Publications by authors named "Takahiro Shimizu"

289 Publications

Aging-related severe hypertension induces detrusor underactivity in rats.

Life Sci 2021 Jul 24:119855. Epub 2021 Jul 24.

Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Japan. Electronic address:

Aims: Aging is an obvious risk factor for detrusor underactivity. We investigated the effects of aging on bladder function in spontaneously hypertensive rats.

Main Methods: Male spontaneously hypertensive rats and Wistar Kyoto rats (used as normotensive controls) at the ages of 18, 36, 54, or 72 weeks were used. Bladder weight, blood pressure, bladder blood flow, and urodynamic and renal parameters were measured. Additionally, detrusor thickness and renal histology were evaluated.

Key Findings: In spontaneously hypertensive rats, significant increases were observed in bladder weight/body weight ratio, blood pressure, detrusor thickness, intercontraction interval, urine output, serum creatinine, and renal glomerular and tubular scores, and decreases in bladder blood flow and urine osmolality at 72 weeks as compared to those at 18 weeks. In spontaneously hypertensive rats, significant increases were observed in single voided volume, post voiding residual urine volume, and bladder capacity, with decrease in voiding efficacy were observed at 54 or 72 weeks than at 18 weeks. However, there were no significant differences in blood pressure, urodynamic and renal parameters, detrusor thickness and renal histology among Wistar Kyoto rats of different ages.

Significance: In spontaneously hypertensive rats, aging induces significant increases in blood pressure, single voided volume, post voiding residual urine volume, intercontraction intervals and urine output, and decreases in voiding efficacy and bladder blood flow indicative of detrusor underactivity. Aging-related severe hypertension could induce voiding dysfunction such as detrusor underactivity via severe bladder ischemia and polyuria. Aged spontaneously hypertensive rats may be useful animal models for detrusor underactivity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lfs.2021.119855DOI Listing
July 2021

Maintenance treatment with infliximab for ulcerative ileitis after intestinal transplantation: A case report.

World J Clin Cases 2021 Jul;9(19):5270-5279

Department of Pediatric Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.

Background: Evidence has been published on the successful applications of the anti-tumor necrosis factor alpha antibody infliximab, such as induction therapy, salvage treatment for acute cellular rejection, and treatment for chronic ulcerative inflammation, in intestinal transplant recipients. However, the optimal protocol for the effective use of infliximab remains largely undetermined due to scarcity of available clinical data. We report a continuative application of infliximab as maintenance therapy for recurrent chronic ulcerative ileitis in a recipient of isolated intestinal transplantation (ITx).

Case Summary: The patient was a 11-year-old boy with intestinal motility disorder classified as a hypogenic type of intestinal dysganglionosis. The patient underwent living-donor related intestinal transplant. His immunosuppression regimen consisted of daclizumab, tacrolimus, and steroids. Although he did not show rejection while on tacrolimus monotherapy, routine screening endoscopy showed several ulcerative lesions in the distal end of the graft 2 years after the intestinal transplant. Endoscopic work up to evaluate the progression of anemia revealed stenosis with ulcerative inflammatory changes and multiple longitudinal ulcers in the graft. Since the endoscopic findings suggested ulcerative lesions in Crohn's disease, infliximab treatment was considered. Treatment with infliximab and a small dose of oral prednisolone afforded successful withdrawal of total parenteral nutrition and maintenance of a well-functioning graft without infectious complications for 5 years since the administration of the first dose of infliximab.

Conclusion: Infliximab is effective as maintenance therapy for recurrent chronic ulcerative ileitis in an isolated ITx patient.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.12998/wjcc.v9.i19.5270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283613PMC
July 2021

Predictive factors for refractory stage I and II anti-resorptive agent-related osteonecrosis of the jaw.

Oral Radiol 2021 Jul 3. Epub 2021 Jul 3.

Department of Oral and Maxillofacial Surgery, and Plastic Surgery, Gunma University Graduate School of Medicine, 3-39-22, Showa-machi, Maebashi, Gunma, 371-8511, Japan.

Objectives: We aimed to predict the possibility of patients with stage I and II anti-resorptive agent-related osteonecrosis of the jaw (ARONJ) developing resistance to our treatment protocol by evaluating their clinical and imaging factors.

Materials And Methods: We enrolled 58 patients with ARONJ who underwent imaging modality. As objective variables, we considered the healing, stage-down, and stable stages as successful outcomes, and the stage-up stage as resistant-to-treatment. As explanatory variables, we investigated the clinical and imaging factors. Furthermore, we examined stage-down as an improvement outcome to compare with the stable and stage-up stages, which were considered as no-improvement outcomes. We conducted unpaired between-group comparisons on all explanatory variables using χ tests for independence.

Results: Among 58 patients, the treatment was successful in 53 (91.4%); however, the disease was resistant in five (8.6%). Among the clinical factors, the resistant patients had a longer duration of administration of bone-modifying agents (BMAs) (cut-off: 1251 days, p = 0.032, odds ratio = 11.2, 95% confidence interval 1.115-122.518). In addition, the target disease that was being treated bone metastasis of malignant tumor was the only significant refractory factor (p = 0.024, OR: 3.667 95% CI 1.159-11.603) CONCLUSIONS: A combination of metabolic and morphological imaging modalities may be useful for oral surgeons to evaluate the disease activity and predict course of refractory ARONJ.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11282-021-00547-1DOI Listing
July 2021

Inhibition of gastric H,K-ATPase by new dihydropyrazole derivative KYY-008.

Biochem Biophys Res Commun 2021 Aug 21;567:177-182. Epub 2021 Jun 21.

Department of Pharmaceutical Physiology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan.

