Biomedical subjects

N Oku

Publications and source records attributed to N Oku.

At least 19 recordsLinked to original sources

PubMed2000

Potential usage of thermosensitive liposomes for site-specific delivery of cytokines.

Long-circulating liposomes reside long in the bloodstream, and transient swelling during phase transition of liposomes with hyper-osmotic internal aqueous phase causes release of macromolecules. Here we examined the applicability of long-circulating thermosensitive liposomes for delivery of tumor necrosis factor (TNF) by the heating of a local tumor-growing site after injection of TNF-loaded liposomes into tumor-bearing mice. Glucuronate modified thermosensitive liposomes with internal solution of two-fold higher osmotic pressure and sized through 200 nm-pore, released encapsulated [(131)I] human serum albumin at 42 degrees C in vitro and showed long-circulating character in vivo. Cytotoxic action of TNF encapsulated in long-circulating thermosensitive-liposomes (LCTS-liposomes) against L929 fibrosarcoma cells was enhanced at 42 degrees C in vitro. Furthermore, the tumor growth tended to be inhibited more by hyperthermia of mice bearing Meth A sarcoma than without heating after injection of TNF encapsulated in LCTS-liposomes. These results suggest that the cytokine can be released at the tumor site from the circulating CLTS-liposomes.

Animals↗

PubMed2000

65Zn localization in rat brain after intracerebroventricular injection of 65Zn-histidine.

Previous studies have shown that 65Zn uptake in the brain expressed relative to plasma 65Zn level is enhanced by histidine infusion into the blood vessel. To study the effect of histidine on zinc uptake in the brain parenchyma via the CSF, the brains of rats injected intracerebroventricularly with 65Zn-His were subjected to autoradiography. Six days after injection, the radioactivity from 65Zn-His was distributed in the major part of the brain parenchyma higher than that from 65ZnCl(2), and relatively concentrated in the hippocampal formation, globus pallidus and hypothalamus. The radioactivity of the aqueduct was also higher in the 65Zn-His group, indicating that CSF clearance of the 65Zn-His group may be lower than that of the 65ZnCl(2) group. These results suggest an enhancement by histidine on zinc uptake in the brain parenchyma via the CSF.

Animals↗

PubMed2000

Hepatic zinc response via metallothionein induction after tumor transplantation.

Based on previous findings that liver zinc and metallothionein (MT) levels increase after tumor transplantation, zinc metabolism in tumor-bearing mice was studied to clarify the role of zinc-MT in host defense systems. Zinc in the hepatic cytosolic MT fraction did not increase in tumor-bearing mice fed a zinc-deficient diet, suggesting that dietary zinc is necessary for apo-MT induction in the liver after tumor transplantation and is then incorporated into the apo-MT. When (65)ZnCl(2) was intravenously injected, liver (65)Zn levels in the tumor-bearing mice were higher than those in control mice for 72 h after the injection. Pancreatic and blood (65)Zn levels in tumor-bearing mice were lower than those in controls for 24 h (pancreas) and 6 h (blood) after the injection. These findings indicate that the hepatic zinc response via MT induction influences zinc metabolism in the body after tumor transplantation. Moreover, (65)Zn uptake in the liver of MT-deficient tumor-bearing mice was lower than that in control tumor-bearing mice 1 h after injection. (65)Zn uptake in the tumor and blood (65)Zn levels in the MT-deficient tumor-bearing mice were higher than those in the control tumor-bearing mice. Tumor weight increased more in MT-deficient mice than in control mice. The formation of zinc-MT in the liver of tumor-bearing mice might decrease blood zinc availability for tumors and other tissues, such as the pancreas.

Animals↗

PubMed2000

Relationship between brain zinc and transient learning impairment of adult rats fed zinc-deficient diet.

The relationship between brain zinc and learning behavior was studied based on the data of 65Zn localization in the hippocampal formation. Learning behavior, tested by passive avoidance performance, of 6-week-old rats improved significantly compared to that of 4-week-old rats and it was maintained at 20 weeks of age. When 8-week-old rats were fed zinc-deficient diet for 4 weeks, the learning behavior was significantly impaired. However, it was recovered to almost normal level by feeding with control (zinc-adequate) diet for 5 weeks. These results demonstrate that a proper zinc supply to the brain is necessary for improvement and maintenance of learning ability. Although an appreciable decrease in brain zinc was not observed in the rats fed zinc-deficient diet for 4 weeks, significant decrease of hippocampal zinc was observed in rats fed zinc-deficient diet for 12 weeks. Moreover, synaptosomal zinc in the hippocampal formation and cerebral cortex was significantly decreased by the 12 weeks of zinc deprivation. These results suggest that the decrease of vesicular zinc in the hippocampal formation and cerebral cortex is involved in the transient learning impairment of adults rats.

