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Abstract We aimed to investigate whether ventilator support time influences the occurrence of dysphagia in pediatric trauma patients. This case-series study was conducted in a single pediatric emergency and critical care center from April 2012 to March 2022. Trauma patients aged

Abstract Background Airway management in children with severe burns is difficult because of airway edema and prolonged duration of ventilatory management. There is insufficient evidence to suggest that tracheostomy is beneficial for children. Case presentation A male child aged 1 year and 4 months was injured when he accidentally fell into a bathtub filled with boiling water. Furthermore, 85% of the burnt area, including the face and neck, consisted of second-degree burns; hence, oral tracheal intubation and resuscitative infusion were required. In this case, the patient was safely switched from oral to nasotracheal intubation using a tracheal tube guide and video laryngoscope, without the use of a bronchoscope, and ventilatory management could be continued for 2 weeks. Conclusion Oral to nasal endotracheal tube exchange using a tracheal tube guide and video laryngoscope may be useful not only for pediatric burn patients but also for adult patients who need to be safely switched from oral to nasotracheal intubation.

Recent research has shown that the Default Mode Network (DMN) typically exhibits increased activation during processing of social and personal information but shows deactivation during working memory (WM) tasks. Previously, we reported the Frontal Parietal Network (FPN) and DMN showed coactivation during task preparation whereas the DMN exhibited deactivation during task execution in working memory tasks. Aging research has shown that older adults exhibited decreased functional connectivity in the DMN relative to younger adults. Here, we investigated whether age-related cognitive decline is related to a reduced relationship between the FPN and DMN using a working memory task during the execution period. First, we replicated our previous finding that the FPN and DMN showed coactivation during the preparation period, whereas the DMN showed deactivation during the execution period. The older adults showed reduced DMN activity during task preparation and reduced deactivation during task execution; however, they exhibited a higher magnitude of activation in the FPN than the young individuals during task execution. Functional connectivity analyses showed that the elderly group, compared to the young group, showed weaker correlations within the FPN and the DMN, weaker positive correlations between the FPN and DMN during task preparation, and weaker negative correlations between the FPN and DMN during execution. The results suggest that cognitive decline in the older adults might be related to reduced connectivity within the DMN as well as between the FPN and DMN.

Abstract Background Adenovirus gastroenteritis is a common cause of diarrhea and vomiting in infants, resulting in prerenal acute kidney injury (AKI). However, postrenal AKI due to urinary stones associated with adenovirus gastroenteritis is extremely rare. Here, we describe postrenal AKI due to obstructive ammonium acid urate stones associated with adenovirus gastroenteritis. Case presentation A previously healthy 6-month-old boy had an 11-day history of severe diarrhea and a 5-day history of vomiting. His stool was positive for adenovirus antigens. We initiated fluid replacement therapy. On the second hospital day, he suddenly developed anuria. Abdominal computed tomography revealed bilateral hydronephrosis, left ureteral stones, and right bladder ureteral junction stones. Laboratory data showed that the creatinine level increased to 1.00 mg/dL. We diagnosed postrenal AKI due to obstructive bilateral urinary stones. Urination with stable urine volume resumed spontaneously after hydration. A few stones were found in the urine, which consisted of ammonium acid urate (> 98%). The serum creatinine level improved to 0.25 mg/dL. He was discharged nine days after admission. Conclusions We suggest that adenovirus gastroenteritis be considered in pediatric patients with postrenal AKI due to urinary stones.

Background: Breakfast is the most important meal of the day and has been associated with longevity. Regular breakfast consumers often have a healthy lifestyle, including a healthy diet and regular physical activity. Methods: We examined the association between breakfast type, chronotype (morningness-eveningness), and physical activity in 3395 Japanese workers using a cross-sectional web survey. Results: Participants who ate Japanese breakfasts showed an early chronotype, while those who ate breakfast cereal exhibited a later chronotype. Physical activity was positively associated with adopting a Japanese breakfast style. Japanese breakfast eaters performed physical activities from 6:00–9:00 compared with other breakfast eaters. Conclusion: Our findings suggest that eating a Japanese breakfast is associated with an earlier chronotype (morningness) and higher physical activity.

Chronic or acute ambient temperature change alter the gut microbiota and the metabolites, regulating metabolic functions. Short-chain fatty acids (SCFAs) produced by gut bacteria reduce the risk of disease. Feeding patterns and gut microbiota that are involved in SCFAs production are controlled by the circadian clock. Hence, the effect of environmental temperature change on SCFAs production is expected depending on the exposure timing. In addition, there is limited research on effects of habitual cold exposure on the gut microbiota and SCFAs production compared to chronic or acute exposure. Therefore, the aim was to examine the effect of cold or heat exposure timing on SCFAs production. After exposing mice to 7 or 37 °C for 3 h a day at each point for 10 days, samples were collected, and cecal pH, SCFA concentration, and BAT weight was measured. As a result, cold exposure at ZT18 increased cecal pH and decreased SCFAs. Intestinal peristalsis was suppressed due to the cold exposure at ZT18. The results reveal differing effects of intermittent cold exposure on the gut environment depending on exposure timing. In particular, ZT18 (active phase) is the timing to be the most detrimental to the gut environment of mice.

