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Background: Eating habits are a contributing factor to obesity. Higher-priced menu items have better nutritional quality/balance, as the relationship between the price of food per serving and nutritional quality/balance has been reported. However, previous studies on the nutritional content of restaurant menu items did not focus on the relationship between the nutritional balance of menu items and prices. Therefore, this study aimed to investigate this relationship., Methods: The nutritional balance score (NBS) was defined and calculated according to each nutritional criterion of men and women aged 18-29 years, covering more than 2,000 menu items in 26 Japanese restaurant chains. Furthermore, NBS distribution by gender and restaurant brand, and the relationship between the menu item's NBS and price were assessed., Results: The results showed that the average NBS of the analyzed menu items differed between the criteria for men and women, with the menu items assessed based on men's criterion being more nutritionally balanced on average. The compositions of the top 10 menu items differed between men and women, and most were set menus or rice bowl menus, which were offered by fast-food restaurants. The relationship between price and NBS in most fast-food and casual restaurants was expressed as a concave function. The maximum NBS based on the criteria for men and women were 64.9 and 64.1, with prices of 639.9 and 530.3 yen, respectively., Discussion: NBS score increased with price to a certain level before decreasing, suggesting that the price at which NBS was the highest differed between men and women. The results of this study could contribute to the development of a methodology for healthy eating out practices, with a focus on price., Competing Interests: The authors declare that they have no competing interests., (© 2024 Ogasawara et al.)

The persistent symptoms of anxiety, depression, and fatigue that follow severe acute respiratory syndrome coronavirus 2 infection and accompany pulmonary inflammation pose significant clinical challenges. However, the correlation between pulmonary inflammation and mental health remains unclear. This study sought to examine the effects of intratracheal injection of lipopolysaccharide (LPS), a bacterial endotoxin, on anxiety-like behaviour in a mouse model suffering with pulmonary inflammation. The reactions of these animal models to new environments were evaluated using light-dark box and hole-board tests as anxiety-inducing stimuli. Microglial responses were evaluated via immunohistochemistry, and serum concentrations of tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) were measured. Both intraperitoneal and intratracheal injections of LPS induced anxiety-like behaviours, as indicated by the outcomes of the light-dark box and hole-board tests. Serum levels of TNF-α and IL-6 considerably increased following both injection routes. The protein levels of the 5-HT 2A and 5-HT 1A receptors, which are crucial for neuropsychological function, in the frontal cortex and hippocampus of mice remained unchanged following LPS injections. Notably, hippocampal levels of brain-derived neurotrophic factor (BDNF) remarkably decreased following LPS injections. In the lungs, the administration of LPS via the intratracheal route led to a significant rise in the number of white blood cells present in the bronchoalveolar lavage fluid compared to the intraperitoneal injection method. These findings suggest that inflammation induced by intratracheal LPS injection may lead to anxiety-like behaviours in mice, potentially involving mechanisms related to hippocampal BDNF expression, which contributes to anxiety after pulmonary inflammation., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Visualizing the distribution of small-molecule drugs in living cells is an important strategy for developing specific, effective, and minimally toxic drugs. As an alternative to fluorescence imaging using bulky fluorophores or cell fixation, stimulated Raman scattering (SRS) imaging combined with bisarylbutadiyne (BADY) tagging enables the observation of small molecules closer to their native intracellular state. However, there is evidence that the physicochemical properties of BADY-tagged analogues of small-molecule drugs differ significantly from those of their parent drugs, potentially affecting their intracellular distribution. Herein, we developed a modified BADY to reduce deviations in physicochemical properties (in particular, lipophilicity and membrane permeability) between tagged and parent drugs, while maintaining high Raman activity in live-cell SRS imaging. We highlight the practical application of this approach by revealing the nuclear distribution of a modified BADY-tagged analogue of JQ1, a bromodomain and extra-terminal motif inhibitor with applications in targeted cancer therapy, in living HeLa cells. The modified BADY, methoxypyridazyl pyrimidyl butadiyne (MPDY), revealed intranuclear JQ1, while BADY-tagged JQ1 did not show a clear nuclear signal. We anticipate that the present approach combining MPDY tagging with live-cell SRS imaging provides important insight into the behavior of intracellular drugs and represents a promising avenue for improving drug development.

Adult neurogenesis in the hippocampus and subventricular zone (SVZ) is impaired by intracerebroventricular administration of streptozotocin (icv-STZ) to rodents. Although neural cells in the several brain regions which connect with the hippocampus or SVZ is thought to be involved in the adult neurogenesis, few studies have investigated morphological alterations of glial cells in these areas. The present study revealed that icv-STZ induces reduction of neural progenitor cells and a dramatic increase in reactive astrocytes and microglia especially in the hippocampus and various hippocampus-connected brain areas. In contrast, there was no significant neuronal damage excluding demyelination of the stria medullaris. The results indicate the hippocampal neurogenesis impairment of this model might be occurred by activated glial cells in the hippocampus, or hippocampus-connected regions., 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 B.V. All rights reserved.)

Sterile alpha and Toll/interleukin receptor motif-containing protein 1 (SARM1) is a NAD+ hydrolase that plays a key role in axonal degeneration and neuronal cell death. We reported that c-Jun N-terminal kinase (JNK) activates SARM1 through phosphorylation at Ser-548. The importance of SARM1 phosphorylation in the pathological process of Parkinson's disease (PD) has not been determined. We thus conducted the present study by using rotenone (an inducer of PD-like pathology) and neurons derived from induced pluripotent stem cells (iPSCs) from healthy donors and a patient with familial PD PARK2 (FPD2). The results showed that compared to the healthy neurons, FPD2 neurons were more vulnerable to rotenone-induced stress and had higher levels of SARM1 phosphorylation. Similar cellular events were obtained when we used PARK2-knockdown neurons derived from healthy donor iPSCs. These events in both types of PD-model neurons were suppressed in neurons treated with JNK inhibitors, Ca2+-signal inhibitors, or by a SARM1-knockdown procedure. The degenerative events were enhanced in neurons overexpressing wild-type SARM1 and conversely suppressed in neurons overexpressing the SARM1-S548A mutant. We also detected elevated SARM1 phosphorylation in the midbrain of PD-model mice. The results indicate that phosphorylated SARM1 plays an important role in the pathological process of rotenone-induced neurodegeneration., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Japanese Biochemical Society.)

