The primary aim of this review is to summarize the current literature on the effects of acute exercise and regular exercise on nuclear factor erythroid 2-related factor 2 (Nrf2) activity and ...downstream targets of Nrf2 signaling. Nrf2 (encoded in humans by the NFE2L2 gene) is the master regulator of antioxidant defenses, a transcription factor that regulates expression of more than 200 cytoprotective genes. Increasing evidence indicates that Nrf2 signaling plays a key role in how oxidative stress mediates the beneficial effects of exercise. Episodic increases in oxidative stress induced through bouts of acute exercise stimulate Nrf2 activation and when applied repeatedly, as with regular exercise, leads to upregulation of endogenous antioxidant defenses and overall greater ability to counteract the damaging effects of oxidative stress. The evidence of Nrf2 activation in response to exercise across variety of tissues may be an important mechanism of how exercise exerts its well-known systemic effects that are not limited to skeletal muscle and myocardium. Additionally there are emerging data that results from animal studies translate to humans.
Controversy over the role of antioxidants in cancer has persisted for decades. Here, we demonstrate that synthesis of the antioxidant glutathione (GSH), driven by GCLM, is required for cancer ...initiation. Genetic loss of Gclm prevents a tumor’s ability to drive malignant transformation. Intriguingly, these findings can be replicated using an inhibitor of GSH synthesis, but only if delivered prior to cancer onset, suggesting that at later stages of tumor progression GSH becomes dispensable potentially due to compensation from alternative antioxidant pathways. Remarkably, combined inhibition of GSH and thioredoxin antioxidant pathways leads to a synergistic cancer cell death in vitro and in vivo, demonstrating the importance of these two antioxidants to tumor progression and as potential targets for therapeutic intervention.
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•The GSH antioxidant pathway is required for cancer initiation•After cancer initiation, GSH is dispensable due to alternative antioxidant pathways•The TXN antioxidant pathway is upregulated in tumors•Inhibition of both GSH and TXN pathways causes synergistic cancer cell death
Harris et al. show that the antioxidant glutathione (GSH) is required for cancer initiation but not for established tumors partly due to upregulation of the thioredoxin (TXN) antioxidant pathway in the latter. Consequently, blocking both GSH and TXN pathways synergistically inhibits tumor growth.
The threats of wide-scale coral bleaching and reef demise associated with anthropogenic climate change are widely known. Moreover, rates of genetic adaptation and/or changes in the coral-zooxanthella ...partnerships are considered unlikely to be sufficiently fast for corals to acquire increased physiological resistance to increasing sea temperatures and declining pH. However, it has been suggested that coral reef resilience to climate change may be improved by good local management of coral reefs, including management of water quality. Here, using major data sets from the Great Barrier Reef (GBR), Australia, we investigate geographic patterns of coral bleaching in 1998 and 2002 and outline a synergism between heat stress and nutrient flux as a major causative mechanism for those patterns. The study provides the first concrete evidence for the oft-expressed belief that improved coral reef management will increase the regional-scale survival prospects of coral reefs to global climate change.
Precipitation extremes are increasing globally due to anthropogenic climate change. However, there remains uncertainty regarding impacts upon flood occurrence and subsequent population exposure. ...Here, we quantify changes in population exposure to flood hazard across the contiguous United States. We combine simulations from a climate model large ensemble and a high‐resolution hydrodynamic flood model—allowing us to directly assess changes across a wide range of extreme precipitation magnitudes and accumulation timescales. We report a mean increase in the 100‐year precipitation event of ~20% (magnitude) and >200% (frequency) in a high warming scenario, yielding a ~30–127% increase in population exposure. We further find a nonlinear increase for the most intense precipitation events—suggesting accelerating societal impacts from historically rare or unprecedented precipitation events in the 21st century.
Plain Language Summary
Heavy rainfall is increasing globally due to human‐caused global warming. However, it is still unclear how these increases in heavy rainfall might affect flood risk. In this paper, we investigate how global warming and population changes together may be affecting the number of people at risk from floods in the United States. We combine simulations from a climate model and flood model—allowing us to consider a wide range of heavy rainfall events. We report a ~20% increase in the size and a >200% increase in the frequency of very heavy and rare rainfall events, which leads to a ~30–127% increase in the number of people at risk from floods. Finally, we find that the heaviest rainfall events increase by the widest margin—suggesting the possibility of major increases in damage and disruption caused by severe floods in the 21st century.
