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Article ; Online: Can calcium channel blockers prevent ischemic stroke in nonvalvular atrial fibrillation patients?-the optimal choice of antihypertensive drug for subtype-specific stroke prevention.

Kiyohara, Takuya / Ago, Tetsuro

Hypertension research : official journal of the Japanese Society of Hypertension

2022 Volume 45, Issue 6, Page(s) 1076–1078

MeSH term(s)	Anticoagulants/adverse effects ; Antihypertensive Agents/therapeutic use ; Atrial Fibrillation/chemically induced ; Atrial Fibrillation/complications ; Atrial Fibrillation/drug therapy ; Calcium Channel Blockers/therapeutic use ; Humans ; Ischemic Stroke ; Risk Factors ; Stroke/chemically induced ; Stroke/prevention & control
Chemical Substances	Anticoagulants ; Antihypertensive Agents ; Calcium Channel Blockers
Language	English
Publishing date	2022-04-01
Publishing country	England
Document type	Editorial ; Comment
ZDB-ID	1175297-x
ISSN	1348-4214 ; 0916-9636
ISSN (online)	1348-4214
ISSN	0916-9636
DOI	10.1038/s41440-022-00907-2
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Zs.A 3898: Show issues

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Article ; Online: Regulation of Derlin-1-mediated degradation of NADPH oxidase partner p22

Miyano, Kei / Okamoto, Shuichiro / Kajikawa, Mizuho / Kiyohara, Takuya / Kawai, Chikage / Yamauchi, Akira / Kuribayashi, Futoshi

Redox biology

2022 Volume 56, Page(s) 102479

Abstract: The transmembrane protein ... ...

Abstract	The transmembrane protein p22
MeSH term(s)	Granulomatous Disease, Chronic ; Humans ; Membrane Proteins/metabolism ; Mutant Proteins ; NADPH Oxidases/genetics ; NADPH Oxidases/metabolism ; Reactive Oxygen Species/metabolism ; Serine ; Sulfhydryl Compounds
Chemical Substances	DERL1 protein, human ; Membrane Proteins ; Mutant Proteins ; Reactive Oxygen Species ; Sulfhydryl Compounds ; Serine (452VLY9402) ; NADPH Oxidases (EC 1.6.3.-) ; CYBA protein, human (EC 1.6.3.1)
Language	English
Publishing date	2022-09-13
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2701011-9
ISSN	2213-2317 ; 2213-2317
ISSN (online)	2213-2317
ISSN	2213-2317
DOI	10.1016/j.redox.2022.102479
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Article ; Online: Association between Early Cognitive Impairment and Short-Term Functional Outcome in Acute Ischemic Stroke.

Kiyohara, Takuya / Kumai, Yasuhiro / Yubi, Tomohiro / Ishikawa, Eiichi / Wakisaka, Yoshinobu / Ago, Tetsuro / Kitazono, Takanari

Cerebrovascular diseases (Basel, Switzerland)

2022 Volume 52, Issue 1, Page(s) 61–67

Abstract: Background: Little is known about the association between poststroke cognitive impairment (PSCI) and functional outcome in the acute care phase of ischemic stroke and the influence of the clinical condition of acute stroke on this association. We ... ...