In traditional Japanese medicine, Rhei Rhizoma is used as a purgative, blood stasis-resolving and antipsychotic drug. The latter two properties are possibly related to anti-inflammatory effects. Microglia regulate inflammation in the central nervous system. M1 microglia induce inflammation, while M2 microglia inhibit inflammation and show neurotrophic effects. This study investigated the effects from water extracts of roots of cultivated Rheum species in Nagano Prefecture, Japan (strain C, a related strain to a Japanese cultivar, 'Shinshu-Daio'; and strain 29, a Chinese strain) and 3 kinds of Rhei Rhizoma available in the Japanese market, and also examined their constituents on the polarization of cultured microglia. All extracts significantly decreased M1 microglia, and strains C and 29 significantly increased M2 microglia. Furthermore, the extracts of both strains significantly increased the M2/M1 ratio. Among the constituents of Rhei Rhizoma, ( +)-catechin (2), resveratrol 4'-O-β-D-(6″-O-galloyl) glucopyranoside (5), isolindleyin (8), and physcion (15) significantly increased the M2/M1 ratio. The contents of the constituents in water extract of each strain were quantified using HPLC. The extracts of strains C and 29 contained relatively large amounts of 2 and 5; and 2, 8, and 15, respectively. This study showed the water extracts of roots of cultivated Rheum strains in Japan had the effects of M2 polarization of microglia, suggesting that these strains become the candidate to develop anti-inflammatory Rhei Rhizoma. Moreover, the suitable chemical composition to possess anti-inflammatory activity in the brain was clarified for the future development of new type of Rhei Rhizoma., (© 2023. The Author(s) under exclusive licence to The Japanese Society of Pharmacognosy.)

Palladium enolates derived from β-ketocarbonyl compounds serve as key intermediates in various catalytic asymmetric reactions. We found that the palladium enolate formed from β-ketoamide is stable in air and moisture and we applied this property to develop a peptide purification system using β-ketoamide as a small affinity tag in aqueous media. A solid-supported palladium complex successfully captured β-ketoamide-tagged molecules as palladium enolates and released them in high yield upon acid treatment. Optimum conditions for the catch and release of tagged peptides from a mixture of untagged peptides were established. To demonstrate the value of this methodology in identifying the binding site of a ligand to its target protein, we purified and identified a peptide containing the ligand-binding site from the tryptic digest of cathepsin B labelled with a covalent cathepsin B inhibitor containing a β-ketoamide tag., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

The stratum corneum (SC), the outermost layer of the skin, has an important function to provide a barrier against dry environments. To evaluate the barrier function and the skin condition, it is crucial to investigate the ability of SC to absorb and retain water. In this study, we demonstrate stimulated Raman scattering (SRS) imaging of three-dimensional SC structure and water distribution when water is absorbed into dried SC sheets. Our results show that the process of water absorption and retention is dependent on the specific sample and can be spatially heterogeneous. We also found that acetone treatment leads to spatially homogeneous retention of water. These results suggest the great potential of SRS imaging in diagnosing skin conditions.

Plants can rapidly respond to different stresses by activating multiple signaling and defense pathways. The ability to directly visualize and quantify these pathways in real time using bioorthogonal probes would have practical applications, including characterizing plant responses to both abiotic and biotic stress. Fluorescence-based labels are widely used for tagging of small biomolecules but are relatively bulky and with potential effects on their endogenous localization and metabolism. This work describes the use of deuterium- and alkyne-derived fatty acid Raman probes to visualize and track the real-time response of plants to abiotic stress within the roots. Relative quantification of the respective signals could be used to track their localization and overall real-time responses in their fatty acid pools due to drought and heat stress without labor-intensive isolation procedures. Their overall usability and low toxicity suggest that Raman probes have great untapped potential in the field of plant bioengineering., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Parkinson's disease (PD) is characterized by motor symptoms based on a loss of nigrostriatal dopaminergic neurons and by non-motor symptoms which precede motor symptoms. Neurodegeneration accompanied by an accumulation of α-synuclein is thought to propagate from the enteric nervous system to the central nervous system. The pathogenesis in sporadic PD remains unknown. However, many reports indicate various etiological factors, such as oxidative stress, inflammation, α-synuclein toxicity and mitochondrial impairment, drive neurodegeneration. Exposure to heavy metals contributes to these etiopathogenesis and increases the risk of developing PD. Metallothioneins (MTs) are cysteine-rich metal-binding proteins; MTs chelate metals and inhibit metal-induced oxidative stress, inflammation and mitochondrial dysfunction. In addition, MTs possess antioxidative properties by scavenging free radicals and exert anti-inflammatory effects by suppression of microglial activation. Furthermore, MTs recently received attention as a potential target for attenuating metal-induced α-synuclein aggregation. In this article, we summarize MTs expression in the central and enteric nervous system, and review protective functions of MTs against etiopathogenesis in PD. We also discuss neuroprotective strategies for the prevention of central dopaminergic and enteric neurodegeneration by targeting MTs. This review highlights multifunctional MTs as a target for the development of disease-modifying drugs for PD.

Background : Myocardial blood flow quantification (MBF) is one of the distinctive features for cardiac positron emission tomography. The MBF calculation is mostly obtained by estimating the input function from the time activity curve in dynamic scan. However, there is a substantial risk of count-loss because the high radioactivity pass through the left ventricular (LV) cavity within a short period. We aimed to determine the optimal intraventricular activity using the noise equivalent count rate (NECR) analysis with simplified phantom model. Methods : Positron emission tomography computed tomography scanner with LYSO crystal and time of flight was used for phantom study. 150 MBq/mL of 13 N was filled in 10 mL of syringe, placed in neck phantom to imitate end-systolic small LV. 3D list-mode acquisition was repeatedly performed along radioactive decay. Net true and random count rate were calculated and compared to the theoretical activity in the syringe. NECR curve analysis was used to determine the optimal radioactive concentration. Result : The attenuation curves showed good correlation to the theoretical activity between 20 to 370, and 370 to 740 MBq (r 2 =1.0 ± 0.0001, p<0.0001; r 2 =0.99 ± 0.0001, p<0.0001 for 20 to 370, and 370 to 740, respectively), while did not over 740 MBq (p=0.62). NECR analysis revealed that the peak rate was at 2.9 Mcps, there at the true counts were significantly suppressed. The optimal radioactive concentration was determined as 36 MBq/mL. Conclusion : Simulative analysis for high-dose of 13 N using the phantom imitating small LV confirmed that the risk of count-loss was increased. The result can be useful information in assessing the feasibility of MBF quantification in clinical routine., Competing Interests: None., (© The Japanese Society of Nuclear Cardiology 2023.)

S-Alk(en)ylcysteine sulfoxides (CSOs), such as methiin, alliin, and isoalliin, are health-beneficial natural products biosynthesized in the genus Allium. Here, we report the induction of multiple callus tissue lines from three Allium vegetables, onion (A. cepa), Welsh onion (A. fistulosum), and Chinese chive (A. tuberosum), and their ability to accumulate CSOs. Callus tissues were initiated and maintained in the presence of picloram and 2-isopentenyladenine as auxin and cytokinin, respectively. For all plant species tested, the callus tissues almost exclusively accumulated methiin as CSO, while the intact plants contained a substantial amount of isoalliin together with methiin. These results suggest that the cellular developmental conditions and the regulatory mechanisms required for the biosynthesis of methiin are different from those of alliin and isoalliin. The methiin content in the callus tissues of onion and Welsh onion was much higher compared to that in the intact plants, and its cellular concentration could be estimated as 1.9-21.7 mM. The activity of alliinase that degrades CSOs in the callus tissues was much lower than that of the intact plants for onion and Welsh onion, but at similar levels as in the intact plants for Chinese chive. Our findings that the callus tissues of onion and Welsh onion showed high methiin content and low alliinase activity highlighted their potential as a plant-based system for methiin production., (© 2022. The Author(s) under exclusive licence to The Japanese Society of Pharmacognosy.)