Age Factors↗

PubMed2000

Neural plasticity detected in short- and long-term cochlear implant users using PET.

The interaction of listening to words and watching sign language in short-term and long-term cochlear implant (CI) users who have learned sign language after becoming deaf was measured using PET. In short-term CI users the auditory cortex was inactive while in long-term CI users it was fully activated with the simultaneous presentation of auditory and visual input. The result suggests the possibility that the interference of rival modalities may be diminished with experience and the preference switchover from the visual input to the auditory input could be accomplished by means of the neural plasticity persisting in the mature human auditory cortex.

Adolescent↗

PubMed2000

Functional brain areas used for the lifting of objects using a precision grip: a PET study.

Positron emission tomography (PET) was performed in 10 normal volunteers to investigate regional cortical and subcortical activation induced by the lifting of an object repetitively using a precision grip between the index finger and thumb. Data were obtained for three object weights (4, 200 and 600 g) and a resting condition. Grip and lift forces on a similar object and the activity of selected muscles in the hand, arm and shoulder were also recorded in separate lifting trials. A comparison between all movement conditions and the resting condition revealed significant activation of the primary motor (M1), primary sensory (S1), dorso-caudal premotor (PM), caudal supplementary motor (SMA) and cingulate motor (CMA) cortices contralateral to the hand used. On the ipsilateral side, activation of the M1, caudal SMA and inferior parietal cortex (BA 40) was also found. In the subcortical areas, the bilateral hemispheres and right vermis of the cerebellum, left basal ganglia and thalamus were activated. Behavioral adaptation to a heavier object weight was revealed in a nearly proportional increase of both grip and lift forces, prolonged force application period and a higher level of hand and arm muscle activities. An increase in the rCBF associated with these changes was noted in several cortical and subcortical areas. However, consistent object weight-dependent activation was observed only in the M1/S1 contralateral to the hand used.

Adult↗

PubMed2000

Possible role of immune surveillance at the initial phase of metastasis produced by B16BL6 melanoma cells.

The relationship among the real-time trafficking of lung metastatic B16BL6 cells, metastatic potential, and the injected number of the cells was examined, since the smaller the number of tumor cells injected, the more clearly the immune defense may be observed. When 1x10(6) or 1x10(5) B16BL6 cells were injected into mice via the tail vein, both numbers of cells accumulated in the lung at a similar rate: there was an approximately 10-fold difference in the number of accumulated cells between the two doses. Elimination from the lung was not dependent on the cell number but on the proportion of accumulated cells. However, the injection of 1x10(4) cells resulted in lung accumulation less than one-tenth of that obtained with 1x10(5) cell injection. Metastasis was observed when 1x10(5) or 1x10(6) B16BL6 cells were injected, but not after injection of 1x10(4) cells. To clarify the roles of the immune defense system at the initial phase of metastasis, we challenged macrophage-depleted mice with 1x10(4) tumor cells. Treatment of mice with 2-chloroadenosine prior to the tumor cell challenge cancelled the suppression of not only metastasis but also the lung accumulation. Furthermore, the administration of 2-chloroadenosine following the tumor cell challenge had little effect on the metastatic potential. These results suggest that the immune surveillance whose action was obvious at the low dose of challenged tumor cells functions strongly at the initial phase but not at the advanced stages of the metastatic process, and that macrophages play an important role in the suppression of metastasis.

2-Chloroadenosine↗

PubMed2000

Suppression of GD1alpha ganglioside-mediated tumor metastasis by liposomalized WHW-peptide.

GD1alpha ganglioside-replica peptides were recently isolated from a phage-displayed random pentadecapeptide library by assaying for inhibition of adhesion of RAW117-H10 lymphosarcoma cells to hepatic sinusoidal microvessel endothelial (HSE) cells. We show here that the Trp-His-Trp (WHW) peptide was identified as a minimal sequence of the GD1alpha-replica peptide WHWRHRIPLQLAAGR. The addition of WHW peptide-attached liposomes displayed efficient inhibition of liver metastasis of RAW117-H10 cells as well as of GD1alpha-mediated adhesion of RAW117-H10 cells to HSE cells in vitro. These results suggest that engineered liposomes for peptide delivery are applicable to treatment for metastasis.

