Biomedical subjects

Nobuo Hashimoto

Publications and source records attributed to Nobuo Hashimoto.

At least 109 records · Page 6Linked to original sources

PubMed2003

Molecular mechanisms for the activation of Ca2+-permeable nonselective cation channels by endothelin-1 in C6 glioma cells.

We recently demonstrated that endothelin-1 (ET-1) activates two types of Ca(2+)-permeable nonselective cation channels (NSCC-1 and NSCC-2) in C6 glioma cells. It is possible to discriminate between these channels by using the Ca(2+) channel blockers SK&F 96365 (1-[beta-(3-[4-methoxyphenyl]propoxy)-4-methoxyphenethyl]-1H-imidazole hydrochloride) and LOE 908 [(R,S)-(3,4-dihydro-6,7-dimethoxy-isoquinoline-1-yl)-2-phenyl-N,N-di-[2-(2,3,4-trimethoxyphenyl)ethyl]-acetamide]. LOE 908 is a blocker for NSCC-1 and NSCC-2, whereas SK&F 96365 is an inhibitor for NSCC-2. The purpose of the present study was to identify the G-proteins that are involved in ET-1-activated Ca(2+) channels in C6 glioma cells. ET-1 activated only NSCC-1 in C6 glioma cells preincubated with U73122 (1-[6-[((17beta)-3-methoxyestra-1,3,5[10]-trien-17-yl)amino]hexyl]-1H-pyrrole-2,5-dione), a phospholipase C (PLC) inhibitor. Microinjection of the dominant negative mutant of G(12)/G(13) (G(12)G228A/G(13)G225A) abolished activation of NSCC-1 and NSCC-2. In contrast, pertussis toxin did not affect any of the Ca(2+) channels in the ET-1-stimulated C6 glioma cells. These results indicate that G(12)/G(13) may couple with endothelin receptors and play an important role in the activation of NSCCs in C6 glioma cells. Moreover, the activation mechanisms of NSCC-1 and NSCC-2 by ET-1 were different. NSCC-1 activation depended upon a G(12)/G(13)-dependent cascade, whereas NSCC-2 activation depended upon both G(q)/PLC- and G(12)/G(13)-dependent cascades.

Acetamides↗

PubMed2003

Adenovirus-mediated gene transfer of fibroblast growth factor-2 increases BrdU-positive cells after forebrain ischemia in gerbils.

BACKGROUND AND PURPOSE: Progenitor cells continue to generate neurons in the adult mammalian brain, and cerebral ischemia induces neurogenesis. We examined the efficacy of the intraventricular injection of a recombinant adenovirus-expressing fibroblast growth factor-2 (FGF-2) (AxCAMAssbFGF) on neurogenesis in both normal and ischemic brains. METHODS: We used a gerbil model of transient global ischemia and counted the number of BrdU-positive cells after injection of AxCAMAssbFGF into the brain with or without ischemia. RESULTS: Intraventricular AxCAMAssbFGF produced robust FGF-2 protein increases in diverse regions of the brain and markedly increased FGF-2 concentrations in cerebrospinal fluid 2 days after administration and evoked significant proliferation of BrdU-positive cells not only in the subventricular zone and dentate gyrus of the hippocampus but also in the cerebral cortex, and some BrdU-positive cells differentiated into neurons. Continuous intraventricular infusion of FGF-2 protein increased FGF-2 concentration in cerebrospinal fluid but not in brain tissues and produced BrdU-positive cell proliferation only in the subventricular zone of the lateral ventricle. CONCLUSIONS: Adenovirally mediated transfer of the FGF-2 gene promoted progenitor cell proliferation more efficiently in widespread regions of the brain after transient global ischemia than continuous intraventricular infusion of FGF-2 protein.

Adenoviridae↗

PubMed2003

Control of axon elongation via an SDF-1alpha/Rho/mDia pathway in cultured cerebellar granule neurons.

