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1.
Materials (Basel) ; 17(2)2024 Jan 19.
Article in English | MEDLINE | ID: mdl-38276423

ABSTRACT

The important factors in obtaining a high-quality superconducting joint were investigated for the superconducting joint of a GdBa2Cu3Ox (GdBCO) bulk superconductor with sintered ErBa2Cu3Ox (ErBCO) using the local melt-growth method. REBCO (RE: rare earth) bulk superconductors can be used as strong magnets by magnetizing them, but they require large bulk sizes for their application. Although the superconducting joint presents a viable solution, many possibilities for property improvement remain, such as property degradation, depending on the joining direction. By varying the joining thermal conditions and confirming the elemental distribution, magnetization properties near the joined part and the effects of these on the joining properties are clarified, and a method for fabricating high-performance joined samples is obtained. Microstructure segregation was rarely observed at the center of the joined part regardless of the joining direction, and the superconducting properties were negligible and small. The Jc-B results are almost identical to those of the GdBCO matrix at a low field, confirming that the joined part minimally interferes with the superconducting current. Furthermore, by lowering the maximum temperature, shortening the holding time at the maximum temperature, and increasing the cooling rate, the region of mutual solid solution was reduced, and the Jc-B under the self-magnetic field was enhanced. These results contribute to the development of the superconducting joining method, a critical aspect of larger bulk superconductors.

2.
PLoS One ; 17(8): e0273242, 2022.
Article in English | MEDLINE | ID: mdl-36006934

ABSTRACT

Reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) is a tumor suppressor and its overexpression has been shown to exert anti-tumor effects as a therapeutic target gene in many human cancers. Recently, we demonstrated the anti-glioma effects of an adenoviral vector carrying REIC/Dkk-3 with the super gene expression system (Ad-SGE-REIC). Anti-vascular endothelial growth factor treatments such as bevacizumab have demonstrated convincing therapeutic advantage in patients with glioblastoma. However, bevacizumab did not improve overall survival in patients with newly diagnosed glioblastoma. In this study, we examined the effects of Ad-SGE-REIC on glioma treated with bevacizumab. Ad-SGE-REIC treatment resulted in a significant reduction in the number of invasion cells treated with bevacizumab. Western blot analyses revealed the increased expression of several endoplasmic reticulum stress markers in cells treated with both bevacizumab and Ad-SGE-REIC, as well as decreased ß-catenin protein levels. In malignant glioma mouse models, overall survival was extended in the combination therapy group. These results suggest that the combination therapy of Ad-SGE-REIC and bevacizumab exerts anti-glioma effects by suppressing the angiogenesis and invasion of tumors. Combined Ad-SGE-REIC and bevacizumab might be a promising strategy for the treatment of malignant glioma.


Subject(s)
Glioblastoma , Glioma , Adenoviridae/genetics , Animals , Apoptosis/genetics , Bevacizumab/pharmacology , Bevacizumab/therapeutic use , Cell Line, Tumor , Chemokines/genetics , Genetic Therapy/methods , Glioblastoma/drug therapy , Glioma/pathology , Humans , Intercellular Signaling Peptides and Proteins/genetics , Mice , Neoplastic Processes
3.
Materials (Basel) ; 14(23)2021 Dec 02.
Article in English | MEDLINE | ID: mdl-34885551

ABSTRACT

In this study, high-density magnesium diboride (MgB2) bulk superconductors were synthesized by spark plasma sintering (SPS) under pressure to improve the field dependence of the critical current density (Jc-B) in MgB2 bulk superconductors. We investigated the relationship between sintering conditions (temperature and time) and Jc-B using two methods, ex situ (sintering MgB2 synthesized powder) and in situ (reaction sintering of Mg and B powder), respectively. As a result, we found that higher density with suppressed particle growth and suppression of the formation of coarse particles of MgB4 and MgO were found to be effective in improving the Jc-B characteristics. In the ex situ method, the degradation of MgB2 due to pyrolysis was more severe at temperatures higher than 850 °C. The sample that underwent SPS treatment for a short time at 850 °C showed higher density and less impurity phase in the bulk, which improved the Jc-B properties. In addition, the in situ method showed very minimal impurity with a corresponding improvement in density and Jc-B characteristics for the sample optimized at 750 °C. Microstructural characterization and flux pinning (fP) analysis revealed the possibility of refined MgO inclusions and MgB4 phase as new pinning centers, which greatly contributed to the Jc-B properties. The contributions of the sintering conditions on fP for both synthesis methods were analyzed.