The gastric proton pump (H,K-ATPase) responsible for the H secretion of gastric acid is an essential therapeutic target for acid-related diseases. H,K-ATPase belongs to a P-type ATPase family. Here, we examined the effects of a newly synthesized dihydropyrazole derivative KYY-008 on the H,K-ATPase. KYY-008 concentration-dependently inhibited the enzyme activity of the ATPase in the membrane fractions prepared from isolated hog gastric mucosa and from human kidney HEK293 cells in which gastric H,K-ATPase is exogenously expressed. The IC values in these samples were 3.4 μM and 3.7 μM, respectively. In addition, KYY-008 significantly inhibited the H,K-ATPase-derived H uptake into the tightly sealed vesicles prepared from the hog gastric mucosa. In contrast, KYY-008 has no effect on the activities of other P-type ATPases such as Na,K-ATPase and Ca-ATPase. KYY-008 did not change the ionic currents of voltage-dependent Ca channels, that were potential targets for some dihydropyrazole derivatives. Together, we discovered a new dihydropyrazole derivative which acts as a selective inhibitor of gastric H,K-ATPase.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2021.06.056DOI Listing
August 2021

[A PEDIATRIC CASE OF DIFFUSE PANBRONCHIOLITIS WHO PREDOMINANTLY SHOWED RESTRICTIVE PULMONARY DYSFUNCTION AND DRAMATICALLY RESPONDED TO MACROLIDE LOW-DOSE LONG-TERM THERAPY.]

Arerugi 2021 ;70(4):310-314

Department of Pediatrics, Saitama Medical University Hospital.

A 12-year-old boy visited our hospital with complaints of chronic cough and dyspnea. Chest X-ray and CT revealed diffuse granular shadow in the bilateral lung fields and "Tree-in-bud appearance" in the peripheral airways, respectively. Sinusitis was present, and restrictive disorder was predominantly found in pulmonary function. The patient was diagnosed with DPB, and long-term therapy was started with low-dose clarithromycin (CAM), The patient showed a dramatic response to CAM, with improvements of both the clinical symptoms and pulmonary function within 1-2 months. According to the relevant literature, in adult patients with this disease, pulmonary dysfunction starts from an obstructive pattern; however, this is not the case in pediatric patients. It was therefore suggested that the mechanisms underlying the development of pulmonary dysfunction in cases of childhood onset differs from those with an adult onset.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.15036/arerugi.70.310DOI Listing
June 2021

Quantitative Evaluation of Cerebellar Function in Multiple System Atrophy with Transcranial Magnetic Stimulation.

Cerebellum 2021 Jun 14. Epub 2021 Jun 14.

Department of Human Neurophysiology, School of Medicine, Fukushima Medical University, Fukushima, Japan.

Objective evaluation of cerebellar dysfunction in neurodegenerative disorders is often difficult because of other overlapping symptoms. Cerebellar inhibition (CBI) tested by dual-coil transcranial magnetic stimulation (TMS) is anticipated as a promising measure to estimate cerebellar function. Cerebellar TMS inhibits the primary motor cortex (M1), which can be measured as the decrease of motor evoked potential (MEP) elicited by a single-pulse TMS over the M1. This study was conducted to quantify cerebellar dysfunction using CBI in cerebellar type multiple system atrophy (MSA-C) patients. First, CBI was measured using MEP elicited from a hand muscle by stimulating the hand motor area of M1. The amount of CBI was defined as the degree of decrease in the MEP amplitude in the presence of cerebellar stimulation compared with the condition of M1 stimulation alone. Results of the MSA-C patients were compared with those of healthy volunteers. Correlation between amounts of CBI and a clinical scale of ataxia, the International Cooperative Ataxia Scale Rating (ICARS), was assessed. Healthy volunteers showed more inhibition than MSA-C patients. Moreover, ICARS showed that the CBI amount in the patients is correlated with the degree of ataxia significantly. Results suggest that CBI can be a good marker of disease progression in MSA-C patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12311-021-01293-0DOI Listing
June 2021

Gastric Hyperplastic Polyps Can Shrink After Discontinuation of Proton Pump Inhibitors: A Case Series Compared With Continuation of Proton Pump Inhibitors.

J Clin Gastroenterol 2021 Jun 9. Epub 2021 Jun 9.

Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine Department of Gastroenterology, National Hospital Organization Kyoto Medical Center, Kyoto Department of Gastroenterology, Osaka Red Cross Hospital, Osaka, Japan.

Goal: This study investigated whether gastric hyperplastic polyps (GHPs) shrink after discontinuation of proton pump inhibitor (PPI) alone.

Background: Long-term use of PPIs has been reported to increase the incidence of GHPs, which sometimes bleed and cause anemia. We experienced a patient whose recurrent hemorrhagic GHPs associated with long-term use of PPIs had disappeared after discontinuation of PPIs.

Study: This study was conducted retrospectively at Kyoto University Hospital. Patients with histologically confirmed GHPs who had been taking PPIs for >6 months and who had undergone a repeat endoscopy within 2 years were included. Polyp shrinkage was defined as the disappearance of polyps or a reduction of >50% in the long diameter of the largest polyp.

Results: Six patients who discontinued PPIs were compared with 17 patients who continued PPIs. Polyp shrinkage was significantly more frequent in the PPI-discontinuation group (5/6, 83%) than in the PPI continuation group (0/17, 0%) (P<0.001). In 2 patients in the PPI-discontinuation group, the polyps completely disappeared finally.

Conclusion: These findings suggest that discontinuation of PPIs can shrink GHPs in patients using PPIs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MCG.0000000000001577DOI Listing
June 2021

Cardiac and Echocardiographic Markers in Cryptogenic Stroke with Incidental Patent Foramen Ovale.

J Stroke Cerebrovasc Dis 2021 Aug 6;30(8):105892. Epub 2021 Jun 6.

Department of Neurology, Juntendo University Urayasu Hospital, Chiba, Japan. Electronic address:

Objective: Some cardiac abnormalities could be a substrate for potential embolic source in cryptogenic stroke (CS). We evaluated whether cardiac and echocardiographic markers were associated with CS in patients with incidental patent foramen ovale (PFO) as defined using the Risk of Paradoxical Embolism (RoPE) score.

