Methylglyoxal-dependent glycative stress and deregulation of SIRT1 functional network in the ovary of PCOS mice

Advanced glycation end-products (AGEs) are involved in the pathogenesis and consequences of polycystic ovary syndrome (PCOS), a complex metabolic disorder associated with female infertility. The most powerful AGE precursor is methylglyoxal (MG), a byproduct of glycolysis, that is detoxified by the glyoxalase system. By using a PCOS mouse model induced by administration of dehydroepiandrosterone (DHEA), we investigated whether MG-dependent glycative stress contributes to ovarian PCOS phenotype and explored changes in the Sirtuin 1 (SIRT1) functional network regulating mitochondrial functions and cell survival. In addition to anovulation and reduced oocyte quality, DHEA ovaries revealed altered collagen deposition, increased vascularization, lipid droplets accumulation and altered steroidogenesis. Here we observed increased intraovarian MG-AGE levels in association with enhanced expression of receptor for AGEs (RAGEs) and deregulation of the glyoxalase system, hallmarks of glycative stress. Moreover, DHEA mice exhibited enhanced ovarian expression of SIRT1 along with increased protein levels of SIRT3 and superoxide dismutase 2 (SOD2), and decreased peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC1 alpha), mitochondrial transcriptional factor A (mtTFA) and translocase of outer mitochondrial membrane 20 (TOMM20). Finally, the presence of autophagy protein markers and increased AMP-activated protein kinase (AMPK) suggested the involvement of SIRT1/AMPK axis in autophagy activation. Overall, present findings demonstrate that MG-dependent glycative stress is involved in ovarian dysfunctions associated to PCOS and support the hypothesis of a SIRT1-dependent adaptive response

Altered inflammasome machinery as a key player in the perpetuation of Rett syndrome oxinflammation

Rett syndrome (RTT) is a progressive neurodevelopmental disorder mainly caused by mutations in the X-linked MECP2 gene. RTT patients show multisystem disturbances associated with an oxinflammatory status. Inflammasomes are multi-protein complexes, responsible for host immune responses against pathogen infections and redox-related cellular stress. Assembly of NLRP3/ASC inflammasome triggers pro-caspase-1 activation, thus, resulting in IL-1β and IL-18 maturation. However, an aberrant activation of inflammasome system has been implicated in several human diseases. Our aim was to investigate the possible role of inflammasome in the chronic subclinical inflammatory condition typical of RTT, by analyzing this complex in basal and lipopolysaccharide (LPS)+ATP-stimulated primary fibroblasts, as well as in serum from RTT patients and healthy volunteers. RTT cells showed increased levels of nuclear p65 and ASC proteins, pro-IL-1β mRNA, and NLRP3/ASC interaction in basal condition, without any further response upon the LPS + ATP stimuli. Moreover, augmented levels of circulating ASC and IL-18 proteins were found in serum of RTT patients, which are likely able to amplify the inflammatory response. Taken together, our findings suggest that RTT patients exhibited a challenged inflammasome machinery at cellular and systemic level, which may contribute to the subclinical inflammatory state feedback observed in this pathology

Delivery status of the ELI-NP gamma beam system

International audienceThe ELI-NP GBS is a high intensity and monochromatic gamma source under construction in Magurele (Romania). The design and construction of the Gamma Beam System complex as well as the integration of the technical plants and the commissioning of the overall facility, was awarded to the Eurogammas Consortium in March 2014. The delivery of the facility has been planned in for 4 stages and the first one was fulfilled in October 31st 2015. The engineering aspects related to the delivery stage 1 are presented

High power test results of the Eli-NP S-Band gun fabricated with the new clamping technology without brazing

High gradient RF photoguns have been a key development to enable several applications of high quality electron beams. They allow the generation of beams with very high peak current and low transverse emittance, thus satisfying the tight demands of free-electron lasers, energy recovery linacs, Compton/Thomson sources and high-energy linear colliders. A new fabrication technique for this type of structures has been recently developed and implemented at the Laboratories of Frascati of the National Institute of Nuclear Physics (INFN-LNF, Italy). It is based on the use of special RF-vacuum gaskets, that allow a brazing-free realization process. The S-band gun of the ELI-NP gamma beam system (GBS) has been fabricated with this new technique. It operates at 100 Hz with 120 MV/m cathode peak field and 1.5 μs long RF pulses to house the 32 bunches necessary to reach the target gamma flux. High gradient tests, performed at full power and full repetition rate, have shown extremely good performances of the structure in terms of breakdown rate. In the paper, we report and discuss all the experimental results, the electromagnetic design and the mechanical realization processes