4.
Materials (Basel) ; 14(11)2021 May 26.
Article in English | MEDLINE | ID: mdl-34073417

ABSTRACT

High-Temperature Superconductors (HTS) considerably accelerate the development of superconducting machines for electrical engineering applications such as fully electrical aircraft. This present contribution is an overview of different superconducting materials that can be used as magnetic screens for the inductor of high specific power electrical machines. The impact of the material properties, such as the critical temperature (Tc) and the critical current density (Jc), on the machine performances is evaluated. In addition, the relevance to flux modulation machines of different HTS bulk synthesis methods are addressed.

5.
ACS Omega ; 5(12): 6250-6259, 2020 Mar 31.
Article in English | MEDLINE | ID: mdl-32258859

ABSTRACT

Growth and physical properties of bulk REBa2Cu3O7-δ (REBCO) superconductors fabricated by the infiltration growth (IG) method strongly depend on the initial size and morphology of the RE2BaCuO5 (211) particles. The present work details the novel method we developed for producing sharp-edged and surface-damaged 211 particles to be added to the REBCO bulks. We employed high-energy ultrasonic irradiation for pretreating the 211 particles and fabricated high-performance bulk single-grain YBa2Cu3O7-δ (YBCO) superconductors via the top-seeded IG process. Increasing the ultrasound irradiation power and time duration mechanically damaged the surface of the 211 particles, producing more fine and sharp edges. Systematic investigations of the microstructural properties of the final YBCO bulks indicated that the size and content of the 211 particles gradually decreased without any additional chemical doping. The effective grain refinement and improved interfacial defect densities enhanced the critical current density by a factor of two at 77 K and self-field as compared to a YBCO sample fabricated without any pretreatment. A maximum trapped field of 0.48 T at 77 K was obtained for a sample (20 mm diameter) with 211 particles treated for 60 min and 300 W ultrasound radiation. The effectiveness of the novel method is demonstrated by the superior performance of the YBCO bulk samples prepared as compared to bulk samples fabricated with the addition of Pt and CeO2. This method is novel, cost effective, and very convenient, maintaining high sample homogeneity, and is free of chemical contaminants as compared to other methods which significantly affect the properties of all REBCO bulk products grown by sintering, melt growth, and IG methods.

6.
NMC Case Rep J ; 7(1): 23-27, 2020 Jan.
Article in English | MEDLINE | ID: mdl-31938678

ABSTRACT

Development of extracranial carotid artery aneurysm (ECCA) after carotid endarterectomy (CEA) is a rare complication, occurring in connection with <1% of all CEAs. The main causes are infection, suture failure, and degeneration of arterial wall or patch. The traditional treatment has been operative repair, which can present a significant technical challenge owing to reoperative neck inflammation and potential cranial nerve injuries. Here, we report a case of successful stent-assisted coil embolization for right noninfectious ECCA. A 63-year-old female was admitted to our hospital for a 3-cm pulsating mass in her right midneck. Doppler examination and digital subtraction angiography revealed a large (15 mm) ECCA at the right common carotid artery (CCA). Thirteen years earlier, eversion CEA with patch angioplasty and abbreviation of the internal carotid artery (ICA) had been performed for a symptomatic 80% diameter stenosis with transient ischemic attack at another hospital. As the patient refused blood transfusion for religious reasons, we treated her with stent-assisted coil embolization, which achieved nearly complete obliteration of the aneurysm while preserving the parent artery patency. Three months after initial treatment, ultrasound revealed complete occlusion of the ECCA, but also showed stent shortening. Hence, we performed an additional stent placement so as to overlap the previous stent by 2.5 cm. Six months after initial treatment, carotid duplex ultrasound confirmed a good outcome. This procedure is an excellent choice for high-risk patients, and a larger case series is needed to establish this technique as the treatment of choice for ECCAs.