Materials And Methods: Among 677 patients enrolled in a multicenter observational CS registry, 300 patients (44%) had PFOs detected by transesophageal echocardiography. They were classified into probable PFO-related stroke (RoPE score>6, n = 32) and stroke with incidental PFO (RoPE score≤6, n = 268) groups, and clinical characteristics, laboratory findings, cardiac and echocardiographic markers (i.e. brain natriuretic peptide, left atrial [LA] diameter, ejection fraction, early transmitral flow velocity/early diastolic tissue Doppler imaging velocity [E/e'], LA appendage flow velocity, spontaneous echo contrast, atrial septal aneurysm, substantial PFO, and aortic arch plaques), stroke recurrence, and excellent outcome (modified Rankin scale score <2) at discharge were compared. Risk factors for low RoPE scores were determined using multiple logistic regression analysis.

Results: Higher brain natriuretic peptide levels (p = 0.032), LA enlargement (p < 0.001), higher E/e' (p = 0.001), lower LA appendage flow velocity (p < 0.001), non-substantial PFO (p = 0.021), and aortic arch plaques (p = 0.002) were associated with the low RoPE score group. Patients with high RoPE scores had excellent outcomes (58% versus 78%, p = 0.035). LA enlargement (age- and sex-adjusted odds ratio, 1.15; 95 % confidence interval, 1.00-1.32; p = 0.039) was an independent predictor of low RoPE scores.

Conclusions: Abnormal cardiac substrate could be associated with CS occurrence in a subset of patients with PFO. Patients with CS who had incidental PFO may be at risk of cardioembolism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.105892DOI Listing
August 2021

Texture analysis of [F]-fluorodeoxyglucose-positron emission tomography/computed tomography for predicting the treatment response of postoperative recurrent or metastatic oral squamous cell carcinoma treated with cetuximab.

Ann Nucl Med 2021 Aug 20;35(8):871-880. Epub 2021 May 20.

Department of Oral and Maxillofacial Surgery, and Plastic Surgery, Gunma University Graduate School of Medicine, Maebashi, Japan.

Objective: To assess the value of the texture analysis of fluorine-F-fluorodeoxyglucose-positron emission tomography/computed tomography (F-FDG-PET/CT) in predicting the treatment response of postoperative recurrent or metastatic oral squamous cell carcinoma (POR/M-OSCC) treated with cetuximab.

Methods: A total of 14 patients undergoing F-FDG-PET/CT with POR/M-OSCC were divided into the responder and non-responder groups according to cetuximab response by Response Evaluation Criteria in Solid Tumors (RECIST). The regions of interest (ROI) were set at the POR/M-OSCC lesions with the highest uptake of F-FDG, and the volumetric and texture features were analyzed. The features with correlation coefficient of 0.6 or more were further evaluated using the logistic regression analysis to create a model.

Results: The SHAPE, SHAPE, metabolic tumor volume (MTV), and gray-level run-length matrix run-length nonuniformity (GLRLM) were significantly different between the responder (n = 6) and non-responder (n = 8) groups (p = 0.044, 0.042, 0.047, and 0.012, respectively). The model's area under the curve (AUC) was found to be 0.83, 0.83, 0.79, and 0.92, respectively. The heatmap with PET feature dendrogram showed four distinct clusters including them in patient's responder and non-responder groups.

Conclusions: Higher MTV, GLRLM, SHAPE, and SHAPE in F-FDG-PET images may have the prediction values for treatment response with POR/M-OSCC treated with cetuximab.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12149-021-01623-6DOI Listing
August 2021

[A CASE OF VOCAL CORD DYSFUNCTION, WHO USED ADRENALIN AUTOINJECTOR (EPIPEN) FREQUENTLY AFTER BEING DIAGNOSED AS ANAPHYLAXIS].

Arerugi 2021 ;70(3):210-214

Department of Pediatrics, Saitama Medical University Hospital.

We experienced a case of vocal cord dysfunction (VCD) in a child to whom an adrenaline autoinjector (Epipen) had been prescribed and frequently used following a diagnosis of exercise-induced anaphylaxis. An exercise test was performed to investigate her frequent episodes of anaphylaxis-like symptoms. A few minutes after starting the test, signs of dyspnea, such as throat tightness and stridor, appeared, although hypoxia was not present and her respiratory sounds were normal. Medications were not effective for treating her respiratory symptoms. Laryngoscopy performed at the test revealed bizarre vocal cord movement, which was diagnosed as VCD. The symptoms gradually diminished after the initiation of biofeedback therapy, including pursed lips breathing and abdominal breathing. Thereafter, she did not use an adrenaline autoinjector when symptoms appeared; instead, she would perform biofeedback therapy before using the adrenaline autoinjector. Thus, VCD should be included in the differential diagnosis of patients who show anaphylactic symptoms that are resistant to preventive therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.15036/arerugi.70.210DOI Listing
May 2021

Survival of detached cancer cells is regulated by movement of intracellular Na,K-ATPase.

iScience 2021 May 15;24(5):102412. Epub 2021 Apr 15.

Department of Pharmaceutical Physiology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.

Beginning of metastasis, cancer cells detach from the primary tumor and they can survive even under loss of anchorage; however, the detachment-elicited mechanisms have remained unknown. Here, we found that Na,K-ATPase α3-isoform (α3NaK) in human cancer cells is dynamically translocated from intracellular vesicles to the plasma membrane when the attached cells are detached and that this mechanism contributes to the survival of the detached (floating) cancer cells. α3NaK was detected in the plasma membrane of floating cancer cells in peritoneal fluids of patients, while it was in the cytoplasm of the cells in primary tumor tissues. On cancer cell detachment, we also found the focal-adhesion-kinase-dependent Ca response that induces the α3NaK translocation via nicotinic acid adenine dinucleotide phosphate pathway. Activation of AMP-activated protein kinase was associated with the translocated α3NaK in the plasma membrane. Collectively, our study identifies a unique mechanism for survival of detached cancer cells, opening up new opportunities for development of cancer medicines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.isci.2021.102412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099779PMC
May 2021

Indolent feature of Helicobacter pylori-uninfected intramucosal signet ring cell carcinomas with CDH1 mutations.

