Critical Role of Nrf2 in Experimental Ischemic Stroke

Ischemic stroke is one of the leading causes of death and long-term disability worldwide; however, effective clinical approaches are still limited. The transcriptional factor Nrf2 is a master regulator in cellular and organismal defense against endogenous and exogenous stressors by coordinating basal and stress-inducible activation of multiple cytoprotective genes. The Nrf2 network not only tightly controls redox homeostasis but also regulates multiple intermediary metabolic processes. Therefore, targeting Nrf2 has emerged as an attractive therapeutic strategy for the prevention and treatment of CNS diseases including stroke. Here, the current understanding of the Nrf2 regulatory network is critically examined to present evidence for the contribution of Nrf2 pathway in rodent ischemic stroke models. This review outlines the literature for Nrf2 studies in preclinical stroke and focuses on the in vivo evidence for the role of Nrf2 in primary and secondary brain injuries. The dynamic change and functional importance of Nrf2 signaling, as well as Nrf2 targeted intervention, are revealed in permanent, transient, and global cerebral ischemia models. In addition, key considerations, pitfalls, and future potentials for Nrf2 studies in preclinical stroke investigation are discussed

Efficacy and Mechanism of Panax Ginseng in Experimental Stroke

Stroke is one of the leading causes of death and long-term disability worldwide. However, effective therapeutic approaches are still limited. The disruption of blood supply triggers complicated temporal and spatial events involving hemodynamic, biochemical, and neurophysiologic changes, eventually leading to pathological disturbance and diverse clinical symptoms. Ginseng (Panax ginseng), a popular herb distributed in East Asia, has been extensively used as medicinal and nutritional supplements for a variety of disorders worldwide. In recent years, ginseng has displayed attractive beneficial effects in distinct neurological disorders including stroke, involving multiple protective mechanisms. In this article, we reviewed the literature on ginseng studies in the experimental stroke field, particularly focusing on the in vivo evidence on the preventive or therapeutic efficacy and mechanisms of ginseng and ginsenosides in various stroke models of mice and rats. We also summarized the efficacy and underlying mechanisms of ginseng and ginsenosides on short- and long-term stroke outcomes

Genetic Deletion of PGF2α-FP Receptor Exacerbates Brain Injury Following Experimental Intracerebral Hemorrhage

Background: The release of inflammatory molecules such as prostaglandins (e.g., PGF2α) is associated with brain damage following an intracerebral hemorrhagic (ICH) stroke; however, the role of PGF2α and its cognate FP receptor in ICH remains unclear. This study focused on investigating the role of the FP receptor as a target for novel neuroprotective drugs in a preclinical model of ICH, aiming to investigate the contribution of the PGF2α-FP axis in modulating functional recovery and anatomical outcomes following ICH.Results: Neurological deficit scores in FP−/− mice were significantly higher compared to WT mice 72 h after ICH (6.1 ± 0.7 vs. 3.1 ± 0.8; P < 0.05). Assessing motor skills, the total time mice stayed on the rotating rod was significantly less in FP−/−mice compared to WT mice 24 h after ICH (27.0 ± 7.5 vs. 52.4 ± 11.2 s; P < 0.05). Using grip strength to quantify forepaw strength, results showed that the FP−/− mice had significantly less strength compared to WT mice 72 h after ICH (96.4 ± 17.0 vs. 129.6 ± 5.9 g; P < 0.01). In addition to the behavioral outcomes, histopathological measurements were made. In Cresyl violet stained brain sections, the FP−/− mice showed a significantly larger lesion volume compared to the WT (15.0 ± 2.2 vs. 3.2 ± 1.7 mm3; P < 0.05 mice.) To estimate the presence of ferric iron in the peri-hematoma area, Perls' staining was performed, which revealed that FP−/− mice had significantly greater staining than the WT mice (186.3 ± 34.4% vs. 86.9 ± 13.0% total positive pixel counts, P < 0.05). Immunoreactivity experiments on brain sections from FP−/− and WT mice post-ICH were performed to monitor changes in microgliosis and astrogliosis using antibodies against Iba1 and GFAP respectively. These experiments showed that FP−/− mice had a trend toward greater astrogliosis than WT mice post-ICH.Conclusion: We showed that deletion of the PGF2α FP receptor exacerbates behavioral impairments and increases lesion volumes following ICH compared to WT-matched controls.Detailed mechanisms responsible for these novel results are actively being pursued

Agriculture et ressources naturelles : de quoi parlons-nous ?

