Impact d’une restriction calorique modérée ou d’un mimétique potentiel, le resvératrol, sur les marqueurs du vieillissement et sur la longévité chez un primate non-humain

Nowadays moderate and chronic calorie restriction (CR); is the only non-genetic intervention known to slow the onset of age-related diseases and to increase longevity in several animal species. Resveratrol (RSV), a natural compound belonging to the polyphenols group, has therapeutic properties and is a promising candidate as CR effects mimetic. To assess the impact of such long-term nutritional protocols, a longitudinal study was conducted on a cohort of 53 males grey mouse lemurs (Microcebus murinus), a relevant primate model for normal and pathological aging research as regards to its high longevity in captivity, up to 12 years. Since the integration of the animals in the study (3 years old) to the current status of the project (8 years of age), physiological and behavioral parameters were assessed regularly in the cohort divided into three groups: a group submitting to a -30% CR and a group supplemented with RSV (200 mg.kg-1.day-1), compared to a control group (CTL). With age, disturbances appeared in CTL mouse lemurs: decreased insulin sensitivity, accumulation of cellular damage, motor and cognitive decline associated with particular type of memory and a decline of certain predictive biomarkers of aging in this species. CR has improved insulin sensitivity and limited the accumulation of markers of oxidative stress, it has not resulted in improved cognitive abilities but in a decreased anxiety, improved motor performances and an increased spontaneous locomotor activity. CR also induced an adaptive metabolic response with body weight loss without lowering energy expenditure, lower hormone levels of IGF-1 and testosterone, supporting a probable trade-off between reproduction and survival. RSV mimicked some of the beneficial effects demonstrated in CR. However, it has improved the spatial memory task, which was not observed in restricted animals. RSV also showed opposite effects to those of CR, as maintained body weight and hormone levels compared to CTL, an increase in energy expenditure and in testosterone levels during the long day’s season. Finally, the current survival data are promising; less than 50% of the CTL animals survived, while more than 50% of CR and RSV animals are still alive, with in addition a mean age at death about 1 year higher compared with CTL animals. Despite heterogeneous, but yet beneficial effects, CR and RSV were able to slow the appearance of some intrinsic age-related declines and to improve the lemurs’ survival, supporting the hypothesis that these effects may be mediated by different mechanisms achieving the same positive outcomes including enhanced life expectancy. These evidences are a real tool for the future understanding of the mechanisms underlying the aging process but also of cellular regulatory pathways that are involved in long term CR and RSV treatment in a primateAujourd’hui la restriction calorique modérée et chronique (RC) est la seule intervention non génétique capable de ralentir l’apparition de pathologies liées à l’âge et d’accroître la longévité chez plusieurs espèces animales. Le resvératrol (RSV), un composé appartenant au groupe des polyphénols, présente des propriétés thérapeutiques intéressantes et constitue un candidat prometteur comme mimétique des effets d’une RC. Afin d’évaluer l’impact de tels protocoles nutritionnels à long terme, une étude longitudinale a été menée sur une cohorte de 53 mâles microcèbes (Microcebus murinus), modèle primate pertinent pour les recherches sur le vieillissement normal ou pathologique au vue de sa longévité maximale de 12 ans en captivité. Depuis l’intégration des animaux dans l’étude (3 ans d’âge) à l’avancement actuel du projet (8 ans d’âge), des paramètres physiologiques et comportementaux ont été évalués régulièrement au sein de la cohorte, partagée en trois groupes: un groupe soumis à une RC (-30%) et un groupe supplémenté en RSV (200 mg.kg-1.jour-1), comparés à un groupe contrôle (CTL). Avec l’âge, chez les microcèbes CTL, des perturbations sont apparues : diminution de la sensibilité à l’insuline, accumulation de dommages cellulaires, déclin moteur et cognitif (mémoire spatiale de reférence) et déclin de certains marqueurs prédictifs du vieillissement chez cette espèce. La RC a permis une amélioration de la sensibilité à l’insuline et a limité l’accumulation de certains marqueurs du stress oxydant, elle n’a pas entraîné d’amélioration des capacités cognitives, mais a diminué l’anxiété, amélioré les performances motrices et augmenté l’activité locomotrice spontanée. La RC a aussi induit une réponse adaptative métabolique avec une perte de masse corporelle sans réduire les dépenses énergétiques, un abaissement des taux hormonaux d’IGF-1 et de la testostérone suggérant un compromis entre reproduction et survie. Le RSV a mimé une partie des effets bénéfiques démontrés sous RC. Cependant il a permis une amélioration de la mémoire spatiale de travail, absente chez les animaux restreints. Le RSV a également montré des effets opposés à ceux de la RC comme un maintien de la masse corporelle et des taux d’hormones par rapport aux CTL, une augmentation des dépenses énergétiques et des niveaux de testostérone pendant la période de jours longs. Finalement les données de survie actuelles sont prometteuses ; moins de 50% de l’effectif de départ des animaux CTL a survécu, alors que plus de 50% des animaux RC et RSV sont encore vivants, présentant de surcroît un âge moyen à la mort plus élevé d’environ 1 an par rapport aux CTL. Malgré des effets hétérogènes et pourtant bénéfiques, la RC et le RSV sont capables de ralentir l’apparition de certains déclins intrinsèques au vieillissement et d’améliorer la survie des microcèbes, soutenant l’hypothèse selon laquelle ces effets pourraient être induits par des mécanismes différents mais permettant d’atteindre les mêmes issues favorables notamment au niveau de l’espérance de vie. Ces résultats constituent un véritable outil pour la compréhension future des mécanismes sous-jacents au processus du vieillissement mais aussi des voies de régulation cellulaires mises en jeu par la RC et le RSV à moyen et long terme chez un primat