Rho-GTPase has been implicated in axon outgrowth. However, not all of the critical steps controlled by Rho have been well characterized. Using cultured cerebellar granule neurons, we show here that stromal cell-derived factor (SDF)-1alpha, a neural chemokine, is a physiological ligand that can turn on two distinct Rho-dependent pathways with opposite consequences. A low concentration of the ligand stimulated a Rho-dependent pathway that mediated facilitation of axon elongation. In contrast, Rho/ROCK activation achieved by a higher concentration of SDF-1alpha caused repression of axon formation and induced no more increase in axon length. However, even at this higher concentration a Rho-dependent axon elongating activity could be recovered upon removal of ROCK activity using Y-27632. SDF-1alpha-induced axon elongating activity under ROCK inhibition was replicated by the dominant-active form of the mammalian homologue of the Drosophila gene Diaphanous (mDia)1 and counteracted by its dominant-negative form. Furthermore, RNAi knockdown of mDia1 abolished SDF-1alpha-induced axon elongation. Together, our results support a critical role for an SDF-1alpha/Rho/mDia1 pathway in mediating axon elongation.

Actins↗

PubMed2003

Absence of linkage of familial intracranial aneurysms to 7q11 in highly aggregated Japanese families.

BACKGROUND AND PURPOSE: We sought to test the linkage of familial intracranial aneurysms (FIAs) to the ELN (elastin) locus in chromosome 7q11 reported previously. METHODS: Intracranial aneurysm (IA) probands were searched from patient records or neurosurgeons' recalls in collaborating hospitals. Members of the participating probands' families who had unknown affection status were screened by MR angiography and diagnosed by digital subtraction angiography. Inclusion criteria of families for genetic analyses were as follows: at least 3 alive affected members or 2 alive affected members with at least 1 unaffected member (>or=60 years). Linkage to the ELN locus was tested with the use of GENEHUNTER by parametric and nonparametric methods. To exclude false-negatives in the linkage analysis, the lowest 5% limits of logarithms of the odds (LOD) and nonparametric LOD (NPL) scores for individual families and for the total set of families were simulated on assumption that the ELN locus is linked to FIAs. RESULTS: Questionnaires were sent to 885 patients, and 563 responded. Seventy-nine probands were positive for family history. One hundred thirty-four family members of unknown affection status were screened. A total of 14 families with 64 members met the criteria. Linkage to the ELN locus was discarded in 11 families and was inconclusive for 3 families. The total LOD and total NPL scores for 14 families were -8.04 and -0.643, respectively. Our conclusion did not change even when the values of penetrance were changed or only affected members were analyzed. CONCLUSIONS: The majority of aggregated IA Japanese families may not have a genetic linkage to chromosome 7q11.

Adult↗

PubMed2003

A first feasibility study of temozolomide for Japanese patients with recurrent anaplastic astrocytoma and glioblastoma multiforme.

BACKGROUND: The efficacy of temozolomide has been evaluated in phase I and phase II trials in patients with recurrent malignant gliomas in the United States and the European Union. We report a feasibility study of the palliative efficacy of temozolomide for patients with recurrent anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM). METHODS: Sixteen patients with at least two prior chemotherapy regimens were enrolled in the study. Nine patients were confirmed to have GBM and 7 patients were confirmed to have AA at the latest pathology review, and all had a Karnofsky performance status (KPS) of over 50%. The median age was 57 years (range, 31-65 years). RESULTS: No cumulative toxicity was observed at any dose level when temozolomide was administered on a once-daily, 5-day schedule. Myelosuppression occurred, with the nadir being mid-late in the cycle (day 14 or 21). National Cancer Institute common toxicity criteria (NCI-CTC) grade 3 or 4 hematological toxicity did not occur. In the 9 GBM patients, the overall response rate (complete response + partial response [CR + PR]) was 0%. The median time to progression (TTP) was 3.5 months, and the rates of progression-free survival (PFS) at 6 and 12 months were 40% and 0%. In the 7 AA patients, the overall response rate (CR + PR) was 29% and median TTP was 9 months, while PFS rates at 6 and 12 months were 80% and 30%. CONCLUSION: The favorable safety profile and the efficacy of temozolomide in Japanese patients are not incompatible with the results seen with patients in the United States and the European Union.

Adult↗

PubMed2003

MR contrast of ferritin and hemosiderin in the brain: comparison among gradient-echo, conventional spin-echo and fast spin-echo sequences.

