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A Fujimura

Publications and source records attributed to A Fujimura.

At least 19 recordsLinked to original sources
PubMed2006

Indoxyl sulfate stimulates proliferation of rat vascular smooth muscle cells.

Vascular smooth muscle cell (VSMC) proliferation is a key event in the progression of arteriosclerosis. Clinical studies show that uremic toxins deteriorate the arteriosclerosis in renal failure patients. Indoxyl sulfate (IS) is a strong protein-bound uremic toxin, but the effect of IS on VSMC proliferation has not been studied. We examined the effect of IS on rat VSMC proliferation, assessed by a cell counting kit (4-[3-[4-lodophenyl]-2-4(4-nitrophenyl)-2H-5-tetrazolio-1,3-benzene disulfonate] assay) and by [(3)H]thymidine incorporation in vitro. We further evaluated a contribution of mitogen-activated protein kinase (MAPK; p44/42 MAPK) to VSMC proliferation by IS. Immunohistochemical staining was performed for VSMCs using antirat organic anion transporter (OAT)3 antibody. The mRNA expressions of platelet-derived growth factor (PDGF)-A and -C chains, and PDGF-beta receptor were evaluated by real-time PCR. IS stimulated the proliferation of VSMCs in a concentration-dependent manner and activated p44/42 MAPK. Concentration of IS needed to stimulate the proliferation of rat VSMC was about 250 microM, which is compatible with that in the serum of end-stage renal failure patients. PD98059 (10 microM), a selective inhibitor of MAPK/extracellular signal-regulated kinase, inhibited the IS-induced (250 microM) VSMC proliferation and phosphorylation of MAPK. Probenecid (0.5 mM), an inhibitor and substrate of OAT, inhibited the IS-induced (250 microM) VSMC proliferation. Rat OAT3 was detected in VSMCs. The mRNA expressions of PDGF-C chain and PDGF-beta receptor were significantly increased by IS. We conclude that IS directly stimulates rat VSMC proliferation and activates MAPK in vitro. This might be one of the mechanisms underlying the progression of atherosclerotic lesions in end-stage renal disease patients.

Animals↗
PubMed2003

DNA microarray analysis of hematopoietic stem cell-like fractions from individuals with the M2 subtype of acute myeloid leukemia.

Acute myeloid leukemia (AML) may develop de novo or secondarily to myelodysplastic syndrome (MDS). Although the clinical outcome of MDS-related AML is worse than that of de novo AML, it is not easy to differentiate between these two clinical courses without a record of prior MDS. Large-scale profiling of gene expression by DNA microarray analysis is a promising approach with which to identify molecular markers specific to de novo or MDS-related AML. This approach has now been adopted with AC133-positive hematopoietic stem cell-like fractions purified from 10 individuals, each with either de novo or MDS-related AML of the M2 subtype. Sets of genes whose activity was associated with either disease course were identified. Furthermore, on the basis of the expression profiles of these genes, it was possible to predict correctly the clinical diagnosis for 17 (85%) of the 20 cases in a cross-validation trial. Similarly, different sets of genes were identified whose expression level was associated with clinical outcome after induction chemotherapy. These data suggest that, at least in terms of gene expression profiles, de novo AML and MDS-related AML are distinct clinical entities.

Antigens, CD↗
PubMed2003

Three dimensional architecture of lymphatic vessels in the tongue.

We have three-dimensionally reconstructed the lymphatic architecture of the rabbit tongue using a computer graphic three-dimensional reconstruction method together with histochemically stained serial cryo-sections. Three collecting lymphatic vessels lying in an anteroposterior orientation were identified in the tongue body. A superior longitudinal muscle accompanying collecting lymphatic (SLCL) that lies in the border between superior longitudinal muscle and transverse muscle was identified in this study, in addition to collecting lymphatics in the lingual septum (LSCL) and deep lingual artery accompanying collecting lymphatics (DLCL) that we reported previously. The vertical muscle accompanying collecting lymphatics (VCL) and the transverse muscle accompanying collecting lymphatics (TCL) were also identified as collecting lymphatics that joined the above three collecting lymphatics. Specific regional lymph flow was identified for each collecting lymphatic. A transverse right/left cross flow was identified for the LSCL, while the SLCL served the upper 1/3 of the tongue and the DLCL served the lower 2/3 of the tongue. Each collecting lymphatic that accompanied the internal lingual muscles joined to the SLCL, DLCL and LSCL, and were derived from blind-ended lymphatic capillaries that ran in the endomysium. Internal lingual muscle accompanying collecting lymphatics joined each other in the endomysium, and their blind-ended lymphatic capillaries had no branches.