7.
Mol Cancer Ther ; 18(8): 1418-1429, 2019 08.
Article in English | MEDLINE | ID: mdl-31092561

ABSTRACT

Anti-VEGF treatments such as bevacizumab have demonstrated convincing therapeutic advantage in patients with glioblastoma. However, bevacizumab has also been reported to induce invasiveness of glioma. In this study, we examined the effects of rapid antiangiogenesis mediated by oncolytic virus (RAMBO), an oncolytic herpes simplex virus-1 expressing vasculostatin, on bevacizumab-induced glioma invasion. The effect of the combination of RAMBO and bevacizumab in vitro was assessed by cytotoxicity, migration, and invasion assays. For in vivo experiments, glioma cells were stereotactically inoculated into the brain of mice. RAMBO was intratumorally injected 7 days after tumor inoculation, and bevacizumab was administered intraperitoneally twice a week. RAMBO significantly decreased both the migration and invasion of glioma cells treated with bevacizumab. In mice treated with bevacizumab and RAMBO combination, the survival time was significantly longer and the depth of tumor invasion was significantly smaller than those treated with bevacizumab monotherapy. Interestingly, RAMBO decreased the expression of cysteine-rich protein 61 and phosphorylation of AKT, which were increased by bevacizumab. These results suggest that RAMBO suppresses bevacizumab-induced glioma invasion, which could be a promising approach to glioma therapy.


Subject(s)
Bevacizumab/pharmacology , Cysteine-Rich Protein 61/metabolism , Glioma/metabolism , Glioma/pathology , Hepevirus/genetics , Oncolytic Virotherapy , Oncolytic Viruses/genetics , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , Animals , Cell Line, Tumor , Cell Movement/drug effects , Combined Modality Therapy , Disease Models, Animal , ErbB Receptors/genetics , Glioma/therapy , Humans , Mice , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/therapy , Xenograft Model Antitumor Assays
8.
Mol Cancer Ther ; 18(4): 812-822, 2019 04.
Article in English | MEDLINE | ID: mdl-30872378

ABSTRACT

The combination of bevacizumab with temozolomide and radiotherapy was shown to prolong progression-free survival in newly diagnosed patients with glioblastoma, and this emphasizes the potential of bevacizumab as a glioma treatment. However, although bevacizumab effectively inhibits angiogenesis, it has also been reported to induce invasive proliferation. This study examined gene expression in glioma cells to investigate the mechanisms of bevacizumab-induced invasion. We made a human glioma U87ΔEGFR cell xenograft model by stereotactically injecting these cells into the brain of animals. We administered bevacizumab intraperitoneally three times per week. At 18 days after tumor implantation, the brains were removed for histopathology and mRNA was extracted. In vivo, bevacizumab treatment increased glioma cell invasion. qRT-PCR array analysis revealed upregulation of δ-catenin (CTNND2) and several other factors. In vitro, bevacizumab treatment upregulated δ-catenin expression. A low concentration of bevacizumab was not cytotoxic, but tumor cell motility was increased in scratch wound assays and two-chamber assays. Overexpression of δ-catenin increased the tumor invasion in vitro and in vivo However, δ-catenin knockdown decreased glioma cell invasiveness. The depth of tumor invasion in the U87ΔEGFR cells expressing δ-catenin was significantly increased compared with empty vector-transfected cells. The increase in invasive capacity induced by bevacizumab therapy was associated with upregulation of δ-catenin expression in invasive tumor cells. This finding suggests that δ-catenin is related to tumor invasion and migration.


Subject(s)
Angiogenesis Inhibitors/therapeutic use , Bevacizumab/therapeutic use , Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , Catenins/genetics , Glioma/drug therapy , Glioma/pathology , Angiogenesis Inhibitors/administration & dosage , Angiogenesis Inhibitors/pharmacology , Animals , Bevacizumab/administration & dosage , Bevacizumab/pharmacology , Brain Neoplasms/mortality , Cell Line, Tumor , Cell Movement/drug effects , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Glioma/mortality , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Invasiveness , RNA, Small Interfering/genetics , Rats , Rats, Nude , Survival Rate , Transfection , Xenograft Model Antitumor Assays , Delta Catenin
9.
Sci Rep ; 7(1): 7391, 2017 08 07.
Article in English | MEDLINE | ID: mdl-28785028

