Biomedical subjects
Publications and source records attributed to Makoto Inoue.
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In this report, we demonstrated that peripheral application of very low dose (amol ranges) of morphine induced flexor response through a substance P (SP) release at the nociceptor endings in mice. The intraplantar (i.pl.) application of morphine produced flexor response in a dose-dependent manner from 0.1 to 1000amol. The mu-opioid receptor (MOP-R) agonist [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO) also produced dose-dependent flexor response in same dose ranges. Morphine-induced flexor responses were markedly inhibited by naloxone and D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr amide (CTOP) both MOP-R antagonists and by intrathecal injection of antisense oligodeoxynucleotide (AS-ODN) for MOP-R which is expected to reduce the receptor expression in sensory nerve endings. Prior incubation with capsaicin, a depletor of SP from polymodal C fibers and [(+)-(2S,3S)-(2-methoxybenzylamino)-2-phenylpiperidine] (CP-99994), a tachykinin 1 receptor antagonist, also blocked the morphine-induced flexor responses. Moreover, pertussis toxin (PTX) which inactivates G(alpha)(i/o); [(1-[6-([(17b)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino)hexyl]-1H-pyrrole-2,5-dione)] (U-73122), an inhibitor of phospholipase C (PLC); ethyleneglycol-bis(beta-aminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA), a Ca(2+) chelating agent; xestospongin C, a membrane-permeable inositol trisphosphate (InsP(3)) receptor antagonist inhibited the morphine-flexor responses. However, thapsigargin, a depletor of intracellular Ca(2+) concentration and diphenhydramine, a histamine (His) H1 receptor antagonist, were unable to block the morphine-induced flexor responses. These results suggest that extremely low doses of morphine can stimulate sensory nerve endings through activation of peripheral MOP-R and its downstream mechanisms include activation of PLC through a SP release from polymodal C fibers.
A clinical survey of Japanese patients with mitochondrial fatty acid beta-oxidation and related disorders (FAODs) was performed with questionnaires sent to 187 institutions, where inborn errors of metabolism could be managed in Japan, including a search of related literature published between 1985 and 2000. Sixty-four patients with ten types of FAODs were found. Carnitine palmitoyltransferase 2 deficiency and glutaric aciduria type 2 were most common (17 and 14 patients, respectively). As of 2000, there were no patients with medium-chain acyl-CoA dehydrogenase deficiency, which is common in Caucasians. Age at onset was under 2 years in 38 (59%) of the patients. Eight (13%) patients had neonatal onset. Twenty-one (55%) of the 38 children with an initial attack under 2 years of age had acute encephalopathy or a Reye syndrome-like illness. Half of the patients presented within 2 years of birth died or were handicapped. On the other hand, 19 (79%) of the 24 with onset after 2 years of age had muscle symptoms and 23 (96%) of the 24 grew and developed normally. Though the precise incidence of FAODs in Japan is still unknown, as a consequence of the development of diagnostic procedures the number of FAOD cases being diagnosed appears to have increased. Mass screening for FAODs during the neonatal period will greatly aid in prevention of attacks and related effects.
BACKGROUND: Dexamethasone is widely used for the treatment of chronic lung disease (CLD), but its mechanism of action is still not clearly understood. METHODS: Respiratory status, bodyweight, blood pressure, urine volume, fluid intake and nutrient intake were investigated in 12 infants with CLD during treatment with dexamethasone. RESULTS: The mean gestational age of the patients was 26.3 +/- 2.5 weeks and their mean birthweight was 807 +/- 232 g. Treatment with dexamethasone was started at a mean age of 41 +/- 23 days. The ventilatory index (VI) improved after treatment was started. Blood pressure and urine volume increased significantly after treatment, but weight gain was poor during this time. Fluid and nutrient intake did not change before and after treatment. The degree of improvement in the VI after treatment was significantly correlated with an increase in urine volume. CONCLUSIONS: The results suggest that a rise in blood pressure as a result of dexamethasone treatment and the subsequent diuretic effect of this rise may play a role in improvement in respiratory status.
The case of a 1-year-8-month-old-boy with cerebral infarction after varicella infection is reported here. Brain magnetic resonance (MR) angiography revealed segmental narrowing of the left middle cerebral artery which became normal 8 months later. The MR angiography well demonstrated the time course of the vascular involvement in the present patient. In cerebral infarction after varicella infection, the proximal portion of the main cerebral arteries were frequently damaged therefore MR angiography is useful for diagnosis and therapeutic decision-making. Moreover, serial MR angiographic studies can clarify the natural course of vascular changes in varicella virus-related cerebral infarction.