Rheumatoid arthritis (RA) is a disease that causes inflammation of joints, resulting in pain and swelling. Reduced barometric pressure induces painful symptom of RA, but there is no appropriate animal model and pharmacological evaluation. Keishinieppiittokajutsubu (KNEIJB), a Kampo medicine used to treat RA; however, its mechanism of action is not clear. Here, we found that KNEIJB suppressed the low barometric pressure (LP)-induced pain response in CFA-induced arthritic model rats. Furthermore, we found that KNEIJB reduced plasma IL-6 levels. These results suggest that KNEIJB might be beneficial in the treatment of RA or some other arthralgia induced by LP., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest regarding this research and/or publication., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Skull base surgery requires anatomical knowledge and appropriate surgical technique in bone drilling. We developed a newly modified three-dimensional (3D) model of the posterior cranial fossa as a learning tool that improves knowledge of skull base anatomy and surgical approaches, including skull base drilling techniques., Methods: This bone model of the posterior cranial fossa was created based on computed tomography data using a 3D printer, and incorporates artificial cranial nerves, cerebral vessels, bony structures, dura mater, and cerebellar tentorial dura. These anatomical components are differentiated with various colors. In addition, the atlanto-occipital junction can be mobilized to fully expose the surface of the cartilage between the C1 condyle and occipital condyle to allow drilling to open the hypoglossal canal under a wide surgical field. The usefulness of the model for practicing skull base surgical approaches was evaluated., Results: Experience of bone drilling, dural dissection, and 3D positioning of important structures, including cranial nerves and blood vessels, was identical to that in actual surgery., Conclusions: This model is designed to facilitate teaching anatomical knowledge and essential epidural procedure-related skills, and is useful for teaching the essential elements of posterior skull base surgery., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Introduction: Aromatic (Ar)-turmerone is a bioactive component of turmeric oil obtained from Curcuma longa . We recently identified a novel analog (A2) of ar-turmerone that protects dopaminergic neurons from toxic stimuli by activating nuclear factor erythroid 2-related factor 2 (Nrf2). D-cysteine increases Nrf2, leading to the activation of chaperone-mediated autophagy (CMA), a pathway in the autophagy-lysosome protein degradation system, in primary cultured cerebellar Purkinje cells. In this study, we attempted to identify novel analogs of ar-turmerone that activate Nrf2 more potently and investigated whether these analogs activate CMA. Methods: Four novel analogs (A4-A7) from A2 were synthesized. We investigated the effects of A2 and novel 4 analogs on Nrf2 expression via immunoblotting and CMA activity via fluorescence observation. Results: Although all analogs, including A2, increased Nrf2 expression, only A4 activated CMA in SH-SY5Y cells. Additionally, A4-mediated CMA activation was not reversed by Nrf2 inhibition, indicating that A4 activated CMA via mechanisms other than Nrf2 activation. We focused on p38, which participates in CMA activation. Inhibition of p38 significantly prevented A4-mediated activation of CMA. Although all novel analogs significantly increased the phosphorylation of p38 6 h after drug treatment, only A4 significantly increased phosphorylation 24 h after treatment. Finally, we revealed that A4 protected SH-SY5Y cells from the cytotoxicity of rotenone, and that this protection was reversed by inhibiting p38. Conclusion: These findings suggest that the novel ar-turmerone analog, A4, activates CMA and protects SH-SY5Y cells through the persistent activation of p38., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Motomura, Ueda, Boateng, Sugiura, Kadoyama, Hitora-Imamura, Kurauchi, Katsuki and Seki.)

Niemann-Pick disease type C (NPC) is a lysosomal lipid storage disorder characterized by progressive neurodegeneration and hepatic dysfunction. A cyclic heptasaccharide, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), is currently under clinical investigation for NPC, but its adverse events remain problematic. We previously identified that a cyclic octasaccharide, 2-hydroxypropyl-γ-cyclodextrin (HP-γ-CD), also ameliorated NPC manifestations with higher biocompatibility than HP-β-CD. However, preclinical studies describing the associations between the biodistribution and pharmacodynamics of these compounds, which are essential for clinical application, are still lacking. Here, we investigated these properties of HP-γ-CD by measuring its organ biodistribution and therapeutic effect after systemic and central administration. The effect of HP-γ-CD on disturbed cholesterol homeostasis appeared within several hours after exposure and persisted for several days in NPC model cells and mice. Tissue distribution indicated that only a small fraction of subcutaneously administered HP-γ-CD rapidly distributed to peripheral organs and contributed to disease amelioration. We found that a subcutaneous dose of HP-γ-CD negligibly ameliorated neurological characteristics because it has limited penetration of the blood-brain barrier; however, an intracerebroventricular microdose unexpectedly attenuated hepatic dysfunction without the detection of HP-γ-CD in the liver. These results demonstrate that central administration of HP-γ-CD can indirectly attenuate peripheral manifestations of NPC., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier Inc.)