ABSTRACT

Despite therapeutic advances, glioblastoma represents a lethal brain tumor. Recently, research to identify prognostic markers for glioblastoma has intensified. Our previous study demonstrated that median progression-free survival (PFS) and overall survival (OS) of patients with high cysteine-rich protein 61 (CCN1) expression was significantly shorter than that of patients with low CCN1 expression. To understand the molecular mechanisms that regulate CCN1 expression, we examined 147 tumour samples from 80 patients with glioblastoma and 67 patients with lower grade glioma. Next-generation and Sanger sequencing showed that PIK3R1Met326Ile was more frequent in the CCN1 high expression group (10/37 cases, 27.0%) than the CCN1 low expression group (3/38 cases, 7.9%) in glioblastoma. This mutation was also detected in corresponding blood samples. In multivariate analysis, high CCN1 expression and PIK3R1Met326Ile in glioblastoma patients were prognostic factors for OS [HR = 2.488 (1.298-4.769), p = 0.006] and [HR = 2.089 (1.020-4.277), p = 0.0439], respectively. Thus, the PIK3R1Met326Ile germline appears to be correlated with CCN1 expression and poor prognosis in glioblastoma.


Subject(s)
Brain Neoplasms/genetics , Cysteine-Rich Protein 61/genetics , Germ-Line Mutation , Glioblastoma/genetics , Phosphatidylinositol 3-Kinases/genetics , Up-Regulation , Adult , Aged , Aged, 80 and over , Amino Acid Substitution , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Class Ia Phosphatidylinositol 3-Kinase , Cysteine-Rich Protein 61/metabolism , Female , Gene Expression Profiling/methods , Gene Expression Regulation, Neoplastic , Glioblastoma/metabolism , Glioblastoma/pathology , High-Throughput Nucleotide Sequencing/methods , Humans , Male , Middle Aged , Neoplasm Staging , Prognosis , Progression-Free Survival , Sequence Analysis, DNA/methods , Survival Analysis , Young Adult
10.
Sci Rep ; 6: 33319, 2016 09 14.
Article in English | MEDLINE | ID: mdl-27625116

ABSTRACT

Reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) is a tumor suppressor and therapeutic gene in many human cancers. Recently, an adenovirus REIC vector with the super gene expression system (Ad-SGE-REIC) was developed to increase REIC/Dkk-3 expression and enhance therapeutic effects compared with the conventional adenoviral vector (Ad-CAG-REIC). In this study, we investigated the in vitro and in vivo effects of Ad-SGE-REIC on malignant glioma. In U87ΔEGFR and GL261 glioma cells, western blotting confirmed that robust upregulation of REIC/Dkk-3 expression occurred in Ad-SGE-REIC-transduced cells, most notably after transduction at a multiplicity of infection of 10. Cytotoxicity assays showed that Ad-SGE-REIC resulted in a time-dependent and significant reduction in the number of malignant glioma cells attaching to the bottom of culture wells. Xenograft and syngeneic mouse intracranial glioma models treated with Ad-SGE-REIC had significantly longer survival than those treated with the control vector Ad-LacZ or with Ad-CAG-REIC. This study demonstrated the anti-glioma effect of Ad-SGE-REIC, which may represent a promising strategy for the treatment of malignant glioma.


Subject(s)
Genetic Therapy , Genetic Vectors/therapeutic use , Glioma/therapy , Intercellular Signaling Peptides and Proteins/therapeutic use , Adaptor Proteins, Signal Transducing , Adenoviridae/genetics , Animals , Apoptosis/genetics , Cell Line, Tumor , Chemokines , Disease Models, Animal , Gene Expression Regulation, Neoplastic , Glioma/genetics , Glioma/pathology , Humans , Intercellular Signaling Peptides and Proteins/genetics , Mice , Xenograft Model Antitumor Assays
11.
J Clin Neurosci ; 33: 148-153, 2016 Nov.
Article in English | MEDLINE | ID: mdl-27452129