Parkinson's disease (PD) is a progressive neurodegenerative disease of both the central and peripheral / enteric nervous systems. Oxidative stress and neuroinflammation are associated with the pathogenesis of PD, suggesting that anti-oxidative and anti-inflammatory compounds could be neuroprotective agents for PD. Eucommia ulmoides (EU) is a traditional herbal medicine which exerts neuroprotective effects by anti-inflammatory and anti-oxidative properties. Our previous study showed that treatment with chlorogenic acid, a component of EU, protected against neurodegeneration in the central and enteric nervous systems in a PD model. In this study, we examined the effects of EU extract (EUE) administration on dopaminergic neurodegeneration, glial response and α-synuclein expression in the substantia nigra pars compacta (SNpc), and intestinal enteric neurodegeneration in low-dose rotenone-induced PD model mice. Daily oral administration of EUE ameliorated dopaminergic neurodegeneration and α-synuclein accumulation in the SNpc. EUE treatment inhibited rotenone-induced decreases in the number of total astrocytes and in those expressing the antioxidant molecule metallothionein. EUE also prevented rotenone-induced microglial activation. Furthermore, EUE treatment exerted protective effects against intestinal neuronal loss in the PD model. These results suggest that EU exerts neuroprotective effects in the central and enteric nervous systems of rotenone-induced parkinsonism mice, in part by glial modification., Competing Interests: No potential conflict of interest relevant to this article was reported.

The small biomolecule methionine (Met) is a fundamental amino acid required for a vast range of biological processes such as protein synthesis, cancer metabolism, and epigenetics. However, it is still difficult to visualize the subcellular distribution of small biomolecules including Met in a minimally invasive manner. Here, we demonstrate stimulated Raman scattering (SRS) imaging of cellular uptake of deuterated methionine (d 8 -Met) in live HeLa cells by way of comparison to the previously used alkyne-labeled Met analogue─homopropargylglycine (Hpg). We show that the solutions of d 8 -Met and Hpg have similar SRS signal intensities. Furthermore, by careful image analysis with background subtraction, we succeed in the SRS imaging of cellular uptake of d 8 -Met with a much greater signal intensity than Hpg, possibly reflecting the increased and minimally invasive uptake kinetics of d 8 -Met compared with Hpg. We anticipate that d 8 -Met and other deuterated biomolecules will be useful for investigating metabolic processes with subcellular resolution.

The timing of surgery for ventricular septal rupture (VSR) after acute myocardial infarction (AMI) remains controversial. This study investigated the benefits and risks of delayed surgery for post-AMI VSR and examined differences in echocardiographic findings between early and delay groups.A total of 38 consecutive patients with post-AMI VSR who underwent surgery at our hospital between May 2003 and November 2020 were retrospectively analyzed. Our strategy was to delay surgery until 2 weeks after AMI. If patients demonstrated organ dysfunction, we considered early surgery. Patients were divided into early (n = 20; 53%) and delay (n = 18; 47%) groups. Risks and benefits were investigated based on echocardiographic findings during the waiting period. The delay group had more preoperative intravenous catheter infections (P = 0.008) but fewer reoperations (P = 0.02) and lower operative mortality (P = 0.04) than the early group. The VSR defect diameter and total pulmonary blood flow to total systemic blood flow (Qp/Qs) increased in both groups while waiting. Nevertheless, the early group had a significantly higher Qp/Qs change rate than the delay group (P = 0.05). The 30 day and hospital mortality rates were 5.3% and 13.2%, respectively.The VSR defect diameter and Qp/Qs in both groups increased with time and can therefore become risk factors. Nonetheless, the benefit of waiting exceeded the risk because our outcomes were better than those previously reported.

Anxiety-like behavior induced by a combination of doxorubicin and cyclophosphamide may be mediated by serotonin (5-HT) 2A receptor hyperactivity. The anxiolytic effects of fluoxetine may be inhibited by this combination. The present study examined the mechanisms underlying anxiety-like behavior induced by the combination doxorubicin and cyclophosphamide in rats. Anxiety-like behavior was induced during a light-dark test by the doxorubicin and cyclophosphamide treatment (once a week for 2 weeks). 5-HT 2A receptor and 5-HT 2A receptor-mediated extracellular signal-related kinase (ERK)1/2 levels were measured using Western blotting. 5-HT reuptake activity in fluoxetine-treated rats was also examined using microdialysis. ( ±)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane, a 5-HT 2A receptor agonist, induced anxiety-like behavior. The fluoxetine treatment increased extracellular 5-HT concentrations in the hippocampus of vehicle- and doxorubicin and cyclophosphamide-treated rats. 5-HT transporter levels in the hippocampus were not affected by chemotherapy. The doxorubicin and cyclophosphamide treatment did not alter 5-HT 2A receptor levels in the frontal cortex. However, chemotherapy increased 5-HT 2A receptor-mediated ERK1/2 phosphorylation levels significantly more than the vehicle treatment. The present results suggest that anxiety-like behavior induced by the combination of doxorubicin and cyclophosphamide is mediated by 5-HT 2A receptor hyperactivity without an increase in 5-HT 2A receptor levels in rats., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

High mobility group box-1 (HMGB1) is a ubiquitous non-histone nuclear protein that plays a key role as a transcriptional activator, with its extracellular release provoking inflammation. Inflammatory responses are essential in methamphetamine (METH)-induced acute dopaminergic neurotoxicity. In the present study, we examined the effects of neutralizing anti-HMGB1 monoclonal antibody (mAb) on METH-induced dopaminergic neurotoxicity in mice. BALB/c mice received a single intravenous administration of anti-HMGB1 mAb prior to intraperitoneal injections of METH (4 mg/kg × 2, at 2-h intervals). METH injections induced hyperthermia, an increase in plasma HMGB1 concentration, degeneration of dopaminergic nerve terminals, accumulation of microglia, and extracellular release of neuronal HMGB1 in the striatum. These METH-induced changes were significantly inhibited by intravenous administration of anti-HMGB1 mAb. In contrast, blood-brain barrier disruption occurred by METH injections was not suppressed. Our findings demonstrated the neuroprotective effects of anti-HMGB1 mAb against METH-induced dopaminergic neurotoxicity, suggesting that HMGB1 could play an initially important role in METH toxicity., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Mycotic aneurysms (MAs) are relatively rare but life-threatening. Some recent reports have described the use of endovascular therapy for their treatment; however, this still is a controversial treatment, and a definite target population has not been determined. Methods: We performed surgery on 34 patients with MAs from March 2005 to March 2019. Twenty patients who underwent open surgery (OS) first comprised the OS group, and 14 patients who underwent endovascular therapy first comprised the stent-graft (SG) group. We analyzed between-group differences, long-term outcomes, and risk factors for death retrospectively. Patients in the OS group had a higher initial white blood cell count than those in the SG group (p = 0.047). The SG group had more patients with a low albumin concentration (≤2.0 mg/dL) than did the OS group (p = 0.026). Results: There were no significant differences in the operative mortality rates between the groups (p = 0.773). Additional procedures were required more often in the SG than the OS group (p = 0.0013). The overall survival rate as estimated by the Kaplan-Meier method was 88% at 1 month, 67% at 1 year, 57% at 3 years, and 45% at 10 years. In the univariable analysis, chronic obstructive pulmonary disease (COPD) was a risk factor for death (p = 0.003). Conclusions: Endovascular therapy for MAs produced reasonable outcomes when patient selection was based on the activity level, nutritional condition, and degree of inflammation. Endovascular therapy may become an option for patients with a low albumin concentration or COPD despite the fact that additional procedures may be needed.