Endothelial cells from umbilical cord of women affected by gestational diabetes: A suitable in vitro model to study mechanisms of early vascular senescence in diabetes

Human umbilical cord endothelial cells (HUVECs) obtained from women affected by gestational diabetes (GD-HUVECs) display durable pro-atherogenic modifications and might be considered a valid in vitro model for studying chronic hyperglycemia effects on early endothelial senescence. Here, we demonstrated that GD- compared to C-HUVECs (controls) exhibited oxidative stress, altered both mitochondrial membrane potential and antioxidant response, significant increase of senescent cells characterized by a reduced NAD-dependent deacetylase sirtuin-1 (SIRT1) activity together with an increase in cyclin-dependent kinase inhibitor-2A (P16), cyclin-dependent kinase inhibitor-1 (P21), and tumor protein p53 (P53) acetylation. This was associated with the p300 activation, and its silencing significantly reduced the GD-HUVECs increased protein levels of P300 and Ac-P53 thus indicating a persistent endothelial senescence via SIRT1/P300/P53/P21 pathway. Overall, our data suggest that GD-HUVECs can represent an “endothelial hyperglycemic memory” model to investigate in vitro the early endothelium senescence in cells chronically exposed to hyperglycemia in vivo

TEX (TEst stand for X-band) at LNF

TEX facility if commissioned for high power testing to characterize accelerating structures and validate them for the operation on future particle accelerators for medical, industrial and research applications. At this aim, TEX is directly involved in the LNF leading project EuPRAXIA@SPARC_Lab. The brief description of the facility and its status and prospective will be provided.Comment: Talk presented at the International Workshop on Future Linear Colliders (LCWS 2023), 15-19 May 2023. C23-05-15.

Technology developments of ELI-NP gamma beam system

The ELI-NP gamma beam system (GBS) is a linac based gamma-source in construction in Magurele (RO) by the European consortium EuroGammaS led by INFN. Photons with tunable energy, from 0.2 to 19.5 MeV, and with intensity and brilliance beyond the state of the art, will be produced by Compton back-scattering between a high quality electron beam (up to 740 MeV) and an intense laser pulse at 100 Hz repetition rate. Production of very intense photon flux with narrow bandwidth requires multi-bunch operation and laser recirculation at the interaction point. In this paper, the main technological developments carried out by the EuroGammaS consortium for the generation of the ELI-NP gamma beam will be described with a special emphasis on the electron linac technology, such as: RF-gun and C-band accelerating structures design fabrication and tests; low level RF (LLRF) and synchronization systems specifications and development. Finally, the laser recirculation apparatus design is briefly described and first results reported

Long Term Running Biphasically Improves Methylglyoxal-Related Metabolism, Redox Homeostasis and Neurotrophic Support within Adult Mouse Brain Cortex

Oxidative stress and neurotrophic support decline seem to be crucially involved in brain aging. Emerging evidences indicate the pro-oxidant methylglyoxal (MG) as a key player in the age-related dicarbonyl stress and molecular damage within the central nervous system. Although exercise promotes the overproduction of reactive oxygen species, habitual exercise may retard cellular aging and reduce the age-dependent cognitive decline through hormetic adaptations, yet molecular mechanisms underlying beneficial effects of exercise are still largely unclear. In particular, whereas adaptive responses induced by exercise initiated in youth have been broadly investigated, the effects of chronic and moderate exercise begun in adult age on biochemical hallmarks of very early senescence in mammal brains have not been extensively studied. This research investigated whether a long-term, forced and moderate running initiated in adult age may affect the interplay between the redox-related profile and the oxidative-/MG-dependent molecular damage patterns in CD1 female mice cortices; as well, we investigated possible exercise-induced effects on the activity of the brain derived neurotrophic factor (BDNF)-dependent pathway. Our findings suggested that after a transient imbalance in almost all parameters investigated, the lately-initiated exercise regimen strongly reduced molecular damage profiles in brains of adult mice, by enhancing activities of the main ROS- and MG-targeting scavenging systems, as well as by preserving the BDNF-dependent signaling through the transition from adult to middle age