Key Points
Population exposure to flood hazard is increasing due to both climate‐driven increases in extreme rainfall as well as demographic shifts
There is a wide range of plausible increases in population exposed to flood hazard, depending strongly on climate and growth scenario
We find a nonlinear increase for most extreme events, suggesting accelerating societal impacts from historically unprecedented rainfall
Triple-negative breast cancer (TNBC) is a breast cancer subtype that lacks targeted treatment options. The activation of the Notch developmental signaling pathway, which is a feature of TNBC, results ...in the secretion of proinflammatory cytokines and the recruitment of protumoral macrophages to the tumor microenvironment. While the Notch pathway is an obvious therapeutic target, its activity is ubiquitous, and predictably, anti-Notch therapies are burdened with significant on-target side effects. Previously, we discovered that, under conditions of cellular stress commonly found in the tumor microenvironment, the deubiquitinase USP9x forms a multiprotein complex with the pseudokinase tribbles homolog 3 (TRB3) that together activate the Notch pathway. Herein, we provide preclinical studies that support the potential of therapeutic USP9x inhibition to deactivate Notch. Using a murine TNBC model, we show that USP9x knockdown abrogates Notch activation, reducing the production of the proinflammatory cytokines, C-C motif chemokine ligand 2 (CCL2) and interleukin-1 beta (IL-1β). Concomitant with these molecular changes, a reduction in tumor inflammation, the augmentation of antitumor immune response, and the suppression of tumor growth were observed. The pharmacological inhibition of USP9x using G9, a partially selective, small-molecule USP9x inhibitor, reduced Notch activity, remodeled the tumor immune landscape, and reduced tumor growth without associated toxicity. Proving the role of Notch, the ectopic expression of the activated Notch1 intracellular domain rescued G9-induced effects. This work supports the potential of USP9x inhibition to target Notch in metabolically vulnerable tissues like TNBC, while sparing normal Notch-dependent tissues.
Triple negative breast cancer (TNBC) is a deadly form of breast cancer due to the development of resistance to chemotherapy affecting over 30% of patients. New therapeutics and companion biomarkers ...are urgently needed. Recognizing the elevated expression of glucose transporter 1 (GLUT1, encoded by SLC2A1) and associated metabolic dependencies in TNBC, we investigated the vulnerability of TNBC cell lines and patient-derived samples to GLUT1 inhibition. We report that genetic or pharmacological inhibition of GLUT1 with BAY-876 impairs the growth of a subset of TNBC cells displaying high glycolytic and lower oxidative phosphorylation (OXPHOS) rates. Pathway enrichment analysis of gene expression data suggests that the functionality of the E2F pathway may reflect to some extent OXPHOS activity. Furthermore, the protein levels of retinoblastoma tumor suppressor (RB1) strongly correlate with the degree of sensitivity to GLUT1 inhibition in TNBC, where RB1-negative cells are insensitive to GLUT1 inhibition. Collectively, our results highlight a strong and targetable RB1-GLUT1 metabolic axis in TNBC and warrant clinical evaluation of GLUT1 inhibition in TNBC patients stratified according to RB1 protein expression levels.
Exercise-induced Nrf2-signaling is impaired in aging Done, Aaron J.; Gage, Matthew J.; Nieto, Nathan C. ...
Free radical biology & medicine,
July 2016, 2016-Jul, 2016-07-00, 20160701, Letnik:
96
Journal Article
Recenzirano
The transcription factor nuclear erythroid-2 like factor-2 (Nrf2) is the master regulator of antioxidant defense. Data from animal studies suggest exercise elicits significant increases in Nrf2 ...signaling, and that signaling is impaired with aging resulting in decreased induction of phase II detoxifying enzymes and greater susceptibility to oxidative damage. We have previously shown that older adults have lower resistance to an oxidative challenge as compared to young, and that this response is modified with physical fitness and phytonutrient intervention. We hypothesized that a single bout of submaximal exercise would elicit increased nuclear accumulation of Nrf2, and that this response to exercise would be attenuated with aging.
Nrf2 signaling in response to 30-min cycling at 70% VO2max was compared in young (23±1y, n=10) and older (63±1, n=10) men. Blood was collected at six time points; pre-exercise, and 10min, 30min, 1h, 4h, and 24h post-exercise. Nrf2 signaling was determined in peripheral blood mononuclear cells by measuring protein expression by western blot of Nrf2 in whole cell and nuclear fractions, and whole cell SOD1, and HMOX, as well as gene expression (RT-PCR) of downstream Nrf2-ARE antioxidants SOD1, HMOX, and NQO1.
Baseline differences in protein expression did not differ between groups. The exercise trial elicited significant increase in whole cell Nrf2 (P=0.003) for both young and older groups. Nuclear Nrf2 levels were increased significantly in the young but not older group (P=0.031). Exercise elicited significant increases in gene expression of HMOX1 and NQO1 in the young (P=0.006, and P=0.055, respectively) whereas gene expression in the older adults was repressed. There were no significant differences in SOD1 or HMOX1 protein expression.
These findings indicate a single session of submaximal aerobic exercise is sufficient to activate Nrf2 at the whole cell level in both young and older adults, but that nuclear import is impaired with aging. Additionally we have shown repressed gene expression of downstream antioxidant targets of Nrf2 in older adults. Together these translational data demonstrate for the first time the attenuation of Nrf2 activity in response to exercise in older adults.
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•A single session of aerobic exercise increases whole-cell Nrf2 expression in humans.•Nuclear accumulation of Nrf2 following exercise is attenuated in older adults.•Downstream Nrf2-ARE antioxidant gene expression was repressed in older adults.•These data suggest impairment of the Nrf2-ARE pathway in response to exercise with aging.