OBJECTIVE: To compare the magnetic resonance image contrasts due to ferritin and hemosiderin in the brain tissue among different pulse sequences. MATERIALS AND METHODS: Fourteen patients with cavernous hemangioma in the brain prospectively underwent MR imaging with T2*-weighted gradient-echo (GRE), T2-weighted conventional spin-echo (SE) and fast spin-echo (FSE) sequences. The relative contrast ratios (CRs) of the hypointense part of cavernous hemangioma, globus pallidus and putamen to the deep frontal white matter were measured on each pulse sequence and statistically analyzed using analysis of variance followed by paired t-test. RESULTS: In the hypointense part of cavernous hemangioma, relative CRs were significantly lower on T2*-weighted GRE than on T2-weighted SE images (P=0.0001), and on T2-weighted SE than on T2-weighted FSE images (P=0.0001). In the globus pallidus, relative CRs were significantly lower on T2-weighted SE than on T2*-weighted GRE images (P=0.002), and on T2*-weighted GRE than on T2-weighted FSE images (P=0.0002). In the putamen, relative CRs were significantly lower on T2-weighted SE than on T2*-weighted GRE images (P=0.001), and there was no significant difference between CRs on T2-weighted FSE and T2*-weighted GRE images (P=0.90). CONCLUSION: Hemosiderin showed best image contrast on T2*-weighted GRE images but ferritin showed more prominent image contrast on T2-weighted SE than on T2*-weighted GRE images, which may help to determine an appropriate pulse sequence in neurological diseases associated with excessive ferritin accumulation.

Adolescent↗

PubMed2003

Distinct cortical areas for motor preparation and execution in human identified by Bereitschaftspotential recording and ECoG-EMG coherence analysis.

OBJECTIVE: To clarify the cortical areas involved in motor preparation and execution by investigating Bereitschaftspotentials (BPs) and electrocorticogram-electromyogram (ECoG-EMG) coherence from subdural electrodes placed around the rolandic area. METHODS: BPs and ECoG-EMG coherence were investigated for presurgical evaluation in a patient with cavernoma in the left frontal lobe. BPs were recorded in association with the tongue, right hand and right foot movements. ECoG-EMG coherence was calculated in association with weak muscle contraction of the right hand. RESULTS: Two cortical areas related to voluntary motor control were identified; one in the primary hand motor area, which generated surface-negative BPs with hand movements and showed significant coherence of ECoG with EMG of the contralateral hand muscle, and the other in the ventral rolandic area posterior to the central sulcus, which generated surface-positive BPs with voluntary movements of multiple sites (hand, tongue and foot) but did not show any ECoG-EMG coherence. CONCLUSIONS: It is postulated that the former area represents the primary motor area involved in both motor preparation and execution, and the latter area represents the non-primary motor area involved in motor preparation. SIGNIFICANCE: BP recording combined with ECoG-EMG coherence analysis could reveal the functional roles of motor cortices and the reorganization induced by structural brain lesion.

Brain Mapping↗

PubMed2003

In vitro growth suppression of human glioma cells by a 16-mer oligopeptide: a potential new treatment modality for malignant glioma.

Fibroblast growth factor-2 (FGF-2) is involved as an autocrine growth factor in the autonomous proliferation of glioma cells. To develop a new strategy for treating patients with glioma, we studied the effect on human glioma cells of a 16-mer oligopeptide with conformational similarity to the putative receptor-binding domain of FGF-2. A synthesized oligonucleotide was assessed its receptor-binding activity by BIAcore instrument. Its biological effect on glioma cell lines was examined in vitro by MTT assay. The peptide suppressed the in vitro growth of human glioma cells U87MG, T98G and U251MG cells, but not of A431 cells whose growth is not dependent on FGF-2. Apoptotic bodies were noted after 24-h incubation in the presence of the peptide; Ac-YVAD-CHO, a caspase-3 inhibitor, suppressed apoptosis. Furthermore, we examined the modulation of the cytotoxic effect of anticancer drugs by the oligopeptide. The addition of this oligopeptide to the chemotherapeutic agents CDDP, ACNU and VP16 had additive effects in vitro. These results suggest that the pathway of the FGF-2 autocrine loop through the FGF receptor plays an important role in the proliferation of glioma cells. New drugs targeting this loop may be highly effective in treating FGF-2-dependent tumors. Our results suggest that its addition to the therapeutic arsenal may lead to improved treatment regimens for patients with FGF-2-dependent tumors.