Animals↗
PubMed2003

Three-dimensional changes in lymphatic architecture around VX2 tongue cancer--dynamics of growth of cancer.

Many questions remain regarding the mechanism of cervical lymph node metastasis via lymphatic vessels. We report here the three-dimensional dynamics of the lymphatic architecture around tumor during growth of implanted VX2 tongue cancer. The tongue and the deep cervical lymph nodes of rabbits were observed at 3, 7 and 10 days after transplantation of VX2 cancer cells (n = 5 in each group). Lymph node metastasis was confirmed histopathologically. Morphological changes of the collecting lymphatic vessels and lymphatic capillaries were observed, and the number and diameter of these lymphatic vessels were measured within 500 microns around the tumor using the combined method of 5'-nucleotidase (5'-Nase) staining and three-dimensional reconstruction imaging. The VX2 cells were uniformly detected in cervical lymph nodes of each rabbit of the 10-day group. The number of lymphatic capillaries and the diameters of collecting lymphatic vessels around the tumor in the 7- and 10-day groups were greater than in the 3-day group. These capillaries arose by sprouting from preexisting lymphatic vessels and showed a tree-like branching pattern. We conclude that the dynamics of the lymphatic architecture around the tumor, especially the increase in number of capillaries on preexisting lymphatic vessels outside the tumor margin, may be associated with lymph node metastasis.

Animals↗
PubMed2003

Three-dimensional changes in lymphatic architecture around VX2 tongue cancer--dynamic changes after administration of antiangiogenic agent.

We examined the three-dimensional changes of the lymphatic architecture in the rabbit VX2 tongue cancer model after administration of an antiangiogenic agent, TNP-470. TNP-470 at 30 mg/kg was administered via the auricular vein to the rabbit four times every other day from 3 days after transplantation of the tumor. The tongue and both sides of deep cervical lymph nodes of rabbit were observed at 10 days after transplantation. Lymph node metastasis was confirmed histopathologically. Morphological changes of collecting lymphatic vessels and lymphatic capillaries were observed, and the number and diameter of lymphatic vessels within 500 microm around the tumor were measured using the combined method with 5'-nucleotidase staining and three-dimensional reconstruction imaging. Tumor growth and lymph node metastasis were suppressed by administration of TNP-470. In the TNP-treatment group, the mean number of lymphatic capillaries was significantly fewer than in the control group. The mean diameter of collecting lymphatic vessels was significantly smaller than in the control group. In conclusion, our results suggest that cancer cell invasion into the lymphatics is probably decreased by inhibiting not only the growth of tumor but also new formation of lymphatic capillaries around the tumor by administration of TNP-470.

Angiogenesis Inhibitors↗
PubMed2001

Chronotherapy with active vitamin D3 in aged stroke-prone spontaneously hypertensive rats, a model of osteoporosis.

The chronotherapeutic effects of 1-alpha-(OH) vitamin D3, a pro-drug of 1,25(OH)2 vitamin D3 (1,25(OH)2D3), were evaluated by repeated dosing of the drug in aged stroke-prone spontaneously hypertensive male rats, a model of osteoporosis. Animals (7 months old) were kept in rooms with a 12-h light/dark cycle. Drug (0.5 microg/kg) or vehicle was given once daily at 2 or 14 h after lights on for 3 months. The severity of adverse effects such as body weight loss, hypercalcemia and hyperphosphatemia was significantly less when the drug was given at 14 h after lights on (14 HALO). Serum 1,25(OH)2 vitamin D3 concentrations of 2 h after lights on (2 HALO) group and 14 HALO group did not differ significantly after dosing. The decrease in parathyroid hormone (PTH) level 12 weeks after the start of the study was greater in the 14 HALO group than in the 2 HALO group. Urinary excretion of inorganic Ca and P in the 2 HALO group was greater than that in the 14 HALO group. Urinary excretion of deoxypyridiniline, an index of the bone resorption capacity of osteoclasts, was much suppressed in the 14 HALO group, suggesting that the efficacy of vitamin D3 for suppressing bone resorption might vary with the dosing time. The increase in bone density of both femurs, determined by dual-energy X-ray absorption at the end of the study, was greater in the 14 HALO group than in the 2 HALO group. This is the first study to show the dosing time-dependent efficacy and toxicity of active vitamin D3 in an animal model of osteoporosis. These results indicate that a chronopharmacological approach is beneficial for establishing a more effective and/or safer regimen of active vitamin D3 for the treatment of osteoporosis.