Abstract	Background: Little is known about the association between poststroke cognitive impairment (PSCI) and functional outcome in the acute care phase of ischemic stroke and the influence of the clinical condition of acute stroke on this association. We examined this issue, taking into account stroke-related factors, in a hospital-based prospective study of patients with acute ischemic stroke. The same analysis was also performed after subsequent rehabilitation to investigate whether the association observed in the acute care phase persisted after that. For comparison, the same analysis was performed for pre-stroke dementia (PreSD). Methods: We included in the study a total of 923 patients with acute ischemic stroke who were admitted to a hospital from 2012 to 2020 in Japan. Cognitive function was assessed using the Mini-Mental State Examination and Raven's Colored Progressive Matrices test at an average of 6.3 days after stroke onset. The subjects were divided into three groups with normal cognition, PSCI, and PreSD. Study outcome was a poor functional outcome, defined as a modified Rankin Scale score of ≥3 at the end of acute care (median 21 days after admission). Among total subjects, 460 were also assessed for poor functional outcome after rehabilitation (median 77 days after admission). A logistic regression model was applied in this study. Results: Patients with PSCI and PreSD had higher median National Institute of Health Stroke Scale scores than those with normal cognition (median [IQR]: 3 [2-6], 4 [2-12], and 2 [1-4], respectively). The age- and sex-adjusted cumulative incidence of poor functional outcome was significantly higher in patients with PSCI and PreSD than in those with normal cognition in the acute care and rehabilitation phases. In the acute care phase, these associations remained significant after adjustment for stroke-related factors and other confounders (multivariable-adjusted odds ratio [95% CI] for PSCI vs. normal cognition: 3.28 [2.07-5.20]; for PreSD: 2.39 [1.40-4.08]). Similar results were observed in the rehabilitation phase (for PSCI: 2.48 [1.31-4.70]; for PreSD: 3.92 [1.94-7.92]). Conclusions: Our findings suggest that PSCI, as well as PreSD, is possibly associated with the development of poor functional outcome in the acute care phase of ischemic stroke, and this association continues thereafter.
MeSH term(s)	Humans ; Ischemic Stroke/complications ; Brain Ischemia/diagnosis ; Brain Ischemia/therapy ; Brain Ischemia/complications ; Prospective Studies ; Cognitive Dysfunction/diagnosis ; Cognitive Dysfunction/etiology ; Stroke/diagnosis ; Stroke/therapy ; Stroke/complications
Language	English
Publishing date	2022-06-03
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1069462-6
ISSN	1421-9786 ; 1015-9770
ISSN (online)	1421-9786
ISSN	1015-9770
DOI	10.1159/000524839
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Zs.A 3181: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Association between decreases in serum uric acid levels and unfavorable outcomes after ischemic stroke: A multicenter hospital-based observational study.

Nakamura, Kuniyuki / Ueki, Kana / Matsuo, Ryu / Kiyohara, Takuya / Irie, Fumi / Wakisaka, Yoshinobu / Ago, Tetsuro / Kamouchi, Masahiro / Kitazono, Takanari

PloS one

2023 Volume 18, Issue 6, Page(s) e0287721

Abstract: Background: The association between clinical outcomes in ischemic stroke patients and decreases in serum uric acid levels, which often occur during the acute phase, remains unknown. Herein, we aimed to investigate the association using a large-scale, ... ...

Abstract	Background: The association between clinical outcomes in ischemic stroke patients and decreases in serum uric acid levels, which often occur during the acute phase, remains unknown. Herein, we aimed to investigate the association using a large-scale, multicenter stroke registry. Methods: We analyzed 4,621 acute ischemic stroke patients enrolled in the Fukuoka Stroke Registry between June 2007 and September 2019 whose uric acid levels were measured at least twice during hospitalization (including on admission). The study outcomes were poor functional outcome (modified Rankin Scale score ≥3) and functional dependence (modified Rankin Scale score 3-5) at 3 months after stroke onset. Changes in uric acid levels after admission were evaluated using a decrease rate that was classified into 4 sex-specific grades ranging from G1 (no change/increase after admission) to G4 (most decreased). Multivariable logistic regression analyses were used to assess the associations between decreases in uric acid levels and the outcomes. Results: The frequencies of the poor functional outcome and functional dependence were lowest in G1 and highest in G4. The odds ratios (95% confidence intervals) of G4 were significantly higher for poor functional outcome (2.66 [2.05-3.44]) and functional dependence (2.61 [2.00-3.42]) when compared with G1 after adjusting for confounding factors. We observed no heterogeneity in results for subgroups categorized according to age, sex, stroke subtype, neurological severity, chronic kidney disease, or uric acid level on admission. Conclusions: Decreases in serum uric acid levels were independently associated with unfavorable outcomes after acute ischemic stroke.
MeSH term(s)	Female ; Male ; Humans ; Ischemic Stroke ; Uric Acid ; Hospitals ; Stroke ; Hospitalization
Chemical Substances	Uric Acid (268B43MJ25)
Language	English
Publishing date	2023-06-29
Publishing country	United States
Document type	Observational Study ; Multicenter Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0287721
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Article ; Online: The downregulation of NADPH oxidase Nox4 during hypoxia in hemangioendothelioma cells: a possible role of p22