Menaquinone-4 (MK-4) is an isoform of vitamin K 2 that has been shown to exert various biological actions besides its functions in blood coagulation and bone metabolism. Here we examined the effect of MK-4 on a mouse model of intracerebral hemorrhage (ICH). Daily oral administration of 200 mg/kg MK-4 starting from 3 h after induction of ICH by intrastriatal collagenase injection significantly ameliorated neurological deficits. Unexpectedly, MK-4 produced no significant effects on various histopathological parameters, including the decrease of remaining neurons and the increase of infiltrating neutrophils within the hematoma, the increased accumulation of activated microglia/macrophages and astrocytes around the hematoma, as well as the injury volume and brain swelling by hematoma formation. In addition, ICH-induced increases in nitrosative/oxidative stress reflected by changes in the immunoreactivities against nitrotyrosine and heme oxygenase-1 as well as the contents of malondialdehyde and glutathione were not significantly affected by MK-4. In contrast, MK-4 alleviated axon tract injury in the internal capsule as revealed by neurofilament-H immunofluorescence. Enhanced preservation of the corticospinal tract by MK-4 was also confirmed by retrograde labeling of neurons in the primary motor cortex innervating the spinal cord. These results suggest that MK-4 produces therapeutic effect on ICH by protecting structural integrity of the corticospinal tract., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Hemorrhage-induced injury of the corticospinal tract (CST) in the internal capsule (IC) causes severe neurological dysfunction in both human patients and rodent models of intracerebral hemorrhage (ICH). A nuclear receptor Nurr1 (NR4A2) is known to exert anti-inflammatory and neuroprotective effects in several neurological disorders. Previously we showed that Nurr1 ligands prevented CST injury and alleviated neurological deficits after ICH in mice. To prove direct effect of Nurr1 on CST integrity, we examined the effect of Nurr1 overexpression in neurons of the primary motor cortex on pathological consequences of ICH in mice. ICH was induced by intrastriatal injection of collagenase type VII, where hematoma invaded into IC. Neuron-specific overexpression of Nurr1 was induced by microinjection of synapsin I promoter-driven adeno-associated virus (AAV) vector into the primary motor cortex. Nurr1 overexpression significantly alleviated motor dysfunction but showed only modest effect on sensorimotor dysfunction after ICH. Nurr1 overexpression also preserved axonal structures in IC, while having no effect on hematoma-associated inflammatory events, oxidative stress, and neuronal death in the striatum after ICH. Immunostaining revealed that Nurr1 overexpression increased the expression of Ret tyrosine kinase and phosphorylation of Akt and ERK1/2 in neurons in the motor cortex. Moreover, administration of Nurr1 ligands 1,1-bis(3'-indolyl)-1-(p-chlorophenyl)methane or amodiaquine increased phosphorylation levels of Akt and ERK1/2 as well as expression of glial cell line-derived neurotrophic factor and Ret genes in the cerebral cortex. These results suggest that the therapeutic effect of Nurr1 on striatal ICH is attributable to the preservation of CST by acting on cortical neurons., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Strong coupling of cavity photons and molecular vibrations creates vibrational polaritons that have been shown to modify chemical reactivity and alter material properties. While ultrafast spectroscopy of vibrational polaritons has been performed intensively in metal complexes, ultrafast dynamics in vibrationally strongly coupled organic molecules remain unexplored. Here, we report ultrafast pump-probe measurement and two-dimensional infrared spectroscopy in diphenylphosphoryl azide under vibrational strong coupling. Early time oscillatory structures indicate coherent energy exchange between the two polariton modes, which decays in ∼2 ps. We observe a large transient absorptive feature around the lower polariton, which can be explained by the overlapped excited-state absorption and derivative-shaped structures around the lower and upper polaritons. The latter feature is explained by the Rabi splitting contraction, which is ascribed to a reduced population in the ground state. These results reassure the previously reported spectroscopic theory to describe nonlinear spectroscopy of vibrational polaritons. We have also noticed the influence of the complicated layer structure of the cavity mirrors. The penetration of the electric field distribution into the layered structure of the dielectric-mirror cavities can significantly affect the Rabi splitting and the decay time constant of polaritonic systems.