National audienceL'agriculture entretient des relations complexes avec les ressources naturelles, complexité due à la diversité des ressources qu'elle mobilise et à la diversité des modalités par lesquelles elle les utilise. Cette complexité est de nature à brouiller l'analyse des relations entre agriculture et gestion des ressources naturelles et à présenter un obstacle à la mise au point de systèmes agricoles protégeant ces ressources. Dans cet article, nous es-sayons de clarifier ce sujet en explorant la diversité des ressources qui peuvent être mobilisées ou impactées lors des processus de production agricole. En particulier, nous proposons une typologie en quatre classes des ressources naturelles selon que celles-ci sont renouvelables, recyclables ou dissipées lors des processus de production agricoles. Nous utilisons cette typologie pour mettre en évidence la diversité des leviers agronomiques et des niveaux d'organisation qu'il convient d'activer pour mieux protéger les ressources naturelles

Biomarker Application for Precision Medicine in Stroke

Stroke remains one of the leading causes of long-term disability and mortality despite recent advances in acute thrombolytic therapies. In fact, the global lifetime risk of stroke in adults over the age of 25 is approximately 25%, with 24.9 million cases of ischemic stroke and 18.7 million cases of hemorrhagic stroke reported in 2015. One of the main challenges in developing effective new acute therapeutics and enhanced long-term interventions for stroke recovery is the heterogeneity of stroke, including etiology, comorbidities, and lifestyle factors that uniquely affect each individual stroke survivor. In this comprehensive review, we propose that future biomarker studies can be designed to support precision medicine therapeutic interventions after stroke. The current challenges in defining ideal biomarkers for stroke are highlighted, including consideration of disease course, age, lifestyle factors, and subtypes of stroke. This overview of current clinical trials includes biomarker collection, and concludes with an example of biomarker design for aneurysmal subarachnoid hemorrhage. With the advent of -omics studies, neuroimaging, big data, and precision medicine, well-designed stroke biomarker trials will greatly advance the treatment of a disease that affects millions globally every year

Science Impacts of the SPHEREx All-Sky Optical to Near-Infrared Spectral Survey II: Report of a Community Workshop on the Scientific Synergies Between the SPHEREx Survey and Other Astronomy Observatories

SPHEREx is a proposed NASA MIDEX mission selected for Phase A study. SPHEREx would carry out the first all-sky spectral survey in the near infrared. At the end of its two-year mission, SPHEREx would obtain 0.75-to-5μm spectra of every 6.2 arcsec pixel on the sky, with spectral resolution R>35 and a 5-σ sensitivity AB>19 per spectral/spatial resolution element. More details concerning SPHEREx are available at http://spherex.caltech.edu. The SPHEREx team has proposed three specific science investigations to be carried out with this unique data set: cosmic inflation, interstellar and circumstellar ices, and the extra-galactic background light. Though these three themes are undoubtedly compelling, they are far from exhausting the scientific output of SPHEREx. Indeed, SPHEREx would create a unique all-sky spectral database including spectra of very large numbers of astronomical and solar system targets, including both extended and diffuse sources. These spectra would enable a wide variety of investigations, and the SPHEREx team is dedicated to making the data available to the community to enable these investigations, which we refer to as Legacy Science. To that end, we have sponsored two workshops for the general scientific community to identify the most interesting Legacy Science themes and to ensure that the SPHEREx data products are responsive to their needs. In February of 2016, some 50 scientists from all fields met in Pasadena to develop these themes and to understand their implications for the SPHEREx mission. The 2016 workshop highlighted many synergies between SPHEREx and other contemporaneous astronomical missions, facilities, and databases. Consequently, in January 2018 we convened a second workshop at the Center for Astrophysics in Cambridge to focus specifically on these synergies. This white paper reports on the results of the 2018 SPHEREx workshop