Miyano, Kei / Okamoto, Shuichiro / Yamauchi, Akira / Kawai, Chikage / Kajikawa, Mizuho / Kiyohara, Takuya / Itsumi, Momoe / Taura, Masahiko / Kuribayashi, Futoshi

Free radical research

2022 Volume 55, Issue 9-10, Page(s) 996–1004

Abstract: NADPH oxidase (Nox) 4 produces ... ...

Abstract	NADPH oxidase (Nox) 4 produces H
MeSH term(s)	Animals ; Humans ; Mice ; Down-Regulation ; Hemangioendothelioma ; Hydrogen Peroxide/metabolism ; Hypoxia/genetics ; NADPH Oxidase 4/genetics ; NADPH Oxidase 4/metabolism ; NADPH Oxidases/genetics ; NADPH Oxidases/metabolism ; Protein Stability ; Reactive Oxygen Species/metabolism
Chemical Substances	Hydrogen Peroxide (BBX060AN9V) ; NADPH Oxidase 4 (EC 1.6.3.-) ; NADPH Oxidases (EC 1.6.3.-) ; NOX4 protein, human (EC 1.6.3.-) ; Nox4 protein, mouse (EC 1.6.3.-) ; Reactive Oxygen Species
Language	English
Publishing date	2022-01-11
Publishing country	England
Document type	Journal Article
ZDB-ID	1194130-3
ISSN	1029-2470 ; 1071-5762
ISSN (online)	1029-2470
ISSN	1071-5762
DOI	10.1080/10715762.2021.2009116
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Zs.A 2236: Show issues

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Article ; Online: T2*-Weighted MRI Detected Dilated Cerebral Veins in a Patient with Acute-Phase Cerebral Venous Sinus Thrombosis-A Case Report.

Kiyohara, Takuya / Abe, Chie / Yokoi, Mio / Sakaki, Yusuke / Kumai, Yasuhiro

Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association

2019 Volume 28, Issue 8, Page(s) e116–e118

Abstract: We describe a 45-year-old man who presented with nausea, vomiting, and strong occipital headache on the right side. Although no abnormalities on neurological examination or computed tomography imaging were found on admission, peripheral blood cell counts ...