Metformin may exert anti-cancer effects through indirect (insulin-mediated) or direct (insulin-independent) mechanisms. We report results of a neoadjuvant “window of opportunity” study of metformin ...in women with operable breast cancer. Newly diagnosed, untreated, non-diabetic breast cancer patients received metformin 500 mg tid after diagnostic core biopsy until definitive surgery. Clinical (weight, symptoms, and quality of life) and blood fasting serum insulin, glucose, homeostasis model assessment (HOMA), C-reactive protein (CRP), and leptin attributes were compared pre- and post-metformin as were terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and Ki67 scores (our primary endpoint) in tumor tissue. Thirty-nine patients completed the study. Mean age was 51 years, and metformin was administered for a median of 18 days (range 13–40) up to the evening prior to surgery. 51 % had T1 cancers, 38 % had positive nodes, 85 % had ER and/or PgR positive tumors, and 13 % had HER2 overexpressing or amplified tumors. Mild, self-limiting nausea, diarrhea, anorexia, and abdominal bloating were present in 50, 50, 41, and 32 % of patients, respectively, but no significant decreases were seen on the EORTC30-QLQ function scales. Body mass index (BMI) (−0.5 kg/m
2
,
p
< 0.0001), weight (−1.2 kg,
p
< 0.0001), and HOMA (−0.21,
p
= 0.047) decreased significantly while non-significant decreases were seen in insulin (−4.7 pmol/L,
p
= 0.07), leptin (−1.3 ng/mL,
p
= 0.15) and CRP (−0.2 mg/L,
p
= 0.35). Ki67 staining in invasive tumor tissue decreased (from 36.5 to 33.5 %,
p
= 0.016) and TUNEL staining increased (from 0.56 to 1.05,
p
= 0.004). Short-term preoperative metformin was well tolerated and resulted in clinical and cellular changes consistent with beneficial anti-cancer effects; evaluation of the clinical relevance of these findings in adequately powered clinical trials using clinical endpoints such as survival is needed.
Abstract
Background
The Ontario Breast Screening Program expanded in July 2011 to screen high-risk women age 30–69 years with annual magnetic resonance imaging (MRI) and digital mammography. This ...study examined the benefits of screening with mammography and MRI by age and risk criteria.
Methods
This prospective cohort study included 8782 women age 30–69 years referred to the High Risk Ontario Breast Screening Program from July 2011 to June 2015, with final results to December 2016. Cancer detection rates, sensitivity, and specificity of MRI and mammography combined were compared with each modality individually within risk groups stratified by age using generalized estimating equation models. Prognostic features of screen-detected breast cancers were compared by modality using Fisher exact test. All P values are two-sided.
Results
Among 20 053 screening episodes, there were 280 screen-detected breast cancers (cancer detection rate = 14.0 per 1000, 95% confidence interval CI = 12.4 to 15.7). The sensitivity of mammography was statistically significantly lower than that of MRI plus mammography (40.8%, 95% CI = 29.3% to 53.5% vs 96.0%, 95% CI = 92.2% to 98.0%, P < .001). In mutation carriers age 30–39 years, sensitivity of the combination was comparable with MRI alone (100.0% vs 96.8%, 95% CI = 79.2% to 100.0%, P = .99) but with statistically significantly decreased specificity (78.0%, 95% CI = 74.7% to 80.9% vs 86.2%, 95% CI = 83.5% to 88.5%, P < .001). In women age 50–69 years, combining MRI and mammography statistically significantly increased sensitivity compared with MRI alone (96.3%, 95% CI = 90.6% to 98.6% vs 90.9%, 95% CI = 83.6% to 95.1%, P = .02), with a small but statistically significant decrease in specificity (84.2%, 95% CI = 83.1% to 85.2% vs 90.0%, 95% CI = 89.2% to 90.9%, P < .001).
Conclusions
Screening high risk women age 30–39 years with annual MRI only may be sufficient for cancer detection and should be evaluated further, particularly for mutation carriers. Among women age 50–69 years, detection is most effective when mammography is included with annual MRI.
The inshore reefs of the Great Barrier Reef (GBR) have undergone significant declines in water quality following European settlement (approx. 1870 AD). However, direct evidence of impacts on coral ...assemblages is limited by a lack of historical baselines prior to the onset of modern monitoring programmes in the early 1980s. Through palaeoecological reconstructions, we report a previously undocumented historical collapse of Acropora assemblages at Pelorus Island (central GBR). High-precision U-series dating of dead Acropora fragments indicates that this collapse occurred between 1920 and 1955, with few dates obtained after 1980. Prior to this event, our results indicate remarkable long-term stability in coral community structure over centennial scales. We suggest that chronic increases in sediment flux and nutrient loading following European settlement acted as the ultimate cause for the lack of recovery of Acropora assemblages following a series of acute disturbance events (SST anomalies, cyclones and flood events). Evidence for major degradation in reef condition owing to human impacts prior to modern ecological surveys indicates that current monitoring of inshore reefs on the GBR may be predicated on a significantly shifted baseline.
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