MARCKSL1 Regulates Spine Formation in the Amygdala and Controls the Hypothalamic-Pituitary-Adrenal Axis and Anxiety-Like Behaviors

Takashi Tanaka, Shoko Shimizu, Masaki Ueno, Yoshitaka Fujihara, Masahito Ikawa, Shingo Miyata, MARCKSL1 Regulates Spine Formation in the Amygdala and Controls the Hypothalamic-Pituitary-Adrenal Axis and Anxiety-Like Behaviors, EBioMedicine, Volume 30, 2018, Pages 62-73, ISSN 2352-3964, https://doi.org/10.1016/j.ebiom.2018.03.018

bFGF Regulates PI3-Kinase-Rac1-JNK Pathway and Promotes Fibroblast Migration in Wound Healing

Fibroblast proliferation and migration play important roles in wound healing. bFGF is known to promote both fibroblast proliferation and migration during the process of wound healing. However, the signal transduction of bFGF-induced fibroblast migration is still unclear, because bFGF can affect both proliferation and migration. Herein, we investigated the effect of bFGF on fibroblast migration regardless of its effect on fibroblast proliferation. We noticed involvement of the small GTPases of the Rho family, PI3-kinase, and JNK. bFGF activated RhoA, Rac1, PI3-kinase, and JNK in cultured fibroblasts. Inhibition of RhoA did not block bFGF-induced fibroblast migration, whereas inhibition of Rac1, PI3-kinase, or JNK blocked the fibroblast migration significantly. PI3-kinase-inhibited cells down-regulated the activities of Rac1 and JNK, and Rac1-inhibited cells down-regulated JNK activity, suggesting that PI3-kinase is upstream of Rac1 and that JNK is downstream of Rac1. Thus, we concluded that PI3-kinase, Rac1, and JNK were essential for bFGF-induced fibroblast migration, which is a novel pathway of bFGF-induced cell migration

Dysbindin Regulates the Transcriptional Level of Myristoylated Alanine-Rich Protein Kinase C Substrate via the Interaction with NF-YB in Mice Brain

BACKGROUND: An accumulating body of evidence suggests that Dtnbp1 (Dysbindin) is a key susceptibility gene for schizophrenia. Using the yeast-two-hybrid screening system, we examined the candidate proteins interacting with Dysbindin and revealed one of these candidates to be the transcription factor NF-YB. METHODS: We employed an immunoprecipitation (IP) assay to demonstrate the Dysbindin-NF-YB interaction. DNA chips were used to screen for altered expression of genes in cells in which Dysbindin or NF-YB was down regulated, while Chromatin IP and Reporter assays were used to confirm the involvement of these genes in transcription of Myristoylated alanine-rich protein kinase C substrate (MARCKS). The sdy mutant mice with a deletion in Dysbindin, which exhibit behavioral abnormalities, and wild-type DBA2J mice were used to investigate MARCKS expression. RESULTS: We revealed an interaction between Dysbindin and NF-YB. DNA chips showed that MARCKS expression was increased in both Dysbindin knockdown cells and NF-YB knockdown cells, and Chromatin IP revealed interaction of these proteins at the MARCKS promoter region. Reporter assay results suggested functional involvement of the interaction between Dysbindin and NF-YB in MARCKS transcription levels, via the CCAAT motif which is a NF-YB binding sequence. MARCKS expression was increased in sdy mutant mice when compared to wild-type mice. CONCLUSIONS: These findings suggest that abnormal expression of MARCKS via dysfunction of Dysbindin might cause impairment of neural transmission and abnormal synaptogenesis. Our results should provide new insights into the mechanisms of neuronal development and the pathogenesis of schizophrenia

Treatment responses and their predictors in patients with rheumatoid arthritis treated with biological agents

Biological agents represent an important advancement in for the treatment of rheumatoid arthritis (RA), but there is a subset of patients who do not improve despite therapy. This study aimed to determine the efficacy of biological agents for RA and to identify clinical factors that are associated with their response. We studied 98 patients with RA who started an initiating biological agent which was selected from infliximab, etanercept, adalimumab and tociliximab at 4 medical institutions. Etanercept was the most frequently used biological agent followed by infliximab although there was a difference in the selection of the biological agents among medical institutions. We found that etanercept achieved the highest treatment response, remission rate and drug survival rate. A high disease activity in the baseline disease activity score-c-reactive protein (CRP) was shown to be a negative predictor of the treatment response, and high patient global assessment was significantly less likely to achieve a good response. At week 4, decreases in 28 swollen joint counts and CRP were useful as predictors for sustaining the efficacy up to week 48. These data demonstrate that assessments of the disease activity at baseline and the early treatment response may be useful in predicting the efficacy and drug survival rate of biological agents