Goreisan is a Kampo medicine used to treat headaches associated with climate change. Here, by using an implantable complementary metal-oxide-semiconductor (CMOS) device, we evaluated the effects of Goreisan and loxoprofen on cerebral blood flow (CBF) dynamics associated with barometric pressure fluctuations in freely moving mice. In the vehicle group, decreasing barometric pressure increased CBF that was prevented by Goreisan and loxoprofen. Notably, Goreisan, but not loxoprofen, reduced CBF after returning to atmospheric pressure. These results indicate that, unlike the mechanism of action of antipyretic analgesics, Goreisan normalizes CBF abnormalities associated with barometric pressure fluctuations by actively reducing CBF increase., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest regarding this research and/or publication., (Copyright © 2023 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Nurr1 (NR4A2) is a member of nuclear receptor superfamily that regulates gene transcription in midbrain dopaminergic neurons and also inhibits nuclear factor-κB-mediated inflammatory responses in brain microglial cells. To date, various compounds have been reported to stimulate transcriptional activity of Nurr1 on neuronal genes, but their anti-inflammatory actions are poorly characterized. The present study examined the effects of three kinds of Nurr1 ligands, amodiaquine, 1,1-bis(3'-indolyl)-1-(p-chlorophenyl)-methane (C-DIM12) and 5-chloronaphthalen-1-amine (5-CNA), on inflammatory responses of microglial BV-2 cells. Lipopolysaccharide (LPS)-induced upregulation of interleukin-1β mRNA and tumor necrosis factor α mRNA was inhibited by all three compounds, whereas upregulation of interleukin-6 mRNA and inducible nitric oxide synthase (iNOS) mRNA was significantly inhibited only by 5-CNA. On the other hand, LPS-induced nuclear translocation of p65 subunit of nuclear factor-κB was prevented only by amodiaquine. C-DIM12 increased nuclear localization of Nurr1 and transiently upregulated Nurr1 protein expression, whereas amodiaquine and 5-CNA had no effect on these parameters. Notably, inhibitory effect of 5-CNA on iNOS mRNA upregulation was reversed by co-application of amodiaquine. Conversely, inhibitory effect of amodiaquine on p65 nuclear translocation was cancelled by 5-CNA. These results reveal distinct characteristics of anti-inflammatory actions of Nurr1 ligands.