ABSTRACT

BCNU wafers are a form of interstitial chemotherapy that is expected to improve the survival of patients with malignant glioma. However, their adverse events, especially brain edema, sometimes cause significant clinical symptoms. In this study, we performed a volumetric analysis of brain edema after the implantation of BCNU wafers and reported on the clinical course, and exacerbation factors of brain edema. Twelve patients who underwent surgical resection of supratentorial malignant glioma and BCNU wafer implantation, were enrolled. Radiographic quantitative analysis was conducted and compared with a historical control. The volume change in brain edema was divided into three groups and correlation with clinical symptoms was then evaluated. Compared with the control group, the brain edema in the BCNU wafer implantation group was significantly prolonged after surgery. Radiographic volumetric analysis revealed an increase of more than 25% at any time after surgery in four patients (33%) and a reduction of less than 25%, 1month after surgery in three patients (25%). Grade 3 clinical deterioration related to brain edema occurred in two patients and Grade 2 in one patient. Univariate analysis revealed that the radiographic deterioration of brain edema had no correlation with age, sex, diagnosis, tumor grade, preoperative volume of brain edema and tumor, residual tumor volume, or number of BCNU wafers. Radiographic quantitative analysis of brain edema indicated that BCNU wafer implantation may induce the prolongation and enlargement of brain edema with or without neurological deterioration. Brain edema may be controlled by intensive perioperative treatment with diuretics and corticosteroids.


Subject(s)
Antineoplastic Agents, Alkylating/adverse effects , Brain Edema/chemically induced , Brain Neoplasms/drug therapy , Carmustine/adverse effects , Drug Implants/adverse effects , Glioma/drug therapy , Adolescent , Adult , Aged , Antineoplastic Agents, Alkylating/administration & dosage , Brain Edema/diagnostic imaging , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/surgery , Carmustine/administration & dosage , Combined Modality Therapy/methods , Drug Implants/administration & dosage , Female , Glioma/diagnostic imaging , Glioma/surgery , Humans , Magnetic Resonance Imaging/methods , Male , Middle Aged , Treatment Outcome , Young Adult
12.
Brain Tumor Pathol ; 32(4): 245-52, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26201842

ABSTRACT

Recently, research efforts in identifying prognostic molecular biomarkers for malignant glioma have intensified. Cysteine-rich protein 61 (CCN1) is one of the CCN family of matricellular proteins that promotes cell growth and angiogenesis in cancers through its interaction with several integrins. In this study, we investigated the relationships among CCN1, O(6)-methylguanine-DNA methyltransferase expression, the tumor removal rate, and prognosis in 46 glioblastoma patients treated at the Okayama University Hospital. CCN1 expression was high in 31 (67 %) of these patients. The median progression-free survival (PFS) and overall survival (OS) times of patients with high CCN1 expression was significantly shorter than those of patients with low CCN1 expression (p < 0.005). In a multivariate Cox analysis, CCN1 proved to be an independent prognostic factor for patient survival [PFS, hazard ratio (HR) = 3.53 (1.55-8.01), p = 0.003 and OS, HR = 3.05 (1.35-6.87), p = 0.007]. Moreover, in the 31 patients who underwent gross total resection, the PFS and OS times of those with high CCN1 expression were significantly shorter than those with low CCN1 expression. It was concluded that CCN1 might emerge as a significant prognostic factor regarding the prognosis of glioblastoma patients.


Subject(s)
Biomarkers, Tumor/analysis , Brain Neoplasms/diagnosis , Brain Neoplasms/genetics , Cysteine-Rich Protein 61/analysis , Glioblastoma/diagnosis , Glioblastoma/genetics , Adult , Aged , Aged, 80 and over , Brain Neoplasms/blood supply , Brain Neoplasms/pathology , Cysteine-Rich Protein 61/genetics , Cysteine-Rich Protein 61/physiology , Female , Gene Expression , Glioblastoma/blood supply , Glioblastoma/pathology , Humans , Immunohistochemistry , Male , Middle Aged , O(6)-Methylguanine-DNA Methyltransferase/analysis , O(6)-Methylguanine-DNA Methyltransferase/genetics , Prognosis , Proportional Hazards Models , Survival Rate , Young Adult
13.
Transl Oncol ; 7(2): 292-302.e1, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24704537