Antineoplastic Agents↗

PubMed2003

Involvement of extracellular Ca2+ influx and epidermal growth factor receptor tyrosine kinase transactivation in endothelin-1-induced arachidonic acid release.

1. Endothelin-1 (ET-1) activates two types of Ca(2+)-permeable nonselective cation channels (designated NSCC-1 and NSCC-2) and a store-operated Ca(2+) channel (SOCC) in vascular smooth muscle cells (VSMCs). These channels can be distinguished by their sensitivity to Ca(2+)-channel blockers, SK&F 96365 and LOE 908. LOE 908 is sensitive to NSCC-1 and NSCC-2, and SK&F 96365 is sensitive to NSCC-2 and SOCC. Moreover, these channels play essential roles in ET-1-induced epidermal growth factor receptor protein tyrosine kinase (EGFR PTK) transactivation. The main purpose of the present study was to demonstrate the involvement of EGFR PTK transactivation in ET-1-induced arachidonic acid release in VSMCs. 2. Both SK&F 96365 and LOE 908 inhibited ET-1-induced arachidonic acid release with the IC(50) values correlated to those of ET-1-induced Ca(2+) influx. Moreover, combined treatment with these blockers abolished ET-1-induced arachidonic acid release. 3. AG1478, a specific inhibitor of EGFR PTK, inhibited ET-1-induced arachidonic acid release and extracellular signal-regulated kinase 1 and 2 (ERK1/2). The IC(50) values of AG1478 for ET-1-induced arachidonic acid release and ERK1/2 correlated well with those for ET-1-induced EGFR PTK transactivation. 4. Mitogen-activated protein kinase kinase inhibitor, PD 98059, inhibited ET-1-induced arachidonic acid release. The IC(50) values of PD 98059 for ET-1-induced arachidonic acid release were similar to those for ET-1-induced ERK1/2 activity. In contrast, PD 98059 failed to inhibit ET-1-induced EGFR PTK transactivation. 5. These results indicate that (1) extracellular Ca(2+) influx through NSCCs and SOCC plays important roles for ET-1-induced arachidonic acid release, (2) EGFR PTK transactivation/ERK1/2 pathways are involved in ET-1-induced arachidonic acid release.

Animals↗

PubMed2003

Conversion of semantic information into phonological representation: a function in left posterior basal temporal area.

A unique feature of Japanese language is that its written sentences consist of both morphograms (kanji) and syllabograms (kana). Despite extensive research by PET, functional MRI and magnetoencephalography, the issues of the difference (or the similarities) between the processing of kanji and kana, and between word reading and object/picture naming have not been resolved as yet. This study investigated the function of the posterior basal temporal area in the language dominant hemisphere in auditory and visual language processing, with special emphasis on semantic and phonological recognition. Subdural electrode grids were placed on the left temporal area of a right-handed woman with intractable temporal lobe epilepsy as part of a pre-surgical evaluation. Her dominant hemisphere for language was shown to be the left on the Wada test. Electric stimulation of 50 Hz was applied to the electrodes during the tasks related to language. Our results showed a clear distinction in the responses and/or performance of the subject depending on the type of characters presented and the tasks employed. Electric stimulation of a localized area in the posterior basal temporal lobe caused neither comprehensive nor productive deficit in the tasks using auditory stimuli. In the tasks using visual stimuli, in contrast, impairments were observed in (i) reading of kanji words and (ii) naming of objects/pictures and geometric designs, but not in (iii) reading of kana, (iv) copying of kanji, kana and geometric designs, and (v) using tools. The subject maintained full comprehension of spoken language, suggesting that the auditory tasks are not processed in the posterior basal temporal area. The fact that the impairment of kanji reading and disturbance of object/picture naming were elicited by electric stimulation of the same area indicates that there is at least one anatomical area that is used commonly for kanji (but not kana) and object processing. The conceptual entity of the test items supposedly was recognized correctly, but the concept failed to be matched to correct phonological representation. The left posterior basal temporal area, therefore, has an important function of connecting visual semantic information into phonological representation.

Adult↗

PubMed2003

Activation of p38 kinase in the gerbil hippocampus showing ischemic tolerance.

