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Biomedical subjects

Daisuke Watanabe

Publications and source records attributed to Daisuke Watanabe.

At least 19 recordsLinked to original sources
PubMed2006

Decreased renal expressions of heat shock protein-72 and -25 are associated with renal dysfunction in biliary cirrhotic rats.

During the course of liver cirrhosis, severe renal complications frequently occur. However, the pathogenesis of renal dysfunction in liver cirrhosis has not been completely understood. In this study, we investigated the association between renal function and expressions of renal heat shock proteins (HSPs) in biliary cirrhotic rats. Following bile duct ligation (BDL), renal function and expressions of HSPs were compared in control and BDL cirrhotic rats. Serum BUN and creatinine levels were significantly higher in cirrhotic rats compared with control rats at 4 weeks post-BDL operation. Renal expressions of HSP72 and HSP25 were decreased with progression of liver cirrhosis in BDL rats by Western blotting. Immunohistochemistry revealed that expression of renal HSP72 was suppressed in tubular epithelial cells, and expression of renal HSP25 was suppressed not only in tubular epithelial cells but also in blood vessels in rats with liver cirrhosis. Renal expressions of HSP90 and HSP60 did not differ between control and BDL rats. Renal function was impaired in biliary cirrhotic rats with decreased expressions of renal HSP72 and HSP25. These findings suggest that decreased expressions of renal HSP72 and HSP25 may be a part of the pathogenesis of renal dysfunction in liver cirrhosis.

Journal Article↗
PubMed2006

Epimorphin expression and stellate cell status in mouse liver injury.

Epimorphin, a mesenchymal morphogenic protein expressed by hepatic stellate cells, is considered important to liver morphogenesis in both healthy and pathologic conditions. However, the stellate cell phenotype, quiescent versus activated, that expresses epimorphin is unknown. We studied the relationship between epimorphin expression and stellate cell status in carbon tetrachloride-induced acute and chronic injury to mouse liver and in mouse liver regeneration following 70% partial hepatectomy. Epimorphin-positive cells in sinusoids expressed desmin, indicating that they are stellate cells. Epimorphin-positive cells were more numerous and larger in pericentral than periportal sinusoids in normal liver. In early-phase acute liver injury and liver regeneration, epimorphin expression transiently decreased while alphaSMA-positive stellate cells increased. In the recovery phase of acute and chronic injury as well as the late phase of liver regeneration, epimorphin expression was strikingly enhanced while alphaSMA-positive stellate cells decreased. This expression pattern was seen in both Balb/c and C57BL6 mouse strains irrespective of their differences in response to the hepatotoxin. In conclusion, stellate cells express epimorphin in their quiescent state and in the recovery phase, respectively associated with maintenance and reconstruction of microscopic liver structure.

Journal Article↗
PubMed2006

Suramin prevents fulminant hepatic failure resulting in reduction of lethality through the suppression of NF-kappaB activity.

AIM: Suramin is a symmetrical polysulfonated naphthylamine derivative of urea. There have been few studies on the effect of suramin on cytokines. We examined the effects of suramin on production of inflammatory cytokines. METHODS: We made an acute liver injury model treated with d-galactosamine (GalN) and lipopolysaccharide (LPS). Plasma AST, ALT, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6 levels were measured. We compared with survival rate, histological found and NF-kappaB activity between with and without treatment of suramin. In macrophage like cell line, TNF-alpha and IL-6 production, TNF-alpha and IL-6 mRNA expression, and NF-kappaB activity was measured. RESULTS: The lethality of mice administered suramin with GalN/LPS was significantly decreased compared with that in mice without suramin. Changes of hepatic necrosis and apoptosis were slight in suramin-treated mice. Serum AST, ALT, TNF-alpha, IL-6 levels and NF-kappaB activity in the liver were significantly lower in mice administered suramin. In an in vitro model, suramin preincubation inhibited TNF-alpha and IL-6 production, TNF-alpha and IL-6 mRNA expression, and NF-kappaB activity. CONCLUSIONS: Suramin inhibits TNF-alpha and IL-6 production through the suppression of NF-kappaB activity from macrophages and shows therapeutic effects on acute liver damage.