ABSTRACT

Glioblastoma is known to secrete high levels of vascular endothelial growth factor (VEGF), and clinical studies with bevacizumab, a monoclonal antibody to VEGF, have demonstrated convincing therapeutic benefits in glioblastoma patients. However, its induction of invasive proliferation has also been reported. We examined the effects of treatment with cilengitide, an integrin inhibitor, on bevacizumab-induced invasive changes in glioma. U87ΔEGFR cells were stereotactically injected into the brain of nude mice or rats. Five days after tumor implantation, cilengitide and bevacizumab were administered intraperitoneally three times a week. At 18 days after tumor implantation, the brains were removed and observed histopathologically. Next, the bevacizumab and cilengitide combination group was compared to the bevacizumab monotherapy group using microarray analysis. Bevacizumab treatment led to increased cell invasion in spite of decreased angiogenesis. When the rats were treated with a combination of bevacizumab and cilengitide, the depth of tumor invasion was significantly less than with only bevacizumab. Pathway analysis demonstrated the inhibition of invasion-associated genes such as the integrin-mediated cell adhesion pathway in the combination group. This study showed that the combination of bevacizumab with cilengitide exerted its anti-invasive effect. The elucidation of this mechanism might contribute to the treatment of bevacizumab-refractory glioma.

14.
No Shinkei Geka ; 40(1): 55-60, 2012 Jan.
Article in Japanese | MEDLINE | ID: mdl-22223524

ABSTRACT

We report here a case of massive nasal bleeding from the sphenopalatine artery three weeks after endonasal transsphenoidal surgery. This 66-year-old male suffered from massive nasal bleeding with the status of hypovolemic shock. Under general anesthesia, an emergent angiography revealed an extravasation from the sphenopalatine artery. Trans-arterial embolization using coil and n-butyl-cyanoacrylate (NBCA) was performed following the diagnostic angiography. Complete occlusion of the injured artery was achieved. The patient showed good recovery from general anesthesia. Delayed nasal bleeding after endonasal transsphenoidal surgery is a rare but important complication. The sphenopalatine artery and its branch are located in the hidden inferior lateral corner of the sphenoid sinus and may be injured during enlargement of the sphenoid opening. When massive delayed nasal bleeding follows transsphenoidal surgery and damage of the internal carotid artery has been ruled out, endovascular treatment of the external carotid artery should be considered.


Subject(s)
Embolization, Therapeutic/methods , Endovascular Procedures/methods , Epistaxis/therapy , Adenoma/surgery , Aged , Humans , Male , Pituitary Neoplasms/surgery , Postoperative Complications , Sphenoid Sinus
15.
Sci Technol Adv Mater ; 10(1): 014610, 2009 Feb.
Article in English | MEDLINE | ID: mdl-27877261

ABSTRACT

We present numerical simulation of separating magnetic particles with different magnetic susceptibilities by magnetic chromatography using a high-temperature superconducting bulk magnet. The transient transport is numerically simulated for two kinds of particles having different magnetic susceptibilities. The time evolutions were calculated for the particle concentration in the narrow channel of the spiral arrangement placed in the magnetic field. The field is produced by the highly magnetized high-temperature superconducting bulk magnet. The numerical results show the flow velocity difference of the particle transport corresponding to the difference in the magnetic susceptibility, as well as the possible separation of paramagnetic particles of 20 nm diameter.

16.
J Pharmacol Sci ; 107(3): 270-6, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18603832

ABSTRACT

Recent studies indicate that an endogenous co-agonist for an N-methyl-D-aspartate (NMDA) receptor-related glycine site, D-serine, is synthesized by serine racemase and is metabolized by D-amino acid oxidase (DAO) and that acute treatment with morphine augments the gene expression of serine racemase and DAO in rat brain. To further elucidate the mechanism underlying the activation of NMDA receptors following chronic opioid administration, we have evaluated the effects of the chronic administration of morphine on the mRNA and protein expressions of serine racemase and DAO and on the contents of D-serine in several areas of the rat brain. Repeated administration of morphine for 30 days produced a significant augmentation of both the mRNA and protein expressions of serine racemase in all the brain regions, whereas no significant change in the protein expression of DAO was observed in all the brain regions. Furthermore, the chronic administration caused a slight but significant elevation in the concentration of D-serine in the cortex, striatum, and hippocampus. These results indicate the elevated D-serine level following the chronic morphine treatment could at least in part be involved in the activation of NMDA receptors via the glycine site.


