Cerebral ischemia/reperfusion injury activates microglia, resident immune cells in the brain, and allows the infiltration of circulating immune cells into the ischemic lesions. Microglia play both ...exacerbating and protective roles in pathological processes and are thus often referred to as “double-edged swords.” In ischemic brains, blood-borne macrophages play a role that is distinct from that of resident activated microglia. Recently, the metabolic alteration of immune cells in the pathogenesis of inflammatory disorders including cerebral infarction has become a critical target for investigation. We begin this review by describing the multifaceted functions of microglia in cerebral infarction. Next, we focus on the metabolic alterations that occur in microglia during pathological processes. We also discuss morphological changes that take place in the mitochondria, leading to functional disturbances, accompanied by alterations in microglial function. Moreover, we describe the involvement of the reactive oxygen species that are produced during aberrant metabolic activity. Finally, we discuss therapeutic strategies to ameliorate aggravative changes in metabolism.
Synaptic strength reduces during sleep, but the underlying mechanisms of this process are unclear. This study showed reduction of synaptic proteins in rat prefrontal cortex (PFC) at AM7 or Zeitgeber ...Time (ZT0), when the light phase or sleeping period for rats started. At this time point, microglia were weakly activated, displaying larger and more granular somata with increased CD11b expression compared with those at ZT12, as revealed by flow cytometry. Expression of opsonins, such as complements or MFG‐E8, matrix metalloproteinases, and microglial markers at ZT0 were increased compared with that at ZT12. Microglia at ZT0 phagocytosed synapses, as revealed by immunohistochemical staining. Immunoblotting detected more synapsin I in the isolated microglia at ZT0 than at ZT12. Complement C3‐ or MFG‐E8‐bound synapses were the most abundant at ZT0, some of which were phagocytosed by microglia. Systemic administration of synthetic glucocorticoid dexamethasone reduced microglial size, granularity and CD11b expression at ZT0, resembling microglia at ZT12, and increased synaptic proteins and decreased the sleeping period. Noradrenaline (NA) suppressed glutamate‐induced phagocytosis in primary cultured microglia. Systemic administration of the brain monoamine‐depleting agent reserpine decreased NA content and synapsin I expression in PFC, and increased expression of microglia markers, C3 and MFG‐E8, while increasing the sleeping period. A NA precursor l‐threo‐dihydroxyphenylserine abolished the reserpine‐induced changes. These results suggest that microglia may eliminate presumably weak synapses during every sleep phase. The circadian changes in concentrations of circulating glucocorticoids and brain NA might be correlated with the circadian changes of microglial phenotypes and synaptic strength.
Main Points
Microglia may be responsible for sleep/wake cycle by eliminating synapses that are opsonized with complement C3 and MFG‐E8 around the onset of sleep.
Circadian changes of glucocorticoids and noradrenaline levels may affect the activity of microglia.
Parkinson's disease (PD) is a frequent neurodegenerative disease causing bradykinesia, tremor, muscle rigidity and postural instability. Although its main pathology is progressive dopaminergic ...(DArgic) neuron loss in the substantia nigra, motor deficits are thought not to become apparent until most DArgic neurons are lost, probably due to compensatory mechanisms that overcome the decline of DA level in the striatum. Even in animal PD models, it is difficult to detect motor deficits when most DArgic neurons are functional. In this study, we performed various behavioral tests (apomorphine-induced rotation, cylinder, forepaw adjustment steps (FAS), beam walking, rota-rod, and open-field), using 6-hydroxydopamine (OHDA) and lipopolysaccharide (LPS)-induced hemi-PD model rats with various striatal DA levels, to find the best way to predict the DA level from earlier disease stages. Different from the 6-OHDA-induced model, reduction in the striatal DA levels in the LPS-model was less significant. Among the behavioral tests, data from cylinder and FAS tests, which evaluate forelimb movements, best correlated with decline of the DA level. They also correlated well with decreased body weight gain. The beam and apomorphine tests showed less significant correlation than the cylinder and FAS tests. Open-field and rota-rod tests were not useful. Expressional levels of mRNA encoding tyrosine hydroxylase (TH), a marker of DArgic neurons, correlated well with the DA level. Metabotropic glutamate receptor 4 mRNA expression correlated with the striatal DA level and may be related to compensatory mechanisms. These results suggest that motor impairments of PD should be evaluated by forelimb movements, or hands and forearms in clinical settings, rather than movement of the body or large joints. The combination of cylinder and FAS tests may be the best to evaluate the rat PD models, in which many DArgic neurons survive.
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•The 6-OHDA- and LPS-induced Parkinson's disease (PD) rat models were used.•Cylinder and FAS tests are suitable to evaluate motor deficits of forelimbs.•Forelimb impairments correlated linearly with striatal dopamine (DA) decline.•Apomorphine-induced rotation was apparent when DArgic neurons were totally lost.•For early detection of PD, examination of hand and forearm movements is suitable.