Alanine Transaminase↗
PubMed2006

Transcatheter arterial embolization for the treatment of liver metastases in a patient with malignant pheochromocytoma.

A 63-year-old male patient was admitted for the treatment of malignant pheochromocytoma with multiple liver metastases. Plasma and urinary levels of catecholamines were elevated. Transcatheter arterial embolization (TAE) with concomitant administration of mitomycin C and gelatin sponge was performed for the treatment of liver metastases. Dose of alpha-1 blocker before TAE was increased to prevent hypertensive crisis during and after TAE. The hepatic metastatic lesion of CT findings was decreased after TAE. Although blood pressure showed a transient hypertension (180/100 mmHg) after every TAE, it returned rapidly to normal. The patient experienced transient abdominal pain, nausea, and loss of appetite after every TAE; however, those symptoms were readily controlled by conventional medications. Slight elevation of liver transaminases was recognized but returned to normal range within 3 weeks. No other major side effects were seen with TAE. While plasma and urinary level of catecholamines were unchanged, plasma chromogranin A (CgA) level was significantly decreased. These results suggest that TAE is a useful treatment for hepatic metastases. Plasma CgA level is a useful marker in the treatment of malignant pheochromocytoma.

Adrenal Gland Neoplasms↗
PubMed2006

EphrinA1 inhibits vascular endothelial growth factor-induced intracellular signaling and suppresses retinal neovascularization and blood-retinal barrier breakdown.

The Eph receptor/ephrin system is a recently discovered regulator of vascular development during embryogenesis. Activation of EphA2, one of the Eph receptors, reportedly suppresses cell proliferation and adhesion in a wide range of cell types, including vascular endothelial cells. Vascular endothelial growth factor (VEGF) plays a primary role in both pathological angiogenesis and abnormal vascular leakage in diabetic retinopathy. In the study described herein, we demonstrated that EphA2 stimulation by ephrinA1 in cultured bovine retinal endothelial cells inhibits VEGF-induced VEGFR2 receptor phosphorylation and its downstream signaling cascades, including PKC (protein kinase C)-ERK (extracellular signal-regulated kinase) 1/2 and Akt. This inhibition resulted in the reduction of VEGF-induced angiogenic cell activity, including migration, tube formation, and cellular proliferation. These inhibitory effects were further confirmed in animal models. Intraocular injection of ephrinA1 suppressed ischemic retinal neovascularization in a dose-dependent manner in a mouse model. At a dose of 125 ng/eye, the inhibition was 36.0 +/- 14.9% (P < 0.001). EphrinA1 also inhibited VEGF-induced retinal vascular permeability in a rat model by 46.0 +/- 10.0% (P < 0.05). These findings suggest a novel therapeutic potential for EphA2/ephrinA1 in the treatment of neovascularization and vasopermeability abnormalities in diabetic retinopathy.

Animals↗
PubMed2005

Genipin prevents fulminant hepatic failure resulting in reduction of lethality through the suppression of TNF-alpha production.

Genipin is a metabolite derived from the herbal medicine Inchinko-to. Little is known about the mechanism of genipin action on acute liver injury through inflammatory cytokines. We examined the effects of genipin on production of TNF-alpha in vivo and in vitro. Mice were given GalN/LPS with or without genipin treatment. All mice not given genipin died within 12h. But in mice given genipin, 8 of 15 mice survived for 24h after GalN/LPS administration. Histologically, hepatic necrosis and inflammatory cells infiltration were significantly slight in mice given genipin. Serum AST and ALT activity were significantly lower in mice given genipin. Serum and liver homogenate TNF-alpha levels were significantly lower in mice given genipin. However, in IL-6 and IL-1beta, there were no significant differences in mice given and not given genipin. TNF-alpha, NF-kappaB activation and TNF-alpha mRNA expression in a cultured mouse macrophage-like cell line J774.1 were significantly suppressed by genipin administration. In conclusion, the present findings suggest that genipin, a metabolite derived form the herbal medicine Inchinko-to improved acute liver dysfunction by suppressive effect of TNF-alpha production.