Natural compounds with sulfur moiety produce various biological actions that may be beneficial for the therapies of several devastative disorders of the central nervous system. Here we investigated potential therapeutic effect of allicin, an organosulfur compound derived from garlic, in a mouse model of intracerebral hemorrhage (ICH) based on intrastriatal collagenase injection. Daily intraperitoneal administration of allicin (50 mg/kg) from 3 h after induction of ICH afforded neuroprotective effects, as evidenced by the increase of surviving neurons in the hematoma, reduction of axonal transport impairment, and prevention of axon tract injury. In addition, allicin inhibited accumulation of activated microglia/macrophages around the hematoma and infiltration of neutrophils within the hematoma. Allicin also suppressed ICH-induced mRNA upregulation of pro-inflammatory factors such as interleukin 6 and C-X-C motif ligand 2 in the brain, suggesting its anti-inflammatory effect. Moreover, ICH-induced increase of malondialdehyde as well as decrease of total glutathione in the brain was attenuated by allicin. Finally, allicin-treated mice showed better recovery of sensorimotor functions after ICH than vehicle-treated mice. These results indicate that allicin produces a therapeutic effect on ICH pathology via alleviation of neuronal damage, inflammatory responses and oxidative stress in the brain., Competing Interests: Declaration of competing interest The authors have no potential conflict of interest., (Copyright © 2023 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Peretinoin is an acyclic retinoid that stimulates retinoic acid receptors (NR1Bs) and produces therapeutic effects on hepatocellular cancer. We have previously shown that NR1B agonists such as Am80 and all trans-retinoic acid suppress pathogenic events in intracerebral hemorrhage. The present study addressed the actions of peretinoin and Am80 against cytotoxicity of a blood protease thrombin on cortico-striatal slice cultures obtained from neonatal rat brains. Application of 100 U/ml thrombin to the slice cultures for 72 h caused cell death in the cortical region and tissue shrinkage in the striatal region. Peretinoin (50 μM) and Am80 (1 μM) counteracted these cytotoxic effects of thrombin, and the effect of peretinoin and Am80 was blocked by LE540, an NR1B antagonist. A broad-spectrum kinase inhibitor K252a (3 μM) attenuated the cytoprotective effect of peretinoin in the cortical region, whereas a specific protein kinase A inhibitor KT5720 (1 μM) attenuated the protective effect of peretinoin in the cortical and the striatal regions. On the other hand, nuclear factor-κB (NF-κB) inhibitors such as pyrrolidine dithiocarbamate (50 μM) and Bay11-7082 (10 μM) prevented thrombin-induced shrinkage of the striatal region. Peretinoin and Am80 as well as Bay11-7082 blocked thrombin-induced nuclear translocation of NF-κB in striatal microglia and loss of striatal neurons. We also found that daily administration of peretinoin reduced histopathological injury and alleviated motor deficits in a mouse model of intracerebral hemorrhage. These results indicate that NR1B agonists including peretinoin may serve as a therapeutic option for hemorrhagic brain injury., Competing Interests: Declaration of competing interest We wish to confirm that there are no known conflicts of interest associated with this work and there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Niemann-Pick disease type C (NPC) is a fatal neurodegenerative disorder caused by abnormal intracellular cholesterol trafficking. Cyclodextrins (CDs), the most promising therapeutic candidates for NPC, but with concerns about ototoxicity, are cyclic oligosaccharides with dual functions of unesterified cholesterol (UC) shuttle and sink that catalytically enhance the bidirectional flux and net efflux of UC, respectively, between the cell membrane and the extracellular acceptors. However, the properties of CDs that regulate these functions and how they could be used to improve treatments for NPC are unclear., Methods: We estimated CD-UC complexation for nine CD derivatives derived from native α-, β-, and γ-CD with different cavity sizes, using solubility and molecular docking analyses. The stoichiometry and complexation ability of the resulting complexes were investigated in relation to the therapeutic effectiveness and toxicity of each CD derivative in NPC experimental models., Findings: We found that shuttle and sink activities of CDs are dependent on cavity size-dependent stoichiometry and substituent-associated stability of CD-UC complexation. The ability of CD derivatives to form 1:1 and 2:1 complexes with UC were correlated with their ability to normalize intracellular cholesterol trafficking serving as shuttle and with their cytotoxicity associated with cellular UC efflux acting as sink, respectively, in NPC model cells. Notably, the ability of CD derivatives to form an inclusion complex with UC was responsible for not only efficacy but ototoxicity, while a representative derivative without this ability negligibly affected auditory function, underscoring its preventability., Conclusions: Our findings highlight the importance of strategies for optimizing the molecular structure of CDs to overcome this functional dilemma in the treatment of NPC., (© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Missense mutations of ubiquilin 2 (UBQLN2) have been identified to cause X-linked amyotrophic lateral sclerosis (ALS). Proteasome-mediated protein degradation is reported to be impaired by ALS-associated mutations of UBQLN2. However, it remains unknown how these mutations affect autophagy-lysosome protein degradation, which consists of macroautophagy (MA), microautophagy (mA), and chaperone-mediated autophagy (CMA). Using a CMA/mA fluorescence reporter we found that overexpression of wild-type UBQLN2 impairs CMA. Conversely, knockdown of endogenous UBQLN2 increases CMA activity, suggesting that normally UBQLN2 negatively regulates CMA. ALS-associated mutant forms of UBQLN2 exacerbate this impairment of CMA. Using cells stably transfected with wild-type or ALS-associated mutant UBQLN2, we further determined that wild-type UBQLN2 increased the ratio of LAMP2A (a CMA-related protein) to LAMP1 (a lysosomal protein). This could represent a compensatory reaction to the impairment of CMA by wild-type UBQLN2. However, ALS-associated mutant UBQLN2 failed to show this compensation, exacerbating the impairment of CMA by mutant UBQLN2. We further demonstrated that ALS-associated mutant forms of UBQLN2 also impair MA, but wild-type UBQLN2 does not. These results support the view that ALS-associated mutant forms of UBQLN2 impair both CMA and MA which may contribute to the neurodegeneration observed in patients with UBQLN2-mediated ALS., Competing Interests: Declaration of competing interest The authors indicated no potential conflicts of interest., (Copyright © 2023 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Recently, retinoid actions on the central nervous system (CNS) have attracted considerable attention from the perspectives of brain disease diagnosis and drug development. Firstly, we successfully synthesized [ 11 C]peretinoin esters (methyl, ethyl, and benzyl) using a Pd(0)-mediated rapid C-[ 11 C]methylation of the corresponding stannyl precursors without geometrical isomerization in 82%, 66%, and 57% radiochemical yields (RCYs). Subsequent hydrolysis of the 11 C-labeled ester produced [ 11 C]peretinoin in 13 ± 8% RCY (n = 3). After pharmaceutical formulation, the resulting [ 11 C]benzyl ester and [ 11 C]peretinoin had high radiochemical purity (>99% each) and molar activities of 144 and 118 ± 49 GBq μmol -1 at total synthesis times of 31 min and 40 ± 3 min, respectively. Rat brain PET imaging for the [ 11 C]ester revealed a unique time-radioactivity curve, suggesting the participation of the acid [ 11 C]peretinoin for the brain permeability. However, the curve of the [ 11 C]peretinoin rose steadily after a shorter time lag to reach 1.4 standardized uptake value (SUV) at 60 min. These various phenomena between the ester and acid became more pronounced in the monkey brain (SUV of > 3.0 at 90 min). With the opportunity to identify high brain uptake of [ 11 C]peretinoin, we discovered CNS activities of a drug candidate called peretinoin, such as the induction of a stem-cell to neuronal cell differentiation and the suppression of neuronal damages., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Matcha tea powder is believed to have various physiological benefits; however, its detailed mechanism of action has been poorly understood. Here, we investigated whether the mental state of mice, due to social isolation stress, affects the antidepressant-like effect of Matcha tea powder by using the tail suspension test. Oral administration of Matcha tea powder reduced the duration of immobility in the stress-susceptible C57BL/6J strain, but not in BALB/c strain. In C57BL/6J mice, SCH23390, a dopamine D1 receptor blocker, prevented Matcha tea powder from exerting its antidepressant-like effect. Matcha tea powder also increased the number of c-Fos-positive cells in the prefrontal cortex (PFC) region and the nucleus accumbens (NAc) region in C57BL/6J mice, but not in BALB/c mice. In contrast, Matcha tea powder did not change the number of c-Fos-positive cells in the ventral tegmental area (VTA) region. Notably, C57BL/6J mice with a shorter immobility time had a higher number of c-Fos-positive cells in the PFC, NAc, and VTA regions. However, no such correlation was observed in the stress-tolerant BALB/c mice. These results suggest that Matcha tea powder exerts an antidepressant-like effect through the activation of the dopaminergic system including the PFC-NAc-VTA circuit and that mental states are important factors affecting the physiological benefits of Matcha tea powder.