Ischemic tolerance is a phenomenon in which brief episodes of ischemia protect against the lethal effects of subsequent periods of prolonged ischemia. The authors investigated the activation of p38 mitogen-activated protein kinase (p38) in the gerbil hippocampus by Western blotting and immunohistochemistry to clarify the role of p38 kinase in ischemic tolerance. After the 2-minute global ischemia, immunoreactivity indicating active p38 was enhanced at 6 hours of reperfusion and continuously demonstrated 72 hours after ischemia in CA1 and CA3 neurons. Pretreatment with SB203580, an inhibitor of active p38 (0-30 micromol/l), 30 minutes before the 2-minute ischemia reduced the ischemic tolerance effect in a dose-dependent manner. Immunoblot analysis indicated that alteration of the phosphorylation pattern of p38 kinase in the hippocampus after subsequent lethal ischemia was induced by the preconditioning. These findings suggest that lasting activation of p38 may contribute to ischemic tolerance in CA1 neurons of the hippocampus and that components of the p38 cascade can be target molecules to modify neuronal survival after ischemia.

Animals↗

PubMed2003

Involvements of voltage-independent Ca2+ channels and phosphoinositide 3-kinase in endothelin-1-induced PYK2 tyrosine phosphorylation.

We demonstrated recently that endothelin-1 (ET-1) activates two types of Ca(2+)-permeable nonselective cation channels [designated nonselective cation channel (NSCC)-1 and NSCC-2] and a store-operated Ca(2+) channel (SOCC) in rabbit internal carotid artery vascular smooth muscle cells (ICA VSMCs). These channels can be distinguished by their sensitivity to Ca(2+) channel blockers 1-(beta-[3-(4-methoxyphenyl) propoxy]-4-methoxyphenethyl)-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). NSCC-1 is sensitive to LOE 908 and resistant to SK&F 96365, NSCC-2 is sensitive to both LOE 908 and SK&F 96365, and SOCC is resistant to LOE 908 and sensitive to SK&F 96365. The purpose of the present study was to identify the Ca(2+) channels involved in the ET-1-induced, proline-rich tyrosine kinase 2 (PYK2) phosphorylation in ICA VSMCs. Based on sensitivity to nifedipine, an L-type voltage-operated Ca(2+) channel (VOCC) blocker, Ca(2+) influx through VOCC seems to play a minor role in the ET-1-induced PYK2 phosphorylation. In the presence of nifedipine, PYK2 phosphorylation was abolished by blocking Ca(2+) influx through NSCC-1, NSCC-2, and SOCC. The phosphoinositide 3-kinase (PI3K) inhibitors wortmannin and 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY 294002), inhibited ET-1-induced Ca(2+) influx through NSCC-2 and SOCC. In addition, these inhibitors blocked PYK2 phosphorylation that depends on Ca(2+) influx through NSCC-2 and SOCC. These results indicate that 1) Ca(2+) influx through NSCC-1, NSCC-2, and SOCC plays essential roles in ET-1-induced PYK2 phosphorylation, 2) NSCC-2 and SOCC are stimulated by ET-1 via a PI3K-dependent cascade, whereas NSCC-1 is stimulated via a PI3K-independent cascade, and 3) PI3K is involved in the PYK2 phosphorylation that depends on Ca(2+) influx through SOCC and NSCC-2.

Acetamides↗

PubMed2003

Characterization of Ca2+ channels and G proteins involved in arachidonic acid release by endothelin-1/endothelinA receptor.