Biofabrication of a tri-layered 3D-bioprinted CSC-based malignant melanoma model for personalized cancer treatment

Conventional in vitro cancer models do not accurately reproduce the tumor microenvironment (TME), so three-dimensional (3D)-bioprinting represents an excellent tool to overcome their limitations. Here, two multicellular tri-layered malignant melanoma (MM) models composed by cancer stem cells (CSCs) isolated from a MM established cell line or a primary-patient derived cell line, fibroblasts, mesenchymal stem cells, and endothelial cells, embedded within an agarose-collagen type I hydrogel were bioprinted. Embedded-cells showed high proliferation and metabolic activity, and actively remodeled their TME. MM hydrogels displayed similar rheological properties that skin and were able to support an early onset of vascularization. Besides, MM hydrogels displayed different response to vemurafenib compared with cell cultures, and supported tumorigenesis in murine xenotransplant achieving more mimetic in vivo models. For the first time a tri-layered 3D-bioprinted CSC-based human MM model is developed recreating TME in vitro and in vivo and response to treatment, being useful for precision treatment regimens against MM.Consejería de Salud y Familias de la Junta de Andalucía (Project No. PIN-0224-2019)Consejería de Economía, Conocimiento, Empresas y Universidad de la Junta de Andalucía (FEDER Funds, Projects PY18-FR-2470, B-CTS-230-UGR18, A-CTS-180-UGR20, PYC20 RE 015 UGR and P18-FR-2465),Ministry de Economía y Competitividad, Instituto de Salud Carlos III (FEDER funds, Projects Nos. DTS19/00145 and DTS21/00098)Chair ‘Doctors Galera-Requena in cancer stem cell research’ (CMCCTS963)Universidad de Granada/CBUA.Plan Andaluz de Investigación, Desarrollo e Innovación (PAIDI 2020— FEDER funds—Ref: DOC_01574)

Tectonic evolution of the Colorado Basin, offshore Argentina, inferred from seismo-stratigraphy and depositional rates analysis