Glutathione (GSH) is the most abundant intrinsic antioxidant in the central nervous system, and its substrate cysteine readily becomes the oxidized dimeric cystine. Since neurons lack a cystine transport system, neuronal GSH synthesis depends on cystine uptake via the cystine/glutamate exchange transporter (xCT), GSH synthesis, and release in/from surrounding astrocytes. Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), a detoxifying master transcription factor, is expressed mainly in astrocytes and activates the gene expression of various phase II drug-metabolizing enzymes or antioxidants including GSH-related molecules and metallothionein by binding to the antioxidant response element (ARE) of these genes. Accumulating evidence has shown the involvement of dysfunction of antioxidative molecules including GSH and its related molecules in the pathogenesis of Parkinson's disease (PD) or parkinsonian models. Furthermore, we found several agents targeting GSH synthesis in the astrocytes that protect nigrostriatal dopaminergic neuronal loss in PD models. In this article, the neuroprotective effects of supplementation and enhancement of GSH and its related molecules in PD pathology are reviewed, along with introducing new experimental findings, especially targeting of the xCT-GSH synthetic system and Nrf2-ARE pathway in astrocytes.

Although Raman spectroscopy has been used for the quantitative analysis of samples in many fields, including material science, biomedical, and pharmaceutical research, its low sensitivity hindered the application of the analytical capability for high-throughput screening. Here, we developed a high-throughput Raman screening system that can analyze hundreds of specimens in a multiwell plate simultaneously. Multiple high numerical aperture (NA) lenses are assembled under each well in the multiwell plate to detect Raman scattering simultaneously with high sensitivity. The Raman spectrum of 192 samples loaded on a standard 384-well plate can be analyzed simultaneously. With the developed system, the throughput of Raman measurement was significantly improved (about 100 times) compared to conventional Raman instruments based on a single-point measurement. By using the developed system, we demonstrated high-throughput Raman screening to investigate drug polymorphism and identify a small-molecule binding site in a protein. Furthermore, the same system was used to demonstrate high-speed chemical mapping of a centimeter-sized pork slice., (© 2021. The Author(s).)

The translation inhibitor rocaglamide A (RocA) has shown promising antitumor activity because it uniquely clamps eukaryotic initiation factor (eIF) 4A onto polypurine RNA for selective translational repression. As eIF4A has been speculated to be a unique target of RocA, alternative targets have not been investigated. Here, we reveal that DDX3 is another molecular target of RocA. Proximity-specific fluorescence labeling of an O-nitrobenzoxadiazole-conjugated derivative revealed that RocA binds to DDX3. RocA clamps the DDX3 protein onto polypurine RNA in an ATP-independent manner. Analysis of a de novo-assembled transcriptome from the plant Aglaia, a natural source of RocA, uncovered the amino acid critical for RocA binding. Moreover, ribosome profiling showed that because of the dominant-negative effect of RocA, high expression of eIF4A and DDX3 strengthens translational repression in cancer cells. This study indicates that sequence-selective clamping of DDX3 and eIF4A, and subsequent dominant-negative translational repression by RocA determine its tumor toxicity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Lactoferrin (Lf) is an iron-binding glycoprotein mainly found in exocrine secretions and the secondary granules of neutrophils. In the central nervous system (CNS), expression of the Lf protein has been reported in the lesions of some neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as in the aged brain. Lf is primarily considered an iron chelator, protecting cells from potentially toxic iron or iron-requiring microorganisms. Other biological functions of Lf include immunomodulation and transcriptional regulation. However, the roles of Lf in the CNS have yet to be fully clarified. In this study, we raised an antiserum against mouse Lf and investigated the immunohistochemical localization of Lf-like immunoreactivity (Lf-LI) throughout the CNS of adult mice. Lf-LI was found in some neuronal populations throughout the CNS. Intense labeling was found in neurons in the olfactory systems, hypothalamic nuclei, entorhinal cortex, and a variety of brainstem nuclei. This study provides detailed information on the Lf-LI distribution in the CNS, and the findings should promote further understanding of both the physiological and pathological significance of Lf in the CNS., Competing Interests: No potential conflict of interest relevant to this article was reported.

Background: Cancer patients can suffer from psychological and cognitive disorders after chemotherapy, which influence quality of life., Objective: Oxidative stress may contribute to the psychological and cognitive disorders induced in rats by chemotherapy. In the present study, we examined the effects of N-acetylcysteine, an anti-oxidant, on anxiety-like behavior and cognitive impairment in rats treated with a combination of doxorubicin and cyclophosphamide., Methods: Rats were intraperitoneally injected with doxorubicin and cyclophosphamide once a week for 2 weeks. The light-dark test and the novel location recognition test were used to assess anxiety-like behavior and spatial cognition, respectively. The rats' hippocampal levels of glutathione (GSH) and glutathione disulfide (GSSG) were measured using a GSSG/GSH quantification kit., Results: Combined treatment with doxorubicin and cyclophosphamide produced anxiety-like behavior and cognitive impairment in rats. N-acetylcysteine reversed the anxiety-like behavior and inhibition of novel location recognition induced by the combination treatment. Furthermore, the combination of doxorubicin and cyclophosphamide significantly reduced the rats' hippocampal GSH/GSSG ratios. N-acetylcysteine reversed the reduction in the GSH/GSSG ratio seen in the doxorubicin and cyclophosphamide-treated rats., Conclusion: These results suggest that N-acetylcysteine inhibits doxorubicin and cyclophosphamide-induced anxiety-like behavior and cognitive impairment by reducing oxidative stress in the hippocampus., (© 2020 S. Karger AG, Basel.)