Innovations in oral immunotherapy have greatly advanced the therapeutic control of allergies. However, these therapeutic effects suffer from the fact that the amount of antigen delivered to antigen-presenting cells is limited given the formulations that are currently available. We recently designed a cell-penetrating albumin and found that this modified albumin enters cells via the induction of macropinocytosis. Herein, we report on a novel system for delivering antigens based on cell-penetrating albumin-inducible macropinocytosis that allows larger amounts of antigens to be delivered to antigen-presenting cells. A treatment with cell-penetrating albumin significantly increased the permeability of ovalbumin (45 kDa) or dextran (2000 kDa) on monolayers derived from human oral squamous carcinoma cells. Flow cytometric analyses showed that the cell-penetrating albumin treatment resulted in a significant elevation in the amount of dextran that was delivered to two types of antigen-presenting cells. Finally, mice that had been sensitized by Japanese cedar pollen extract (JCPE) and cell-penetrating albumin showed a decline in the frequency of nose-rubbing against a subsequent intranasal administration of JCPE. These findings suggest that the sublingual administration of cell-penetrating albumin efficiently delivers antigens to antigen-presenting cells via the induction of macropinocytosis, resulting in an enhancement in the therapeutic effect of sublingual immunotherapy., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2022. Published by Elsevier B.V.)

Vibrational strong coupling and the formation of vibrational polaritons are a result of strong light-matter interaction between a cavity photon and a molecular vibrational mode. The Rabi splitting parameter, which reflects the microscopic light-matter interaction strength, reveals information about the molecular alignment and concerted vibrational motion inside the cavity. We have investigated vibrational strong coupling of 4-cyano-4'-octylbiphenyl liquid crystal molecules in isotropic and smectic A phases. We observed a ∼30% change in the Rabi splitting with the phase transition from isotropic to smectic A by controlling the temperature, together with the onset of polarization-dependent anisotropy of the Rabi splitting in the smectic A phase. Based on the estimated orientational distribution function, we show that the observed Rabi splitting difference in the isotropic and smectic A phases can only be explained by taking into account the influence of collective vibrational motion in the cavity, which affects the molecular properties under the vibrational strong coupling regime.

Niemann-Pick disease type C (NPC) is a fatal disorder with abnormal intracellular cholesterol trafficking resulting in neurodegeneration and hepatosplenomegaly. A cyclic heptasaccharide with different degrees of substitution of 2-hydroxypropyl groups, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), acts as a strong cholesterol solubilizer and is under investigation for treating this disease in clinical trials, but its physicochemical properties and ototoxicity remain a concern. Here, we evaluated the potential of mono-6-O-α-maltosyl-γ-CD (G2-γ-CD), a single-maltose-branched cyclic octasaccharide with a larger cavity than HP-β-CD, for treating NPC. We identified that G2-γ-CD ameliorated NPC manifestations in model mice and showed lower ototoxicity in mice than HP-β-CD. To investigate the molecular mechanisms of action behind the differential ototoxicity of these CDs, we performed cholesterol solubility analysis, proton nuclear magnetic resonance spectroscopy, and molecular modeling, and estimated that the cholesterol inclusion mode of G2-γ-CD maintained solely the 1:1 inclusion complex, whereas that of HP-β-CD shifted to the highly-soluble 2:1 complex at higher concentrations. We predicted the associations of these differential complexations of CDs with cholesterol with the profile of disease attenuation and of the auditory cell toxicity using specific cell models. We proposed that G2-γ-CD can serve as a fine-tuned cholesterol solubilizer for treating NPC, being highly biocompatible and physicochemically suitable for clinical application., Competing Interests: Conflict of Interest Statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Competing Interests: None