International audienceBased on a dense 2D seismic reflection dataset and information from 8 exploration wells, we reinterpreted the stratigraphic evolution of the Colorado Basin. The basin is located on the continental shelf and slope within 50 to 2250 m of bathymetry. The total sediment fill can be up to 16,000 m. Seismic-to-well log correlations provide a chrono-stratigraphic framework for the interpreted seismic sequences. We show that the Colorado Basin records the development of a Permian pre-rift period, a Triassic/Jurassic to Early Cretaceous rift phase and a Lower Cretaceous to Tertiary drift phase. This passive margin represents the evolution of lithospheric extension from active rifting to the thermal subsidence/drift stage. Several Cretaceous to Cenozoic slumping episodes were identified and related to progradation of the sequences and sediment build-up in the slope, as well as to the development of seaward dipping extensional faults

Impact of an abbreviated protocol for breast MRI in diagnostic accuracy

PURPOSE:We aimed to compare the diagnostic accuracy and interpretation time of an abbreviated protocol relative to the complete protocol of breast magnetic resonance imaging (MRI) with the use of breast imaging reporting and data system (BI-RADS). Between-reader and between-protocol variability for BI-RADS classification and influence of reader expertise on diagnostic accuracies were also evaluated.METHODS:We conducted a retrospective reader study in 90 women who underwent breast MRI: 30 benign examinations (graded as American College of Radiology [ACR] 1 or 2), 30 examinations graded as ACR 3 and 30 examinations requiring a histologic proof (graded as ACR 4 or 5). Two radiologists independently reviewed the protocols. The reference standard was 24 months of imaging follow-up (66.6%, n=60), percutaneous biopsy at the12th month imaging follow-up (5.5%, n=5), and breast surgery (27.9%, n=25). Analysis was done on a per-breast basis. There were 26 cancers in 168 breasts (15.1%)RESULTS:Interpretation time was higher for the complete protocol (mean difference: 84 s, 95% CI [67;101] for senior and 83 s, 95% CI [70;95] for junior reader; P < 0.001). The reliability of BI-RADS classification between both protocols was very good with intraclass correlation coefficient of 0.89 for junior reader and 0.98 for senior reader; the inter-reader reliability was 0.94 and 0.90 for the complete and abbreviated protocols, respectively. For senior reader, the abbreviated and complete protocols yielded 95.1% and 94.4% specificity and 100% sensitivity.CONCLUSION:Our data provide corroborating evidence that abbreviated protocols decrease interpretation time without compromising sensitivity or specificity. There was a high level of concordance between the abbreviated and complete protocols and between the two readers

Evaluation of Phenolic Compounds and Pigments Content in Yellow Bell Pepper Wastes

This research was supported by the Aula de Empresa "Vellsam-UGR para la Innovacion en Nutricion y Salud". Vito Verardo thanks the Spanish Ministry of Economy and Competitiveness (MINECO) for "Ramon y Cajal" contract (RYC-2015-18795).Bell peppers are one of the most important species consumed and cultivated in Spain. Peppers are a source of carotenoids and phenolic compounds widely associated with biological activities such as antimicrobial, antiseptic, anticancer, counterirritant, cardioprotective, appetite stimulator, antioxidant, and immunomodulator. However, undersized and damaged fruits are usually wasted. Thus, in order to evaluate the phenolic content, a Box–Behnken design has been carried out to optimize the extraction from Capsicum annuum yellow pepper by ultrasound-assisted extraction (UAE). The independent factors were time (min), ethanol/water (% v/v) and solvent/sample ratio (v/w). The model was validated by ANOVA and confirmed. Furthermore, the whole pepper and the pepper without peduncles and seeds were extracted using optimal conditions and characterized by HPLC-ESI-TOF-MS. Moreover, their antioxidant activities, measured by three different methods (DPPH, ABTS, and FRAP), carotenoid composition, assessed by HPLC-MS, and chlorophyll content, assessed by a spectrophotometric method, were compared. A total of 38 polar compounds were found of which seven have been identified in pepper fruit extracts for the first time. According to the results, whole pepper (WP) samples presented higher content in phenolic acids; meanwhile, the edible portion (EP) was higher in flavonoids. No differences were found in the antioxidant activity except for the FRAP assay where the WP sample showed higher radical scavenging activity. EP samples showed the highest content of carotenoids and WP ones in chlorophylls.Aula de Empresa "Vellsam-UGR para la Innovacion en Nutricion y Salud"Spanish Ministry of Economy and Competitiveness (MINECO) for "Ramon y Cajal" RYC-2015-1879