PURPOSE: To determine whether a novel photocrosslinkable polymer synthesized from hyaluronic acid would seal experimental full-thickness corneal lacerations in a rabbit model. METHODS: A solution of hyaluronic acid was modified with methacrylate groups (HA-MA), precipitated, dried, reconstituted in an aqueous solution, and sterilized before use. The viscous polymer solution was applied to 38 of 43 experimental corneal lacerations in rabbits and subsequently irradiated with a low-intensity argon laser beam to produce a clear flexible polysaccharide hydrogel patch. The ability of this sealant to repair corneal lacerations was evaluated in four types of full-thickness, 3-mm corneal wounds (linear, linear + epithelium removed, stellate, and stellate + epithelium removed). Slit-lamp examinations, measurements of intraocular pressure, Seidel tests, and histologic studies were performed at selected intervals to evaluate the wound and determine the rate of healing. RESULTS: Corneal perforations were completely sealed and the anterior chambers had reformed by 6 hours in HA-MA-treated eyes. There was no evidence of leakage at this or later times in 37 of the 38 eyes. Intraocular pressure had risen to near-normal levels by day 7 in all four groups, and the sealant was still present in most eyes at day 7. In contrast, the anterior chambers did not re-form in control eyes (five) with untreated perforations because of aqueous leakage through the wounds. Minimal inflammation was observed clinically or in histologic sections of treated corneas. There was extensive proliferation of stromal cells and formation of new extracellular matrix at the wound edges, which became tightly adherent between days 4 and 7. CONCLUSION: Our novel photocrosslinkable methacrylated hyaluronan polymer sealed 97% (37/38) of the experimental corneal lacerations. HA-MA may prove useful for sealing corneal lacerations in patients and for other sutureless ophthalmic surgical procedures.
SUMMARY: [11C](+)McN5652 is a selective serotonin reuptake inhibitor with subnanomolar potency for the serotonin transporter, and is currently being used for positron emission tomography studies. However, quantification of the regional [11C](+)McN5652 binding potential in vivo is a controversial issue because of its complex characteristics. The authors examined the regional differences in nonspecific binding and proposed simple methods for estimating the binding potential of [11C](+)McN5652. The regional difference in nonspecific binding was evaluated by the activity ratio of the thalamus compared with the cerebellum for inactive-isomer [11C](-)McN5652 and [11C](+)McN5652 saturation studies. The distribution volume of the thalamus was approximately 1.16 times larger than that of the cerebellum. The thalamus-to-cerebellum distribution volume ratio was estimated by nonlinear least square and graphical methods, with and without arterial input function. The graphical method with k2; without blood sampling was practical and most applicable for estimation of the distribution volume ratio because this method is more stable than the nonlinear least square method in the simulation study. Binding potential estimated with the distribution volume ratio of [11C](+)McN5652 and the correction with distribution volume ratio of [11C](-)McN5652 represent the most reliable parameters for the assessment of serotonin transporter binding.
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BACKGROUND: Recently, two isoforms of cyclooxygenase (COX) have been identified, a constitutive form (COX-1) and a mitogen-inducible form (COX-2). Several studies have suggested that COX is activated in renal insufficiency, but little is known about the relationship between progression of renal insufficiency and the COX isoforms. METHODS: Five-sixths-nephrectomized (NX) rats were used. 4, 8, and 12 weeks after nephrectomy, the renal cortical prostaglandin contents and the expression levels of the two isoforms of COX were determined by enzyme immunoassay and Western-blotting, respectively. The localization of COX was examined by immunohistochemistry. RESULTS: Renal cortical prostacyclin (PGI2) and COX-2 were significantly upregulated 8 and 12 weeks after NX, while COX-1 remained at the basal level. There was a high correlation between COX-2 and creatinine clearance (r = -0.845). There was also a high correlation between COX-2 and PGI2 (r = 0.816). Immunohistochemistry revealed the expression of COX-2 to be enhanced in the macula densa in NX rats. CONCLUSIONS: Renal cortical COX-2 and prostacyclin were upregulated corresponding to the progression of renal insufficiency in NX rats. These results suggest enhancement of COX-2 expression in the macula densa, perhaps stimulated by a decrease in renal blood flow which upregulates PGI2 synthesis to protect the kidney from ischemia in renal insufficiency.