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) in Chinese hamster ovary cells expressing endothelinA receptors (CHO-ETAR). These channels can be distinguished by their sensitivity to Ca2+ channel blockers 1-(beta-[3-(4-methoxyphenyl) propoxy]-4-methoxyphenethyl)-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). NSCC-1 is sensitive to LOE 908 and resistant to SK&F 96365; NSCC-2 is sensitive to both blockers, and SOCC is resistant to LOE 908 and sensitive to SK&F 96365. In this study, we examined the mechanism of ET-1-induced arachidonic acid (AA) release. Both SK&F 96365 and LOE 908 inhibited ET-1-induced AA release with the IC50 values correlated to those of ET-1-induced Ca2+ influx. Moreover, combined treatment with these blockers abolished ET-1-induced AA release. Wortmannin and LY294002, inhibitors of phosphoinositide 3-kinase (PI3K), partially inhibited ET-1-induced AA release. LOE 908, but not SK&F 96365, inhibited ET-1-induced AA release in wortmannin-treated CHO-ETAR. ET-1 also induced AA release in CHO cells expressing ETAR truncated at the carboxyl terminal downstream of Cys385 (CHO-ETARDelta385) or an unpalmitoylated (Cys383 Cys385-388--> Ser383Ser385-388) ETAR (CHO-SerETAR), each of which is coupled with Gq or Gs/G12, respectively. In CHO-SerETAR, a dominant-negative mutant of G12 inhibited AA release. SK&F 96365 inhibited ET-1-induced AA release in CHO-ETARDelta385, whereas LOE 908 inhibited it in CHO-SerETAR. These results indicate the following: 1) ET-1-induced AA release depends on Ca2+ influx through NSCC-1, NSCC-2, and SOCC in CHO-ETAR; 2) Gq and G12 mediate AA release through ETAR in CHO cells; and 3) PI3K is involved in ET-1-induced AA release, which depends on NSCC-2 and SOCC.

Animals↗

PubMed2003

Liliequist membrane: three-dimensional constructive interference in steady state MR imaging.

PURPOSE: To evaluate the Liliequist membrane in healthy volunteers by using three-dimensional (3D) Fourier transformation constructive interference in steady state (CISS) magnetic resonance (MR) imaging. MATERIALS AND METHODS: In 31 volunteers, the authors performed 3D CISS MR imaging. They divided the membrane into three segments: the sellar, diencephalic, and mesencephalic segments. MR images were evaluated to identify the segments, superior and inferior attachments, lateral border, and thickness of the Liliequist membrane. RESULTS: Three-dimensional CISS MR imaging depicted the sellar, diencephalic, and mesencephalic segments of the Liliequist membrane in the sagittal plane in 25 (81%), 16 (52%), and five (16%) of the 31 subjects, respectively. Transverse MR imaging depicted these segments in 24 (77%), 10 (32%), and two (6%) subjects, respectively, and coronal MR imaging depicted them in 24 (77%), 12 (39%), and two (6%) subjects, respectively. Clear attachment of the membrane to the dorsum sellae was observed in 22 (88%) of 25 subjects in whom the sellar segment was identified. Clear attachment to the mamillary body was identified in eight (50%) of 16 subjects in whom the diencephalic segment was identified. The Liliequist membrane was attached to the oculomotor nerve on seven (14%) of 50 sides of the lateral border and to the arachnoid membrane around the oculomotor nerve on 28 (56%) sides. In the sagittal plane, the thickness of the membrane was less than one-half the thickness of the third ventricle floor in 22 (88%) of 25 subjects. CONCLUSION: The Liliequist membrane can be visualized by using 3D CISS MR sequences.

Adult↗

PubMed2003

Role of phosphoinositide 3-kinase in the nonselective cation channel activation by endothelin-1/endothelinB 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) in Chinese hamster ovarian cells expressing endothelin(B) receptor (CHO-ET(B)R). These channels can be discriminated using the Ca(2+) channel blockers, LOE 908 and SK&F 96365. LOE 908 is a blocker of NSCC-1 and NSCC-2, whereas SK&F 96365 is a blocker of NSCC-2. In this study, we investigated the possible role of phosphoinositide 3-kinase (PI3K) in the ET-1-induced activation of NSCCs in CHO-ET(B)R using wortmannin and LY-294002, inhibitors of PI3K. ET-1-induced Ca(2+) influx was partially inhibited in CHO-ET(B)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(B)R were sensitive to LOE 908 and resistant to SK&F 96365. In conclusion, NSCC-2 is stimulated by ET-1 via PI3K-dependent cascade, whereas NSCC-1 is stimulated independently of the PI3K pathway. Moreover, PI3K seems to be required for the initiation of the Ca(2+) entry through NSCC-2 but not for its maintenance.

Acetamides↗

PubMed2003

Effects of nonselective cation channels and PI3K on endothelin-1-induced PYK2 tyrosine phosphorylation in C6 glioma cells.