Unraveling the Potential of miRNAs from CSCs as an Emerging Clinical Tool for Breast Cancer Diagnosis and Prognosis

This research was funded by Consejería de Salud y Familias de la Junta de Andalucía (project no. PIN-0224-2019 and PEMP-0205-2022 FEDER funds); the Ministerio de Ciencia e Innovación (project no. PID2022-140151OB-C22); the Convocatoria de Proyectos Intramurales ibs.GRANADA (project no. INTRAIBS-2020-1 and INTRAIBS-2021-09) and by the Chair “Doctors Galera-Requena in cancer stem cell research” (CMC-CTS963).Breast cancer (BC) is the most diagnosed cancer in women and the second most common cancer globally. Significant advances in BC research have led to improved early detection and effective therapies. One of the key challenges in BC is the presence of BC stem cells (BCSCs). This small subpopulation within the tumor possesses unique characteristics, including tumor-initiating capabilities, contributes to treatment resistance, and plays a role in cancer recurrence and metastasis. In recent years, microRNAs (miRNAs) have emerged as potential regulators of BCSCs, which can modulate gene expression and influence cellular processes like BCSCs' self-renewal, differentiation, and tumor-promoting pathways. Understanding the miRNA signatures of BCSCs holds great promise for improving BC diagnosis and prognosis. By targeting BCSCs and their associated miRNAs, researchers aim to develop more effective and personalized treatment strategies that may offer better outcomes for BC patients, minimizing tumor recurrence and metastasis. In conclusion, the investigation of miRNAs as regulators of BCSCs opens new directions for advancing BC research through the use of bioinformatics and the development of innovative therapeutic approaches. This review summarizes the most recent and innovative studies and clinical trials on the role of BCSCs miRNAs as potential tools for early diagnosis, prognosis, and resistance.Consejería de Salud y Familias de la Junta de Andalucía PIN-0224-2019, PEMP-0205-2022 FEDERMinisterio de Ciencia e Innovación PID2022-140151OB-C22Convocatoria de Proyectos Intramurales ibs.GRANADA INTRAIBS-2020-1, INTRAIBS-2021-09Chair “Doctors Galera-Requena in cancer stem cell research” CMC-CTS96

Colorado Basin 3D structure and evolution, Argentine passive margin

International audienceThis 3D structural model of the Colorado Basin provides new insights into the crustal geometry of the basin and its evolution in relation with the Argentine passive margin. Three NW-SE segments (oblique to the N30°E-trending margin) structure the basin. The oldest infill is generally thought to be coeval with the rifting of the South Atlantic margins in Late Jurassic-Early Cretaceous. This coeval development of the Colorado Basin and of the passive margin is still under debate and gives rise to several hypotheses that we investigate in the light of our observations. We propose that reactivation of inherited structures is predominant in the evolution of the Colorado Basin: (1) the Western segment follows the continental continuation of the Colorado transfer zone; (2) the Central segment consists in the continental continuation of the Tona deformation zone; (3) the Eastern segment is superimposed over the Palaeozoic Claromecó Basin. In addition to the 3 segments, the Central High, separating the Central segment to the Eastern segment, corresponds to the Palaeozoic Sierras Australes Fold Belt. The direction of extension responsible for the South Atlantic opening cannot explain the syn-rift infill and thinning of the basin. The structural analysis shows two phases of syn-rift deformation with different directions. Thus, we suggest that the Colorado Basin and the South Atlantic margin are not coeval but that a first extensional event, probably oblique, predates the extension responsible for the South Atlantic opening. This event is then followed by the formation of the N30°-trending distal margin and the reactivation of Palaeozoic N70°-trending faults occurs under the NW-SE opening of the South Atlantic. This two-phase evolution is consistent with the fault chronology and the two directions of thinned crust observed in the distal margin

