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Abstract Monocarpic plants flower only once and then produce seeds. Many monocarpic plants require a cold treatment known as vernalization before they flower. This requirement delays flowering until the plant senses warm temperatures in the spring. Exposure to high temperatures following vernalization causes devernalization, which cancels the vernalized state, inhibiting flowering and promoting vegetative growth. In this study, we screened over 16,000 chemical compounds and identified five small molecules (devernalizers; DVRs) that induce devernalization in Arabidopsis thaliana at room temperature without requiring a high-temperature treatment. Treatment with DVRs reactivated the expression of FLOWERING LOCUS C (FLC), a master repressor of flowering, by reducing the deposition of repressive histone modifications, thereby delaying flowering time. Three of the DVRs identified shared two structures: a hydantoin-like region and a spiro-like carbon. Treatment with DVR06, which has a simple chemical structure containing these domains, delayed flowering time and reduced the deposition of repressive histone modifications at FLC. RNA-seq and ChIP-seq analyses revealed both shared and specific transcriptomic and epigenetic effects between DVR06- and heat-induced devernalization. Overall, our extensive chemical screening indicated that hydantoin and spiro are key chemical signatures that reduce repressive histone modifications and promote devernalization in plants.

Abstract Age-related hearing loss (ARHL) is one of the most prevalent types of sensory decline in a superaging society. Although various studies have focused on the effect of oxidative stress on the inner ear as an inducer of ARHL, there are no effective preventive approaches for ARHL. Recent studies have suggested that oxidative stress-induced DNA damage responses (oxidative DDRs) drive cochlear cell senescence and contribute to accelerated ARHL, and autophagy could function as a defense mechanism against cellular senescence in auditory cells. However, the underlying mechanism remains unclear. Sodium arsenite (NaAsO2) is a unique oxidative stress inducer associated with reactive oxygen species (ROS) that causes high-tone hearing loss similar to ARHL. Transcription factor EB (TFEB) functions as a master regulator of the autophagy‒lysosome pathway (ALP), which is a potential target during aging and the pathogenesis of various age-related diseases. Here, we focused on the function of TFEB and the impact of intracellular ROS as a potential target for ARHL treatment in a NaAsO2-induced auditory premature senescence model. Our results suggested that short exposure to NaAsO2 leads to DNA damage, lysosomal damage and mitochondrial damage in auditory cells, triggering temporary signals for TFEB transport into the nucleus and, as a result, causing insufficient autophagic flux and declines in lysosomal function and biogenesis and mitochondrial quality. Then, intracellular ROS derived from damaged mitochondria play a role as a second messenger to induce premature senescence in auditory cells. These findings suggest that TFEB activation via transport into the nucleus contributes to anti-senescence activity in auditory cells and represents a new therapeutic target for ARHL. We have revealed the potential function of TFEB as a master regulator of the induction of oxidative stress-induced premature senescence and the senescence-associated secretion phenotype (SASP) in auditory cells, which regulates ALP and controls mitochondrial quality through ROS production.

Heavy metals such as lead (Pb) are significantly harmful to human health and may have disastrous effects on the ecosystem. Consequently, Pb-contaminated soil necessitates remediation to bring Pb levels below the standard threshold of 150 mg/kg. This study aimed to devise processes for extracting and enriching Pb using chelation reactions. Pb was effectively extracted from the soil using EDTA as the chelating agent, forming a complex ([Pb-HEDTA]-) that is solubilized in the solution. Extraction efficiency increased with higher EDTA/Pb molar ratios, remaining relatively constant at 100 or above. Elevated temperatures also enhanced Pb extraction; concentrations below 150 mg/kg were achieved at 25 °C or higher. The desorption of Pb followed the Langmuir equation, indicating uniform one-to-one Pb desorption. The addition of the chelating flocculant diethyldithiocarbamic acid (DDTC) concentrated Pb in the solid phase, reducing sludge volume. Pb transfer rate rose with increasing DDTC/[Pb-EDTA]2− ratio, peaking at 90 % with a ratio of 50. The presence and extraction of other elements (Fe, Cu, and Zn) did not impede Pb extraction and enrichment. Therefore, this study and its findings could provide the basis for further development of the Pb extraction process and mitigate the problem of Pb-contaminated soil when designing Pb extraction plants.