Abstract	We describe a 45-year-old man who presented with nausea, vomiting, and strong occipital headache on the right side. Although no abnormalities on neurological examination or computed tomography imaging were found on admission, peripheral blood cell counts showed polycythemia (hemoglobin 20.6 g/dL) and electrocardiography demonstrated atrial fibrillation. Therefore, anticoagulant treatment with heparin was started immediately. On the following day, the occipital headache continued. Brain T2-weighted (T2WI) magnetic resonance imaging (MRI) and, to a lesser extent, susceptibility-weighted imaging showed dilation of numerous cortical veins, suggesting the possibility of cerebral venous thrombosis (CVT). MR venography (MRV) showed a deficit of the right transverse sinus. Contrast-enhanced MRI revealed partial defects of the right transverse sinus, and led to the definite diagnosis of CVT, and the anticoagulation therapy was continued. On day 7 the headache disappeared, and MRV on day 16 showed the recanalization of the right transverse sinus. There were no complications subsequent to the CVT. On day 25, the patient was discharged with no after-effect. We speculate that the dilation of cortical veins on T2*WI is a helpful sign in detecting acute-phase CVT.
MeSH term(s)	Anticoagulants/therapeutic use ; Cerebral Angiography/methods ; Cerebral Veins/diagnostic imaging ; Cerebral Veins/pathology ; Diffusion Magnetic Resonance Imaging ; Dilatation, Pathologic ; Heparin/therapeutic use ; Humans ; Magnetic Resonance Angiography ; Male ; Middle Aged ; Phlebography/methods ; Predictive Value of Tests ; Sinus Thrombosis, Intracranial/diagnostic imaging ; Sinus Thrombosis, Intracranial/drug therapy ; Sinus Thrombosis, Intracranial/pathology ; Treatment Outcome
Chemical Substances	Anticoagulants ; Heparin (9005-49-6)
Language	English
Publishing date	2019-06-03
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	1131675-5
ISSN	1532-8511 ; 1052-3057
ISSN (online)	1532-8511
ISSN	1052-3057
DOI	10.1016/j.jstrokecerebrovasdis.2019.05.024
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Zs.A 3519: Show issues

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Article ; Online: β-Cell Function and Clinical Outcome in Nondiabetic Patients With Acute Ischemic Stroke.

Kiyohara, Takuya / Matsuo, Ryu / Hata, Jun / Nakamura, Kuniyuki / Wakisaka, Yoshinobu / Kamouchi, Masahiro / Kitazono, Takanari / Ago, Tetsuro

Stroke

2021 Volume 52, Issue 8, Page(s) 2621–2628

Abstract: Background and purpose: Little is known about how β-cell dysfunction affects clinical outcome after ischemic stroke. We examined whether β-cell function is associated with clinical outcome after acute ischemic stroke and if so, whether insulin ... ...

Abstract	Background and purpose: Little is known about how β-cell dysfunction affects clinical outcome after ischemic stroke. We examined whether β-cell function is associated with clinical outcome after acute ischemic stroke and if so, whether insulin resistance influences this association in a prospective study of patients with acute stroke. Methods: A total of 3590 nondiabetic patients with acute ischemic stroke (mean age, 71 years) were followed up for 3 months. β-Cell function was assessed using the homeostasis model assessment for β-cell function (HOMA-β). Study outcomes were poor functional outcome (modified Rankin Scale score, 3–6) and stroke recurrence at 3 months after stroke onset and neurological deterioration (≥2-point increase in the National Institutes of Health Stroke Scale score) at discharge. Logistic regression analysis was used to evaluate the association between quintile levels of serum HOMA-β and clinical outcomes. Results: The age- and sex-adjusted odds ratios for poor functional outcome and neurological deterioration increased significantly with decreasing HOMA-β levels (P for trend, <0.001 and 0.001, respectively). These associations became more prominent after adjustment for HOMA-insulin resistance and were substantially unchanged even after further adjustment for other confounders, namely, body mass index, dyslipidemia, hypertension, estimated glomerular filtration rate, stroke subtype, National Institutes of Health Stroke Scale score on admission, and reperfusion therapy (odds ratio [95% CI] for the first versus fifth quintile of HOMA-β, 3.30 [2.15–5.08] for poor functional outcome and 10.69 [4.99–22.90] for neurological deterioration). Such associations were not observed for stroke recurrence. In stratified analysis for the combination of HOMA-β and HOMA-insulin resistance levels, lower HOMA-β and higher HOMA-insulin resistance levels were independently associated with increased risks of poor functional outcome and neurological deterioration. Conclusions: Our findings suggest that β-cell dysfunction is significantly associated with poor short-term clinical outcome independently of insulin resistance in nondiabetic patients with acute ischemic stroke.
MeSH term(s)	Aged ; Aged, 80 and over ; B-Lymphocytes/metabolism ; Cohort Studies ; Diabetes Mellitus ; Female ; Hospitalization/trends ; Humans ; Insulin Resistance/physiology ; Ischemic Stroke/blood ; Ischemic Stroke/diagnosis ; Male ; Middle Aged ; Prospective Studies ; Registries ; Treatment Outcome
Language	English
Publishing date	2021-05-14
Publishing country	United States
Document type	Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
ZDB-ID	80381-9
ISSN	1524-4628 ; 0039-2499 ; 0749-7954
ISSN (online)	1524-4628
ISSN	0039-2499 ; 0749-7954
DOI	10.1161/STROKEAHA.120.031392
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Zs.A 448: Show issues