Gastric Cancer 2021 May 7. Epub 2021 May 7.

Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Background: In Helicobacter pylori (Hp)-uninfected individuals, diffuse-type gastric cancer (DGC) was reported as the most common type of cancer. However, the carcinogenic mechanism of Hp-uninfected sporadic DGC is largely unknown.

Methods: We performed whole-exome sequencing of Hp-uninfected DGCs and Hp-uninfected normal gastric mucosa. For advanced DGCs, external datasets were also analyzed.

Results: Eighteen patients (aged 29-78 years) with DGCs and nine normal subjects (28-77 years) were examined. The mutation burden in intramucosal DGCs (10-66 mutations per exome) from individuals aged 29-73 years was not very different from that in the normal gastric glands, which showed a constant mutation accumulation rate (0.33 mutations/exome/year). Unbiased dN/dS analysis showed that CDH1 somatic mutation was a driver mutation for intramucosal DGC. CDH1 mutation was more frequent in intramucosal DGCs (67%) than in advanced DGCs (27%). In contrast, TP53 mutation was more frequent in advanced DGCs (52%) than in intramucosal DGCs (0%). This discrepancy in mutations suggests that CDH1-mutated intramucosal DGCs make a relatively small contribution to advanced DGC formation. Among the 16 intramucosal DGCs (median size, 6.5 mm), 15 DGCs were pure signet ring cell carcinoma (SRCC) with reduced E-cadherin expression and a low proliferative capacity (median Ki-67 index, 2.4%). Five SRCCs reviewed endoscopically over 2-5 years showed no progression.

Conclusions: Impaired E-cadherin function due to CDH1 mutation was considered as an early carcinogenic event of Hp-uninfected intramucosal SRCC. Genetic and clinical analyses suggest that Hp-uninfected intramucosal SRCCs may be less likely to develop into advanced DGCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10120-021-01191-8DOI Listing
May 2021

Genetic Pathogenesis of Inflammation-Associated Cancers in Digestive Organs.

Pathogens 2021 Apr 9;10(4). Epub 2021 Apr 9.

Department of Gastroenterology, Red Cross Osaka Hospital, Osaka 543-8555, Japan.

Epidemiological, clinical, and biological studies convincingly demonstrate that chronic inflammation predisposes to the development of human cancers. In digestive organs, inflammation-associated cancers include colitis-associated colorectal cancers, -associated gastric cancer, as well as Barrett's esophagus and esophageal adenocarcinoma associated with chronic duodenogastric-esophageal reflux. Cancer is a genomic disease, and stepwise accumulation of genetic and epigenetic alterations of tumor-related genes leads to the development of tumor cells. Recent genome analyses show that genetic alterations, which are evoked by inflammation, are latently accumulated in inflamed epithelial cells of digestive organs. Production of reactive oxygen and aberrant expression of activation-induced cytidine deaminase, a nucleotide-editing enzyme, could be induced in inflamed gastrointestinal epithelial cells and play a role as a genomic modulator of inflammation-associated carcinogenesis. Understanding the molecular linkage between inflammation and genetic alterations will open up a new field of tumor biology and provide a novel strategy for the prevention of inflammation-associated tumorigenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/pathogens10040453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069378PMC
April 2021

Stepwise generation of AID knock-in and conditional knockout mice from a single gene-targeting event.

Int Immunol 2021 Jun;33(7):387-398

Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.

Activation-induced cytidine deaminase (AID) encoded by the Aicda gene initiates class-switch recombination and somatic hypermutation of immunoglobulin genes. In addition to this function, AID is also implicated in the epigenetic regulation in pluripotent stem cells and in the oncogenesis of lymphoid and non-lymphoid origins. To examine AID's role in specific cell types, we developed mouse strains of conditional knockout (Aicda-FL) and knock-in with a red fluorescent protein gene (RFP) inserted into the Aicda locus (Aicda-RFP). These two strains were obtained from a single targeting event in embryonic stem cells by a three-loxP or tri-lox strategy. Partial and complete recombination among the three loxP sites in the Aicda-RFP locus gave rise to Aicda-FL and AID-deficient loci (Aicda-KO), respectively, after mating Aicda-RFP mice with Cre-expressing mice driven by tissue-non-specific alkaline phosphate promoter. We confirmed RFP expression in B cells of germinal centers of intestine-associated lymphoid tissue. Mice homozygous for each allele were obtained and were checked for AID activity by class-switch and hypermutation assays. AID activity was normal for Aicda-FL but partially and completely absent for Aicda-RFP and Aicda-KO, respectively. Aicda-FL and Aicda-RFP mice would be useful for studying AID function in subpopulations of B cells and in non-lymphoid cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/intimm/dxab019DOI Listing
June 2021

Different aspects of early and late development of atrial fibrillation during hospitalization in cryptogenic stroke.

Sci Rep 2021 Mar 29;11(1):7127. Epub 2021 Mar 29.

Department of Neurology, Juntendo University Urayasu Hospital, Chiba, Japan.

The detection of underlying atrial fibrillation (AF) has become increasingly possible by insertable cardiac monitoring (ICM). During hospitalization for cryptogenic stroke, factors related to the early and late development of AF have not been studied. CHALLENGE ESUS/CS is a multicenter registry of cryptogenic stroke patients undergoing transesophageal echocardiography. Twelve-lead electrocardiogram, continuous cardiac monitoring, and 24-h Holter electrocardiogram were all used for the detection of AF. Early and late detection of AF was determined with an allocation ratio of 1:1 among patients with AF. A total of 677 patients (68.7 ± 12.8 years; 455 men) were enrolled, and 64 patients developed AF during hospitalization. Four days after admission was identified as the approximate median day to classify early and late phases to detect AF: ≤ 4 days, 37 patients; > 4 days, 27 patients. Multiple logistic regression analysis showed that spontaneous echo contrast (SEC) (OR 5.91; 95% CI 2.19-15.97; p < 0.001) was associated with AF ≤ 4 days, whereas a large infarction > 3 cm in diameter (OR 3.28; 95% CI 1.35-7.97; p = 0.009) was associated with AF > 4 days. SEC and large infarctions were important predictors of in-hospital AF detection, particularly in the early and late stages, respectively; thus, they could serve as indications for recommending ICM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-86620-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007744PMC
March 2021

Life-long oligodendrocyte development and plasticity.