Abstract Background Quantification of gene expression such as RNA-Seq is a popular approach to study various biological phenomena. Despite the development of RNA-Seq library preparation methods and sequencing platforms in the last decade, RNA extraction remains the most laborious and costly step in RNA-Seq of tissue samples of various organisms. Thus, it is still difficult to examine gene expression in thousands of samples. Results Here, we developed Direct-RT buffer in which homogenization of tissue samples and direct-lysate reverse transcription can be conducted without RNA purification. The DTT concentration in Direct-RT buffer prevented RNA degradation but not RT in the lysates of several plant tissues, yeast, and zebrafish larvae. Direct reverse transcription on these lysates in Direct-RT buffer produced comparable amounts of cDNA to those synthesized from purified RNA. To maximize the advantage of the Direct-RT buffer, we integrated Direct-RT and targeted RNA-Seq to develop a cost-effective, high-throughput quantification method for the expressions of hundreds of genes: DeLTa-Seq (Direct-Lysate reverse transcription and Targeted RNA-Seq). The DeLTa-Seq method could drastically improve the efficiency and accuracy of gene expression analysis. DeLTa-Seq analysis of 1056 samples revealed the temperature-dependent effects of jasmonic acid and salicylic acid in Arabidopsis thaliana. Conclusions The DeLTa-Seq method can realize large-scale studies using thousands of animal, plant, and microorganism samples, such as chemical screening, field experiments, and studies focusing on individual variability. In addition, Direct-RT is also beneficial for gene expression analysis in small tissues from which it is difficult to purify enough RNA for the experiments.

Background: We investigated whether multiple food allergies could be safely prevented by simultaneously administering very small amounts of multiple foods. Methods: Infants 3–4 months old with atopic dermatitis from 14 primary care pediatric clinics in Japan were enrolled in this randomized, placebo-controlled trial. The infants were administered either mixed allergenic food powder (MP) containing egg, milk, wheat, soybean, buckwheat, and peanuts, or placebo powder (PP). The amount of powder was increased in a stepwise manner on weeks 2 and 4, and continued until week 12. The occurrence of food allergy episodes after powder intervention was assessed at 18 months old. This trial was registered with the University Hospital Medical Information Network Clinical Trials Registry (number UMIN000027837). Results: A total of 163 participants were randomly allocated to either the MP group (n = 83) or the PP group (n = 80). The incidence of food allergy episodes by 18 months was significantly different between the MP and PP groups (7/83 vs. 19/80, respectively; risk ratio 0.301 [95% CI 0.116–0.784]; P = 0.0066). Egg allergies were reduced in the MP group. In addition, food allergy episodes from any of the other five foods were significantly reduced, although the reductions in those due to individual foods were not significant. Conclusions: Gradually increasing the intake of very small amounts of multiple foods in early infancy can safely reduce the incidence of egg allergies. Other foods may also suppress food allergies, but no definitive conclusions could be reached.

Acclimation to high temperature increases tolerance of heat shock in plants. Here the authors show that JUMONJI H3K27me3 demethylases are needed for heat acclimation in Arabidopsis and act at loci encoding HEAT SHOCK PROTEINS to facilitate induction upon heat stress.