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Article ; Online: Low-dose sodium-glucose cotransporter 2 inhibitor ameliorates ischemic brain injury in mice through pericyte protection without glucose-lowering effects.

Takashima, Masamitsu / Nakamura, Kuniyuki / Kiyohara, Takuya / Wakisaka, Yoshinobu / Hidaka, Masaoki / Takaki, Hayato / Yamanaka, Kei / Shibahara, Tomoya / Wakisaka, Masanori / Ago, Tetsuro / Kitazono, Takanari

Communications biology

2022 Volume 5, Issue 1, Page(s) 653

Abstract: Antidiabetic sodium-glucose cotransporter 2 (SGLT2) inhibitors have attracted attention for their cardiorenal-protective properties beyond their glucose-lowering effect. However, their benefits in ischemic stroke remain controversial. Here we show the ... ...

Abstract	Antidiabetic sodium-glucose cotransporter 2 (SGLT2) inhibitors have attracted attention for their cardiorenal-protective properties beyond their glucose-lowering effect. However, their benefits in ischemic stroke remain controversial. Here we show the effects of luseogliflozin, a selective SGLT2 inhibitor, in acute ischemic stroke, using a permanent middle cerebral artery occlusion (pMCAO) model in non-diabetic mice. Pretreatment with low-dose luseogliflozin, which does not affect blood glucose levels, significantly attenuated infarct volume, blood-brain barrier disruption, and motor dysfunction after pMCAO. SGLT2 was expressed predominantly in brain pericytes and was upregulated in peri- and intra-infarct areas. Notably, luseogliflozin pretreatment reduced pericyte loss in ischemic areas. In cultured pericytes, luseogliflozin activated AMP-activated protein kinase α and increased mitochondrial transcription factor A expression and number of mitochondria, conferring resistance to oxygen-glucose deprivation. Collectively, pre-stroke inhibition of SGLT2 induces ischemic tolerance in brain pericytes independent of the glucose-lowering effect, contributing to the attenuation of ischemic brain injury.
MeSH term(s)	Animals ; Brain Injuries/metabolism ; Glucose/metabolism ; Infarction/metabolism ; Ischemic Stroke ; Mice ; Pericytes/metabolism ; Sodium/metabolism ; Sodium-Glucose Transporter 2/metabolism
Chemical Substances	Sodium-Glucose Transporter 2 ; Sodium (9NEZ333N27) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2022-07-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-022-03605-4
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Article ; Online: Constitutive activity of NADPH oxidase 1 (Nox1) that promotes its own activity suppresses the colon epithelial cell migration.

Miyano, Kei / Okamoto, Shuichiro / Yamauchi, Akira / Kajikawa, Mizuho / Kiyohara, Takuya / Taura, Masahiko / Kawai, Chikage / Kuribayashi, Futoshi

Free radical research

2020 Volume 54, Issue 8-9, Page(s) 640–648

Abstract: Superoxide producing NADPH oxidase 1 (Nox1), abundantly expressed in the colon epithelium, plays a crucial role in mucosal host defenses. In this study, we found that pre-treatment of cells with edaravone, a free radical scavenger, inhibited Nox1 ... ...

