Resveratrol activates antioxidant protective mechanisms in cellular models of Alzheimer’s disease inflammation

Resveratrol is a natural phenolic compound with known benefits against neurodegeneration. We analyzed in vitro the protective mechanisms of resveratrol against the proinflammatory monomeric C-reactive protein (mCRP). mCRP increases the risk of AD after stroke and we previously demonstrated that intracerebral mCRP induces AD-like dementia in mice. Here, we used BV2 microglia treated with mCRP for 24 h in the presence or absence of resveratrol. Cells and conditioned media were collected for analysis. Lipopolysaccharide (LPS) has also been implicated in AD progression and so LPS was used as a resveratrol-sensitive reference agent. mCRP at the concentration of 50 µg/mL activated the nitric oxide pathway and the NLRP3 inflammasome pathway. Furthermore, mCRP induced cyclooxygenase-2 and the release of proinflammatory cytokines. Resveratrol effectively inhibited these changes and increased the expression of the antioxidant enzyme genes Cat and Sod2. As central mechanisms of defense, resveratrol activated the hub genes Sirt1 and Nfe2l2 and inhibited the nuclear translocation of the signal transducer NF-ĸB. Proinflammatory changes induced by mCRP in primary mixed glial cultures were also protected by resveratrol. This work provides a mechanistic insight into the protective benefits of resveratrol in preventing the risk of AD induced by proinflammatory agents

Antioxidant Molecular Brain Changes Parallel Adaptive Cardiovascular Response to Forced Running in Mice

Physically active lifestyle has huge implications for the health and well-being of people of all ages. However, excessive training can lead to severe cardiovascular events such as heart fibrosis and arrhythmia. In addition, strenuous exercise may impair brain plasticity. Here we investigate the presence of any deleterious effects induced by chronic high-intensity exercise, although not reaching exhaustion. We analyzed cardiovascular, cognitive, and cerebral molecular changes in young adult male mice submitted to treadmill running for eight weeks at moderate or high-intensity regimens compared to sedentary mice. Exercised mice showed decreased weight gain, which was significant for the high-intensity group. Exercised mice showed cardiac hypertrophy but with no signs of hemodynamic overload. No morphological changes in the descending aorta were observed, either. High-intensity training induced a decrease in heart rate and an increase in motor skills. However, it did not impair recognition or spatial memory, and, accordingly, the expression of hippocampal and cerebral cortical neuroplasticity markers was maintained. Interestingly, proteasome enzymatic activity increased in the cerebral cortex of all trained mice, and catalase expression was significantly increased in the high-intensity group; both first-line mechanisms contribute to maintaining redox homeostasis. Therefore, physical exercise at an intensity that induces adaptive cardiovascular changes parallels increases in antioxidant defenses to prevent brain damage

Gelatinas y colas para el uso en tratamientos de restauración. Estado de la cuestión

Las gelatinas y colas son sustancias proteicas de diferente pureza provenientes de la desnaturalización del colágeno. Debido a su origen natural variado y sus distintos procesos de extracción, pueden diferir en sus características físico-químicas. En ambos casos se trata de sustancias comúnmente utilizadas en la pintura tradicional y constituyen aún hoy en día uno de los materiales más versátiles empleados en los tratamientos de restauración. Aun tratándose de productos de características bien conocidas en el ámbito de la tecnología de los alimentos, la escasa información existente en torno a sus características, origen y composición en el campo de la conservación y restauración, hacen que su idoneidad y efectividad resulte a menudo cuestionable.Bailach Bartra, C.; Fuster López, L.; Yusa Marco, DJ.; Talens Oliag, P.; Vicente Palomino, S. (2011). Gelatinas y colas para el uso en tratamientos de restauración. Estado de la cuestión. Arché. (6):17-22. http://hdl.handle.net/10251/330411722

Immune-Mediated Mechanisms in Cofactor-Dependent Food Allergy and Anaphylaxis: Effect of Cofactors in Basophils and Mast Cells

Cofactors may explain why in some cases food ingestion leads to anaphylaxis while in others elicits a milder reaction or tolerance. With cofactors, reactions become more severe and/or have a lower allergen threshold. Cofactors are present in up to 58% of food anaphylaxis (FAn). Exercise, NSAIDs, and alcohol are the most frequently described, although the underlying mechanisms are poorly known. Several hypotheses have suggested the influence of these cofactors on basophils and mast cells (MCs). Exercise has been suggested to enhance MC activation by increasing plasma osmolarity, redistributing blood flow, and activating adenosine and eicosanoid metabolism. NSAIDs' cofactor effect has been related with cyclooxygenase inhibition and therefore, prostaglandin E2 (PGE2) production. Indeed, overexpression of adenosine receptor 3 (A3) gene has been described in NSAID-dependent FAn; A3 activation potentiates FcϵRI-induced MC degranulation. Finally, alcohol has been related with an increase of histamine levels by inhibition of diamino oxidase (DAO) and also with and increase of extracellular adenosine by inhibition of its uptake. However, most of these mechanisms have limited evidence, and further studies are urgently needed. In conclusion, the study of the immune-related mechanisms involved in food allergic reactions enhanced by cofactors is of the utmost interest. This knowledge will help to design both tailored treatments and prophylactic strategies that, nowadays, are non-existent

Soluble epoxide hydrolase inhibitors: design, synthesis, in vitro profiling and in vivo evaluation in murine models of pain

