil-to-lymphocyte ratio, serum plasminogen activator inhibitor-1 levels, and skin advanced glycation end-products levels demonstrated significant correlation with serum DHEA-S and estradiol levels. In conclusion, lower testosterone levels did not affect ED in men with normal testosterone levels, whereas serum DHEA-S and estradiol levels were significantly associated with ED.

Iron has played an important role in energy production since the beginning of life, as iron-catalyzed redox reactions are required for energy production. Oxygen, a highly efficient electron acceptor with high reduction potential, facilitates highly efficient energy production in eukaryotic cells. However, the increasing atmospheric oxygen concentration produces new threats to the organism, as oxygen reacts with iron and produces reactive oxygen species unless its levels are strictly regulated. As the size of multicellular organisms increases, these organisms must transport oxygen to the peripheral tissues and begin to employ red blood cells containing hemoglobin. This system is potentially a double-edged sword, as hemoglobin autoxidation occurs at a certain speed and releases free iron into the cytoplasm. Nrf2 belongs to the CNC transcription factor family, in which NF-E2p45 is the founding member. NF-E2p45 was first identified as a transcription factor that binds to the erythroid gene regulatory element NF-E2 located in the promoter region of the heme biosynthetic porphobilinogen deaminase gene. Human Nrf2 was also identified as a transcription factor that binds to the regulatory region of the β-globin gene. Despite these original findings, NF-E2p45 and Nrf2 knockout mice exhibit few erythroid phenotypes. Nrf2 regulates the expression of a wide range of antioxidant and detoxification enzymes. In this review article, we describe and discuss the roles of Nrf2 in various iron-mediated bioreactions and its possible coevolution with iron and oxygen.

The 36-item Short-Form Health Survey (SF-36) is widely used to assess health-related quality of life. However, only few studies have examined longitudinal SF-36 trajectories in general populations, and even fewer have explored their relationships with lifestyle factors, including sleep quality. We conducted a longitudinal analysis of SF-36 subscale trajectories among 910 Japanese individuals aged ≥ 60 years from 2007 to 2018 (4,799 records). Using latent class mixed models, we identified distinct trajectory patterns for each subscale. Notably, the role-physical (RP) and role-emotional (RE) subscales exhibited multiple patterns, including rapid decline and non-decline trajectories. We further examined predictors that differentiated between these two trajectory patterns—rapid decline and non-decline—with similar baseline scores. Consequently, poor performance on the open-eye one-leg standing test and higher depression scores on the Centre for Epidemiologic Studies Depression Scale predicted RP and RE declines, respectively. Importantly, poor sleep quality, as measured by the Pittsburgh Sleep Quality Index—particularly the total score and component 7 (daytime dysfunction)—was associated with subsequent RP and RE declines. In contrast, sleep timing variables (bedtime, sleep onset, and wake-up time) were not predictive. These findings suggest that preserving good sleep quality may help prevent future limitations in daily physical and emotional roles.

This study analysed the effects of visceral fat on metabolic syndrome (MetS) and developed an algorithm to predict its onset using health examination data from the Iwaki Health Promotion Project in Japan. The dataset included 213 cases of MetS onset within three years and 1320 non-onset cases. The data was split into training and test sets with an 8:2 ratio. In the training set, the MetS onset group had significantly higher visceral fat area than the non-onset group (p < 0.00001). A cut-off value of 82 cm2 for the visceral fat area was determined, with an AUC of 0.86. Additionally, a machine learning algorithm utilizing seven non-invasive factors, including visceral fat, achieved high accuracy with a five-fold cross-validation AUC of 0.90 in the training set and 0.88 in the test set. Visceral fat was identified as the main factor, as supported by the SHAP value. In conclusion, this study found visceral fat to be crucial in predicting the onset of MetS, and a high-accuracy onset prediction algorithm based on non-invasive parameters, including visceral fat, was developed.