Amino Acid Sequence↗

PubMed2000

The neural basis of perceptual and conceptual word priming--a PET study.

Positron emission tomography scans were obtained in 13 normal subjects during perceptual and conceptual word priming tasks with the aim to investigate the neural system specific to the two priming conditions. In the prescan phase, subjects were primed perceptually or conceptually with two separate procedures, while in the scan phase, they performed the same stem completion task. Therefore we could compare the results of the two priming tasks in a direct manner. A fixation control task and a baseline task (completion of stems that did not correspond to previously seen words) were also given. A specific blood flow decrease was found in the left inferior temporal cortex in the perceptual word priming condition and in the left superior temporal / inferior parietal cortex in the conceptual word priming condition. Each blood flow change may reflect transient changes in the cortical areas subserving the processing of the perceptual and conceptual components of word priming.

Adult↗

PubMed2000

New isomalabaricane triterpenes from the marine sponge Stelletta globostellata that induce morphological changes in rat fibroblasts.

Three new isomalabaricane triterpenes, 29-hydroxystelliferin D (2), 3-epi-29-hydroxystelliferin E (3), and 3-epi-29-hydroxystelliferin A (4), were isolated from the marine sponge Stelletta globostellata. Their structures, including absolute stereochemistry, were determined on the basis of spectral data and chemical methods. Rat fibroblasts treated with 0.2 microM of 2-4 exhibited unusual morphological characteristics, followed by death in 5 days.

Acetylation↗

PubMed2000

Magnetic resonance lymphography of profundus lymph nodes with liposomal gadolinium-diethylenetriamine pentaacetic acid.

Lymphography, especially imaging of profundus lymph nodes, is a useful tool for diagnosis of cancer metastases in lymph nodes. However, positive enhancement agents for magnetic resonance lymphography (MRL) have not been available, since the positive imaging agents so far introduced are low-molecular-weight materials that are not trapped in lymph nodes. For the purpose of improved positive enhanced MRL, we employed liposomes as carriers of a positive enhancer, gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA). Magnetic resonance (MR) imaging was performed after subcutaneous injection of Gd-liposomes into the hind feet of rabbits which had reactive enlarged retroperitoneal lymph nodes. As a result, not only popliteal but also profundus retroperitoneal lymph nodes were positively enhanced by Gd-liposomes, especially after 20 min massage of the injected sites. Gd-Liposomes containing dipalmitoylphosphatidylglycerol were more effective than Gd-liposomes containing palmityl-D-glucuronide, a type of long-circulating liposomes, suggesting that liposomal accumulation in lymph node is, at least partly, mediated by the trapping of liposomes by macrophages. These data show that liposomes modified with Gd-DTPA are effective for positive enhancement of both regional and profundus lymph nodes in MR lymphography.

Animals↗

PubMed1999

Anticancer therapy using glucuronate modified long-circulating liposomes.

Since conventional liposomes tend to be trapped by the reticuroendothelial systems (RES), their use as drug carriers is limited when the targets are not RES cells. Therefore, many attempts have been made to avoid the RES-trapping of liposomes. Favorable results were obtained by a modification of liposomes with a glucuronic acid derivative, PGlcUA, and polyethyleneglycol. These liposomes have a long-circulating character, and showed the further advantage for passive targeting to tumor tissues, since the vasculature in tumor tissues is leaky enough for small-sized liposomes to extravasate. Thus long-circulating liposomes are useful for tumor imaging and treatment. PGlcUA-modified liposomes were actually found to accumulate effectively in tumor tissue, and showed enhanced efficacy of antitumor agents, such as adriamycin and vincristine when they were encapsulated into the liposomes. Usefulness of PGlcUA liposomes as drug carriers was also observed in photodynamic therapy and in treatment of cancer by amphiphilic novel antitumor agents.

Journal Article↗

PubMed1999

Release of zinc from the brain of El (epilepsy) mice during seizure induction.