BACKGROUND: Hemodialysis patients who had been treated with anti-platelet aggregation drugs, including ticlopidine, sometimes developed hypotension. The mechanism by which ticlopidine lowers the blood pressure in hemodialysis patients is unclear. To elucidate the mechanism of the action of this drug, we investigated cytokine-stimulated nitric oxide (NO) metabolism by ticlopidine in cultured rat vascular smooth muscle cells (VSMC). METHODS: Nitrite, a stable metabolite of NO, and intracellular cAMP and cGMP contents were assayed by the Griess method and enzyme immunoassay, respectively. iNOS mRNA and protein expressions were analyzed by Northern blotting and Western blotting. RESULTS: Ticlopidine enhanced interleukin-1beta (IL-1beta)-induced nitrite production in a dose- and time-dependent manner. The mRNA and protein expressions of inducible NO synthase were upregulated by ticlopidine in a dose- and time-dependent manner. IL-1beta alone stimulated both intracellular cAMP and cGMP contents, and the addition of ticlopidine further enhanced their contents. KT 5720, a selective inhibitor of protein kinase A, but not KT 5823, a selective inhibitor of protein kinase G, abolished the enhancement of IL-1beta-induced nitrite production by ticlopidine. In addition, a phosphodiesterase inhibitor, isobutylmethylxanthine, enhanced IL-1beta and ticlopidine induced nitrite production. CONCLUSION: We concluded that ticlopidine enhanced the IL-1beta-induced NO production via cAMP and subsequent activation of protein kinase A in cultured rat VSMC.
Pancratistatin derivatives, 1-O-(3-hydroxybutyryl)pancratistatin (HBP) and 1-O-(3-O-beta-D-glucopyranosylbutyryl)pancratistatin (GBP), showed strong cytostatic activity against rat embryo fibroblast 3Y1 at concentrations less than 1 microM. When the effect on cell cycle progression was examined in 3Y1 fibroblasts arrested at G0/G1 phase by serum deprivation, HBP, GBP, and pancratistatin inhibited the progression of 3Y1 fibroblasts from G0/G1 to S phase. In addition, when the effect on cell cycle progression was studied in 3Y1 fibroblasts synchronized at late G1/early S phases by treating with hydroxyurea, HBP blocked further progression through S phase, while GBP and pancratistatin did not affect the progression, but retarded it. On the other hand, when the effect of HBP and GBP on the progression was evaluated in promyelocytic leukemia HL-60RG cells synchronized at G0/G1 phase, the cells did not progress into S phase and accumulated in sub G0/G1 phase, which indicated apoptotic cells. These findings suggest that of Amaryllidaceae alkaloids, HBP blocks the progression of cell cycle at least at G0/G1 and S phases and GBP does at least at G0/G1 phase, resulting in apoptosis induction in tumor cells.
Biological activities of five Veronica species (Scrophulariaceae), V. cymbalaria, V. hederifolia, V. pectinata var. glandulosa, V. persica and V. polita were studied for their anti-inflammatory and cytotoxic activities. Their methanol extracts showed both the inhibitory activity of nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated macrophages and cytotoxic activity against KB epidermoid carcinoma and B16 melanoma. When the methanol extracts were fractionated between water and chloroform, water fractions significantly inhibited NO production without any cytotoxicity, while chloroform fractions showed cytotoxicity dose-dependently. When the radical scavenging activity was determined using 2,2-diphenyl-1-picryl-hydrazyl (DPPH), water fractions of the five Veronica species scavenged free radicals effectively, suggesting that the inhibitory effect of this species on NO production was due to their radical scavenging activity. On the other hand, chloroform fractions of Veronica species except for V. cymbalaria showed similar cytotoxic activity against KB and B16 melanoma cells.
We examined the antimetastatic effect of acteoside, a phenylethanoid glycoside widely distributed in the plant kingdom, on lung metastasis using a mouse model injected with B16 melanoma cells intravenously. Male C57BL/6 mice were injected intravenously with 2 x 10(5) of B16 melanoma cells, while acteoside at a dose of 50 mg/kg was administered intraperitoneally every other day from 13 d before B16 melanoma cell injection until all mice had succumbed to the metastatic tumor burden in the lung. Administration of acteoside prolonged survival time significantly and the average survival time was 63.3 +/- 3.4d compared with 52.1 +/- 2.5d in control mice. This result suggests that acteoside showed suppressive effect on lung metastasis of B16 melanoma cells.
Shichimotsu-koka-to (SKT) is a Kampo (traditional Japanese herbal) medicine, which is used in Japan to treat hypertension and atherosclerosis. We investigated the inhibitory effect of SKT on experimental pulmonary metastasis of B16 melanoma cells. The intake of SKT at a dose of 430 mg/kg for 6 weeks from 2 weeks before tumor inoculation significantly reduced the number of metastatic surface nodules in the lung and extended the life span. When the duration of SKT intake was examined, survival time was not affected by preintake before B16 melanoma cell inoculation and was slightly extended by postintake after B16 melanoma cell inoculation, although the life span was prolonged by intake throughout the experiment. To address the mechanism underlying the antimetastatic effect of SKT, we studied whether SKT modulated macrophage function, which is involved in killing tumor cells. The intake of SKT for 6 weeks dose dependently increased nitric oxide (NO) production by macrophages following stimulation with lipopolysaccharide. The elevated NO was found to serve as a cytotoxic mediator against B16 melanoma cells in co-culture with macrophages. On the contrary, B16 melanoma-conditioned medium reduced NO production by macrophages. However, SKT treatment reversed the reduction in NO production by the conditioned medium significantly. These findings may suggest that macrophage function-modulating activity by SKT appears to underlie its antimetastatic activity, which leads to a decrease in the number of lung metastatic surface nodules and the extension of life span.