Aging↗
PubMed2001

Different potentiating effects of imidapril and enalapril on kaolin-induced writhing reaction in mice.

Effects of the angiotensin-converting enzyme (ACE) inhibitors, imidapril and enalapril, on kaolin-induced writhing reaction, which is believed to be caused by bradykinin (BK), were examined in mice. The number of writhes was increased significantly by 200 microg/kg of imidapril and by 100 and 200 microg/kg of enalapril. The intensity of writhing reaction was significantly suppressed by 1,000 nmol/kg of icatibant, a selective bradykinin B2 receptor antagonist, in the imidapril-, but not in the enalapril-treated groups. These results suggest that the potentiating effect of enalapril on kaolin-induced writhing reaction is greater than that of imidapril. This might depend on the difference of their inhibitory effects on BK degradation.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

Preventive effect of platelet-activating factor antagonist, Y-24180, against cyclosporine-induced acute nephrotoxicity.

To evaluate the effect of Y-24180, a potent and long-acting antagonist to platelet-activating factor (PAF) receptors, on cyclosporine A (CsA)-induced acute renal failure, the influence of its pretreatment on the CsA-induced alterations in renal hemodynamics was examined in male Wistar rats under anesthesia. CsA decreased the clearances of inulin and p-aminohippuric acid (PAH) in a dose-dependent manner. Y-24180 (3 mg/kg, i.v.) tended to attenuate the CsA-induced reduction in inulin clearance. Y-24180 (0.3 and 3 mg/kg) significantly prevented the reductions in PAH clearance and the increase in calculated renal vascular resistance (RVR) in a dose-dependent manner. Serum endothelin-1 (Et) concentration in the CsA-treated group was higher than that in the vehicle-treated group. Y-24180 did not influence such the elevated Et concentration. Serum thromboxane B2 (TxB2) concentration did not increase by treatment with CsA. A significant correlation was observed between RVR and Et, but not TxB2 concentration. The present study showed that a PAF receptor antagonist, Y-24180, has the preventive effect against CsA-induced acute renal failure, which indicates that PAF may partly be involved in the mechanism of renal vasoconstriction induced by CsA. The present findings also support the idea that Et contributes to the CsA-induced acute nephrotoxicity.

Animals↗
PubMed2001

Simplified method of heterotopic rat heart transplantation using the cuff technique: application to sublethal dose protocol of methotrexate on allograft survival.

Rodent heterotopic heart transplantation (HHT) models have been developed for the study of transplantation immunology. Most of these transplantations are performed by hand-suture techniques, requiring several months of training. We describe a modified technique of rat HHT in the neck, using a cuff method that can be mastered by beginners within a few weeks. Our main modification of the rat HHT in the neck is that the right superior vena cava of the graft is chosen as an outflow duct, while the pulmonary artery has been taken as an effluent drainage in the ordinary HHT models. The aorta of the donor is anastomosed with the carotid artery of the recipient. Donation can be completed within 5 min and vascular connections in the recipient done within 3 min, resulting in a minimum of ischemia time. Using this minimum surgical intervention model, we tested the immunosuppressive effect of a sublethal dose of methotrexate (MTX), which has been widely used in cancer therapy. Our results showed that high doses of MTX severely suppressed the recipient bone marrow, but prolonged heart allografts for more than 365 days after HHT. In conclusion, the new model simplified the rat HHT procedure and made it possible for the beginner of rodent transplantation to master this skill within a few weeks. Using this minimized intervention technique, we found that the high doses of MTX can significantly prolong the survival of fully mismatched DA heart graft in PVG/c recipient.

Animals↗
PubMed2001

Improvement of macromolecular clearance via lymph flow in hamster gingiva by low-power carbon dioxide laser-irradiation.