Brain distribution after i.v. injection of 65ZnCl2 into El mice, an animal model of genetically determined epilepsy, was studied by autoradiography to study the utilization of zinc in the brain. The distribution of 65Zn in the brain of El mice 6 days after injection was almost the same as that of ddY (normal) mice, suggesting that the uptake of zinc by the brain of El mice is normal. To study the movement of zinc in the brain in the course of seizure induction, the concentrations of 65Zn in the brain of seizure-afflicted and untreated control El mice were compared 20 days after 65Zn injection. The concentration of 65Zn in the brain of seized El mice was overall lower than that of control El mice; the concentration of 65Zn was decreased notably in the piriform cortex and amygdaloid nuclei complex during convulsion. These results suggest that the release of zinc from the El mouse brain is enhanced during convulsion. The decrease in actively functioning zinc in the brain may be associated with the increase in susceptibility to seizure in the El mouse.

Animals↗

PubMed1999

Delivery of contrast agents for positron emission tomography imaging by liposomes.

Liposomes encapuslating positron emitters are applicable for diagnostic imaging and are useful to investigate the real-time liposomal trafficking in vivo. Long-circulating liposomes encapsulaing [2-(18)F]-2-fluoro-2-deoxyglucose were administrated to tumor-bearing mice, and a PET scan was performed. Small-sized long-circulating liposomes (100 nm) tended to accumulate in tumor tissues of tumor-bearing mice as compared with conventional liposomes. Then the size effect on trafficking of long-circulating liposomes was investigated. Large-sized liposomes (>300 nm) accumulated in liver and spleen in a time dependent manner. On the contrary, small-sized ones (<200 nm) were transiently accumulated in the liver right after injection, but the accumulation decreased time dependently, suggesting that, although the majority of small long-circulating liposomes remain in bloodstream, some extravasate once into interstitial spaces in liver which re-enter into bloodstream again. Next the trafficking of so-called long-circulating liposomes, i.e., liposomes modified with ganglioside GM1, palmityl glucuronide (PGlcUA), and polyethylene glycol (PEG), in tumor-bearing mice was examined. The accumulation of all three kinds of long-circulating liposomes in liver decreased time-dependently, and PGlcUA-liposomes could avoid liver-trapping the most efficiently. Tumor accumulation of liposomes was obvious for PGlcUA-liposomes and PEG-liposomes from immediately after injection, but not for GM1-liposomes. Finally, the trafficking of differently charged liposomes was investigated in normal mice. The accumulation of positively charged liposomes containing 1,2-dimyristyloxypropyl-3-dimethyl-hydroxyethyl bromide was different from that of neutral and negatively charged DCP-liposomes. The agglutinability of and serum protein ginding to positively charged liposomes were marked, suggesting that these factors affect the high accumulation of DMRIE-liposomes in liver. Non-invasive PET analysis of liposomal trafficking is beneficial for obtaining information about liposomal drug delivery, and long-circulating liposomes might be useful for diagnostic tumor imaging by PET.

Journal Article↗

PubMed1999

109Cd transport in rat brain.

The brain distribution of 109CdCl2 following administration into either the tail vein, the lateral ventricle or the olfactory bulb was studied to clarify permeability of the brain barrier system to cadmium (Cd) and Cd movement in the cerebrospinal fluid (CSF) and the brain extracellular fluid. One hour after intravenous (i.v.) injection, 109Cd was largely concentrated in the choroid plexus, and 109Cd concentration in the major part of the brain parenchyma, except for the circumventricular organs such as the pineal gland and the regions around them, was low. Six days after i.v. injection, 109Cd concentration in the choroid plexus was still high, and 109Cd was also detected highly in the pineal gland and small part around the median eminence. 109Cd concentration in the major part of the brain parenchyma was decreased in parallel with that in the blood. In the case of injection of 109CdCl2 into the lateral ventricle, a large portion of 109Cd was detected in the ventricular system 6 days after injection, and 109Cd concentration in the major part of the brain parenchyma was less than the detection limit. These results suggest that Cd cannot easily get into the brain and is blocked not only by the blood- brain and the blood-CSF barriers, but also by the ependymal and pial surfaces. In the case of injection of 109CdCl2 into the olfactory bulb, a large portion of 109Cd was detected in the injected area 24 h after injection, and, the next 24 h later, 109Cd distribution in the brain was not changed appreciably. These results suggest that Cd cannot easily move in the brain extracelular space, and is taken up into the brain parenchyma.

Animals↗

PubMed1999

Application of surface-coated liposomes for oral delivery of peptide: effects of coating the liposome's surface on the GI transit of insulin.

