The antigenotoxic potential of dietary flavonoids

Human exposure to genotoxic agents has dramatically increased. Both endogenous (reactive species generated during physiological and pathological processes) and exogenous (UV light, ionizing radiation, alkylating agents, antimetabolites and topoisomerase inhibitors, air, water and food pollutants) factors can impair genomic stability. The cumulative DNA damage causes mutations involved in the development of cancer and other disorders (neuromuscular and neurodegenerative diseases, immune deficiencies, infertility, cardiovascular diseases, metabolic syndrome and aging). Dietary flavonoids have protective effects against DNA damage induced by different genotoxic agents such as mycotoxins, food processing-derived contaminants (polycyclic aromatic hydrocarbons, N-nitrosamines), cytostatic agents, other medications (estrogenic and androgenic hormones), nicotine, metal ions (Cd²⁺, Cr⁶⁺), radiopharmaceuticals and ionizing radiation. Dietary flavonoids exert their genoprotection by reducing oxidative stress and modulation of enzymes responsible for bioactivation of genotoxic agents and detoxification of their reactive metabolites. Data on structure–activity relationship is sometimes contradictory. Free hydroxyl groups on the B ring (catechol moiety) and C-3 position of the C ring are important structural features for the antigenotoxic activity. As dietary flavonoids are extensively metabolized, more in vivo studies are needed for a better characterization of their antigenotoxic potential.     

Signal Intensities in Preoperative MRI Do Not Reflect Proliferative Activity in Meningioma

BACKGROUND: Identification of high-grade meningiomas in preoperative magnetic resonance imaging (MRI) is important for optimized surgical strategy and best possible resection. Numerous studies investigated subjectively determined morphological features as predictors of tumor biology in meningiomas. The aim of this study was to identify the predictive value of more reliable, quantitatively measured signal intensities in MRI for differentiation of high- and low-grade meningiomas and identification of meningiomas with high proliferation rates, respectively. PATIENTS AND METHODS: Sixty-six patients (56 World Health Organization [WHO] grade I, 9 WHO grade II, and 1 WHO grade I) were included in the study. Preoperative MRI signal intensities (fluid-attenuated inversion recovery [FLAIR], T1 precontrast, and T1 postcontrast as genuine and normalized values) were correlated with Ki-67 expression in tissue sections of resected meningiomas. Differences between the groups (analysis of variance) and Spearman rho correlation were computed using SPSS 22. RESULTS: Mean values of genuine signal intensities of meningiomas in FLAIR, T1 native, and T1 postcontrast were 323.9 ± 59, 332.8 ± 67.9, and 768.5 ± 165.3. Mean values of normalized (to the contralateral white matter) signal intensities of meningiomas in FLAIR, T1 native, and T1 postcontrast were 1.5 ± 0.3, 0.8 ± 0.1, and 1.9 ± 0.4. There was no significant correlation between MRI signal intensities and WHO grade or Ki-67 expression. Signal intensities did not differ significantly between WHO grade I and II/III meningiomas. Ki-67 expression was significantly increased in high-grade meningiomas compared with low-grade meningiomas (P < 0.01). Objectively measured values of MRI signal intensities (FLAIR, T1 precontrast, and T1 postcontrast enhancement) did not distinguish between high-grade and low-grade meningiomas. Furthermore, there was no association between MRI signal intensities and Ki-67 expression representing proliferative activity.Meningiomas are among the most common brain tumors. Their incidence is about 1%, and they account for almost one third of all primary intracranial masses. The majority of meningiomas are very slowly growing and nonsymptomatic or minimally symptomatic entities, discovered as incidental findings on neuroimaging [1]. The World Health Organization (WHO) classification system distinguishes 3 histological grades and 15 subtypes and is a well-accepted tool for prediction of prognosis. Although most meningiomas are benign masses, certain histological subtypes reveal very high recurrence rates despite the tumors’ seemingly total removal. Grade II (atypical) and grade III (anaplastic) meningiomas are associated with an increased risk of recurrence, are more aggressive, and show invasive behavior [2]. Grade I meningiomas are generally considered as benign tumors, but recent studies indicate substantial neurological deficits and impaired long-term survival due to tumor recurrence and stroke despite their low histopathological grading in a considerable proportion of cases [3], [4]. Increased mitotic activity (more than 4 mitoses per 10 high-power fields) and elevated Ki-67 expression (Ki-67 index of more than 5% of nuclei) are reliable histopathological markers for tumor recurrence [2].Because histopathological grading alone does not predict outcome satisfyingly, numerous studies investigated the value of preoperative magnetic resonance imaging (MRI) for prognostics. For example, Liu et al. demonstrated that hyperintensity on diffusion-weighted imaging, heterogeneous gadolinium enhancement, disruption of the arachnoid at brain tumor interface, T2 hyperintense peritumoral edema, and irregular tumor shape were independent predictors of non–grade I meningioma [5]. Other works produced comparable results, although some of these studies underline the importance of positive capsular enhancement [6], [7], whereas others emphasize the predictive value of peritumoral edema [5], [8]. All the above-cited works investigated morphological features of meningiomas summarized in subjective scoring systems, but not one of the studies objectively analyzed values of SIs in commonly used preoperative MRI sequences.Therefore, the aim of this study was to investigate the predictive value of genuine and normalized SIs of standardized preoperative MRI (T1 pre- and postcontrast, T2, and fluid-attenuated inversion recovery [FLAIR]) as in vivo predictors of proliferative activity of meningiomas.     