We have previously reported that amodiaquine, a compound that binds to the ligand-binding domain of a nuclear receptor Nurr1, attenuates inflammatory responses and neurological deficits after intracerebral hemorrhage (ICH) in mice. 1,1-Bis(3'-indolyl)-1-(p-chlorophenyl)methane (C-DIM12) is another Nurr1 ligand that recognizes a domain of Nurr1 different from the ligand-binding domain. In the present study, mice were treated daily with C-DIM12 (50 or 100 mg/kg, p.o.) or amodiaquine (40 mg/kg, i.p.), or twice daily with 1400 W (20 mg/kg, i.p.), an inducible nitric oxide synthase (iNOS) inhibitor, from 3 h after ICH induction by microinjection of collagenase into the striatum. C-DIM12 improved the recovery of neurological function and prevented neuron loss in the hematoma, while suppressed activation of microglia/macrophages and expression of inflammatory mediators interleukin-6 and CC chemokine ligand 2. In addition, C-DIM12 as well as amodiaquine preserved axonal structures in the internal capsule and axonal transport function. We also found that C-DIM12 and amodiaquine suppressed the increases of iNOS mRNA expression after ICH. Moreover, 1400 W improved neurological function and prevented neuron loss, activation of microglia/macrophages and axonal transport dysfunction. These results suggest that suppression of iNOS induction contributes to several features of the therapeutic effects of Nurr1 ligands., (© 2022. The Author(s).)

We developed a spacerless flow-cell cavity for the observation of vibrational strong coupling and demonstrate its availability in two samples with a C≡N bond: a metal complex (aq) and an ionic liquid. It is shown that the cavity length can be tuned over a wide range to investigate coupling with different order Fabry-Pérot cavity modes without reassembling the cavity. In the ionic liquid, analyses based on the coupled harmonic oscillator model with multiple vibrational modes show that the Rabi splitting parameters and the square root of the integrated absorption intensity are proportional among the three neighboring vibrational modes. Our spacerless cell structure simplifies the comparison of the different vibrational strong coupling measurements, such as the mode order dependence and the coupling to different molecular vibrations.

Chaperone-mediated autophagy (CMA) is a pathway in the autophagy-lysosome protein degradation system. CMA impairment has been implicated to play a role in spinocerebellar ataxia (SCA) pathogenesis. D-cysteine is metabolized by D-amino acid oxidase (DAO), leading to hydrogen sulfide generation in the cerebellum. Although D-cysteine alleviates the disease phenotypes in SCA-model mice, it remains unknown how hydrogen sulfide derived from D-cysteine exerts this effect. In the present study, we investigated the effects of D-cysteine and hydrogen sulfide on CMA activity using a CMA activity marker that we have established. D-cysteine activated CMA in Purkinje cells (PCs) of primary cerebellar cultures where DAO was expressed, while it failed to activate CMA in DAO-deficient AD293 cells. In contrast, Na 2 S, a hydrogen sulfide donor, activated CMA in both PCs and AD293 cells. Nuclear factor erythroid 2-related factor 2 (Nrf2) is known to be activated by hydrogen sulfide and regulate CMA activity. An Nrf2 inhibitor, ML385, prevented CMA activation triggered by D-cysteine and Na 2 S. Additionally, long-term treatment with D-cysteine increased the amounts of Nrf2 and LAMP2A, a CMA-related protein, in the mouse cerebellum. These findings suggest that hydrogen sulfide derived from D-cysteine enhances CMA activity via Nrf2 activation.

Significance: Intrinsic optical signals (IOS) generated in the cortical tissue as a result of various interacting metabolic processes are used extensively to elucidate the underlying mechanisms that govern neurovascular coupling. However, current IOS measurements still often rely on bulky, tabletop imaging systems, and there remains a dearth of studies in freely moving subjects. Lightweight, miniature head-mounted imaging devices provide unique opportunities for investigating cortical dynamics in small animals under a variety of naturalistic behavioral settings., Aim: The aim of this work was to monitor IOS in the somatosensory cortex of wild-type mice by developing a lightweight, biocompatible imaging device that readily lends itself to animal experiments in freely moving conditions., Approach: Herein we describe a method for realizing long-term IOS imaging in mice using a 0.54-g, compact, CMOS-based, head-mounted imager. The two-part module, consisting of a tethered sensor plate and a base plate, allows facile assembly prior to imaging sessions and disassembly when the sensor is not in use. LEDs integrated into the device were chosen to illuminate the cortical mantle at two different wavelengths in the visible regime (λcenter: 535 and 625 nm) for monitoring volume- and oxygenation state-dependent changes in the IOS, respectively. To test whether the system can detect robust cortical responses, we recorded sensory-evoked IOS from mechanical stimulation of the hindlimbs (HL) of anesthetized mice in both acute and long-term implantation conditions., Results: Cortical IOS recordings in the primary somatosensory cortex hindlimb receptive field (S1HL) of anesthetized mice under green and red LED illumination revealed robust, multiphasic profiles that were time-locked to the mechanical stimulation of the contralateral plantar hindpaw. Similar intrinsic signal profiles observed in S1HL at 40 days postimplantation demonstrated the viability of the approach for long-term imaging. Immunohistochemical analysis showed that the brain tissue did not exhibit appreciable immune response due to the device implantation and operation. A proof-of-principle imaging session in a freely behaving mouse showed minimal locomotor impediment for the animal and also enabled estimation of blood flow speed., Conclusions: We demonstrate the utility of a miniature cortical imaging device for monitoring IOS and related hemodynamic processes in both anesthetized and freely moving mice, cueing potential for applications to some neuroscientific studies of sensation and naturalistic behavior.