BACKGROUND AND OBJECTIVE: Although therapeutic effects of low-power laser-irradiation on periodontal disease have been reported, little is known about the biological effects of laser-irradiation in the gingiva. Recently we reported that topical warming stimulated macromolecular clearance via lymph flow in hamster gingiva. This study was conducted to investigate whether low-power laser-irradiation affects macromolecular clearance via the lymph flow in the gingiva. STUDY DESIGN/MATERIALS AND METHODS: We injected 14C-methylated albumin into the mandibular gingiva of anesthetized hamsters followed by topical carbon dioxide (CO2) laser-irradiation (30 seconds, 0.5-1.5 W). We measured the clearance of radiolabeled albumin from the gingiva and its drainage into submandibular lymph nodes during 10 minutes. RESULTS: The clearance of the radiolabeled albumin from the gingiva and the influx into the submandibular lymph nodes were increased by CO2 laser-irradiation. CONCLUSION: Low-power CO2 laser-irradiation improves macromolecular clearance via the lymph flow in hamster gingiva.

Albumins↗
PubMed2001

Protein kinase C and phosphatidylinositol 3-kinase independently contribute to P-glycoprotein-mediated drug secretion in the mouse proximal tubule.

We have recently reported that the apical membrane of the proximal tubule S2 segment from wild-type mice (WT mice) has the capacity for P-glycoprotein- (P-gp-) mediated drug efflux, whereas mice in which both mdr1a and mdr1b genes are disrupted (KO mice) do not. To examine the intracellular regulatory mechanisms of drug-transporting P-gp activity, we isolated and perfused proximal tubule S2 segments from WT and KO mice, and measured luminal efflux of the intracellular fluorescence of rhodamine 123, a fluorescent substrate of P-gp. The decay half-time of the intracellular fluorescence (t1/2) was regarded as an index of the drug-transporting P-gp activity. In the WT mice, the t1/2 was 36+/-5 s (n=35) during the basal period, and was significantly increased to 440+/-45 s by the luminal addition of verapamil (an inhibitor of P-gp). The addition of phorbol 12-myristate 13-acetate (PMA) [a protein kinase C (PKC) activator] to the bath increased t1/2, but 4alpha-phorbol (the inactive form of PMA) did not. The PMA-induced increase in t1/2 was further increased by the luminal addition of verapamil, and was partially inhibited by co-treatment with staurosporine or H-7 (inhibitors of PKC). Pretreatment with wortmannin or LY294002 [inhibitors of phosphatidylinositol 3-kinase (PI 3-kinase)] added to the bath also increased t1/2. The wortmannin- and LY294002-induced increase in t1/2 was also further increased by the luminal addition of verapamil. The effects of PMA on t1/2 were additive after cotreatment with wortmannin or LY294002. In the KO mice, t1/2 was 440+/-25 s (n=18) during the basal period, and was no longer affected by the addition of verapamil, staurosporine, H-7, wortmannin, or LY294002. Based on the use of pharmacological agents, we conclude that in the proximal tubule from WT mice, P-gp-mediated drug secretion occurs independently via PKC- and PI 3-kinase-dependent processes, whereas it is not present in KO mice, independently of PKC- and PI 3-kinase.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2001

Enhanced neutrophil superoxide anion production and its modification by beraprost sodium in spontaneously hypertensive rats.

To clarify the function of polymorphonuclear leukocytes (PMN) in spontaneously hypertensive rats (SHR) and the effect of beraprost sodium (BS) on these functions, we examined superoxide anion (O2-) production and adherent activity by PMN, as well as modification of these functions by BS ex vivo and in vitro. In study 1, we measured PMN functions in 4-week-old SHR and Wistar-Kyoto (WKY) rats. In study 2 (ex vivo), 14-week-old SHR received vehicle (n = 6) and BS (30 microg/kg/day [n = 6] and 100 microg/kg/day [n = 7]) once daily for 4 weeks. In study 3 (in vitro), PMN from 18-week-old SHR were incubated with BS (0.1 and 1 micromol/L) and theophylline (200 micromol/L), which is reported to inhibit the PMN O2- production. Systolic blood pressure, platelet counts, and PMN O2- production stimulated by phorbol ester myristate acetate were significantly elevated in 4-week-old SHR compared with WKY (P < .05). Beraprost sodium decreased the ex vivo PMN O2- production, serum superoxide dismutase activity, and platelet counts (P < .05); however, BS did not reduce the in vitro PMN O2- production. These data support our hypothesis that the enhanced PMN function contributes to the cardiovascular damages during the early phase of SHR, and that BS has merit for preventing the O2- related organ damages in this model.

Animals↗
PubMed2001

Gender- or age-related binding characteristics of valproic acid to serum proteins in adult patients with epilepsy.