Hyperosmotic stress-dependent NFkappaB activation is regulated by reactive oxygen species and IGF-1 in cultured cardiomyocytes

We have recently shown that hyperosmotic stress activates p65/RelB NFkappaB in cultured cardiomyocytes with dichotomic actions on caspase activation and cell death. It remains unexplored how NFkappaB is regulated in cultured rat cardiomyocytes exposed to hyperosmotic stress. We study here: (a) if hyperosmotic stress triggers reactive oxygen species (ROS) generation and in turn whether they regulate NFkappaB and (b) if insulin-like growth factor-1 (IGF-1) modulates ROS production and NFkappaB activation in hyperosmotically-stressed cardiomyocytes. The results showed that hyperosmotic stress generated ROS in cultured cardiac myocytes, in particular the hydroxyl and superoxide species, which were inhibited by N-acetylcysteine (NAC). Hyperosmotic stress-induced NFkappaB activation as determined by IkappaBalpha degradation and NFkappaB DNA binding. NFkappaB activation and procaspase-3 and -9 fragmentation were prevented by NAC and IGF-1. However, this growth factor did not decrease ROS generation induced by hyperosmotic stress, suggesting that its actions over NFkappaB and caspase activation may be due to modulation of events downstream of ROS generation. We conclude that hyperosmotic stress induces ROS, which in turn activates NFkappaB and caspases. IGF-1 prevents NFkappaB activation by a ROS-independent mechanism.     

Long-Range Enhancer Interactions Are Prevalent in Mouse Embryonic Stem Cells and Are Reorganized upon Pluripotent State Transition

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Tracking through Life Stages: Adult,Immature and Juvenile Autumn Migration in a Long-Lived Seabird