Trabajo presentado en el ASPET Annual Meeting at Experimental Biology 2022, celebrado en Philadelphia, PA (Estados Unidos), del 2 al 5 de abril de 2022This research by the Grant PID2020-118127RB-I00 funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe” to S.V. Financial support from Fundació Bosch i Gimpera, Universitat de Barcelona (F2I grant), to S.V., and from the Xunta de Galicia (ED431G 2019/02 and ED431C 2018/21) to M.I.L. are acknowledged. Partial support was provided by NIH-NIEHS River Award R35 ES03443, NIH-NIEHS Superfund Program P42 ES004699, NINDS R01 DK107767, and NIDDK R01 DK103616 to B.D.H. S.C. acknowledges a PhD fellowship from the Universitat de Barcelona (APIF grant)

Discovery and In Vivo Proof of Concept of a Highly Potent Dual Inhibitor of Soluble Epoxide Hydrolase and Acetylcholinesterase for the Treatment of Alzheimer's Disease

With innumerable clinical failures of target-specific drug candidates for multifactorial diseases, such as Alzheimer's disease (AD), which remains inefficiently treated, the advent of multitarget drug discovery has brought a new breath of hope. Here, we disclose a class of 6-chlorotacrine (huprine)‒TPPU hybrids as dual inhibitors of the enzymes soluble epoxide hydrolase (sEH) and acetylcholinesterase (AChE), a multitarget profile to provide cumulative effects against neuroinflammation and memory impairment. Computational studies confirmed the gorge-wide occupancy of both enzymes, from the main site to a secondary site, including a so far non-described AChE cryptic pocket. The lead compound displayed in vitro dual nanomolar potencies, adequate brain permeability, aqueous solubility, and human microsomal stability and lack of neurotoxicity, and rescued memory, synaptic plasticity and neuroinflammation in an AD mouse model, after low dose chronic oral administration

Aproximación al estudio físico-químico de colas animales para su uso en tratamientos de restauración

[ES] Las gelatinas y colas son sustancias proteicas de diferente pureza provenientes de la desnaturalización del colágeno. Debido a su origen natural variado y sus distintos procesos de extracción, pueden diferir en sus características fisico-químicas. En ambos casos, se trata de sustancias comúnmente utilizadas en la pintura tradicional y constituyen, aún hoy en día, uno de los materiales más versátiles empelados en los tratamientos de restauración. Sin embargo, la escasa información existente en torno a sus características exactas, origen y composición hace que su idoneidad y efectividad resulten a menudo cuestionables. Este estudio empieza con una revisión completa de las fuentes antiguas y modernas en relación al uso, comportamiento y composición de las colas animales, con el fin de entender mejor su estabilidad a medio y largo plazo y discriminar su uso en los diferentes tratamientos de intervención. A partir de estos datos se hace un estudio físico-químico de las propiedades de cinco gelatinas técnicas elegidas de entre las disponibles en el mercado. Los resultados permiten conocer sus características concretas y su comportamiento ante el envejecimiento, lo que permite prever su estabilidad futura y facilita al restaurador la elección de la cola animal más idónea para cada caso.[EN] Gelatin and glue are proteinaceous substances of different purity coming from the denaturalization of collagen. Due to their varied natural origin and extraction process, they may differ in their physicochemical characteristics. In both cases, they are substances commonly used in traditional painting and are still today one of the most versatile materials used for the restoration treatments. However, the limited information available about their exact characteristics, origin and composition, make their suitability and effectiveness often questionable. This study begins on a complete review of ancenti and modern sources regarding their use, behaviour and composition in order to understand better their stability at medium and long term and discriminate its use in the different intervention treatments. From all these information, its been made a physicochemical study about the properties of five tecnic gelatin chosen from those available on the market. The results obtained allow us to know their specific characteristics and behavior on aging, which allows to anticipate its future stability and facilitates to the restorator the choice of the most suitable animal glue for each case.Bailach Bartra, C. (2012). Aproximación al estudio físico-químico de colas animales para su uso en tratamientos de restauración. http://hdl.handle.net/10251/18329Archivo delegad

Pharmacological inhibition of soluble epoxide hydrolase during brain development induces long-term benefices in 5XFAD mice

Trabajo presentado en el XII Simposi de Neurobiologia, Societat Catalana de Biologia, celebrado en Barcelona (España), los días 7 y 8 de junio de 2022Modulation of the risk of Alzheimer¿s disease (AD) may begin early in life. During embryo development and maturation, the brain receives maternal physiological influences and establishes new epigenetic patterns that build its level of resilience to late diseases. We treated wild-type pregnant mice with the soluble epoxide hydrolase (sEH) inhibitor TPPU until their pups were weaned. The male progenitors were AD transgenic mice from the strain 5XFAD. At two months of age, male and female mice were blindly analyzed for learning and memory performance and their brain tissue was preserved for further analysis. Once genotyped, we found that 5XFAD mice worn from vehicle-treated mothers showed a poor response in cognitive tests of object recognition and spatial location. Notably, those 5XFAD mice from TPPU-treated mothers showed similar performance to their wild-type siblings. At the molecular level, tau pathology shown by increased hippocampal p-tau levels in 5XFAD mice was totally prevented in those whose mothers were treated with TPPU. Furthermore, TPPU treatment also modified the expression of epigenetic markers. Overall, we confirmed the potential of the enzyme sEH as a new target to fight AD and demonstrated that its inhibition in the developing brain produces long-term preventive effects against neurodegeneration.MCIN/AEI (PID2019-106285RB); AGAUR (2017-SGR-106); CSIC (2019AEP038)