We examined the effect of an immunomodulator hydroxychloroquine, also known as a Nurr1 ligand and an autophagy inhibitor, on a mouse model of intracerebral hemorrhage (ICH). Daily administration of hydroxychloroquine (100 mg/kg, i.p.) from 3 h after induction of ICH alleviated neurological deficits of mice, increased the number of surviving neurons in the hematoma and prevented fragmentation of axon structures in the internal capsule. Unexpectedly, hydroxychloroquine did not inhibit either upregulation of pro-inflammatory mediators or autophagic responses in the brain. Hence, hydroxychloroquine may produce therapeutic effects on ICH primarily via neuroprotection including preservation of the axon tract integrity., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Hydrogen sulfide and polysulfides are increasingly recognized as bioactive signaling molecules to produce various actions and regulate (patho)physiological processes. Here we examined the effects of sodium sulfide (Na 2 S) and sodium trisulfide (Na 2 S 3 ) on an experimental model of intracerebral hemorrhage (ICH) in mice. Na 2 S or Na 2 S 3 (25 µmol/kg, intraperitoneally (i.p.)) was administered 30 min before ICH induction by intrastriatal injection of collagenase. We found that Na 2 S significantly ameliorated sensorimotor functions of mice after ICH. Histopathological examinations revealed that Na 2 S inhibited neuron loss in the striatum, prevented axon degeneration in the internal capsule, and ameliorated axonal transport dysfunction in the striatum and the cerebral cortex where the edge of hematoma was located. Although Na 2 S did not suppress accumulation of activated microglia/macrophages in the peri-hematoma region, it suppressed ICH-induced upregulation of inflammatory mediators such as C-X-C motif ligand 2. On the other hand, Na 2 S 3 did not ameliorate ICH-induced sensorimotor dysfunction. Although the effect of Na 2 S 3 on several parameters such as axon degeneration and axonal transport dysfunction was comparable to that of Na 2 S, Na 2 S 3 did not significantly inhibit neuron loss and upregulation of inflammatory mediators. These results suggest that the regulation of multiple pathological events is involved in the effect of Na 2 S leading to amelioration of neurological symptoms associated with ICH.

Clinical and basic research suggests that exercise is a safe behavioral intervention and is effective for improving cognitive function in cerebrovascular diseases, including subcortical ischemic vascular dementia (SIVD). However, most of the basic research uses young animals to assess the effects of exercise, although SIVD is an age-related disease. In this study, therefore, we used middle-aged mice to examine how treadmill exercise changes the cognitive function of SIVD mice. As a mouse model of SIVD, prolonged cerebral hypoperfusion was induced in 8-month-old male C57BL/6J mice by bilateral common carotid artery stenosis. A week later, the mice were randomly divided into two groups: a group that received 6-week treadmill exercise and a sedentary group for observation. After subjecting the mice to multiple behavioral tests (Y-maze, novel object recognition, and Morris water maze tests), the treadmill exercise training was shown to only be effective in ameliorating cognitive decline in the Y-maze test. We previously demonstrated that the same regimen of treadmill exercise was effective in young hypoperfused-SIVD mice for all three cognitive tests. Therefore, our study may indicate that treadmill exercise during cerebral hypoperfusion has only limited effects on cognitive function in aging populations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ohtomo, Ishikawa, Kinoshita, Chung, Hamanaka, Ohtomo, Takase, Wrann, Katsuki, Iwata, Lok, Lo and Arai.)

This review provides an overview of researches on the NR1 and NR4 nuclear receptors involved in the regulation of microglial functions. Nuclear receptors are attractive candidates for drug targets in the therapies of the central nervous system disorders, because the activation of these receptors is expected to regulate the functions and the phenotypes of microglia, by controlling the expression of specific gene subsets and also by regulating the cellular signaling mechanisms in a nongenomic manner. Several members of NR1 nuclear receptor subfamily have been examined for their ability to regulate microglial functions. For example, stimulation of vitamin D receptor inhibits the production of pro-inflammatory factors and increases the production of anti-inflammatory cytokines. Similar regulatory actions of nuclear receptor ligands on inflammation-related genes have also been reported for other NR1 members such as retinoic acid receptors, peroxisome proliferator-activated receptors (PPARs), and liver X receptors (LXRs). In addition, stimulation of PPARγ and LXRs may also result in increased phagocytic activities of microglia. Consistent with these actions, the agonists at nuclear receptors of NR1 subfamily are shown to produce therapeutic effects on animal models of various neurological disorders such as experimental allergic encephalomyelitis, Alzheimer's disease, Parkinson's disease, and ischemic/hemorrhagic stroke. On the other hand, increasing lines of evidence suggest that the stimulation of NR4 subfamily members of nuclear receptors such as Nur77 and Nurr1 also regulates microglial functions and alleviates neuropathological events in several disease models. Further advancement of these research fields may prove novel therapeutic opportunities., (© 2021 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.)