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Nobuo Hashimoto

Publications and source records attributed to Nobuo Hashimoto.

138 records · Page 8Linked to original sources

Beyond conservatism and the boundaries of a medical discipline: a short history of the department of neurosurgery at kyoto university graduate school of medicine.

CONSTANT CHANGE AND the occasional fusion of two different entities can result in the creation of masterpieces, not only in art but also in neurosurgery. Chisato Araki is one of the pioneers of neurosurgery in Japan; his 2-year sojourn in the United States and Europe provided him with an extraordinary amount of experience. He traveled throughout the world at a time when it took 30 days to journey from Yokohama to New York, and he visited with most of the leading contemporary neurosurgeons and observed their operations, never abandoning his highly honed critical insights. Driven by passion and a deep sense of duty to pass on his knowledge and perspective, he became a beacon of hope and encouragement for young physicians working in a country devastated by war. His successor, Hajime Handa, established neurosurgery as one of the branches of neuroscience and fostered the collaborations and exchanges among different disciplines that have become a tradition and hallmark of our Department of Neurosurgery. Through anecdotes and glimpses of the evolution of neurosurgery at our institution, we offer insights into the unique nature of Japanese neurosurgery that may illuminate the path toward the resolution of some of the recent and enduring problems encountered in our specialty.

Education, Medical, Graduate↗

Molecular mechanism for endothelin-1-induced stress-fiber formation: analysis of G proteins using a mutant endothelin(A) receptor.

The purposes of the present study were to clarify the significance of the palmitoylation site and the cytoplasmic tail of the endothelin(A) receptor (ET(A)R) in coupling with G proteins and to determine the subtypes of G protein that are involved in actin stress-fiber formation in Chinese hamster ovary cells that stably express ET(A)R (CHO-ET(A)R). For these purposes, we constructed CHO cells stably expressing an unpalmitoylated (Cys(383)Cys(385-388)-->Ser(383)Ser(385-388)) ET(A)R (CHOSerET(A)R) and a series of truncated ET(A)Rs that lacked the cytoplasmic tail downstream of either of the five cysteine residues (Cys(383)Cys(385-388)). All truncated ET(A)Rs but not SerET(A)R failed to stimulate adenylyl cyclase. With the truncated ET(A)Rs holding Cys(385), ET-1 stimulated formation of inositol phosphates, but such stimulation failed with truncated ET(A)Rs lacking Cys(385). With wild-type ET(A)Rs, ET-1 induced actin stress-fiber formation, which was inhibited by (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide (Y-27632), a Rho-associated coiled-coil-forming protein kinase (ROCK) inhibitor. The formation was unaffected by 1-(6-[[17beta-3-methoxyestra-1,3.5(10)-trien-17-yl] amino]hexyl)-1Hpyrrole-2,5-dione (U73122), a phospholipase C (PLC) inhibitor, or dominant negative mutants of G(12) (G(12)G228A) or G(13) (G(13)G225A), whereas it was inhibited by U73122 in combination with G(12)G228A but not G(13)G225A. Dibutyryl cAMP alone did not induce stress-fiber formation. With unpalmitoylated or truncated ET(A)Rs, the formation was sensitive to G(12)G228A or U73122, respectively. These results indicate that 1) Cys(385) of ET(A)R is critical for coupling with G(q), 2) the cytoplasmic tail downstream of the palmitoylation sites of ET(A)R is essential for coupling with G(s) and G(12), and 3) the signal for ET-1-induced stress-fiber formation is transmitted through the G(q)/PLC- and G(12)-dependent pathway to the Rho/ROCK system.

Amino Acid Sequence↗

Molecular mechanisms for the activation of voltage-independent Ca2+ channels by endothelin-1 in chinese hamster ovary cells stably expressing human endothelin(A) receptors.