Semin Cell Dev Biol 2021 Aug 16;116:25-37. Epub 2021 Mar 16.

Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK. Electronic address:

Oligodendrocyte precursor cells (OPCs) originate in localized germinal zones in the embryonic neural tube, then migrate and proliferate to populate the entire central nervous system, both white and gray matter. They divide and generate myelinating oligodendrocytes (OLs) throughout postnatal and adult life. OPCs express NG2 and platelet-derived growth factor receptor alpha subunit (PDGFRα), two functionally important cell surface proteins, which are also widely used as markers for OPCs. The proliferation of OPCs, their terminal differentiation into OLs, survival of new OLs, and myelin synthesis are orchestrated by signals in the local microenvironment. We discuss advances in our mechanistic understanding of paracrine effects, including those mediated through PDGFRα and neuronal activity-dependent signals such as those mediated through AMPA receptors in OL survival and myelination. Finally, we review recent studies supporting the role of new OL production and "adaptive myelination" in specific behaviours and cognitive processes contributing to learning and long-term memory formation. Our article is not intended to be comprehensive but reflects the authors' past and present interests.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.semcdb.2021.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292179PMC
August 2021

Utility of transoral motion-mode ultrasonography to detect tongue fasciculation in patients with amyotrophic lateral sclerosis.

Muscle Nerve 2021 06 16;63(6):909-913. Epub 2021 Mar 16.

Division of Neurology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.

Introduction: Increasing evidence suggests the utility of the submandibular approach for ultrasonography to detect tongue fasciculation in amyotrophic lateral sclerosis (ALS). We hypothesized that transoral motion-mode ultrasonography (TOMU) would be useful to detect tongue fasciculation in patients with ALS.

Methods: Patients with sporadic ALS showing clinically definite tongue fasciculation were enrolled, and the ultrasonography findings of patients' tongues on TOMU and ultrasonography by the conventional submandibular approach were analyzed.

Results: Six patients with clinically definite ALS were enrolled in this study. Although small, irregular muscle movements of 5 to 10 mm in amplitude and 0.1 to 0.2 second in duration were detected in all patients by TOMU, similar muscle movements were detected in only two of the six patients by the submandibular approach.

Discussion: TOMU appeared to be useful for detecting tongue fasciculation in ALS patients. Further study is needed to better determine its role as a diagnostic tool for ALS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mus.27218DOI Listing
June 2021

Stimulation of brain α7-nicotinic acetylcholine receptors suppresses the rat micturition through brain GABAergic receptors.

Biochem Biophys Res Commun 2021 Apr 23;548:84-90. Epub 2021 Feb 23.

Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Kochi, 783-8505, Japan.

Brain nicotinic acetylcholine receptors (nAChRs) reportedly suppress the micturition, but the mechanisms responsible for this suppression remain unclear. We previously reported that intracerebroventricularly administered (±)-epibatidine (non-selective nAChR agonist) activated the sympatho-adrenomedullary system, which can affect the micturition. Therefore, we investigated (1) whether intracerebroventricularly administered (±)-epibatidine-induced effects on the micturition were dependent on the sympatho-adrenomedullary system, and (2) brain nAChR subtypes involved in the (±)-epibatidine-induced effects in urethane-anesthetized male Wistar rats. Plasma noradrenaline and adrenaline (catecholamines) were measured just before and 5 min after (±)-epibatidine administration. Evaluation of urodynamic parameters, intercontraction intervals (ICI) and maximal voiding pressure (MVP) by cystometry was started 1 h before (±)-epibatidine administration or intracerebroventricular pretreatment with other drugs and continued 1 h after (±)-epibatidine administration. Intracerebroventricularly administered (±)-epibatidine elevated plasma catecholamines and prolonged ICI without affecting MVP, and these changes were suppressed by intracerebroventricularly pretreated mecamylamine (non-selective nAChR antagonist). Acute bilateral adrenalectomy abolished the (±)-epibatidine-induced elevation of plasma catecholamines, but had no effect on the (±)-epibatidine-induced ICI prolongation. The latter was suppressed by intracerebroventricularly pretreated methyllycaconitine (selective α7-nAChR antagonist), SR95531 (GABA antagonist), and SCH50911 (GABA antagonist), but not by dihydro-β-erythroidine (selective α4β2-nAChR antagonist). Intracerebroventricularly administered PHA568487 (selective α7-nAChR agonist) prolonged ICI without affecting MVP, similar to (±)-epibatidine. These results suggest that stimulation of brain α7-nAChRs suppresses the rat micturition through brain GABA/GABA receptors, independently of the sympatho-adrenomedullary outflow modulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2021.02.051DOI Listing
April 2021

Oncogenic transcriptomic profile is sustained in the liver after the eradication of the hepatitis C virus.