Parkinson's disease (PD) is a progressive neurodegenerative disease with motor symptoms, such as tremor, akinesia/bradykinesia, rigidity and postural instability due to a loss of nigrostriatal dopaminergic neurons; PD patients also exhibit non-motor symptoms, such as hyposmia, orthostatic hypotension and constipation, which precede motor symptoms. Pathologically, Lewy bodies and neurites, which contains α-synuclein, are observed in the central and peripheral nervous system. To date, it is hypothesized that PD pathology appears first in the olfactory bulb and the enteric nervous system, and propagates progressively through the substantia nigra to finally reach the cerebral cortex. Major medications at present are nosotropic treatments to improve motor dysfunction in PD. Therefore, development of disease-modifying drug is required to slow or prevent PD progression. Astrocytes are known to play an important role in the maintenance of the neuronal environment and exert neuroprotective effects by production of antioxidants and neurotrophic factors and clearing toxic molecules. In the previous study, we demonstrated that astrocytes produced antioxidative molecules metallothionein (MT)-1/2 in response to oxidative stress and protected dopaminergic neurons against oxidative stress. MTs are cysteine-rich proteins possessing antioxidative properties. MTs bind to metals such as zinc (Zn) and copper (Cu) and function in metal homeostasis and detoxification; MTs regulate Zn-mediated transcriptional activation of various genes. Recently, it is reported that MTs prevent Cu-induced aggregation of α-synuclein. In this article, we review a new therapeutic strategy of neuroprotection in PD by targeting MTs in astrocytes.

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. The loss of nigrostriatal dopaminergic neurons produces its characteristic motor symptoms, but PD patients also have non-motor symptoms such as constipation and orthostatic hypotension. The pathological hallmark of PD is the presence of α-synuclein-containing Lewy bodies and neurites in the brain. However, the PD pathology is observed in not only the central nervous system (CNS) but also in parts of the peripheral nervous system such as the enteric nervous system (ENS). Since constipation is a typical prodromal non-motor symptom in PD, often preceding motor symptoms by 10-20 years, it has been hypothesized that PD pathology propagates from the ENS to the CNS via the vagal nerve. Discovery of pharmacological and other methods to halt this progression of neurodegeneration in PD has the potential to improve millions of lives. Astrocytes protect neurons in the CNS by secretion of neurotrophic and antioxidative factors. Similarly, astrocyte-like enteric glial cells (EGCs) are known to secrete neuroprotective factors in the ENS. In this article, we summarize the neuroprotective function of astrocytes and EGCs and discuss therapeutic strategies for the prevention of neurodegeneration in PD targeting neurotrophic and antioxidative molecules in glial cells., Competing Interests: No potential conflict of interest relevant to this article was reported.

Recently, it has been reported that dysfunction of astrocytes is involved vulnerability of neuronal cells in several neurological disorders. Glutathione (GSH) is the most abundant intrinsic antioxidant in the central nervous system, and its substrate cysteine is readily becomes the oxidized dimeric cystine. Since neurons lack a cystine transport system, neuronal GSH synthesis depends on cystine uptake via the cystine/glutamate exchange transporter (xCT), GSH synthesis and release in/from surrounding astrocytes. The expression and release of the zinc-binding protein metallothionein (MT) in astrocytes, which is a strong antioxidant, is induced and exerts neuroprotective in the case of dopaminergic neuronal damage. In addition, the transcription factor Nrf2 induces expression of MT-1 and GSH related molecules. We previously revealed that several antiepileptic drugs, serotonin 5-HT1A receptor agonists, plant-derived chemicals (phytochemicals) increased xCT expression, Nrf2 activation, GSH or MT expression and release in/from astrocytes, and exerted a neuroprotective effect against dopaminergic neurodegeneration in Parkinson's disease model. Our serial studies on neuroprotection via antioxidant defense mechanism of astrocytes have found three target molecular systems of astrocytes for neuroprotection: (1) xCT-GSH synthetic system, (2) Nrf2 system and (3) 5-HT1A receptor-Nrf2-MT system, 5-HT1A-S100β system. In this article, possible neuroprotective strategy for Parkinson's disease has been reviewed targeting antioxidative molecules in astrocytes.

Parkinson's disease (PD) is the second most common neurodegenerative disease. PD patients exhibit motor symptoms such as akinesia/bradykinesia, tremor, rigidity, and postural instability due to a loss of nigrostriatal dopaminergic neurons. Although the pathogenesis in sporadic PD remains unknown, there is a consensus on the involvement of non-neuronal cells in the progression of PD pathology. Astrocytes are the most numerous glial cells in the central nervous system. Normally, astrocytes protect neurons by releasing neurotrophic factors, producing antioxidants, and disposing of neuronal waste products. However, in pathological situations, astrocytes are known to produce inflammatory cytokines. In addition, various studies have reported that astrocyte dysfunction also leads to neurodegeneration in PD. In this article, we summarize the interaction of astrocytes and dopaminergic neurons, review the pathogenic role of astrocytes in PD, and discuss therapeutic strategies for the prevention of dopaminergic neurodegeneration. This review highlights neuron-astrocyte interaction as a target for the development of disease-modifying drugs for PD in the future.

Mirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA), is known to activate serotonin (5-HT) 1A receptor. Our recent study demonstrated that stimulation of astrocytic 5-HT1A receptors promoted astrocyte proliferation and upregulated antioxidative property in astrocytes to protect dopaminergic neurons against oxidative stress. Here, we evaluated the neuroprotective effects of mirtazapine against dopaminergic neurodegeneration in models of Parkinson's disease (PD). Mirtazapine administration attenuated the loss of dopaminergic neurons in the substantia nigra and increased the expression of the antioxidative molecule metallothionein (MT) in the striatal astrocytes of 6-hydroxydopamine (6-OHDA)-injected parkinsonian mice via 5-HT1A receptors. Mirtazapine protected dopaminergic neurons against 6-OHDA-induced neurotoxicity in mesencephalic neuron and striatal astrocyte cocultures, but not in enriched neuronal cultures. Mirtazapine-treated neuron-conditioned medium (Mir-NCM) induced astrocyte proliferation and upregulated MT expression via 5-HT1A receptors on astrocytes. Furthermore, treatment with medium from Mir-NCM-treated astrocytes protected dopaminergic neurons against 6-OHDA neurotoxicity, and these effects were attenuated by treatment with a MT-1/2-specific antibody or 5-HT1A antagonist. Our study suggests that mirtazapine could be an effective disease-modifying drug for PD and highlights that astrocytic 5-HT1A receptors may be a novel target for the treatment of PD.

Abstract: Hospital-acquired infections caused by extended-spectrum β-lactamase (ESBL)-producing Escherichia coli are a global problem. Healthy people can carry ESBL-producing E. coli in the intestines; thus, E. coli from healthy people can potentially cause hospital-acquired infections. Therefore, the transmission routes of ESBL-producing E. coli from healthy persons should be determined. A foodborne outbreak of human norovirus (HuNoV) GII occurred at a restaurant in Shizuoka, Japan, in 2018. E. coli O25:H4 was isolated from some of the HuNoV-infected customers. Pulsed-field gel electrophoresis showed that these E. coli O25:H4 strains originated from one clone. Because the only epidemiological link among the customers was eating food from this restaurant, the customers were concurrently infected with E. coli O25:H4 and HuNoV GII via the restaurant food. Whole genome analysis revealed that the E. coli O25:H4 strains possessed genes for regulating intracellular iron and expressing the flagellum and flagella. Extraintestinal pathogenic E. coli often express these genes on the chromosome. Additionally, the E. coli O25:H4 strains had plasmids harboring nine antimicrobial resistance genes. These strains harbored ESBL-encoding blaCTX-M-14 genes on two loci of the chromosome and had higher ESBL activity. Multilocus sequence typing and fimH subtyping revealed that the E. coli O25:H4 strains from the outbreak belonged to the subclonal group, ST131-fimH30R, which has been driving ESBL epidemics in Japan. Because the E. coli O25:H4 strains isolated in the outbreak belonged to a subclonal group spreading in Japan, foods contaminated with ESBL-producing E. coli might contribute to spreading these strains among healthy persons. The isolated E. coli O25:H4 strains produced ESBL and contained plasmids with multiple antimicrobial resistance genes, which may make it difficult to select antimicrobials for treating extraintestinal infections caused by these strains., (Copyright ©, International Association for Food Protection.)