A Clinical Trial Evaluating the Usefulness of Tailored Antimicrobial Prophylaxis Using Rectal-culture Screening Media Prior to Transrectal Prostate Biopsy: A Multicenter, Randomized Controlled Trial

The aim of this report is to introduce an on-going, multicenter, randomized controlled trial to evaluate whether tailored antimicrobial prophylaxis guided by rectal culture screening prevents acute bacterial prostatitis following transrectal prostate biopsy (TRPB). Patients will be randomized into an intervention or non-intervention group; tazobactam-piperacillin or levofloxacin will be prophylactically administered according to the results of rectal culture prior to TRPB in the intervention group whereas levofloxacin will be routinely given in the non-intervention group. The primary endpoint is the occurrence rate of acute bacterial prostatitis after TRPB. Recruitment begins in April, 2021 and the target total sample size is 5,100 participants

Factors Influencing Pregnant Women\u27s Injuries and Fetal Loss Due to Motor Vehicle Collisions: A National Crash Data-Based Study.

To examine the factors that influence substantial injuries for pregnant women and negative fetal outcomes in motor vehicle collisions (MVCs), a retrospective analysis using the National Automotive Sampling System/Crashworthiness Data System was performed in Shiga University of Medical Science. We analyzed data from 736 pregnant women who, between 2001 and 2015, had injuries that were an abbreviated injury scale (AIS) score of one or more. The mean age was 25.9 ± 6.4 years and the mean gestational age was 26.2 ± 8.2 weeks. Additionally, 568 pregnant women had mild injuries and 168 had moderate to severe injuries. Logistic regression analysis revealed that seatbelt use (odds ratio (OR), 0.30), airbag deployment (OR, 2.00), and changes in velocity (21-40 km/h: OR, 3.03; 41-60 km/h: OR, 13.47; ≥61 km/h: OR, 44.56) were identified as independent predictors of having a moderate to severe injury. The positive and negative outcome groups included 231 and 12 pregnant women, respectively. Injury severity in pregnant women was identified as an independent predictor of a negative outcome (OR, 2.79). Avoiding moderate to severe maternal injuries is a high priority for saving the fetus, and education on appropriate seatbelt use and limiting vehicle speed for pregnant women is required

Yokukansan Inhibits Neuronal Death during ER Stress by Regulating the Unfolded Protein Response

Recently, several studies have reported Yokukansan (Tsumura TJ-54), a traditional Japanese medicine, as a potential new drug for the treatment of Alzheimer's disease (AD). Endoplasmic reticulum (ER) stress is known to play an important role in the pathogenesis of AD, particularly in neuronal death. Therefore, we examined the effect of Yokukansan on ER stress-induced neurotoxicity and on familial AD-linked presenilin-1 mutation-associated cell death.We employed the WST-1 assay and monitored morphological changes to evaluate cell viability following Yokukansan treatment or treatment with its components. Western blotting and PCR were used to observe the expression levels of GRP78/BiP, caspase-4 and C/EBP homologous protein.Yokukansan inhibited neuronal death during ER stress, with Cnidii Rhizoma (Senkyu), a component of Yokukansan, being particularly effective. We also showed that Yokukansan and Senkyu affect the unfolded protein response following ER stress and that these drugs inhibit the activation of caspase-4, resulting in the inhibition of ER stress-induced neuronal death. Furthermore, we found that the protective effect of Yokukansan and Senkyu against ER stress could be attributed to the ferulic acid content of these two drugs.Our results indicate that Yokukansan, Senkyu and ferulic acid are protective against ER stress-induced neuronal cell death and may provide a possible new treatment for AD

Plasma Corticosterone Activates SGK1 and Induces Morphological Changes in Oligodendrocytes in Corpus Callosum

Repeated stressful events are known to be associated with onset of depression. Further, stress activates the hypothalamic–pituitary–adrenocortical (HPA) system by elevating plasma cortisol levels. However, little is known about the related downstream molecular pathway. In this study, by using repeated water-immersion and restraint stress (WIRS) as a stressor for mice, we attempted to elucidate the molecular pathway induced by elevated plasma corticosterone levels. We observed the following effects both, in vivo and in vitro: (1) repeated exposure to WIRS activates the 3-phosphoinositide-dependent protein kinase (PDK1)–serum glucocorticoid regulated kinase (SGK1)–N-myc downstream-regulated gene 1 (NDRG1)–adhesion molecule (i.e., N-cadherin, α-catenin, and β-catenin) stabilization pathway via an increase in plasma corticosterone levels; (2) the activation of this signaling pathway induces morphological changes in oligodendrocytes; and (3) after recovery from chronic stress, the abnormal arborization of oligodendrocytes and depression-like symptoms return to the control levels. Our data strongly suggest that these abnornalities of oligodendrocytes are possibly related to depression-like symptoms