Journal Article↗
PubMed2005

Effects of pulmonary surfactant system on rifampicin release from rifampicin-loaded PLGA microspheres.

Pulmonary surfactants little affected the release ratio of rifampicin from rifampicin-loaded poly(lactide-co-glycolide) PLGA microspheres. The release ratio of rifampicin was depending on pH of pulmonary surfactant solution, showing that rifampicin-loaded PLGA microspheres have an ideal property to deliver rifampicin into alveolar macrophages inside of which Mycobacterium tuberculosis bacilli reside and to kill them. That is, little amount of rifampicin is released in alveolar lining liquid before the microspheres are phagocytosed by alveolar macrophages, then rifampicin is released in phagosome or cytoplasm, but little amount of rifampicin is released in lysosome of alveolar macrophages after the microspheres are internalized. Pulmonary surfactants also little affected the changes in molecular weight of residual PLGA during its hydrolytic degradation process. From the electrophoretic mobility measurements of PLGA microspheres, it was shown that pulmonary surfactants changed the surface charge density of PLGA microspheres by adsorbing on their surfaces.

Lactic Acid↗
PubMed2005

Erythropoietin as a retinal angiogenic factor in proliferative diabetic retinopathy.

BACKGROUND: Although vascular endothelial growth factor (VEGF) is a primary mediator of retinal angiogenesis, VEGF inhibition alone is insufficient to prevent retinal neovascularization. Hence, it is postulated that there are other potent ischemia-induced angiogenic factors. Erythropoietin possesses angiogenic activity, but its potential role in ocular angiogenesis is not established. METHODS: We measured both erythropoietin and VEGF levels in the vitreous fluid of 144 patients with the use of radioimmunoassay and enzyme-linked immunosorbent assay. Vitreous proliferative potential was measured according to the growth of retinal endothelial cells in vitro and with soluble erythropoietin receptor. In addition, a murine model of ischemia-induced retinal neovascularization was used to evaluate erythropoietin expression and regulation in vivo. RESULTS: The median vitreous erythropoietin level in 73 patients with proliferative diabetic retinopathy was significantly higher than that in 71 patients without diabetes (464.0 vs. 36.5 mIU per milliliter, P<0.001). The median VEGF level in patients with retinopathy was also significantly higher than that in patients without diabetes (345.0 vs. 3.9 pg per milliliter, P<0.001). Multivariate logistic-regression analyses indicated that erythropoietin and VEGF were independently associated with proliferative diabetic retinopathy and that erythropoietin was more strongly associated with the presence of proliferative diabetic retinopathy than was VEGF. Erythropoietin and VEGF gene-expression levels are up-regulated in the murine ischemic retina, and the blockade of erythropoietin inhibits retinal neovascularization in vivo and endothelial-cell proliferation in the vitreous of patients with diabetic retinopathy in vitro. CONCLUSIONS: Our data suggest that erythropoietin is a potent ischemia-induced angiogenic factor that acts independently of VEGF during retinal angiogenesis in proliferative diabetic retinopathy.

Animals↗
PubMed2005

De novo formation of left-right asymmetry by posterior tilt of nodal cilia.

In the developing mouse embryo, leftward fluid flow on the ventral side of the node determines left-right (L-R) asymmetry. However, the mechanism by which the rotational movement of node cilia can generate a unidirectional flow remains hypothetical. Here we have addressed this question by motion and morphological analyses of the node cilia and by fluid dynamic model experiments. We found that the cilia stand, not perpendicular to the node surface, but tilted posteriorly. We further confirmed that such posterior tilt can produce leftward flow in model experiments. These results strongly suggest that L-R asymmetry is not the descendant of pre-existing L-R asymmetry within each cell but is generated de novo by combining three sources of spatial information: antero-posterior and dorso-ventral axes, and the chirality of ciliary movement.