We recently demonstrated that endothelin-1 (ET-1) activates two types of Ca2+-permeable nonselective cation channels (designated NSCC-1 and NSCC-2) in C6 glioma cells. In the present study, we investigated the effects of NSCCs on the ET-1-induced proline-rich tyrosine kinase 2 (PYK2) phosphorylation in C6 glioma cells. In addition, we examined the effects of phosphoinositide 3-kinase (PI3K) on the ET-1-induced NSCCs activation and PYK2 phosphorylation. The PI3K inhibitors wortmannin and LY-294002 inhibited ET-1-induced Ca2+ influx through NSCC-2 but not NSCC-1. On the other hand, addition of these inhibitors after stimulation with ET-1 failed to suppress Ca2+ influx through NSCC-2. PYK2 phosphorylation was abolished by blocking Ca2+ influx through NSCCs. The PI3K inhibitors blocked the NSCC-2-dependent part of ET-1-induced PYK2 phosphorylation. These results indicate that 1) NSCC-2 is stimulated by ET-1 via a PI3K-dependent cascade, whereas NSCC-1 is stimulated via a PI3K-independent cascade; 2) PI3K seems to be required for the activation of the Ca2+ entry, but not for its maintenance; 3) Ca2+ influx through NSCC-1 and NSCC-2 plays an essential role in ET-1-induced PYK2 phosphorylation; and 4) PI3K is involved in the ET-1-induced PYK2 phosphorylation that depends on the Ca2+ influx through NSCC-2.

Androstadienes↗

PubMed2003

Acceleration of aneurysm healing by controlled release of basic fibroblast growth factor with the use of polyethylene terephthalate fiber coils coated with gelatin hydrogel.

OBJECTIVE: The aims of this study were to develop an endovascular delivery system containing gelatin hydrogels for the controlled release of basic fibroblast growth factor (bFGF) with the use of polyethylene terephthalate fiber coils and to analyze whether such a system would promote healing in an experimental aneurysm. METHODS: Carotid aneurysms were constructed in 66 rabbits with venous pouches. The polyethylene terephthalate fiber coils coated with and without gelatin hydrogels with different water volumes containing 0, 10, 50, and 100 microg bFGF were implanted into the aneurysms. Histological specimens were harvested at 1, 2, and 3 weeks and at 6 months after implantation. A histological evaluation was performed while the area occupied by the fibrosis in the aneurysms was calculated. RESULTS: Three weeks after the application of the coils coated with gelatin hydrogels (95 vol%) containing 100 microg bFGF, all aneurysmal orifices were completely closed with neointima. When the coils coated with gelatin hydrogel (98 vol%) containing 100 microg bFGF were used, the orifices in three of the six aneurysms were closed. In contrast, the orifice of the aneurysm was not obliterated when other materials were used. After implanting the coils coated with gelatin hydrogel (95 vol%) containing 100 microg bFGF more than 3 weeks later, the aneurysm was histologically suffused with fibrous tissue, and the area occupied by fibrosis was significantly larger than that observed in the other groups (P < 0.05). CONCLUSION: Local, controlled release of sufficient amounts of bFGF with polyethylene terephthalate fiber coils coated with gelatin hydrogel accelerated the organization of aneurysms.

Aneurysm↗

PubMed2003

Large vertebral arteriovenous fistula treated with stent-grafts--case report.

A 24-year-old woman presented with neck bruit and thrill. Neurological examination revealed no focal abnormality. Angiography and magnetic resonance imaging showed an arteriovenous fistula (AVF) at the C4-5 levels of the right vertebral artery (VA). The fistula had a single orifice that drained into the epidural veins via the C4-5 intervertebral foramen. A stent-graft was made of a 3.9 cm balloon-expandable stent and an expandable polytetrafluoroethylene graft sutured outside the stent. The stent-graft was advanced through the femoral artery up to the VA but did not pass far enough distally to seal the entire fistula because of the high friction between the bulky device and the small vessel. Another 2 cm stent-graft was delivered and successfully positioned across the fistula. The AVF completely disappeared and the right VA was well preserved. Follow-up angiography at 3 weeks and 5 months after the treatment showed no fistula and no stenosis inside the stent-grafts. Stent-grafts are useful to treat AVF with a large orifice. The stent-graft is a promising technology to treat neurovascular diseases, although improvement is required for use in smaller vessels.

Adult↗