In the present study, B16 melanoma cells were found to produce inhibitory and cytotoxic substances with a molecular weight lower than 3000 Da against macrophages in a conditioned medium. The B16 melanoma-conditioned medium suppressed nitric oxide (NO) production only by mouse peritoneal macrophages and the mouse macrophage-like cell line, RAW264.7 cells, but not by rat peritoneal macrophages. In addition, it showed cytotoxicity against mouse peritoneal macrophages and mouse macrophage-like cell lines, RAW264.7 and J774A.1 cells, but not against rat cells (peritoneal macrophages, 3Y1, hepatocytes), human cells (HeLa, KB, MCF-7), or mouse 3T3-L1 cells. The inhibitory activity of NO production was not affected by trypsin treatment or arginine supplementation, but it was abolished by heat treatment at 95 degrees C for 3 min. On the other hand, the cytotoxicity was not influenced by these treatments. Inducible NO synthase induction following lipopolysaccharide stimulation was reduced by treatment of mouse peritoneal macrophages with B16 melanoma-conditioned medium. These results suggest that metastatic B16 melanoma cells produce two distinct substances: to suppress NO production by macrophages and to kill macrophages and macrophage-like cell lines. We propose that these activities may help metastatic B16 melanoma cells to escape a host immunosurveillance system and to metastasize to target organs.
A known phenylethanoid glycoside, ehrenoside (1), was isolated together with three new phenylethanoid glycosides, verpectoside A (2), B (3) and C (4) from the aerial parts of Veronica pectinata var. glandulosa. On the basis of spectral analysis (UV, FAB-MS, 1H-, 13C- and 2D-NMR), compounds 2-4 were determined to be 2-(3,4-dihydroxyphenyl)ethyl-O-alpha-L-arabinopyranosyl-(1-->2)-[alpha-L-rhamnopyranosyl-(1-->3)]-(4-O-trans-feruloyl)-beta-D-glucopyranoside, 2-(3,4-dihydroxyphenyl)ethyl-O-beta-D-glucopyranosyl-(1-->2)-[alpha-L-rhamnopyranosyl-(1-->3)]-(4-O-trans-caffeoyl)-beta-D-glucopyranoside and 2-(3,4-dihydroxyphenyl)ethyl-O-beta-D-glucopyranosyl-(1-->2)-[alpha-L-rhamnopyranosyl-(1-->3)]-(4-O-trans-feruloyl)-beta-D-glucopyranoside, respectively. Isolated phenylethanoid glycosides exhibited potent radical scavenging activity against the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical.
A new phenylethanoid glycoside, persicoside (1) and three known phenylethanoid glycosides, acteoside (2), isoacteoside (3) and lavandulifolioside (4) were isolated from the aerial parts of Veronica persica. On the basis of spectral analyses, the structure of the new compound was elucidated to be 3,4-dihydroxy-beta-phenylethoxy-O-[beta-D-glucopyranosyl-(1-->2)]-[beta-D-glucopyranosyl-(1-->3)]-4-O-caffeoyl-beta-D-glucopyranoside. Persicoside (1) and acteoside (2) exhibited radical scavenging activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical. Beside phenylethanoid glycosides, a hexitol, dulcitol (5) and seven known iridoid glucosides, aucubin (6), veronicoside (7), amphicoside (8), 6-O-veratroyl-catalpol (9), catalposide (10), verproside (11) and verminoside (12) were isolated.
The objective of the present study was to establish that HDL3 has a greater antiperoxidative effect on the peroxidative modification of LDL than HDL2 has. The protective influence of HDL subfractions on this form of LDL modification was examined in samples by measuring the concentration of thiobarbituric acid-reactive substance (TBARS), as well as the electrophoretic mobility of LDL. LDL was incubated for 96 hours in phosphate-buffered saline (PBS) alone, without the addition of transition-metal ions or in the presence of PBS and HDL2 or HDL3. All samples were subjected to agarose gel electrophoresis. Both HDL2 and HDL3 significantly inhibited peroxidative modification of LDL, as assessed by electrophoretic mobility, but this effect was much more pronounced with HDL3. HDL3 may play a more important role than HDL2 in the prevention of atherosclerosis in vivo by more effectively inhibiting LDL peroxidation.