We demonstrated recently that in Chinese hamster ovary cells stably expressing human recombinant endothelin(A) receptors (CHO-ET(A)R), endothelin-1 (ET-1) activates two types of Ca2+-permeable nonselective cation channels (designated NSCC-1 and NSCC-2) and a store-operated Ca2+ channel (SOCC), which can be distinguished by Ca(2+) channel blockers such as 1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenylethyl]-1H-imidazole hydrochloride (SK&F 96365) and (R,S)-(3,4-dihydro-6,7-dimethoxy-isochinolin-1-yl)-2-phenyl-N,N-di[2-(2,3,4-trimethoxyphenyl)ethyl]acetamid mesylate (LOE 908). We also reported that CHO-ET(A)R couples with G12 in addition to G(q) and G(s). The purpose of the present study was to identify the G proteins involved in the activation of these Ca2+ channels by ET-1, using mutated ET(A)Rs with coupling to either G(q) or G(s)/G12 (designated ET(A)RDelta385 and SerET(A)R, respectively) and a dominant-negative mutant of G12 (G12G228A). ET(A)RDelta385 is truncated immediately downstream of Cys385 in the C terminus as palmitoylation sites, whereas SerET(A)R is unpalmitoylated because of substitution of all the cysteine residues to serine (Cys383Cys385-388 --> Ser383Ser385-388). In CHO-ET(A)RDelta385, stimulation with ET-1 activated only SOCC. In CHO-SerET(A)R or CHO-ET(A)R pretreated with U73122, an inhibitor of phospholipase C (PLC), ET-1 activated only NSCC-1. Dibutyryl cAMP alone did not activate any Ca2+ channels in the resting and ET-1-stimulated CHO-SerET(A)R. Microinjection of G12G228A abolished the activation of NSCC-1 and NSCC-2 in CHO-ET(A)R and that of NSCC-1 in CHO-SerET(A)R. These results indicate that ET(A)R activates three types of Ca2+ channels via different G protein-related pathways. NSCC-1 is activated via a G12-dependent pathway, NSCC-2 via G(q)/PLC- and G12-dependent pathways, and SOCC via a G(q)/PLC-dependent pathway.

Amino Acid Substitution↗

Effects of phosphoinositide 3-kinase on the endothelin-1-induced activation of voltage-independent Ca(2+) channels and mitogenesis in Chinese hamster ovary cells stably expressing endothelin(a) receptor.

We recently demonstrated that endothelin-1 (ET-1) activates two types of Ca(2+)-permeable nonselective cation channel (designated NSCC-1 and NSCC-2) and a store-operated Ca(2+) channel (SOCC) in Chinese hamster ovary cells expressing endothelin(A) receptor (CHO-ET(A)R). In addition, these channels can be discriminated using Ca(2+) channel blockers (R,S)-(3,4-dihydro-6,7-dimethoxy-isochinolin-1-yl)-2-phenyl-N,N-di[2-(2,3,4-trimethoxyphenyl)ethyl]acetamid mesylate (LOE 908) and 1-(beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl)-1H-imidazole (SK&F 96365). LOE 908 is a blocker of NSCC-1 and NSCC-2, whereas SK&F 96365 is a blocker of SOCC and NSCC-2. In this study, we investigated the effects of phosphoinositide 3-kinase (PI3K) on the ET-1-induced activation of these channels and mitogenesis in CHO-ET(A)R using wortmannin and 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY 294002), inhibitors of phosphoinositide 3-kinase (PI3K). ET-1-induced Ca(2+) influx was partially inhibited in CHO-ET(A)R pretreated with wortmannin or LY 294002. In contrast, addition of wortmannin or LY 294002 after stimulation with ET-1 did not suppress Ca(2+) influx. The Ca(2+) channels activated by ET-1 in wortmannin or LY 294002-treated CHO-ET(A)R were sensitive to LOE 908 and resistant to SK&F 96365. Wortmannin also partially inhibited ET-1-induced mitogenesis. LOE 908, but not SK&F 96365, abolished the wortmannin-resistant part of mitogenesis. The IC(50) values (~30 nM) of wortmannin for the ET-1-induced Ca(2+) influx and mitogenesis were similar to those for the ET-1-induced PI3K activation. In conclusion, NSCC-2 and SOCC are stimulated by ET-1 via PI3K-dependent cascade, whereas NSCC-1 is stimulated via PI3K-independent cascade. Moreover, PI3K seems to be required for the activation of the Ca(2+) entry, but not for its maintenance. In addition, PI3K is involved in the ET-1-induced mitogenesis that depends on the extracellular Ca(2+) influx through SOCC and NSCC-2.

Acetamides↗

Ca(2+) channels involved in endothelin-induced mitogenic response in carotid artery vascular smooth muscle cells.

Endothelin (ET)-1 activates two types of Ca(2+)-permeable nonselective cation channels (NSCC-1 and NSCC-2) and a store-operated Ca(2+) channel (SOCC) in rabbit internal carotid artery (ICA) vascular smooth muscle cells (VSMCs) in addition to the voltage-operated Ca(2+) channel (VOCC). These channels can be discriminated using the Ca(2+) channel blockers SK&F-96365 and LOE-908. SK&F-96365 is sensitive to NSCC-2 and SOCC, and LOE-908 is sensitive to NSCC-1 and NSCC-2. On the basis of sensitivity to nifedipine, a specific blocker of the L-type VOCC, VOCCs have a minor role in ET-1-induced mitogenesis. Both LOE-908 and SK&F-96365 inhibited ET-1-induced mitogenesis in a concentration-dependent manner, and the combination of LOE-908 and SK&F-96365 abolished it. The IC(50) values of these blockers for ET-1-induced mitogenesis correlated well with those of the ET-1-induced intracellular free Ca(2+) concentration responses. These results indicate that the inhibitory action of these blockers on ET-1-induced mitogenesis may be mediated by blockade of NSCC-1, NSCC-2, and SOCC. Collectively, extracellular Ca(2+) influx through NSCC-1, NSCC-2, and SOCC may be essential for ET-1-induced mitogenesis in ICA VSMCs.