We prepared two kinds of surface-coated liposomes and investigated their potencies as oral dosage forms for peptide drugs by focusing on their effects on the gastrointestinal (GI) transit of drugs. The surface of the liposomes was coated with poly(ethylene glycol) 2000 (PEG-Lip) or the sugar chain of mucin (Mucin-Lip). As a model peptide drug, insulin was encapsulated in these liposomes. Coating the surface with poly(ethylene glycol) was found to reduce the transit rate of liposomes in the small intestine after oral administration to rats in vivo. Mucin-Lip was retained in the stomach longer than PEG-Lip or uncoated liposomes. The effect of surface coating on the intestinal transit of liposomes was determined by means of in situ single pass perfusion in the rat small intestine. Statistical moment analysis was applied to the outflow pattern of both liposomes and encapsulated insulin. The mean transit time (MTT) and deviation of transit time (DTT) in the intestinal tract were calculated. The MTT of PEG-Lip was much longer than those of uncoated liposomes and Mucin-Lip and was significantly shortened after removal of the intestinal mucous layer. These results indicated that PEG-Lip interacts strongly with the intestinal mucous layer, leading to its slow transit in the intestine. In contrast, coating the liposome's surface with mucin did not affect either the MTT or DTT of liposomes in the intestine. This result is in accordance with the in vivo observation that Mucin-Lip was highly retained in the stomach, but not in any region of the small intestine in vivo. Both the MTT and DTT values of insulin encapsulated in PEG-Lip and Mucin-Lip were almost the same as those of liposomes themselves, suggesting that surface-coated liposomes retained insulin in the intestinal tract. However, MTT and DTT of insulin were significantly shorter than those of uncoated liposomes because these liposomes degraded and released significant amounts of insulin during single pass perfusion. The ability of surface-coated liposomes, especially of PEG-Lip, to interact with the mucus layer and slow the transit rate in the GI tract is considered desirable for oral delivery of peptide drugs. Modification of the liposomal surface with appropriate materials, therefore, should be an effective method by which to achieve the oral delivery of peptide drugs.

Animals↗

PubMed1999

Perception and conception: separate memory systems in the medial temporal lobe.

The purpose of the present study was to investigate, by using positron emission tomography, whether the functionally different types of information are subserved by different memory systems in human medial temporal lobe structures. Before explicit retrieval tests during scans, subjects studied words in perceptually and conceptually processed manners separately. It was found that different parts of the medial temporal lobe structures were involved in each of the different conditions. These results indicated that perceptually and conceptually processed types of information were subserved by at least two partially segregated memory systems in human medial temporal lobe structures.

Adult↗

PubMed1998

GD1alpha-replica peptides functionally mimic GD1alpha, an adhesion molecule of metastatic tumor cells, and suppress the tumor metastasis.

A novel peptide technology to produce mimicking peptides of carbohydrate moiety (which we propose to name glyco-replica peptides) is a useful tool to elucidate the functions of glycoconjugate. Carbohydrate moiety of ganglioside GD1alpha functions as a molecule involved in the adhesion between murine highly metastatic lymphoma RAW117-H10 cells and hepatic sinusoidal endothelial (HSE) cells. To prepare peptides which mimic the carbohydrate structure of GD1alpha, phage clones expressing peptides which bound to a monoclonal antibody against GD1alpha (KA17) were isolated from a phage-displayed random peptide library. Four phage clones having affinity to the monoclonal antibody KA17 were isolated, and these clones showed inhibitory effect on the binding of KA17 to GD1alpha. The amino acid sequences of the displayed pentadecamers were determined, and one of the phages displaying sequence WHWRHRIPLQLAAGR bound to HSE cells directly and showed the highest inhibitory effect on the adhesion between RAW117-H10 cells and HSE cells. The synthesized peptides having the same sequences to the displayed 15mers in the four isolated phage clones also showed the inhibitory effect on the adhesion of RAW117-H10 cells to HSE cells, and, again, the WHWRHRIPLQLAAGR peptide showed the highest inhibitory effect. Furthermore, intravenous injection of the peptide brought almost complete inhibition of the metastasis of RAW117-H10 cells to lung and spleen, and about 50% inhibition of the liver metastasis. These results indicate that GD1alpha plays an important role for metastasis of RAW117-H10 cells, and the peptides obtained by the present procedure are able to mimic the functional role of the glycoconjugate.

Amino Acid Sequence↗