Subject(s)
Brain/drug effects , D-Amino-Acid Oxidase/metabolism , Morphine/pharmacology , Racemases and Epimerases/metabolism , Serine/metabolism , Analgesics, Opioid , Animals , Brain/enzymology , D-Amino-Acid Oxidase/genetics , Gene Expression Regulation, Enzymologic/drug effects , Male , RNA, Messenger/metabolism , Racemases and Epimerases/genetics , Rats , Rats, Wistar , Time
17.
J Pharmacol Sci ; 106(2): 295-300, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18296865

ABSTRACT

Previous in vitro studies have shown that the degradation of [Leu(5)]enkephalin during incubation with cerebral membrane preparations is almost completely prevented by a mixture of three peptidase inhibitors: amastatin, captopril, and phosphoramidon. The present in vivo study shows that the inhibitory effect of [Leu(5)]enkephalin administered intra-third-ventricularly on the tail-flick response was increased more than 500-fold by the intra-third-ventricular pretreatment with the three peptidase inhibitors. The antinociceptive effect produced by the [Leu(5)]enkephalin in rats pretreated with any combination of two peptidase inhibitors was significantly smaller than that in rats pretreated with the three peptidase inhibitors, indicating that any residual single peptidase could inactivate significant amounts of the [Leu(5)]enkephalin. The present data, together with those obtained from previous studies, clearly demonstrate that amastatin-, captopril-, and phosphoramidon-sensitive enzymes play important roles in the inactivation of short endogenous opioid peptides, such as penta-, hepta-, and octa-peptides, administered intra-third-ventricularly to rats.


Subject(s)
Captopril/pharmacology , Enkephalin, Leucine/pharmacology , Glycopeptides/pharmacology , Pain/drug therapy , Peptides/pharmacology , Protease Inhibitors/pharmacology , Animals , Drug Synergism , Guinea Pigs , Ileum/drug effects , Ileum/physiology , Injections, Intraventricular , Male , Mice , Mice, Inbred ICR , Muscle Contraction/drug effects , Pain/physiopathology , Rats , Rats, Wistar , Vas Deferens/drug effects , Vas Deferens/physiology
18.
J Pharmacol Sci ; 105(1): 117-21, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17878706

ABSTRACT

Previous in vitro studies have shown that the degradation of [Met(5)]enkephalin-Arg(6)-Phe(7) during incubation with cerebral membrane preparations is largely prevented by a mixture of three peptidase inhibitors: amastatin, captopril, and phosphoramidon. The present in vivo study shows that the inhibitory effect of [Met(5)]enkephalin-Arg(6)-Phe(7) administered intra-third-ventricularly on the tail-flick response was increased more than 1000-fold by the intra-third-ventricular pretreatment with three peptidase inhibitors. The antinociceptive effect produced by the [Met(5)]enkephalin-Arg(6)-Phe(7) in rats pretreated with any combination of two peptidase inhibitors was significantly smaller than that in rats pretreated with three peptidase inhibitors, indicating that any residual single peptidase could inactivate significant amounts of the [Met(5)]enkephalin-Arg(6)-Phe(7). The present data, together with those obtained from previous studies, clearly show that amastatin-, captopril-, and phosphoramidon-sensitive enzymes play important roles in the inactivation of endogenous opioid peptides, such as [Met(5)]enkephalin, [Met(5)]enkephalin-Arg(6)-Phe(7), [Met(5)]enkephalin-Arg(6)-Gly(7)-Leu(8), and dynorphin A (1-8), administered intra-third-ventricularly to rats.