Crossed cerebellar diaschisis (CCD) is a state of hypoperfusion and hypometabolism in the contralesional cerebellar hemisphere caused by a supratentorial lesion, but its pathophysiology is not fully understood. We evaluated chronological changes in cerebellar blood flow (CbBF) and gene expressions in the cerebellum using a rat model of transient middle cerebral artery occlusion (MCAO). CbBF was analyzed at two and seven days after MCAO using single photon emission computed tomography (SPECT). DNA microarray analysis and western blotting of the cerebellar cortex were performed and apoptotic cells in the cerebellar cortex were stained. CbBF in the contralesional hemisphere was significantly decreased and this lateral imbalance recovered over one week. Gene set enrichment analysis revealed that a gene set for "oxidative phosphorylation" was significantly upregulated while fourteen other gene sets including "apoptosis", "hypoxia" and "reactive oxygen species" showed a tendency toward upregulation in the contralesional cerebellum. MCAO upregulated the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in the contralesional cerebellar cortex. The number of apoptotic cells increased in the molecular layer of the contralesional cerebellum. Focal cerebral ischemia in our rat MCAO model caused CCD along with enhanced expression of genes related to oxidative stress and apoptosis.

Epidemiological studies demonstrated that pesticide exposure, such as rotenone and paraquat, increases the risk of Parkinson's disease (PD). Chronic systemic exposure to rotenone, a mitochondrial complex I inhibitor, could reproduce many features of PD. However, the adoption of the models is limiting because of variability in animal sensitivity and the inability of other investigators to consistently reproduce the PD neuropathology. In addition, most of rotenone models were produced in rats. Here, we tried to establish a high-reproducible rotenone model using C57BL/6J mice. The rotenone mouse model was produced by chronic systemic exposure to a low dose of rotenone (2.5 mg/kg/day) for 4 weeks by subcutaneous implantation of rotenone-filled osmotic mini pump. The rotenone-treated mice exhibited motor deficits assessed by open field, rotarod and cylinder test and gastrointestinal dysfunction. Rotenone treatment decreased the number of dopaminergic neuronal cells in the substantia nigra pars compacta (SNpc) and lesioned nerve terminal in the striatum. In addition, we observed significant reduction of cholinergic neurons in the dorsal motor nucleus of the vagus (DMV) and the intestinal myenteric plexus. Moreover, α-synuclein was accumulated in neuronal soma in the SNpc, DMV and intestinal myenteric plexus in rotenone-treated mice. These data suggest that the low-dose rotenone mouse model could reproduce behavioral and central and peripheral neurodegenerative features of PD and be a useful model for investigation of PD pathogenesis.

Bisphenol A diglycidyl ether (BADGE) is an epoxy resin used for the inner coating of canned food and beverages. BADGE can easily migrate from the containers and become a contaminant. In this study, we examined the effects of BADGE exposure to the dams on the behavioral, structural, and developmental abnormalities in the offspring. Female pregnant mice were fed with a diet containing BADGE (0.15 or 1.5 mg/kg/day) during gestation and lactation periods. In an open field test, the time spent in the corner area significantly increases in male mice of high-dose BADGE group at 5 weeks old. The histological analysis using offspring brain at postnatal day 1 delivered from BADGE (1.5 mg/kg/day)-treated dams demonstrates that positive signals of Forkhead box P2- and COUP-TF interacting protein 2 are restricted in each cortical layer, but not in the control brain. In addition, the maternal BADGE exposure reduces nestin-positive fibers of the radial glia and T-box transcription factor 2-positive intermediate progenitors in the inner subventricular zone. Furthermore, a direct BADGE exposure promotes neurite outgrowth and neuronal connection in the primary cultured cortical neurons. These data suggest that maternal BADGE exposure can accelerate neuronal differentiation in fetuses and induce anxiety-like behavior in juvenile mice., 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 © 2020 Elsevier Ltd. All rights reserved.)

For chemical modification of cysteines in a protein, the regioselectivity among cysteine residues on the protein surface is an issue to be considered. To elucidate the determinants of cysteine reactivities on protein surfaces, we have investigated the chemical modification of the adenylate kinase A55C/C77S/V169C mutant as an experimental model. Although Cys55 and Cys169 are commonly located on the protein surface, Cys55 showed the ca. 3-6-fold higher reactivity compared to Cys169 in a reaction with a pyrene derivative. By a further conjugation of a phenanthroline derivative into the vacant Cys thiol, fluorescence quenching was attained by a pyrene-phenanthroline interaction that occurred by the conformational change of the protein. The K50A mutation further enhanced the regioselectivity of pyrene conjugation in Cys55, which is attributed to the effects of structural flexibility in the vicinity of Cys55 on its reactivity. To regioselectively conjugate different types of synthetic molecules onto the surface of a protein, perturbation in the local structural flexibility around the conjugation sites will be a useful strategy.

Objectives　The present study examined factors that affect learning about dental caries and periodontal disease before or after graduation or completion of training for dietitians and registered dietitians.Methods　A questionnaire survey was conducted with members of the Aomori Prefectural Dietetic Association between October and November 2019, and 276 participants were included in the analysis. A multiple logistic regression analysis was performed to assess the characteristics associated with learning about dental caries and periodontal disease; odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. The following independent variables were assessed: age (<30, 30-39, 40-49, 50-59, or ≥60 years), license (dietitian or registered dietitian), and occupational field (medical institution [nutrition management or food service], administrative agency, nursing care insurance facility, school-related work, training instructor in training facility for dietitians and registered dietitians, or other).Results　The multiple logistic regression analysis showed that dietitians and registered dietitians who had learned about dental caries and periodontal disease during training tended to be below the age of 40 years and have a registered dietitian license (dental caries: OR=2.79, 95% CI=1.08-7.24; periodontal disease: OR=6.51, 95% CI=1.71-24.84). Furthermore, dietitians and registered dietitians who had learned about dental caries and periodontal disease after graduation or training completion tended to be over the age of 40, have studied at a training facility (dental caries: OR=3.21, 95% CI=1.65-6.27; periodontal disease: OR=3.06, 95% CI=1.32-7.12), and be employed in the field of school-related work (dental caries: OR=4.23, 95% CI=1.03-17.27; periodontal disease: OR=5.56, 95% CI=1.15-26.98).Conclusions　To facilitate increased cooperation among practitioners in the fields of nutrition and dental health, necessary opportunities for learning about dental caries and periodontal disease alongside experts should be provided to those who do not have a registered dietitian license and have not studied at training facilities.