Seasonal long-distance migration is likely to be experienced in a contrasted manner by juvenile, immature and adult birds, leading to variations in migratory routes, timing and behaviour. We provide the first analysis of late summer movements and autumn migration in these three life stages, which were tracked concurrently using satellite tags, geolocators or GPS recorders in a long-ranging migratory seabird, the Scopoli’s shearwater (formerly named Cory’s shearwater, Calonectris diomedea ) breeding on two French Mediterranean islands. During the late breeding season, immatures foraged around their colony like breeding adults, but they were the only group showing potential prospecting movements around non-natal colonies. Global migration routes were broadly comparable between the two populations and the three life stages, with all individuals heading towards the Atlantic Ocean through the strait of Gibraltar and travelling along the West African coast, up to 8000 km from their colony. However, detailed comparison of timing, trajectory and oceanographic conditions experienced by the birds revealed remarkable age-related differences. Compared to adults and immatures, juveniles made a longer stop-over in the Balearic Sea (10 days vs 4 days in average), showed lower synchrony in crossing the Gibraltar strait, had more sinuous pathways and covered longer daily distances (240 km.d^-1 vs 170 km.d^-1). Analysis of oceanographic habitats along migratory routes revealed funnelling selection of habitat towards coastal and more productive waters with increasing age. Younger birds may have reduced navigational ability and learn progressively fine-scale migration routes towards the more profitable travelling and wintering areas. Our study demonstrates the importance of tracking long-lived species through the stages, to better understand migratory behavior and assess differential exposure to at-sea threats. Shared distribution between life stages and populations make Scopoli’s shearwaters particularly vulnerable to extreme mortality events in autumn and winter. Such knowledge is key for the conservation of critical marine habitats.     

Sunlight Effects on the Osmotrophic Uptake of DMSP-Sulfur and Leucine by Polar Phytoplankton

Even though the uptake and assimilation of organic compounds by phytoplankton has been long recognized, very little is still known about its potential ecological role in natural marine communities and whether it varies depending on the light regimes the algae experience. We combined measurements of size-fractionated assimilation of trace additions of ³H-leucine and ³⁵S-dimethylsulfoniopropionate (DMSP) with microautoradiography to assess the extent and relevance of osmoheterotrophy in summer phytoplankton assemblages from Arctic and Antarctic waters, and the role of solar radiation on it was further investigated by exposing samples to different radiation spectra. Significant assimilation of both substrates occurred in the size fraction containing most phytoplankton (>5 µm), sunlight exposure generally increasing ³⁵S-DMSP-sulfur assimilation and decreasing ³H-leucine assimilation. Microautoradiography revealed that the capacity to take up both organic substrates seemed widespread among different polar algal phyla, particularly in pennate and centric diatoms, and photosynthetic dinoflagellates. Image analysis of the microautoradiograms showed for the first time interspecific variability in the uptakes of ³⁵S-DMSP and ³H-leucine by phytoplankton depending on the solar spectrum. Overall, these results suggest that the role of polar phytoplankton in the utilization of labile dissolved organic matter may be significant under certain conditions and further confirm the relevance of solar radiation in regulating heterotrophy in the pelagic ocean.     

Increased Serum Hepcidin Levels in Subjects with the Metabolic Syndrome: A Population Study

The recent discovery of hepcidin, the key iron regulatory hormone, has changed our view of iron metabolism, which in turn is long known to be linked with insulin resistant states, including type 2 diabetes mellitus and the Metabolic Syndrome (MetS). Serum ferritin levels are often elevated in MetS (Dysmetabolic hyperferritinemia - DHF), and are sometimes associated with a true mild-to-moderate hepatic iron overload (dysmetabolic iron overload syndrome - DIOS). However, the pathophysiological link between iron and MetS remains unclear. This study was aimed to investigate, for the first time, the relationship between MetS and hepcidin at population level. We measured serum hepcidin levels by Mass Spectrometry in 1,391 subjects from the Val Borbera population, and evaluated their relationship with classical MetS features. Hepcidin levels increased significantly and linearly with increasing number of MetS features, paralleling the trend of serum ferritin. In multivariate models adjusted for relevant variables including age, C-Reactive Protein, and the HFE C282Y mutation, ferritin was the only significant independent predictor of hepcidin in males, while in females MetS was also independently associated with hepcidin. Overall, these data indicate that the fundamental iron regulatory feedback is preserved in MetS, i.e. that hepcidin tends to progressively increase in response to the increase of iron stores. Due to recently discovered pleiotropic effects of hepcidin, this may worsen insulin resistance and contribute to the cardiovascular complications of MetS.