The aim of the present study was to determine the gender- or age-related binding characteristics of valproic acid (VPA) to serum proteins in the adult population. Serum samples examined in the study were obtained from 70 adult patients (36 males, 34 females) with epilepsy on VPA monotherapy. Their age ranged from 16 to 68 years (mean age with (SD), 37.7 (15.7) years; <45 years, n=44; >/=45 years, n=26). The in vivo population binding parameters of VPA to serum proteins and theoretical minimal unbound serum VPA fraction (Fu) were determined using an equation derived from the Scatchard equation in: (1), all; (2), male and female subgroups; and (3), younger (<45 years) and older (>/=45 years) subgroups. There was a significant difference in serum concentration of unbound VPA between male and female patients. The mean association constant (K) was 0.010 microM(-1) in all, male, and female patients. The mean total concentration of binding sites (n(Pt)) was 1453 microM for all patients, and 1561 and 1394 microM for male and female patients, respectively. The Fu was 0.064 for all patients, and 0.060 and 0.067 for male and female patients, respectively. There were no significant differences in the binding characteristics of VPA to serum proteins between the male and female groups. On the other hand, there were significant differences in the serum albumin concentration and molar concentration ratio of free fatty acids to albumin in serum between the younger and older patients. The mean value of K was 0.016 microM(-1) for the younger patients and 0.007 microM (-1) for the older patients. The mean n(Pt) was 1157 microM for the younger patients and 1703 microM for the older patients. The Fu was 0.051 for the younger patients and 0.077 for the older patients. Thus, significant differences were observed in the binding characteristics of VPA to serum proteins between the younger and older groups. Our results show that age, but not gender, has significant influences on the binding characteristics of VPA to serum proteins in our patient population.

Adolescent↗
PubMed2001

Diurnal variation in the biliary excretion of flomoxef in patients with percutaneous transhepatic biliary drainage.

AIMS: To examine diurnal variation in biliary excretion of flomoxef. METHODS: Flomoxef (1 g) was injected intravenously in eight patients with percutaneous transhepatic cholangiography with drainage at 09.00 h and 21.00 h by a cross-over design with a 36 h washout period. Drained biliary fluid was collected for 6 h after each dosing. These patients still had mild to moderate hepatic dysfunction. RESULTS: Bile flow and bile acid excretion for 6 h after dosing did not differ significantly between the 09.00 h and 21.00 h treatments. The maximum concentration of biliary flomoxef was significantly greater and its total excretion for 6 h tended to be greater after the 21.00 h dose [maximum concentration (microg ml(-1)): 34.2 +/- 29.9 (09.00 h dose) vs 43.5 +/- 28.3 (21.00 h dose) (95% confidence interval for difference: 2.6 approximately 15.9, P = 0.013); total excretion (mg 6 h(-1)): 1.4 +/- 1.3 (09.00 h dose) vs 1.6 +/- 1.2 (21.00 h dose) (95% confidence interval for difference: -26.8, 313.7, P = 0.087)]. The period that biliary flomoxef remained above the minimal inhibitory concentration did not differ significantly between the two treatment times. CONCLUSIONS: These results suggest that biliary excretion of flomoxef shows diurnal variation. However, as the difference was relatively small, flomoxef could be given at any time of day without any dosage adjustments.

Bile↗
PubMed2001

Effect of bile acids on absorption of nitrendipine in healthy subjects.

AIMS: To examine whether bile acids such as ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) can influence the absorption of nitrendipine, a highly lipophilic calcium channel blocker. METHODS: Six healthy subjects received nitrendipine (10 mg) with and without UDCA (50 mg) and CDCA (200 and 600 mg) with an interval of 1 approximately 2 weeks between study phases. RESULTS: Bile acids decreased the Cmax (ng ml(-1)) [control 10.9 +/- 5.8 (mean+/- s.d.), UDCA 5.0 +/- 4.7 (95% confidence interval for difference; 3.9, 7.8, P = 0.0006), CDCA (600 mg) 5.0 +/- 3.9 (2.6, 9.2, P = 0.0059)] and AUC (ng ml(-1) h) [(control; 60 +/- 36, UDCA 15 +/- 13 (20, 73, P = 0.0064), CDCA (600 mg) 19 +/- 19 (21, 63, P = 0.0038)] of nitrendipine, while elimination half-life remained unchanged. CONCLUSIONS: These results suggest that the amount of nitrendipine absorbed was decreased when the drug was administered with UDCA and CDCA.

Adult↗