Background: There have been no reports of treatment effect persistence after long-term sublingual immunotherapy (SLIT) in patients with Japanese cedar (JC) pollinosis. Therefore, we conducted a post-marketing clinical trial to investigate the efficacy, safety, and effect persistence of JC pollen SLIT drops after approximately 3 years of treatment. Methods: This was an open-label trial of 233 patients with JC pollinosis who were treated with JC pollen SLIT drops for approximately 3 years (2015–2017) and followed-up for an additional 2 years (2018–2019). Efficacy and effect persistence were evaluated using nasal and ocular symptom scores, daily use of rescue medication, and Japanese Rhinoconjunctivitis Quality of Life Questionnaire scores recorded during the JC pollen dispersal season of each year. Safety was evaluated by monitoring adverse events and adverse drug reactions. Results: The mean combined total nasal symptom and medication score (range 0–18) during the peak symptom periods of 2015 through 2019 were 5.47 ± 3.38, 4.52 ± 3.13, 3.58 ± 2.63, 5.28 ± 4.01, and 6.83 ± 4.65, respectively. The percentage of patients who used no rescue medications during the same periods was 64.8%, 75.2%, 80.3%, 63.7%, and 50.3%, respectively. A total of 138 adverse drug reaction incidents were recorded in 73 of the 233 patients (31.3%), of which 134 incidents (97.1%) were mild in severity. Conclusions: JC pollen SLIT drops demonstrated treatment duration-dependent efficacy with effects that persisted for 2 years after cessation of treatment. The drug had a favorable safety profile over the 5-year study period.

Abstract Background Bow Hunter’s Syndrome (BHS) is known as one of cervical diseases which causes vertigo, but the details of its vertigo, especially nystagmus and eye movement, are still incompletely understood. This time, we reported the first case of BHS with a nystagmus chart with video record of transitional nystagmus. Case presentation The patient, a 47-year-old female, complained of vertigo caused by head rotation. When she turned her head leftward, leftward nystagmus appeared, and this was followed by dullness of the right arm. After her head was returned to the central position, downbeat nystagmus appeared, which changed to rightward nystagmus. She was diagnosed with BHS by her symptoms and images. We recorded a nystagmus video and nystagmus chart of this transitional nystagmus including downbeat nystagmus. Her vertigo was cured by the modification of a prescription for her past medical history: hypertension. Conclusion The vertigo of BHS accompanies nystagmus. In this present case, the transitional nystagmus was observed, and it occurred toward the healthy side. Then the nystagmus direction was changed to the affected side via downbeat nystagmus. This is the first report with both a nystagmus chart with video of BHS. Nowadays, various kinds of vertigo induced by neck movement are known. BHS is a rare disease among vertigo diseases, but we should consider it as a different diagnosis of vertigo patients. A precise interview and proper examination are required to make the final diagnosis.

This study aimed to examine the types and causes of dizziness experienced by individuals after a major earthquake. This cross-sectional study enrolled healthy participants who experienced the 2016 Kumamoto earthquakes and their aftershocks. Participants completed a questionnaire survey on their symptoms and experiences after the earthquakes. The primary outcome was the occurrence of dizziness and the secondary outcome was the presence of autonomic dysfunction and anxiety. Among 4,231 eligible participants, 1,543 experienced post-earthquake dizziness. Multivariate logistic regression analysis revealed that age (≥21, P < .001), female sex (P < .001), floor on which the individual was at the time (≥3, P = .007), tinnitus/ear fullness (P < .001), anxiety (P < .001), symptoms related to autonomic dysfunction (P = .04), and prior history of motion sickness (P = .002) were significantly associated with the onset of post-earthquake dizziness. Thus suggesting that earthquake-related effects significantly affect inner ear symptoms, autonomic function, and psychological factors. Earthquake-induced disequilibrium may be further influenced by physical stressors, including sensory disruptions induced by earthquake vibrations, changes in living conditions, and autonomic stress. This study increases our understanding of human equilibrium in response to natural disasters.

Molecular chaperon SERPINA3 colocalizes with accumulated amyloid peptide in Alzheimer's disease (AD) patient's brain. From the QTL analysis, we narrowed down Serpina3 with two SNPs in senescence-accelerated mouse prone (SAMP) 8 strain. Our study showed SAMP8 type Serpina3 prolonged retention of oligomeric Aβ 42 for longer duration (72 hr) while observing under transmission electron microscope (TEM). From Western blot results, we confirmed presence of Aβ 42 oligomeric forms (trimers, tetramers) were maintained for longer duration only in the presences of SAMP8 type Serpina3. Using SH-SY5Y neuroblastoma cell line, we observed until 36 hr preincubated Aβ 42 with SAMP8 type Serpina3 caused neuronal cell death compared to 12 hr preincubated Aβ 42 with SAMR1 or JF1 type Serpina3 proteins. Similar results were found by extending this study to analyze the effect of polymorphism of SERPINA3 gene of the Japanese SNP database for geriatric research (JG-SNP). We observed that polymorphic SERPINA3 I308T (rs142398813) prolonged toxic oligomeric Aβ 42 forms till 48 hr in comparison to the presence wild type SERPINA3 protein, resulting neuronal cell death. From this study, we first clarified pathogenic regulatory role of polymorphic SERPINA3 in neurodegeneration.