The space environment is regularly used for experiments addressing astrobiology research goals. The specific conditions prevailing in Earth orbit and beyond, notably the radiative environment ...(photons and energetic particles) and the possibility to conduct long-duration measurements, have been the main motivations for developing experimental concepts to expose chemical or biological samples to outer space, or to use the reentry of a spacecraft on Earth to simulate the fall of a meteorite. This paper represents an overview of past and current research in astrobiology conducted in Earth orbit and beyond, with a special focus on ESA missions such as Biopan, STONE (on Russian FOTON capsules) and EXPOSE facilities (outside the International Space Station). The future of exposure platforms is discussed, notably how they can be improved for better science return, and how to incorporate the use of small satellites such as those built in cubesat format.
Abstract
The Kelch-like ECH-associated protein 1–nuclear factor erythroid 2-related factor 2 (KEAP1–NRF2) system plays a central role in redox homeostasis and inflammation control. Oxidative stress ...or electrophilic compounds promote NRF2 stabilization and transcriptional activity by negatively regulating its inhibitor, KEAP1. We have previously reported that bromovalerylurea (BU), originally developed as a hypnotic, exerts anti-inflammatory effects in various inflammatory disease models. However, the molecular mechanism underlying its effect remains uncertain. Herein, we found that by real-time multicolor luciferase assay using stable luciferase red3 (SLR3) and green-emitting emerald luciferase (ELuc), BU potentiates NRF2-dependent transcription in the human hepatoblastoma cell line HepG2 cells, which lasted for more than 60 h. Further analysis revealed that BU promotes NRF2 accumulation and the transcription of its downstream cytoprotective genes in the HepG2 and the murine microglial cell line BV2. Keap1 knockdown did not further enhance NRF2 activity, suggesting that BU upregulates NRF2 by targeting KEAP1. Knockdown of Nfe2l2 in BV2 cells diminished the suppressive effects of BU on the production of pro-inflammatory mediators, like nitric oxide (NO) and its synthase NOS2, indicating the involvement of NRF2 in the anti-inflammatory effects of BU. These data collectively suggest that BU could be repurposed as a novel NRF2 activator to control inflammation and oxidative stress.
Graphical Abstract
Graphical Abstract
An in-situ cosmic-dust instrument called the Mercury Dust Monitor (MDM) had been developed as a part of the science payload for the Mio (Mercury Magnetospheric Orbiter, MMO) stage of the joint ...European Space Agency (ESA)–JAXA Mercury-exploration mission. The BepiColombo spacecraft was successfully launched by an Ariane 5 rocket on October 20, 2018, and commissioning tests of the science payload were successfully completed in near-earth orbit before injection into a long journey to Mercury. MDM has a sensor consisting of four plates of piezoelectric lead zirconate titanate (PZT), which converts the mechanical stress (or strain) induced by dust-particle impacts into electrical signals. After the commencement of scientific operations, MDM will measure the impact momentum at which dust particles in orbit around the Sun collide with the sensor and record the arrival direction. This paper provides basic information concerning the MDM instrument and its predicted scientific operation as a future reference for scientific articles concerning the MDM’s observational data.
The Tanpopo experiment was the first Japanese astrobiology mission on board the International Space Station. It included exposure experiments of microbes and organic compounds as well as a capture ...experiment of hypervelocity impacting microparticles. We deployed three Exposure Panels, each consisting of 20 Exposure Units that contained microbes, organic compounds, an alanine UV dosimeter or an ionizing radiation dosimeter. The three Exposure Panels were situated on the zenith face of the Exposed Experiment Handrail Attachment Mechanism (ExHAM) that was pointing in zenith direction toward space, which was attached on a handrail of the Japanese Experiment Module (Kibo) Exposed Facility (JEM-EF) outside the International Space Station. The three Exposure Panels were one by one retrieved and returned to the ground after approximately 1, 2, and 3 years of exposure to the space environment. Capture Panels, each of which contained one or two blocks of amorphous silica aerogel, were exposed to collect hypervelocity impact microparticles. Possible captured particles may include micrometeoroids, human-made orbital debris, and natural terrestrial particles. Each year, Capture Panels containing from 11 to 12 aerogel blocks were attached to the three faces of the ExHAM (pointing to zenith, ram, and port); they remained in place for about 1 year and were then returned to the laboratory. This process was repeated three times, in total, during 2015-2018. Additional exposure of a Capture Panel facing ram was conducted between 2018 and 2019. Once the aerogel blocks were returned to the laboratory, they were encapsulated in dedicated transparent plastic cases and optically inspected by a specially designed microscopic system. Once located and recorded, hypervelocity impact signatures were excavated one by one and distributed for further detailed analyses. The apparatus, operation, and environmental factors of all the Tanpopo experiments are summarized in this article.