Abstract	Superoxide producing NADPH oxidase 1 (Nox1), abundantly expressed in the colon epithelium, plays a crucial role in mucosal host defenses. In this study, we found that pre-treatment of cells with edaravone, a free radical scavenger, inhibited Nox1 constitutive activity even after washout without affecting Nox1 trafficking to the plasma membrane and membrane recruitment of the cytosolic regulators Noxo1 and Noxa1. These results suggest that a Nox1-derived product is involved in the step that initiates the electron transfer reaction after the formation of the Nox1-Noxo1-Noxa1 complex. Furthermore, we show that the mean migration directionality and velocity of epithelial cells were significantly enhanced by the inhibition of constitutive Nox1 activity. Thus, the constitutive Nox1 activity limits undesired cell migration in resting cells while participating in a positive feedback loop toward its own oxidase activity.
MeSH term(s)	Cell Movement ; Epithelial Cells/metabolism ; Humans ; NADPH Oxidase 1/metabolism ; Reactive Oxygen Species ; Transfection
Chemical Substances	Reactive Oxygen Species ; NADPH Oxidase 1 (EC 1.6.3.-) ; NOX1 protein, human (EC 1.6.3.-)
Language	English
Publishing date	2020-09-28
Publishing country	England
Document type	Journal Article
ZDB-ID	1194130-3
ISSN	1029-2470 ; 1071-5762
ISSN (online)	1029-2470
ISSN	1071-5762
DOI	10.1080/10715762.2020.1823383
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Article ; Online: The NADPH oxidase NOX4 promotes the directed migration of endothelial cells by stabilizing vascular endothelial growth factor receptor 2 protein.

Miyano, Kei / Okamoto, Shuichiro / Yamauchi, Akira / Kawai, Chikage / Kajikawa, Mizuho / Kiyohara, Takuya / Tamura, Minoru / Taura, Masahiko / Kuribayashi, Futoshi

The Journal of biological chemistry

2020 Volume 295, Issue 33, Page(s) 11877–11890

Abstract: Directed migration of endothelial cells (ECs) is an important process during both physiological and pathological angiogenesis. The binding of vascular endothelial growth factor (VEGF) to VEGF receptor-2 (VEGFR-2) on the EC surface is necessary for ... ...

Abstract	Directed migration of endothelial cells (ECs) is an important process during both physiological and pathological angiogenesis. The binding of vascular endothelial growth factor (VEGF) to VEGF receptor-2 (VEGFR-2) on the EC surface is necessary for directed migration of these cells. Here, we used TAXIScan, an optically accessible real-time horizontal cell dynamics assay approach, and demonstrate that reactive oxygen species (ROS)-producing NADPH oxidase 4 (NOX4), which is abundantly expressed in ECs, mediates VEGF/VEGFR-2-dependent directed migration. We noted that a continuous supply of endoplasmic reticulum (ER)-retained VEGFR-2 to the plasma membrane is required to maintain VEGFR-2 at the cell surface. siRNA-mediated NOX4 silencing decreased the ER-retained form of VEGFR-2, resulting in decreased cell surface expression levels of the receptor. We also found that ER-localized NOX4 interacts with ER-retained VEGFR-2 and thereby stabilizes this ER-retained form at the protein level in the ER. We conclude that NOX4 contributes to the directed migration of ECs by maintaining VEGFR-2 levels at their surface.
MeSH term(s)	Cell Line ; Cell Movement ; Endoplasmic Reticulum/metabolism ; Endothelial Cells/cytology ; Endothelial Cells/metabolism ; HeLa Cells ; Humans ; NADPH Oxidase 4/metabolism ; Protein Stability ; Reactive Oxygen Species/metabolism ; Vascular Endothelial Growth Factor Receptor-2/metabolism
Chemical Substances	Reactive Oxygen Species ; NADPH Oxidase 4 (EC 1.6.3.-) ; NOX4 protein, human (EC 1.6.3.-) ; KDR protein, human (EC 2.7.10.1) ; Vascular Endothelial Growth Factor Receptor-2 (EC 2.7.10.1)
Language	English
Publishing date	2020-07-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.RA120.014723
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