Carcinogenesis 2021 May;42(5):672-684

Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Hepatocellular carcinoma (HCC) developing after hepatitis C virus (HCV) eradication is a serious clinical concern. However, molecular basis for the hepatocarcinogenesis after sustained virologic response (SVR) remains unclear. In this study, we aimed to unveil the transcriptomic profile of post-SVR liver tissues and explore the molecules associated with post-SVR carcinogenesis. We analysed 90 RNA sequencing datasets, consisting of non-cancerous liver tissues including 20 post-SVR, 40 HCV-positive and 7 normal livers, along with Huh7 cell line specimens before and after HCV infection and eradication. Comparative analysis demonstrated that cell cycle- and mitochondrial function-associated pathways were altered only in HCV-positive non-cancerous liver tissues, whereas some cancer-related pathways were up-regulated in the non-cancerous liver tissues of both post-SVR and HCV-positive cases. The persistent up-regulation of carcinogenesis-associated gene clusters after viral clearance was reconfirmed through in vitro experiments, of which, CYR61, associated with liver fibrosis and carcinogenesis in several cancer types, was the top enriched gene and co-expressed with cell proliferation-associated gene modules. To evaluate whether this molecule could be a predictor of hepatocarcinogenesis after cure of HCV infection, we also examined 127 sera from independent HCV-positive cohorts treated with direct-acting antivirals (DAAs), including 60 post-SVR-HCC patients, and found that the elevated serum Cyr61 was significantly associated with early carcinogenesis after receiving DAA therapy. In conclusion, some oncogenic transcriptomic profiles are sustained in liver tissues after HCV eradication, which might be a molecular basis for the liver cancer development even after viral clearance. Among them, up-regulated CYR61 could be a possible biomarker for post-SVR-HCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/carcin/bgab014DOI Listing
May 2021

Difficulty in prenatal diagnosis of the volvulus of the small intestine: A peculiar clinical course of two cases with massive bowel dilatation and loss of peristalsis.

J Obstet Gynaecol Res 2021 May 15;47(5):1903-1908. Epub 2021 Feb 15.

Department of Obstetrics and Gynecology, School of Medicine, Kurume University, Kurume, Japan.

We report two cases of fetal intestinal volvulus (jejunum in case A, ileum in case B) with massive bowel dilatation and loss of peristalsis, which suddenly appeared in the third trimester. The bowel was dilated to different sizes and there were various echogenic patterns of the intestines in case A and a sausage-like appearance in case B. Case A developed polyhydramnios, whereas case B did not. Among 47 cases of fetal intestinal volvulus (29 articles) in which 32 were diagnosed prenatally, almost all cases with a prenatal diagnosis showed "whirlpool sign" or "coffee bean sign" by sonography and/or findings indicating intestinal hemorrhage. Even without these findings, the presence of dilatation of the intestines and loss of peristalsis occurring in the third trimester were diagnostic clues. The presence of different sizes and various patterns of bowel dilation and hydramnios may be helpful for predicting the involved site of intestinal volvulus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jog.14706DOI Listing
May 2021

Soleal vein dilatation in the early phase of hospitalization is associated with subsequent development of deep vein thrombosis in patients with acute stroke.

J Med Ultrason (2001) 2021 Jan 29;48(1):97-104. Epub 2021 Jan 29.

Division of Neurology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae, Kawasaki, Kanagawa, 216-8511, Japan.

Purpose: To evaluate the usefulness of soleal vein (SOV) diameter as a predictor of new onset of deep vein thrombosis (DVT) in acute stroke patients.

Methods: A total of 121 acute stroke patients who were admitted within 48 h of onset underwent a calf vein ultrasonography (CVUS) examination within 7 days after hospitalization. They were evaluated for the presence of DVT and risk factors including maximum SOV diameter. Next, the patients in whom DVT was not detected at the first CVUS examination underwent a second CVUS examination on the 21st hospital day, and were evaluated for the presence of new DVT.

Results: DVT was detected in 27 of 121 patients at the first CVUS examination. A significant association was noted between the presence of DVT and higher levels of soluble fibrin monomer, D-dimer, and C-reactive protein, and a higher rate of having cancer concomitantly. Furthermore, 50 of 94 patients without DVT at the first CVUS examination underwent a second CVUS examination. Of the 94 patients, 44 were excluded, because they were discharged by the 21st day. Note that DVT was newly developed in 12 of the 50 patients who underwent the second CVUS. A significant association was found between the presence of new DVT and the rate of history of stroke, hematocrit level, and maximum SOV diameter at the first examination.

Conclusion: In our acute stroke patients, SOV dilation, history of stroke, and elevated hematocrit level were found to be associated with risk of developing a new DVT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10396-020-01075-xDOI Listing
January 2021

Predictive factors for dental inflammation with exacerbation during cancer therapy with FDG-PET/CT imaging.

Support Care Cancer 2021 Aug 7;29(8):4277-4284. Epub 2021 Jan 7.

Department of Oral and Maxillofacial Surgery, and Plastic Surgery, Gunma University Graduate School of Medicine, 3-39-22, Showamachi, Maebashi, Gunma, 371-8511, Japan.

Purpose: Oral adverse events, such as dental inflammation with exacerbation, are stressful and lead to poor nutrition in patients undergoing cancer therapy. Thus, the prediction of risk factors for dental inflammation with exacerbation is important before cancer therapy is initiated. We hypothesized that, during cancer therapy (DIECT), fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) imaging could be useful to predict dental inflammation with exacerbation.

Methods: We enrolled 124 patients who underwent FDG-PET/CT for diagnostic staging before cancer treatment. We then assessed DIECT outcomes after basic perioperative oral treatment. Moreover, we evaluated clinical parameters, therapeutic strategies, periodontal examination (probing depth (PD) and bleeding on probing (BOP)), dental imaging, and FDG-PET/CT imaging results of patients with and without DIECT. Furthermore, PET/CT images were assessed as per the FDG accumulation of the dental lesion (PAD) grading system.

Results: Univariate analysis demonstrated significant differences in age, periodontal examination (PD and BOP), and PAD grade between patients with and without DIECT. Furthermore, multivariate logistic regression analysis identified independent predictive factors for a positive periodontal examination (PD) (odds ratio (OR) 5.9, 95% confidence interval (CI) 1.8-19.7; P = 0.004) and PAD grade (OR 11.6, 95% CI 3.2-41.2; P = 0.0002). In patients with cancer, PAD grade using FDG-PET/CT imaging was an independent and informative risk factor for DIECT.

Conclusion: Our results suggested that, for patients with DIECT, periodontal examination and PAD grade were independent predictive factors. Hence, regardless of the presence or absence of any lesion on dental imaging, PAD grade might be an additional tool, in addition to periodontal examination that potentially improves oral care management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00520-020-05909-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236470PMC
August 2021

Age-related differences in responses to hydrogen sulfide in the bladder of spontaneously hypertensive rats.