Acetamides↗

Characterization of Ca2+ channels involved in ET-1-induced transactivation of EGF receptors.

The purpose of this study was to demonstrate the involvement of Ca(2+) influx through voltage-independent Ca(2+) channels (VICCs) in endothelin-1 (ET-1)-induced transactivation of epidermal growth factor receptor protein tyrosine kinase (EGFR PTK) using the Ca(2+) channel blockers LOE-908 and SK&F-96365 in rabbit internal carotid artery vascular smooth muscle cells. ET-1-induced EGFR PTK transactivation was completely inhibited by AG-1478, which is a specific inhibitor of EGFR PTK. In the absence of extracellular Ca(2+), the magnitude of EGFR PTK transactivation was near the basal level. Based on sensitivity to nifedipine, which is a specific blocker of voltage-operated Ca(2+) channels (VOCCs), VOCCs have minor roles in EGFR PTK transactivation. In contrast, Ca(2+) influx through VICCs plays an important role in EGFR PTK transactivation. Moreover, based on the sensitivity of VICCs to SK&F-96365 and LOE-908, VICCs were shown to consist of two types of Ca(2+)-permeable nonselective cation channels (NSCCs), which are designated NSCC-1 and NSCC-2, and a store-operated Ca(2+) channel. In summary, Ca(2+) influx through VICCs plays an essential role in ET-1-induced EGFR PTK transactivation in rabbit internal carotid artery vascular smooth muscle cells.

Acetamides↗

Mouse model of cerebral aneurysm: experimental induction by renal hypertension and local hemodynamic changes.

BACKGROUND AND PURPOSE: Rupture of cerebral aneurysm (CA) is the major cause of subarachnoid hemorrhage. Molecular mechanisms of this disease, however, remain unknown. To make possible genetic analysis of CA formation with genetically altered mice, we have successfully established a mouse model of saccular CA that recapitulates the essential features of human saccular CA. METHODS: In C57black/6 male mice, various stages of CAs were experimentally induced at the right anterior cerebral artery-olfactory artery bifurcations by ligations of left common carotid arteries and posterior branches of bilateral renal arteries with high salt diet. Both light and electron microscopic studies were performed with the longitudinal sections of anterior cerebral artery-olfactory artery bifurcations. RESULTS: In the treated group, various aneurysmal changes were detected in 14 of 18 mice. On the other hand, in the control group, no aneurysmal changes were found in 15 mice. In microscopic studies, aneurysmal changes were shown to include mainly fragmentation of internal elastic lamina, thinning of the smooth muscle cell layer, and degeneration of adventitial tissue, which were very similar to critical changes in human saccular CA. CONCLUSIONS: This mouse model of CA will be useful for studying the effects of complex determinants on CA formation and makes it possible to understand the pathogenesis of CA at the molecular level.

Animals↗

Hypoxia-ischemia induces thioredoxin expression and nitrotyrosine formation in new-born rat brain.

Thioredoxin (TRX) is a 13 kDa protein with antioxidant effect and redox regulating functions. Peroxynitrite is a strong oxidizing and nitrating agent which can react with all classes of biomolecules. In the present study, we focused on the association between TRX and nitrotyrosine, which served as a marker of peroxynitrite formation, in the neonatal hypoxia-ischemia (HI) rat brain. At 4-16 h after HI, the immunoreactivity for TRX was diminished in the injured region in the cortex and striatum, whereas nitrotyrosine immunoreactivity was enhanced. In contrast, around the injured region, TRX immunoreactivity was enhanced in survival neurons at 4-24 h after HI, while the immunoreactivity for nitrotyrosine was mostly not detected. Northern blot analysis showed increased TRX mRNA induction in the cerebral hemisphere ipsilateral to the carotid ligation from 4-24 h after HI but not in the contralateral hypoxic hemisphere. These findings suggest that production of peroxynitrite is involved in HI brain injury, and that induced TRX plays a neuroprotective role against oxidative stress resulting from HI.

Animals↗

Clinical application of a new bioabsorbable artificial dura mater.