Astrocytes exert neuroprotective effects through production of antioxidant molecules and neurotrophic factors. A recent study showed that stimulation of astrocyte serotonin 1A (5-HT1A) receptors promotes astrocyte proliferation and upregulation of the antioxidant molecules metallothionein (MT)-1,2, which protect dopaminergic neurons against oxidative stress. Rotigotine, an anti-parkinsonian drug, can bind to dopamine and 5-HT1A receptors. In this study, we examined neuroprotective effects of rotigotine in models of Parkinson's disease and involvement of astrocyte 5-HT1A receptors in neuroprotective effects of rotigotine against dopaminergic neurodegeneration. Rotigotine increased the number of astrocytes and MT-1,2 expression in cultured astrocytes. Pretreatment with conditioned media from rotigotine-treated astrocytes significantly inhibited 6-hydroxydopamine (6-OHDA)-induced dopaminergic neurotoxicity. These effects were completely blocked by a 5-HT1A antagonist or MT-1,2 specific antibody. Subcutaneous administration of rotigotine increased MT-1,2 expression in striatal astrocytes and prevented reduction of dopaminergic neurons in the substantia nigra of a 6-OHDA-lesioned mouse model of Parkinson's disease. These effects were blocked by co-administration with a 5-HT1A antagonist. These results suggest that rotigotine exerts neuroprotective effects through upregulation of MT expression in astrocytes by targeting 5-HT1A receptors. Our findings provide a possible therapeutic application of rotigotine to prevent dopaminergic neurodegeneration in Parkinson's disease., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In order to develop new domestic production of Rhei Rhizoma (RR) from Rheum specimens cultivated in the Sugadaira Medicinal Plant Cultivation Test Field (SMPCF), the ITS sequences of 12 SMPCF specimens and Chinese Rheum specimens of four species, as well as RR samples produced in North Korea, China and Japan, were determined by subcloning and their sequences were compared. As the ITS sequences of 10 SMPCF specimens showed significant intra-individual polymorphism, identification of pseudogenes was conducted by detecting the three motifs of the 5.8S sequence and the stability of the 5.8S secondary structure. Approximately 46% of sequences obtained from the SMPCF specimens were putative pseudogenes. The maximum likelihood tree based on ITS sequences showed three main groups-the outer group and inner clusters I and II; clones from 10 SMPCF specimens including putative pseudogenes belonged to the outer group. Cluster I was composed of two clades, one including clones from R. officinale specimens and R. palmatum-derived samples with matK genotype Rp9, and another including clones from R. coreanum-derived samples. Cluster II consisted of three clades, one including clones from R. palmatum specimens with genotype Rp5, another including clones mainly from R. tanguticum specimens with genotype Rt4, and the third including clones from R. palmatum or R. tanguticum specimens with various matK genotypes. Clones from SMPCF specimen RC5 showed a close relationship with those from R. tanguticum specimens with matK genotype Rt4, whereas those from specimen RC9 related to R. coreanum-derived samples. As a result, specimens RC5 and RC9 were considered as candidates for the development of domestic RR.

Objectives:: Patients with chronic aortic dissection often require repeat interventions due to enlargement of the pressurized false lumen or disseminated intravascular coagulation even after additional thoracic endovascular aortic repair (TEVAR) to occlude the entry tear. Residual false lumen flow can persist even after performing the candy-plug technique or branched stent-graft placement in some cases. We have devised a new method for false lumen closure., Methods:: From December 2010 to May 2017, 5 patients (mean age: 57 [13] years, range: 43-77 years) with chronic dissection at the aortic arch and descending aorta, who underwent initial TEVAR, required additional treatment. Using an open surgical approach, the endograft was fixed with an outer felt under cardiopulmonary bypass after the endograft with stent was expanded by fenestration. The false lumen was closed using this procedure, and the aortotomy was repaired by direct closure in 2 cases and by graft replacement in 3 cases., Results:: No major operative complications occurred, such as respiratory failure or paraplegia. Postoperative enhanced computed tomography (CT) images showed that the false lumen flow disappeared in all cases. All patients were discharged under normal conditions. They were all followed up and their CT did not indicate any complications for a mean of 33.6 (20.3) months., Conclusions:: Our combined procedure was effective and provided a higher success rate compared with endovascular therapy alone. This staged treatment approach, using a combination of TEVAR and false lumen closure, is less invasive compared with open surgery alone and may represent a valid treatment option for chronic type B dissection.

Epidemiological studies have shown that coffee consumption decreases the risk of Parkinson's disease (PD). Caffeic acid (CA) and chlorogenic acid (CGA) are coffee components that have antioxidative properties. Rotenone, a mitochondrial complex I inhibitor, has been used to develop parkinsonian models, because the toxin induces PD-like pathology. Here, we examined the neuroprotective effects of CA and CGA against the rotenone-induced degeneration of central dopaminergic and peripheral enteric neurons. Male C57BL/6J mice were chronically administered rotenone (2.5 mg/kg/day), subcutaneously for four weeks. The animals were orally administered CA or CGA daily for 1 week before rotenone exposure and during the four weeks of rotenone treatment. Administrations of CA or CGA prevented rotenone-induced neurodegeneration of both nigral dopaminergic and intestinal enteric neurons. CA and CGA upregulated the antioxidative molecules, metallothionein (MT)-1,2, in striatal astrocytes of rotenone-injected mice. Primary cultured mesencephalic or enteric cells were pretreated with CA or CGA for 24 h, and then further co-treated with a low dose of rotenone (1⁻5 nM) for 48 h. The neuroprotective effects and MT upregulation induced by CA and CGA in vivo were reproduced in cultured cells. Our data indicated that intake of coffee components, CA and CGA, enhanced the antioxidative properties of glial cells and prevents rotenone-induced neurodegeneration in both the brain and myenteric plexus.

In previous studies, we found regional differences in the induction of antioxidative molecules in astrocytes against oxidative stress, postulating that region-specific features of astrocytes lead region-specific vulnerability of neurons. We examined region-specific astrocytic features against dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA) as an oxidative stress using co-culture of mesencephalic neurons and mesencephalic or striatal astrocytes in the present study. The 6-OHDA-induced reduction of mesencephalic dopamine neurons was inhibited by co-culturing with astrocytes. The co-culture of midbrain neurons with striatal astrocytes was more resistant to 6-OHDA than that with mesencephalic astrocytes. Furthermore, glia conditioned medium from 6-OHDA-treated striatal astrocytes showed a greater protective effect on the 6-OHDA-induced neurotoxicity and oxidative stress than that from mesencephalic astrocytes. The cDNA microarray analysis showed that the number of altered genes in both mesencephalic and striatal astrocytes was fewer than that changed in either astrocyte. The 6-OHDA treatment, apparently up-regulated expressions of Nrf2 and some anti-oxidative or Nrf2-regulating phase II, III detoxifying molecules related to glutathione synthesis and export in the striatal astrocytes but not mesencephalic astrocytes. There is a profound regional difference of gene expression in astrocytes induced by 6-OHDA. These results suggest that protective features of astrocytes against oxidative stress are more prominent in striatal astrocytes, possibly by secreting humoral factors in striatal astrocytes.