Int J Urol 2021 04 5;28(4):459-465. Epub 2021 Jan 5.

Departments of, Department of, Pharmacology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan.

Objectives: To investigate whether a response to hydrogen sulfide donors (GYY4137 and sodium hydrosulfide) and the endogenous hydrogen sulfide system (hydrogen sulfide level and expression of cysteine aminotransferase, cystathionine β-synthase, cystathionine γ-lyase, and 3-mercaptopyruvate sulfurtransferase) in the spontaneously hypertensive rat bladder differ with age, we compared the responses of hydrogen sulfide donors to micturition and bladder relaxation, and the endogenous hydrogen sulfide system in the bladder of 18-week versus 12-week-old spontaneously hypertensive rats.

Methods: GYY4137 was intravesically administered and cystometry was performed in anesthetized rats. The responses of sodium hydrosulfide were evaluated in carbachol-mediated precontracted bladder strips. Bladder hydrogen sulfide levels and expression levels of each enzyme were investigated using the methylene blue method and Western blotting, respectively.

Results: GYY4137 treatment significantly prolonged intercontraction intervals only in 12-week-old rats. Sodium hydrosulfide-induced bladder relaxation was significantly attenuated in the strips of 18-week-old rats compared with that in 12-week-old rats. In the bladder dome, significant increases in hydrogen sulfide levels and in the expression of cystathionine β-synthase, 3-mercaptopyruvate sulfurtransferase, and cysteine aminotransferase were observed in 18-week-old rats compared with 12-week-old rats. However, cystathionine γ-lyase bands were not detected in bladder tissues of either group.

Conclusions: Bladder relaxation induced by hydrogen sulfide may be attenuated in spontaneously hypertensive rats in an age-dependent manner.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/iju.14478DOI Listing
April 2021

[The neuroprotective role of EAAC1 in hippocampal injury following ischemia-reperfusion].

Nihon Yakurigaku Zasshi 2021 ;156(1):21-25

Department of Pharmacology, Kochi Medical School, Kochi University.

Ischemic stroke is one of the most prevalent brain disorders and the major cause of long-term disability. In particularly, hippocampal injury after ischemia-reperfusion is a serious problem as it contributes to vascular dementia. Many researches have revealed that ischemia-reperfusion causes increase in reactive oxygen species production and disruption of neuronal Zn homeostasis in the hippocampus, which induces hippocampal neuron death. Glutathione (GSH) is present in all mammalian cells and plays a crucial role in neuronal cell defense against oxidative stress. On the other hand, thiol group of GSH chemically chelates Zn and functions as a regulator of neuronal Zn homeostasis. These evidences suggest that neuronal GSH levels could be an important factor affecting neuronal surviving. The synthesis of GSH is largely influenced by intracellular cysteine availability. In neurons, excitatory amino acid carrier type 1 (EAAC1) acts as a cysteine transporter and provides cysteine substrate for GSH synthesis. Recently, several animal studies have revealed that promotion of neuronal GSH synthesis through EAAC1 reduces ischemia-induced hippocampal neuron death. This review aims to describe neuroprotective role of GSH against hippocampal injury following ischemia-reperfusion, focusing on EAAC1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1254/fpj.20069DOI Listing
January 2021

Design and synthesis of 14 and 15-membered macrocyclic scaffolds exhibiting inhibitory activities of hypoxia-inducible factor 1α.

Bioorg Med Chem 2021 01 13;30:115949. Epub 2020 Dec 13.

Department of Chemistry, School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Electronic address:

Inspired by the privileged molecular skeletons of 14- and 15-membered antibiotics, we adopted a relatively unexplored synthetic approach that exploits alkaloidal macrocyclic scaffolds to generate modulators of protein-protein interactions (PPIs). As mimetics of hot-spot residues in the α-helices responsible for the transcriptional regulation, three hydrophobic sidechains were displayed on each of the four distinct macrocyclic scaffolds generating diversity of their spatial arrangements. Modular assembly of the building blocks followed by ring-closing olefin metathesis reaction and subsequent hydrogenation allowed concise and divergent synthesis of scaffolds 1-4. The 14-membered alkaloidal macrocycles 2-4 demonstrated similar inhibition of hypoxia-inducible factor (HIF)-1α transcriptional activities (IC between 8.7 and 10 µM), and 4 demonstrated the most potent inhibition of cell proliferation in vitro (IC = 12 µM against HTC116 colon cancer cell line). A docking model suggested that 4 could mimic the LLxxL motif in HIF-1α, in which the three sidechains are capable of matching the spatial arrangements of the protein hot-spot residues. Unlike most of the stapled peptides, the 14-membered alkaloidal scaffold has a similar size to the α-helix backbone and does not require additional atoms to induce α-helix mimetic structure. These experimental results underscore the potential of alkaloidal macrocyclic scaffolds featuring flexibly customizable skeletal, stereochemical, substitutional, and conformational properties for the development of non-peptidyl PPI modulators targeting α-helix-forming consensus sequences responsible for the transcriptional regulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2020.115949DOI Listing
January 2021

Therapeutic effects of losartan on prostatic hyperplasia in spontaneously hypertensive rats.

Life Sci 2021 Feb 19;266:118924. Epub 2020 Dec 19.

Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Japan. Electronic address:

Aims: We investigated the therapeutic effects of losartan, an angiotensin II type 1 receptor blocker, on prostatic hyperplasia in spontaneously hypertensive rats (SHRs).

Main Methods: Male SHRs (age, 36 weeks) were perorally treated with losartan (3 or 10 mg·kg) or vehicle once daily for 18 weeks. Age-matched Wistar Kyoto rats (WKYs) were used as vehicle-treated controls (n = 8). The effects of losartan were evaluated by analyzing prostate weight, blood pressure, and prostatic blood flow. The tissue malondialdehyde (MDA), interleukin-6 (IL-6), and basic fibroblast growth factor (bFGF) levels were measured. Histological analysis for the ventral prostate involved hematoxylin and eosin staining and TdT-mediated dUTP nick-end labeling (TUNEL) assay.