Summary: Background/Objective: We compared the surgery data of the department of otorhinolaryngology of the university hospitals in Japan and Thailand to make each feature and the differences of both otorhinolaryngology surgeries clear. There are some medical meetings and congresses between Japan and Thailand, but so far it has not reported about the comparison of surgery data. Methods: Retrospectively, we analyzed the surgical statistics of department of otorhinolaryngology of Nihon University Itabashi Hospital (Japan) and Thammasat University Hospital (Thailand) between 2013 and 2014. Results: In Japan, there were many surgeries involving the middle ear and paranasal sinuses whereas in Thailand, tracheotomy and tonsillectomy were more frequently performed. Statistical analysis of the surgical data revealed specific tendencies in the nature of the operations performed at each university. Conclusion: This study revealed that there are rather differences between two hospitals' surgeries features. It was thought that it would be beneficial to both institutions to gain a deeper understanding of the areas of expertise of each university in order to foster an environment conducive to increasing future international collaborations. Keywords: Asian countries, Japan, Nihon University School of Medicine, Otolaryngology-Head and Neck Surgery, Thailand, Thammasat University Faculty of Medicine

The runner reed (Phragmites japonica) is the dominant species on riverbanks, whereas the common reed (Phragmites australis) thrives in continuously flooded areas. Here, we aimed to identify the key root anatomical traits that determine the different adaptative responses of the two Phragmites species to water-deficit and low-oxygen conditions. Growth measurements revealed that P. japonica tolerated high osmotic conditions, whereas P. australis preferred low-oxygen conditions. Root anatomical analysis revealed that the ratios of the cortex to stele area and aerenchyma (gas space) to cortex area in both species increased under low-oxygen conditions. However, a higher ratio of cortex to stele area in P. australis resulted in a higher ratio of aerenchyma to stele, which includes xylem vessels that are essential for water and nutrient uptakes. In contrast, a lower ratio of cortex to stele area in P. japonica could be advantageous for efficient water uptake under high-osmotic conditions. In addition to the ratio of root tissue areas, rigid outer apoplastic barriers composed of a suberised exodermis may contribute to the adaptation of P. japonica and P. australis to water-deficit and low-oxygen conditions, respectively. Our results suggested that root anatomical plasticity is essential for plants to adapt and respond to different soil moisture levels. [ABSTRACT FROM AUTHOR]

Abstract The purpose of this study was to clarify the relationship among X-box-binding protein 1 unspliced, spliced (XBP1u, s), Forkhead box O1 (FoxO1) and autophagy in the auditory cells under endoplasmic reticulum (ER) stress. In addition, the relationship between ER stress that causes unfolded protein response (UPR) and autophagy was also investigated. The present study reported ER stress induction by tunicamycin treatment that resulted in IRE1α-mediated XBP1 mRNA splicing and autophagy. XBP1 mRNA splicing and FoxO1 were found to be involved in ER stress-induced autophagy. This inference was based on the observation that the expression of LC3-II was suppressed by knockdown of IRE1α, XBP1 or FoxO1. In addition, XBP1u was found to interact with XBP1s in auditory cells under ER stress, functioning as a negative feedback regulator that was based on two important findings. Firstly, there was a significant inverse correlation between XBP1u and XBP1s expressions, and secondly, the expression of XBP1 protein showed different dynamics compared to the XBP1 mRNA level. Furthermore, our results regarding the relationship between XBP1 and FoxO1 by small interfering RNA (siRNA) paradoxically showed negative regulation of FoxO1 expression by XBP1. Our findings revealed that the XBP1-FoxO1 interaction regulated the ER stress-induced autophagy in auditory cells.