Nitric oxide (NO) is a key signaling molecule that has various effects via S-nitrosylation, a reversible post-translational modification that affects the enzymatic activity, localization, and metabolism of target proteins. As chronic nitrosative stress correlates with neurodegeneration, the targets have received focused attention. Macrophage migration inhibitory factor (MIF) plays a pivotal role in the induction of gene expression to control inflammatory responses. MIF acts as a ligand for CD74 receptor and activates the Src-p38 mitogen-activated protein kinase (MAPK) cascade. MIF also elevates the expression of brain-derived neurotrophic factor (BDNF), which contributes to the viability of neurons. Here, we show that MIF is S-nitrosylated by a physiological NO donor. Interestingly, the induction of S-nitrosylation resulted in a loss of MIF activity following stimulation of the Src and p38 MAPK signaling pathways and the induction of BDNF expression. Our results shed light on the pathogenic mechanisms of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease.

We examined whether combination treatment with doxorubicin and cyclophosphamide, a traditional chemotherapy for breast cancer, induced anxiety-like behavior in rats. Furthermore, we evaluated the role of the serotonin (5-HT) 2A receptor subtype in the anxiety-like behavior induced by such chemotherapy. Rats were intraperitoneally injected with doxorubicin and cyclophosphamide once a week for 2 weeks. This caused the rats to display anxiety-like behavior during the light-dark test. In addition, we examined the rats' 5-HT 2A receptor-mediated behavioral responses. Combination treatment with doxorubicin and cyclophosphamide significantly increased (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, (a 5-HT 2A receptor agonist)-induced wet-dog shake activity. This anxiety-like behavior was significantly inhibited by mirtazapine, a 5-HT 2A receptor antagonist/5-HT 1A receptor agonist, and tandospirone, a partial 5-HT 1A receptor agonist, but not by fluoxetine, a selective serotonin reuptake inhibitor. The anxiety-like behavior induced by doxorubicin and cyclophosphamide combination treatment is mediated by hyperfunctioning of the 5-HT 2A receptor. Thus, 5-HT 2A receptor antagonists or 5-HT 1A receptor agonists might be useful for treating chemotherapy-induced anxiety disorders., (Copyright © 2018 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

We tried to clarify the applicability of a single prolonged stress (SPS) protocol as post-traumatic stress disorder (PTSD) model in mice. To investigate PTSD pathophysiology, we conducted hypothalamo-pituitary-adrenal (HPA) negative feedback testing at 1, 4, 8 and 12 weeks after the SPS by administrating a dexamethasone (DEX) suppression test. The SPS induced over-suppression of the HPA system by DEX treatment at 8 and 12 weeks. To investigate PTSD-like behavioral characteristics, we subjected mice to testing in a light/dark box (to assess anxiety), a Y-maze (working memory), a cliff avoidance (visual cognition), and an open field (locomotor activity) at 1, 4, 8 and 12 weeks after the SPS. In the light/dark box test, the SPS-applied mice spent significantly less time in the light box at 8 or 12 weeks. In the cliff avoidance test, the SPS-applied mice spent significantly less time in the open area at 1 week. However, in both the Y-maze test and the open field test, SPS-applied mice tended toward slight decreases in a time-dependent manner until 12 weeks. Therefore, SPS-applied mice may thus be useful for assessing characteristics relevant to PTSD that coincide with changes in the HPA axis., Competing Interests: No potential conflict of interest relevant to this article was reported.

Objectives: Nuclear factor erythroid 2-related factor (Nrf2) in astrocyte plays important roles in brain homeostasis. Fermented papaya preparation (FPP) has anti-oxidative, anti-inflammatory, immunoregulatory properties. The present study investigated the effects of FPP on activation of Nrf2 and release of Nrf2-regulated neuroprotective antioxidants and detoxifying molecules., Methods: Primary cultured astrocytes from rat embryos were treated with FPP for 6 or 24 hours. The expression levels of nuclear Nrf2 and cytoplasmic Nrf2-regulated molecules were determined by western blot analysis and immunohistochemistry. Glutathione levels were measured in cells and medium. Dopaminergic neurons were exposed 6-hydroxydopamine (6-OHDA) with/without pre-treatment with FPP astrocytes. Mice were treated orally with FPP for 2 weeks., Results: FPP increased nuclear translocation of Nrf2 in striatal astrocytes, induced up-regulation of NAD(P)H quinine oxidoreductase-1, glutathione-S transferase and hemeoxygenase-1, and increased glutathione level and the percentage of metallothionein-expressing astrocytes. Moreover, FPP suppressed 6-OHDA-induced dopaminergic neuronal loss in not only neuron-astrocyte mixed culture, but also neuron-rich cultures pre-treated with glial conditioned medium. Two-week oral treatment of mice with FPP resulted in Nrf2 activation and increase in glutathione level in striatum., Discussion: The results indicated that FPP enhances the anti-oxidative capacity through activation of Nrf2 in astrocytes, suggesting it may provide neuroprotection in oxidative stress-related neurodegenerative diseases.

We herein propose a simple affinity-labeling method using a ligand-4-azidophthalimide (AzPI) conjugate. As a proof of concept, we show that two different ligand-AzPI conjugates enabled highly specific fluorescence labeling of their individual target proteins even in crude cell lysates. This method was also applied to label endogenous target proteins inside living cells.

In the present study, we examined the effects of nicotine on cognitive impairment, anxiety-like behavior, and hippocampal cell proliferation in rats treated with a combination of doxorubicin and cyclophosphamide. Combined treatment with doxorubicin and cyclophosphamide produced cognitive impairment and anxiety-like behavior in rats. Nicotine treatment reversed the inhibition of novel location recognition induced by the combination treatment. This effect of nicotine was blocked by methyllycaconitine, a selective α7 nicotinic acetylcholine receptor (nAChR) antagonist, and dihydro-β-erythroidine, a selective α4β2 nAChR antagonist. In addition, nicotine normalized the amount of spontaneous alternation seen during the Y-maze task, which had been reduced by the combination treatment. This effect of nicotine was inhibited by dihydro-β-erythroidine. In comparison, nicotine did not affect the anxiety-like behavior induced by the combination treatment. Furthermore, the combination treatment reduced the number of proliferating cells in the subgranular zone of the hippocampal dentate gyrus, and this was also prevented by nicotine. Finally, the combination of doxorubicin and cyclophosphamide significantly reduced hippocampal α7 nAChR mRNA expression. These results suggest that nicotine inhibits doxorubicin and cyclophosphamide-induced cognitive impairment via α7 nAChR and α4β2 nAChR, and also enhances hippocampal neurogenesis.