Subject(s)
Analgesics/pharmacology , Enkephalin, Methionine/analogs & derivatives , Protease Inhibitors/pharmacology , Analgesics/administration & dosage , Animals , Captopril/administration & dosage , Captopril/pharmacology , Dose-Response Relationship, Drug , Drug Synergism , Enkephalin, Methionine/administration & dosage , Enkephalin, Methionine/pharmacology , Glycopeptides/administration & dosage , Glycopeptides/pharmacology , Injections, Intraventricular , Injections, Subcutaneous , Male , Naloxone/administration & dosage , Naloxone/pharmacology , Narcotic Antagonists/administration & dosage , Narcotic Antagonists/pharmacology , Pain/physiopathology , Pain/prevention & control , Pain Measurement/methods , Peptides/administration & dosage , Peptides/pharmacology , Protease Inhibitors/administration & dosage , Rats , Rats, Wistar
19.
Rinsho Ketsueki ; 48(7): 559-64, 2007 Jul.
Article in Japanese | MEDLINE | ID: mdl-17695305

ABSTRACT

A 70-year-old man was admitted to the hospital with left ankle pain, also exhibiting severe consciousness disturbance. Laboratory findings showed not only hypercalcemia, but also increased serum levels of PTHrP and a few of proinflammatory cytokines, such as TNF-alpha, and IL-6. The X-ray and CT examinations revealed multiple osteolytic lesions, including the left tibia and fibula. Bone marrow aspiration revealed increased lymphoblasts (48%), and the patient was diagnosed as having acute lymphoblastic leukemia (ALL, L2). The hypercalcemia was successfully treated with calcitonin and bisphosphonate, and subsequently his consciousness status recovered rapidly. The bone marrow lymphoblast count decreased following combination chemotherapy, and a tendency towards improvement of the left ankle pain was also noted. However, he died of acute pneumonia and gastrointestinal bleeding. The postmortem findings showed leukemic cell involvement of the left tibia. The present case suggested that not only humoral hypercalcemia or local osteolytic hypercalcemia, but also proinflammatory cytokines were associated with multiple osteolysis and hypercalcemia.


Subject(s)
Cytokines/physiology , Hypercalcemia/etiology , Osteolysis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/physiopathology , Aged , Fibula/diagnostic imaging , Humans , Interleukin-6/blood , Male , Parathyroid Hormone-Related Protein/blood , Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications , Radiography , Tibia/diagnostic imaging , Tumor Necrosis Factor-alpha/blood
20.
Eur J Pharmacol ; 565(1-3): 89-97, 2007 Jun 22.
Article in English | MEDLINE | ID: mdl-17383634

ABSTRACT

Although there is a variety of information concerning the effects of the N-methyl-D-aspartate (NMDA) receptor on opioid-induced antinociception at the spinal level, little is known about the effects at the supraspinal level. To clarify the role of the NMDA receptor on the morphine-induced antinociception at the supraspinal level, we investigated the effects of the intracerebroventricular (i.c.v.) administration of D-serine, a selective agonist for the glycine site of the NMDA receptors, alone or in combination with morphine using the tail-flick test. The i.c.v. administration of D-serine, but not L-serine, alone produced a dose-dependent antinociception in the tail-flick response. D-Serine also dose-dependently potentiated the antinociceptive effect induced by the i.c.v. administration of morphine and the simultaneous administration produced an additive effect. The potentiation of the antinociception produced by both D-serine alone or in combination with morphine was dose-dependently attenuated by the i.c.v. administration of L-701,324, a selective antagonist for the glycine site of the NMDA receptors. In addition, the potentiation of the D-serine-induced antinociception was antagonized by the i.c.v. administration of naloxone, a nonselective opioid receptor antagonist. These observations, together with the fact that D-serine is an endogenous and selective co-agonist for the glycine site of the NMDA receptors, strongly suggested that the activation of the supraspinal NMDA receptors by D-serine leads to the potentiation of the antinociception in the tail-flick test and that endogenous D-serine could modulate the mu-opioid receptor mediated antinociception via the glycine site of the NMDA receptors at the supraspinal level.


Subject(s)
Analgesics/pharmacology , Morphine/pharmacology , Receptors, N-Methyl-D-Aspartate/drug effects , Serine/pharmacology , Spinal Cord/drug effects , Animals , Drug Synergism , Male , Naloxone/pharmacology , Pain Measurement , Quinolones/pharmacology , Rats , Rats, Wistar , Receptors, N-Methyl-D-Aspartate/physiology , Receptors, Opioid, mu/physiology , Stereoisomerism
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