Objectives We aimed to elucidate the prognostic factors of the patients with taste disorders who were treated with popular and common medication in Japan. Materials and methods A retrospective study on the medical charts of a total of 255 patients with taste disorders who were treated primarily with oral medication including a zinc agent. Results The factors below were significantly linked with poor prognosis: 1) male gender, 2) taste disorders that began 3 months before starting treatment and 3) a severe taste disorder grade at the initial visit. Conclusions We have concluded that the prognosis for the patients with taste disorders who were treated by popular and standard medication therapy in Japan recently was significantly linked to gender, the period of 3 months before starting the treatment and the severity of the disorder at the time of diagnosis. In addition, we recognized some limitations we should resolve in further research including a method of measuring “umami” and so on. Clinical relevance Better awareness of these factors should be clinically useful when we manage patients with taste disorders. Earlier treatment should be started to cure the symptoms.

Background: Bilastine, a novel non-sedating second-generation H1 antihistamine, has been approved in most European countries since 2010. This study aimed to evaluate the superiority of bilastine over placebo in Japanese patients with perennial allergic rhinitis (PAR). Methods: This randomized, double-blind, placebo-controlled, parallel-group, phase III study (trial registration number JapicCTI-142600) evaluated the effect of a 2-week treatment period with bilastine (20 mg once daily), fexofenadine (60 mg twice daily), or a matched placebo (double dummy) in patients with PAR. All patients were instructed to record individual nasal and ocular symptoms in diaries daily. The primary endpoint was the mean change in total nasal symptom scores (TNSS) from baseline to Week 2 (Days 10–13). Results: A total of 765 patients were randomly allocated to receive bilastine, fexofenadine, or placebo (256, 254, and 255 patients, respectively). The mean change in TNSS from baseline at Week 2 was significantly decreased by bilastine (−0.98) compared to placebo (−0.63, P = 0.023). Bilastine and fexofenadine showed no significant difference in the primary endpoint. However, the mean change in TNSS from baseline on Day 1 was more significantly decreased by bilastine (−0.99) than by placebo (−0.28, P

Tinnitus and dizziness are common complaints encountered in the department of otolaryngology. We hypothesized that when patients complain of both tinnitus and dizziness, perceived handicap, impairment of quality of life, and emotional distress are more severe than the patient who complain of either tinnitus or dizziness. The subjects for this study were 736 patients who visited Hino Municipal Hospital between August 2010 and March 2012, complaining of tinnitus or dizziness. The subjects were divided into three groups depending upon their chief complaints—group B had patients with both tinnitus and dizziness (N = 75), group T had patients with tinnitus (N = 145), and group D had patients with dizziness (N = 516). Assessments were performed using Tinnitus Handicap Inventory (THI) for groups B and T, Dizziness Handicap Inventory (DHI) for groups B and D, Medical Outcomes Study 8-items Short-Form Health Survey (SF-8), and Hospital Anxiety and Depression Scale (HADS). The THI score of group B was higher than that of group T. The scores of PCS (physical component of SF-8) of groups B and D were lower than that of group T. However, there were no significant differences in the DHI scores of groups B and D, and the HADS scores of the three groups. While the physical quality of life was found to vary depending on the presence of dizziness in patients with tinnitus, it was not found to vary depending on the presence of tinnitus in patients with dizziness. It is therefore important to consider the functional impact resulting from dizziness in patients with tinnitus.

Endoplasmic reticulum (ER)-associated degradation (ERAD) is a protective mechanism against ER stress in which unfolded proteins accumulated in the ER are selectively transported to the cytosol for degradation by the ubiquitin–proteasome system. We cloned the novel ubiquitin ligase HRD1, which is involved in ERAD, and showed that HRD1 promoted amyloid precursor protein (APP) ubiquitination and degradation, resulting in decreased generation of amyloid β (Aβ). In addition, suppression of HRD1 expression caused APP accumulation and promoted Aβ generation associated with ER stress and apoptosis. Interestingly, HRD1 levels were significantly decreased in the cerebral cortex of patients with Alzheimer’s disease (AD), and the brains of these patients experienced ER stress. Our recent study revealed that this decrease in HRD1 was due to its insolubilization; however, controversy persists about whether the decrease in HRD1 protein promotes Aβ generation or whether Aβ neurotoxicity causes the decrease in HRD1 protein levels. Here, we review current findings on the mechanism of HRD1 protein loss in the AD brain and the involvement of HRD1 in the pathogenesis of AD. Furthermore, we propose that HRD1 may be a target for novel AD therapeutics. Keywords:: Alzheimer’s disease, amyloid β, endoplasmic reticulum–associated degradation, HRD1, neurodegenerative disease