OBJECT: In their pursuit of a better substitute for dura mater in neurosurgical procedures, the authors review their experience with GM972. METHODS: A newly developed synthetic dural substitute composed of bioabsorbable polymers (GM972) was placed in 53 patients during neurosurgical procedures. The handling properties of the material, surgical wound features. and findings of hematological, computerized tomography, and/or magnetic resonance imaging examinations were evaluated. The average follow-up period was 35.5 months. The handling properties and biocompatibility of this new dural substitute were highly satisfactory, and no significant complication was observed. In patients who underwent a second surgery performed more than 18 months after the initial operation, this new dural substitute was found to have been replaced by autologous collagenous tissue. Because of its bioabsorbability, chronic foreign body reactions to this synthetic dural substitute were negligible. CONCLUSIONS: In this report the authors support the effectiveness and safety of this bioabsorbable artificial dural substitute that provides a reduced risk of transmission of latent infection.

Absorbable Implants↗

Cerebral hemodynamics and metabolism in patients with cerebral arteriovenous malformations: an evaluation using positron emission tomography scanning.

OBJECT: The purpose of this study was to evaluate cerebral hemodynamic and metabolic features in patients with arteriovenous malformations (AVMs) by using positron emission tomography (PET) scanning. METHODS: Twenty-four patients with supratentorial cerebral AVMs participated in PET studies in which 15O inhalation steady-state methods were used. The authors recorded the values of regional cerebral blood flow (rCBF), regional cerebral blood volume (rCBV), the regional oxygen extraction fraction (rOEF), and the regional cerebral metabolic rate of O2 (rCMRO2) at three designated regions of interest (ROIs) in each patient. These ROIs included perilesional (ROI-p), ipsilateral remote (ROI-i), and contralateral symmetrical (ROI-c) brain regions. To identify the factors that exert a direct effect on the hemodynamics of brains affected by AVM, we also separated the lesions according to their size and flow type shown on angiograms, and grouped the patients according to the presence or absence of progressive neurological deficits. We then compared the PET parameters at different ROIs in individual patients and evaluated the mean values obtained for all 24 patients according to AVM flow type and size, and the presence or absence of progressive neurological deficits. CONCLUSIONS: Overall, mean rCBV and rOEF values were significantly higher in ROI-p than in ROI-c (p = 0.00046 and p = 0.015, respectively). No significant differences were seen between the ROI-i and ROI-c with respect to rCBF, rCBV, and rOEF. Mean rCMRO2 values were similar in the three ROIs; however, the mean rCBF was significantly lower in the ROI-p than in the ROI-c in patients with high-flow AVMs (p = 0.019), large AVMs (p = 0.017), and progressive neurological deficits (p = 0.021). Furthermore, the mean rOEF values were significantly higher in the ROI-p than in the ROI-c in patients with high-flow AVMs (p = 0.005), large AVMs (p = 0.019), and progressive neurological deficits (p = 0.017). The PET studies revealed hemodynamic impairment characterized by decreased rCBF and increased rOEF and rCBV values in the ROI-p of patients with large, high-flow AVMs regardless of whether they exhibited progressive neurological deficits.

Adolescent↗

High expression of Aurora-B/Aurora and Ipll-like midbody-associated protein (AIM-1) in astrocytomas.

OBJECTIVE: Impaired regulation of Aurora-B/AIM-1 expression in human cells causes chromosomal abnormality and instability, and recent observations of high expression but not mutation of Aurora-B/AIM-1 in human cancers imply that Aurora-B/AIM-1 might be a candidate molecule for cancer progression. We analyzed the effects of modification of Aurora-B/AIM-1 expression on the growth of a human glioma cell line and the expression of Aurora-B/AIM-1 in astrocytomas. METHODS: A glioma cell line, U251MG was transfected with wild type (WT) of Aurora-B/AIM-1 or kinase-inactive mutant of Aurora-B/AIM-1 in order to test the effects of overexpression of WT or kinase-inactive Aurora-B/AIM-1 on cell morphology and cell growth. Brain tissue samples were obtained during surgery and processed for reverse transcription-polymerase chain reaction, immunofluorescence in order to analyze the expression of Aurora-B/AIM-1 mRNA and protein. RESULTS: Exogenous overexpression of WT of Aurora-B/AIM-1 in cultured cells of U251MG produced multinuclearity and increased ploidy, and inhibited the growth of tumor cells. Exogenous overexpression of kinase-inactive Aurora-B/AIM-1 in a human glioma cell line also suppressed the tumor cell growth without affecting ploidy. Aurora-B/AIM-1 was highly expressed in astrocytomas and U251MG, and mRNA and protein levels of Aurora-B/AIM-1 in tumor tissues well correlated with their histological malignancy (World Health Organization grading). Survival time also negatively correlated with the levels of Aurora-B/AIM-1 mRNA in tumor samples. CONCLUSION: Aurora-B/AIM-1 was highly expressed in high-grade gliomas and its expression was well correlated with histological malignancy and clinical outcomes. The modification of the level of Aurora-B/AIM-1 expression might be a new target for glioma therapy.

Adult↗