Key Findings: Compared to the vehicle-treated WKYs, the vehicle-treated SHRs had significantly higher prostate weight, prostate weight/body weight ratio (PBR), blood pressure, glandular epithelial area, and tissue MDA, IL-6, and bFGF levels in the ventral prostate and lower prostatic blood flow. Treatment with losartan caused significant recovery of blood flow and decreased PBR and glandular epithelial area as well as tissue MDA, IL-6, and bFGF levels in the SHR ventral prostate without affecting blood pressure. High-dose losartan significantly decreased blood pressure and increased TUNEL-positive cells in the ventral prostate in SHRs.

Significance: Chronic losartan treatment could ameliorate prostatic hyperplasia via recovery of reduced prostatic blood flow and induction of apoptosis in the ventral prostate in SHRs. Losartan might have therapeutic effects on not only hypertension but also prostatic hyperplasia in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lfs.2020.118924DOI Listing
February 2021

Elongated Styloid Process With Skeletal Mandibular Protrusion.

J Craniofac Surg 2021 Jun;32(4):e377-e378

Department of Oral and Maxillofacial Surgery, and Plastic Surgery, Gunma University Graduate School of Medicine, Showa-machi, Maebashi, Japan.

Abstract: An elongated styloid process (ESP) causes symptoms such as pharyngeal pain, swallowing pain, and discomfort during mouth opening. The main treatment is surgical resection of the ESP. The authors present a case of ESP with skeletal mandibular protrusion. Because mandibular setback by sagittal splitting ramus osteotomy (SSRO) may lead to deterioration of symptoms of ESP, resection of ESP and bilateral SSRO were performed simultaneously. The patient was a 50-year-old man who visited our department with chief complaints of mandibular protrusion and pain in the left pharynx on mouth opening and swallowing. A lateral cephalogram helped in diagnosis of skeletal mandibular protrusion. In addition, an approximately 42-mm left styloid process elongated inferomedially was observed. Left styloidectomy was first performed via the cervical approach, followed by SSRO. Occlusion, facial appearance, and preoperative symptoms due to the ESP improved after surgery. The cervical appearance was esthetically satisfactory. In a case of ESP with skeletal mandibular protrusion with potential aggravation of symptoms because of mandibular setback of the ESP, resection of the styloid process is necessary together with orthognathic surgery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/SCS.0000000000007298DOI Listing
June 2021

DNA methyltransferase 3B plays a protective role against hepatocarcinogenesis caused by chronic inflammation via maintaining mitochondrial homeostasis.

Sci Rep 2020 12 4;10(1):21268. Epub 2020 Dec 4.

Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

Most hepatocellular carcinomas (HCCs) develop on the basis of chronic hepatitis, but the mechanism of epigenetic regulation in inflammatory hepatocarcinogenesis has yet to be elucidated. Among de novo DNA methyltransferases (DNMTs), DNMT3B has lately been reported to act specifically on actively transcribed genes, suggesting the possibility that it plays a role in the pathogenesis of cancer. We confirmed that DNMT3B isoforms lacking its catalytic domain were highly expressed in HCCs compared with non-tumorous liver tissue. To elucidate the role of DNMT3B in hepatocarcinogenesis, we generated a genetically engineered mouse model with hepatocyte-specific Dnmt3b deletion. The liver of the Dnmt3b-deficient mice exhibited an exacerbation of thioacetamide-induced hepatitis, progression of liver fibrosis and a higher incidence of HCC compared with the liver of the control mice. Whole-genome bisulfite sequencing verified a lower CG methylation level in the Dnmt3b-deficient liver, demonstrating differentially methylated regions throughout the genome. Transcriptome analysis revealed decreased expression of genes related to oxidative phosphorylation in the Dnmt3b-deficient liver. Moreover, primary hepatocytes isolated from the Dnmt3b-deficient mice showed reduced mitochondrial respiratory capacity, leading to the enhancement of oxidative stress in the liver tissue. Our findings suggest the protective role of DNMT3B against chronic inflammation and HCC development via maintaining mitochondrial homeostasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-78151-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719166PMC
December 2020

The role of diurnal fluctuations in excitatory amino acid carrier 1 levels in post-ischemic hippocampal Zn accumulation.

Exp Neurol 2021 Feb 27;336:113538. Epub 2020 Nov 27.

Department of Pharmacology, Kochi Medical School, Kochi University, Kohasu, Okoh-cho, Nankoku 783-8505, Japan. Electronic address:

Accumulating evidence indicates time-of-day variations in ischemic neuronal injury. Under ischemic conditions, Zn is massively released from hippocampal glutamatergic neurons, and intracellular Zn accumulation results in neuron death. Notably, excitatory amino acid carrier 1 (EAAC1), known as a cysteine transporter, is involved in Zn homeostasis, and its expressions exhibit a diurnal fluctuation. This study aimed to investigate whether time of day of an ischemic insult affects Zn accumulation and neuronal injury and determine whether altered Zn accumulation is modulated by EAAC1 diurnal fluctuation in the hippocampus in a mouse model of ischemic stroke. Mice subjected to transient global ischemia for 40 min at Zeitgeber time 18 (ZT18) (23:00) exhibited reduced Zn accumulation and neuronal death in the hilar region of the hippocampus compared to those at ZT4 (09:00). The EAAC1 protein expression in the hippocampus was increased at ZT18 relative to ZT4. Intracerebroventricular injection of a non-selective excitatory amino acid transporter inhibitor, DL-threo-β-benzyloxyaspartate, or a selective EAAC1 inhibitor, L-aspartic acid β-hydroxamate, increased ischemia-induced Zn accumulation and neuronal death in the hilus at ZT18. These findings suggest that ischemia-induced Zn accumulation displays circadian fluctuations through diurnal variations in EAAC1 expressions and affects susceptibility to ischemic neuronal injury in the hippocampal hilar region.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.expneurol.2020.113538DOI Listing
February 2021
-->