Abstract.: Neural stem/progenitor cells (NSCs) reside in the subventricular zone (SVZ) and subgranular zone of the hippocampal dentate gyrus in adult mammals. The ubiquitin ligase HRD1 is associated with degradation of amyloid precursor protein and believed to be specifically expressed in neurons and not in astrocytes. We investigated expression of HRD1 using immunohistochemistry and found colocalization of HRD1 with the NSC marker protein nestin and glial fibrillary acidic protein in the NSCs of the SVZ (the SVZ astrocytes) but not in the hippocampus. In the hippocampal dentate gyrus, HRD1 is localized in the nucleus of nestin-positive cells. Keywords:: HRD1, hippocampus, subventricular zone

Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of diseases such as neurodegenerative disease. In the present study, we established the ER stress–resistant SH-SY5Y cell line, and through microarray analysis, we found that TEK/Tie2 expression is up-regulated in this cell line. Moreover, we found that TEK/Tie2 expression was markedly decreased in ER-stressed cells. The effect was time-dependent (2 – 24 h), which began to decrease from 2-h time point. Our findings suggest that TEK/Tie2 expression is involved in cell survival, whereas when severe ER stress occurs, TEK/Tie2 expression is down-regulated, resulting in cell death. Keywords:: neurodegenerative disease, Akt, microarray

Endoplasmic reticulum–associated degradation (ERAD) is a quality control mechanism in which unfolded proteins are retro-translocated to the cytosol for degradation. Our recent study showed that suppression of expression of ubiquitin ligase HRD1, which is involved in ERAD, caused amyloid precursor protein (APP) accumulation and amyloid-β (Aβ) production. Furthermore, HRD1 protein levels were significantly lower in the cerebral cortex of Alzheimer’s disease (AD) patients. To assess whether HRD1 is involved in AD pathology, we analyzed the relationship between HRD1 protein levels and Aβ production. We found that the HRD1 level was negatively correlated with the Aβ level, suggesting the possible involvement of HRD1 in Aβ generation. Keywords:: HRD1, endoplasmic reticulum–associated degradation (ERAD), amyloid-β

Human ubiquitin ligase HRD1 is involved in endoplasmic reticulum-associated degradation (ERAD). We recently reported that HRD1 interacts with Parkin-associated endothelin receptor-like receptor (Pael-R), a substrate of Parkin, and promotes Pael-R degradation, resulting in the protection of cells from the lethal accumulation of Pael-R. However, except for RING-finger domain that is necessary for ubiquitin ligase activity, the roles of other human HRD1 domains are unclear. Here, we show that the proline-rich domain of HRD1 is necessary to promote the degradation of Pael-R and that the protein’s transmembrane domain is necessary to transfer Pael-R from the endoplasmic reticulum (ER) to the cytosol. A HRD1 mutant defective in the transmembrane domain is markedly more unstable than wild-type HRD1. These results suggest that HRD1 has diverse functions besides ubiquitin ligase activity. Keywords:: HRD1, endoplasmic reticulum (ER)-associated degradation (ERAD), ubiquitin ligase, proteasome, ER stress