Science Impacts of the SPHEREx All-Sky Optical to Near-Infrared Spectral Survey II: Report of a Community Workshop on the Scientific Synergies Between the SPHEREx Survey and Other Astronomy Observatories

SPHEREx is a proposed NASA MIDEX mission selected for Phase A study. SPHEREx would carry out the first all-sky spectral survey in the near infrared. At the end of its two-year mission, SPHEREx would obtain 0.75-to-5μm spectra of every 6.2 arcsec pixel on the sky, with spectral resolution R>35 and a 5-σ sensitivity AB>19 per spectral/spatial resolution element. More details concerning SPHEREx are available at http://spherex.caltech.edu. The SPHEREx team has proposed three specific science investigations to be carried out with this unique data set: cosmic inflation, interstellar and circumstellar ices, and the extra-galactic background light. Though these three themes are undoubtedly compelling, they are far from exhausting the scientific output of SPHEREx. Indeed, SPHEREx would create a unique all-sky spectral database including spectra of very large numbers of astronomical and solar system targets, including both extended and diffuse sources. These spectra would enable a wide variety of investigations, and the SPHEREx team is dedicated to making the data available to the community to enable these investigations, which we refer to as Legacy Science. To that end, we have sponsored two workshops for the general scientific community to identify the most interesting Legacy Science themes and to ensure that the SPHEREx data products are responsive to their needs. In February of 2016, some 50 scientists from all fields met in Pasadena to develop these themes and to understand their implications for the SPHEREx mission. The 2016 workshop highlighted many synergies between SPHEREx and other contemporaneous astronomical missions, facilities, and databases. Consequently, in January 2018 we convened a second workshop at the Center for Astrophysics in Cambridge to focus specifically on these synergies. This white paper reports on the results of the 2018 SPHEREx workshop

Haptoglobin Treatment for Aneurysmal Subarachnoid Hemorrhage: Review and Expert Consensus on Clinical Translation

Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating form of stroke frequently affecting young to middle-aged adults, with an unmet need to improve outcome. This special report focusses on the development of intrathecal haptoglobin supplementation as a treatment by reviewing current knowledge and progress, arriving at a Delphi-based global consensus regarding the pathophysiological role of extracellular hemoglobin and research priorities for clinical translation of hemoglobin-scavenging therapeutics. After aneurysmal subarachnoid hemorrhage, erythrocyte lysis generates cell-free hemoglobin in the cerebrospinal fluid, which is a strong determinant of secondary brain injury and long-term clinical outcome. Haptoglobin is the body's first-line defense against cell-free hemoglobin by binding it irreversibly, preventing translocation of hemoglobin into the brain parenchyma and nitric oxide-sensitive functional compartments of cerebral arteries. In mouse and sheep models, intraventricular administration of haptoglobin reversed hemoglobin-induced clinical, histological, and biochemical features of human aneurysmal subarachnoid hemorrhage. Clinical translation of this strategy imposes unique challenges set by the novel mode of action and the anticipated need for intrathecal drug administration, necessitating early input from stakeholders. Practising clinicians (n=72) and scientific experts (n=28) from 5 continents participated in the Delphi study. Inflammation, microvascular spasm, initial intracranial pressure increase, and disruption of nitric oxide signaling were deemed the most important pathophysiological pathways determining outcome. Cell-free hemoglobin was thought to play an important role mostly in pathways related to iron toxicity, oxidative stress, nitric oxide, and inflammation. While useful, there was consensus that further preclinical work was not a priority, with most believing the field was ready for an early phase trial. The highest research priorities were related to confirming haptoglobin's anticipated safety, individualized versus standard dosing, timing of treatment, pharmacokinetics, pharmacodynamics, and outcome measure selection. These results highlight the need for early phase trials of intracranial haptoglobin for aneurysmal subarachnoid hemorrhage, and the value of early input from clinical disciplines on a global scale during the early stages of clinical translation