Cognitive Performances Are Selectively Enhanced during Chronic Caloric Restriction or Resveratrol Supplementation in a Primate

Effects of an 18-month treatment with a moderate, chronic caloric restriction (CR) or an oral supplementation with resveratrol (RSV), a potential CR mimetic, on cognitive and motor performances were studied in non-human primates, grey mouse lemurs (Microcebus murinus)

Effects of Chronic Calorie Restriction or Dietary Resveratrol Supplementation on Insulin Sensitivity Markers in a Primate, Microcebus murinus

The prevalence of diabetes and hyperinsulinemia increases with age, inducing metabolic failure and limiting lifespan. Calorie restriction (CR) without malnutrition delays the aging process, but its long-term application to humans seems difficult. Resveratrol (RSV), a dietary polyphenol, appears to be a promising CR mimetic that can be easily administered in humans. In this work, we hypothesized that both CR and RSV impact insulin sensitivity in a non-human primate compared to standard-fed control (CTL) animals. Four- to five-year-old male grey mouse lemurs (Microcebus murinus) were assigned to three dietary groups: a CTL group, a CR group receiving 30% fewer calories than the CTL and a RSV group receiving the CTL diet supplemented with RSV (200 mg·day−1·kg−1). Insulin sensitivity and glycemia were assessed using an oral glucose tolerance test (OGTT) and the homeostasis model assessment of insulin resistance (HOMA-IR index) evaluation after 21 or 33 months of chronic treatment. Resting metabolic rate was also measured to assess the potential relationships between this energy expenditure parameter and insulin sensitivity markers. No differences were found after a 21-month period of treatment, except for lower glucose levels 30 min after glucose loading in CR animals. After 33 months, CR and RSV decreased glycemia after the oral glucose loading without decreasing fasting blood insulin. A general effect of treatment was observed on the HOMA-IR index, with an 81% reduction in CR animals and 53% in RSV animals after 33 months of treatment compared to CTL. Chronic CR and dietary supplementation with RSV affected insulin sensitivity by improving the glucose tolerance of animals without disturbing their baseline insulin secretion. These results suggest that both CR and RSV have beneficial effects on metabolic alterations, although these effects are different in amplitude between the two anti-aging treatments and potentially rely on different metabolic changes

Lipidome determinants of maximal lifespan in mammals

Maximal lifespan of mammalian species, even if closely related, may differ more than 10-fold, however the nature of the mechanisms that determine this variability is unresolved. Here, we assess the relationship between maximal lifespan duration and concentrations of more than 20,000 lipid compounds, measured in 669 tissue samples from 6 tissues of 35 species representing three mammalian clades: primates, rodents and bats. We identify lipids associated with species’ longevity across the three clades, uncoupled from other parameters, such as basal metabolic rate, body size, or body temperature. These lipids clustered in specific lipid classes and pathways, and enzymes linked to them display signatures of greater stabilizing selection in long-living species, and cluster in functional groups related to signaling and protein-modification processes. These findings point towards the existence of defined molecular mechanisms underlying variation in maximal lifespan among mammals.The National Natural Science Foundation of China (grant 31420103920), Strategic Priority Research Program of the Chinese Academy of Sciences (grant XDB13010200), the National Natural Science Foundation of China (grant 91331203), the National One Thousand Foreign Experts Plan (grant WQ20123100078), the Bureau of International Cooperation, Chinese Academy of Sciences (grant GJHZ201313) and the Federal Targeted Program for Research and Development in Priority Areas of Advancement of the Russian Scientific and Technological Complex for 2014–2020 (the Ministry of Education and Science of the Russian Federation), grant № 14.615.21.0002, the Unique identifier of the agreement: RFMEFI61515×0002. Additional support was obtained from the European Research Council (advanced grant 294678 to GRL).http://www.nature.com/scientificreportsam2017Zoology and Entomolog