Abstract.: Among the 14 kinds of serotonin (5-hydroxytryptamine, 5-HT) receptor subtypes (5-HTR), 5-HT2C receptor (5-HT2CR) has been intensively investigated because of its physiologically and pathophysiologically important role in the brain. 5-HT2CR has been suggested to be involved in depressive disorders based on findings from pharmacological/neurochemical/behavioral studies using autopsy preparations of humans suffering from depression, animal models of depression, and animals treated with antidepressant drugs. Recently the editing of 5-HT2CR mRNA has been reported to participate in the pathogenesis of depressive disease. The RNA editing of 5-HT2CR induced by the presumable alteration of deaminase during a pathological state in depression causes changes of a base to another base (e.g., adenosine to guanosine, cytidine to uracil (thymidine)), followed by changes in amino acids constituting the second intracellular transmembrane loop that couples G proteins. Thus 5-HT2CR receptor-mediated signal transduction is changed. In the present review, the pathopharmacological significance of 5-HT2CR in special reference to RNA editing of receptors is reviewed and discussed from the aspect of development of novel therapeutics for depression. Keywords:: 5-HT2C receptor, RNA editing, depression, antidepressant

Senescence-accelerated mouse prone 8 (SAMP8) and prone 10 (SAMP10) are useful murine model of accelerated aging. SAMP8 shows marked impairment of learning and memory, whereas SAMP10 shows brain atrophy and aging-associated depressive behavior. This study examined the expression of glial cell line-derived neurotrophic factor (GDNF) in SAMP8 and SAMP10 brains, relative to that in SAM resistant 1 (SAMR1) controls, which age normally. Hippocampal GDNF mRNA expression decreased in an age-dependent manner (10- vs 2-month-old animals) in the SAMR1, but not in the SAMP8 or SAMP10 strains. Furthermore, GDNF mRNA expression in 2-month-old SAMP8 and SAMP10 strains was less than in SAMR1 specimens of the same age. The number of surviving neurons in the CA1 region decreased with age in SAMP8 and SAMP10, and also decreased relative to the number of neurons in 10-month-old SAMR1 controls. Immunohistochemistry revealed that cells that were positive for GDNF-like activity in 10-month-old SAMP8 and SAMP10 were diffusely distributed, in part, around the pyramidal cell layer in the hippocampus. These findings suggest that low GDNF expression in young SAMP8 and SAMP10 may be involved in hippocampal dysfunctions, such as age-related learning impairment and neuronal death.

ABSTRACT: Interleukin (IL)-6 has been shown to protect neuronal cells from cell death induced by various stimulants. Although neuronal cells including PC12 cells were shown to produce IL-6, little is known about the effects of dopaminergic neurotoxins, 1,2,3,4-tetrahydroisoquinoline (TIQ) and 1-methyl-4-phenylpyridinium ion (MPP+), on IL-6 expression in PC12 cells. In the present study, we investigated the role of IL-6 in the TIQ- and MPP+-induced cell death in PC12 cells. Treatment with 3.2 mM TIQ for 24 h caused a delayed cell death (lactate dehydrogenase (LDH) leakage and nuclear DNA fragmentation) markedly 72 h after the addition. Addition of 0.4 mM MPP+ caused LDH leakage and nuclear DNA fragmentation 24 h after the addition. The cell death induced by MPP+ was inhibited by an inhibitor of caspases, z-Val-Ala-Asp(OMe)-fluoromethylketone. The cell death induced by TIQ or MPP+ was inhibited by nerve growth factor and 10% serum and significantly enhanced by the treatment with anti-IL-6 antibody. Both neurotoxins decreased the IL-6 mRNA level in PC12 cells without changing the other tested mRNA levels (IL-1α, β-actin, etc.). These findings suggest that dopaminergic neurotoxins cause cell death in PC12 cells at least partially by changing IL-6 expression.