Microglia and blood‐borne macrophages in injured or diseased brains are difficult to distinguish because they share many common characteristics. However, the identification of microglia‐specific ...markers and the use of flow cytometry have recently made it easy to discriminate these types of cells. In this study, we analyzed the features of blood‐borne macrophages, and activated and resting microglia in a rat traumatic brain injury (TBI) model. Oxidative injury was indicated in macrophages and neurons in TBI lesions by the presence of 8‐hydroxy‐2'‐deoxyguanosine (8‐OHdG). Generation of mitochondrial reactive oxygen species (ROS) was markedly observed in granulocytes and macrophages, but not in activated or resting microglia. Dihydroethidium staining supported microglia not being the major source of ROS in TBI lesions. Furthermore, macrophages expressed NADPH oxidase 2, interleukin‐1β (IL‐1β), and CD68 at higher levels than microglia. In contrast, microglia expressed transforming growth factor β1 (TGFβ1), interleukin‐6 (IL‐6), and tumor necrosis factor α at higher levels than macrophages. A hypnotic, bromovalerylurea (BU), which has anti‐inflammatory effects, reduced both glycolysis and mitochondrial oxygen consumption. BU administration inhibited chemokine CCL2 expression, accumulation of monocytes/macrophages, 8‐OHdG generation, mitochondrial ROS generation, and proinflammatory cytokine expression, and markedly ameliorated the outcome of the TBI model. Yet, BU did not inhibit microglial activation or expression of TGFβ1 and insulin‐like growth factor 1 (IGF‐1). These results indicate that macrophages are the major aggravating cell type in TBI lesions, in particular during the acute phase. Activated microglia may even play favorable roles. Reduction of cellular energy metabolism in macrophages and suppression of CCL2 expression in injured tissue may lead to amelioration of TBI.
Main Points
Infiltrated macrophages express/generate more IL‐1β and reactive oxygen species and less TGFβ1 than resident microglia in injured brains during the acute phase.
Reduced CCL2 expression and cellular energy metabolism may ameliorate the recovery outcome.
Japan Aerospace Exploration Agency (JAXA) launched the asteroid exploration probe “Hayabusa2” in December 3rd, 2014, following the 1st Hayabusa mission. With technological and scientific improvements ...from the Hayabusa probe, we plan to visit the C-type asteroid 162137 Ryugu (1999 JU3), and to sample surface materials of the C-type asteroid that is likely to be different from the S-type asteroid Itokawa and contain more pristine materials, including organic matter and/or hydrated minerals, than S-type asteroids. We developed the Hayabusa2 sampler to collect a minimum of 100 mg of surface samples including several mm-sized particles at three surface locations without any severe terrestrial contamination. The basic configuration of the sampler design is mainly as same as the 1st Hayabusa (Yano et al. in Science, 312(5778):1350–1353,
2006
), with several minor but important modifications based on lessons learned from the Hayabusa to fulfill the scientific requirements and to raise the scientific value of the returned samples.
In this paper, we will report the details of the sampling system of Hayabusa2 with results of performance tests during the development and the current status of the sampling system.
Ischemic brain injuries caused release of damage-associated molecular patterns (DAMPs) that activate microglia/macrophages (MG/MPs) by binding to Toll-like receptors. Using middle cerebral artery ...transiently occluded rats, we confirmed that MG/MPs expressed inducible nitric oxide synthase (iNOS) on 3days after reperfusion (dpr) in ischemic rat brain. iNOS expression almost disappeared on 7dpr when transforming growth factor-β1 (TGF-β1) expression was robustly increased. After transient incubation with TGF-β1 for 24h, rat primary microglial cells were incubated with lipopolysaccharide (LPS) and released NO level was measured. The NO release was persistently suppressed even 72h after removal of TGF-β1. The sustained TGF-β1 effects were not attributable to microglia-derived endogenous TGF-β1, as revealed by TGF-β1 knockdown and in vitro quantification studies. Then, boiled supernatants prepared from ischemic brain tissues showed the similar sustained inhibitory effects on LPS-treated microglial cells that were prevented by the TGF-β1 receptor-selective blocker SB525334. After incubation with TGF-β1 for 24h and its subsequent removal, LPS-induced phosphorylation of IκB kinases (IKKs), IκB degradation, and NFκB nuclear translocation were inhibited in a sustained manner. SB525334 abolished all these effects of TGF-β1. In consistent with the in vitro results, phosphorylated IKK-immunoreactivity was abundant in MG/MPs in ischemic brain lesion on 3dpr, whereas it was almost disappeared on 7dpr. The findings suggest that abundantly produced TGF-β1 in ischemic brain displays sustained anti-inflammatory effects on microglial cells by persistently inhibiting endogenous Toll-like receptor ligand-induced IκB degradation.
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•Microglia/macrophages in ischemic brain express iNOS only at the early phase.•High expression of TGF-β1 was observed at the later phase of the ischemic event.•Once incubated with TGF-β1, cultured microglia became unresponsive to LPS.•The inhibitory TGF-β1 effects were sustained for days after its removal.•TGF-β1 caused sustained inhibition of LPS-induced IKK phosphorylation.
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