The serotonergic pathway has been implicated in the pathogenesis of impulsivity, and sensitivity to aversive outcomes may be linked to serotonin (5-HT) levels. Polymorphisms in the gene that encodes the serotonin transporter (5-HTT), which have differential effects on the level of serotonin transmission, display alternate responses to aversive stimuli. However, recent studies have shown that 5-HT does not affect motor function, which suggests that the functioning of the serotonin-transporter-linked polymorphic region (5-HTTLPR) does not directly affect the behavioral regulatory process itself, but instead exerts an effect via the evaluation of the potential risk associated with particular behavioral outputs. The aim of the present study was to examine the effect of specific 5-HTTLPR genotypes on the motor regulatory process, as observed during a Go/Nogo punishment feedback task. 5-HTT gene-linked promoter polymorphisms were analyzed by polymerase chain reaction, using lymphocytes from 61 healthy Japanese volunteers. Impulsivity was defined as the number of commission errors (responding when one should not) made during a Go/Nogo task. We found that the s/s genotype group made fewer impulsive responses, specifically under aversive conditions for committing such errors, compared to those in the s/l group, without affecting overall motor inhibition. These results suggest that 5-HTTLPRs do not directly affect the behavioral regulatory process itself, but may instead exert an effect on the evaluation of potential risk. The results also indicate that under such aversive conditions, decreased expression of 5-HTT may promote motor inhibitory control.

Members of the epidermal growth factor family play important roles in the regulation of cell growth, proliferation, and survival. However, the specific roles of each epidermal growth factor family member with respect to brain injury are not well understood. Gene chip assay screens have revealed drastic increases in the expression of the epidermal growth factor family members amphiregulin and epiregulin following lipopolysaccharide stimulation, which activates an immune response. Both immune activity and endoplasmic reticulum stress are activated during cerebral ischemia. We found that the expression levels of amphiregulin and epiregulin were significantly increased under conditions of cerebral ischemia. Because endoplasmic reticulum stress increased the expression of amphiregulin and epiregulin in glial cells, endoplasmic reticulum stress may be a key mediatory factor of pathophysiological activity. Recombinant epiregulin and amphiregulin proteins effectively inhibited endoplasmic reticulum stress and the subsequent induction of neuronal cell death. Therefore, the upregulation of the epidermal growth factor family members epiregulin and amphiregulin may play a critical role in preventing endoplasmic reticulum stress-induced cell death, thus providing a potential therapy for brain injury.

The E3 ubiquitin ligase HRD1 is found in the endoplasmic reticulum membrane of brain neurons and is involved in endoplasmic reticulum-associated degradation. We previously demonstrated that suppression of HRD1 expression in neurons causes accumulation of amyloid precursor protein, resulting in amyloid β production associated with endoplasmic reticulum stress and apoptosis. Furthermore, HRD1 levels are significantly decreased in the cerebral cortex of Alzheimer's disease patients because of its insolubility. The mechanisms that affect HRD1 solubility are not well understood. We here show that HRD1 protein was insolubilized by oxidative stress but not by other Alzheimer's disease-related molecules and stressors, such as amyloid β, tau, and endoplasmic reticulum stress. Furthermore, we raise the possibility that modifications of HRD1 by 4-hydroxy-2-nonenal, an oxidative stress marker, decrease HRD1 protein solubility and the oxidative stress led to the accumulation of HRD1 into the aggresome. Thus, oxidative stress-induced HRD1 insolubilization might be involved in a vicious cycle of increased amyloid β production and amyloid β-induced oxidative stress in Alzheimer's disease pathogenesis.

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are neurodegenerative disorders with a severe medical and social impact. Further insights from clinical and scientific studies are essential to develop effective therapies. Various stresses on the endoplasmic reticulum (ER) cause unfolded/misfolded proteins to aggregate, initiating unfolded protein responses (UPR), one of which is the induction of neuronal cell death. Some of the pathogenic factors for AD and PD are associated with UPR. ER molecules such as ubiquitin ligases (E3s) and chaperones are also produced during UPR to degrade and refold aberrant proteins that accumulate in the ER. In this review, we examine the role of HMG-CoA reductase degradation protein 1 (HRD1) and the chaperone protein-disulfide isomerase (PDI), which are both produced in the ER in response to stress. We discuss the importance of HRD1 in degrading amyloid precursor protein (APP) and Parkin-associated endothelin receptor-like receptor (Pael-R) to protect against neuronal death. PDI and the chemical chaperone 4-phenyl-butyrate also exert neuroprotective effects. We discuss the pathophysiological roles of ER stress, UPR, and the induction and neuroprotective effects of HRD1 and PDI, which may represent significant targets for novel AD and PD therapies.