Animals↗
PubMed2005

Ion association dynamics in aqueous solutions of sulfate salts as studied by Raman band shape analysis.

A new perspective is shown on the interaction between the sulfate ion and its counter cation in aqueous solutions. We propose the dynamic exchange model of ion association instead of the conventional static equilibrium model. The concentration dependence of the Raman band shape of the totally symmetric (a(1)) SO stretch mode of the sulfate ion is investigated systematically for four sulfate ions, MgSO(4), (NH(4))(2)SO(4), K(2)SO(4), and Li(2)SO(4). The concentration dependence of the a(1) Raman band shape in the MgSO(4) system is successfully reproduced by the analysis based on the dynamic exchange model. As a result, quantitative information about the extremely dynamic nature of the ion association has been obtained: the mean time between associations is a few picoseconds and the mean lifetime of association is several hundred femtoseconds.

Journal Article↗
PubMed2005

Angiopoietin-1 attenuates H2O2-induced SEK1/JNK phosphorylation through the phosphatidylinositol 3-kinase/Akt pathway in vascular endothelial cells.

Oxidative stress activates various signal transduction pathways, including Jun N-terminal kinase (JNK) and its substrates, that induce apoptosis. We reported here the role of angiopoietin-1 (Ang1), which is a prosurvival factor in endothelial cells, during endothelial cell damage induced by oxidative stress. Hydrogen peroxide (H2O2) increased apoptosis of endothelial cells through JNK activation, whereas Ang1 inhibited H2O2-induced apoptosis and concomitant JNK phosphorylation. The inhibition of H2O2-induced JNK phosphorylation was reversed by inhibitors of phosphatidylinositol (PI) 3-kinase and dominant-negative Akt, and constitutively active-Akt attenuated JNK phosphorylation without Ang1. These data suggested that Ang1-dependent Akt phosphorylation through PI 3-kinase leads to the inhibition of JNK phosphorylation. H2O2-induced phosphorylation of SAPK/Erk kinase (SEK1) at Thr261, which is an upstream regulator of JNK, was also attenuated by Ang1-dependent activation of the PI 3-kinase/Akt pathway. In addition, Ang1 induced SEK1 phosphorylation at Ser80, suggesting the existence of an additional signal transduction pathway through which Ang1 attenuates JNK phosphorylation. These results demonstrated that Ang1 attenuates H2O2-induced SEK1/JNK phosphorylation through the PI 3-kinase/Akt pathway and inhibits the apoptosis of endothelial cells to oxidative stress.

Angiopoietin-1↗
PubMed2005

Gabexate mesilate, a synthetic protease inhibitor, attenuates carbon tetrachloride-induced liver injury in rats.

BACKGROUND: Gabexate mesilate, a synthetic protease inhibitor, is used to treat acute pancreatitis and disseminated intravascular coagulation because it inhibits various serine proteases; however, whether gabexate mesilate prevents acute liver failure has not yet been studied. The aim of the present study was to investigate the effect of gabexate mesilate in carbon tetrachloride (CCl4)-induced liver injury in rats. METHODS: Acute hepatic failure was induced by administration of CCl4 intragastrically to male Sprague-Dawley rats. The effects of gabexate mesilate were examined in terms of serum transaminase levels, liver histology, and the prognosis of rats. RESULTS: Gabexate mesilate treatment significantly decreased the elevation of serum transaminase levels and improved liver histology 24 h after the administration of CCl4 (0.2 ml/100 g rat weight). Plasma tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) decreased significantly in the gabexate mesilate-treated rats compared with saline-treated rats. Gabexate mesilate treatment also significantly improved survival rate after a lethal dose of CCl4 (0.5 ml/100 g rat weight) from 0% to 20%. CONCLUSIONS: Gabexate mesilate treatment attenuated CCl4-induced liver injury via a suppression of proinflammatory cytokine production. In addition, these investigations suggest that gabexate mesilate treatment may provide therapeutic strategies for human acute liver failure.

Animals↗
PubMed2005

Vitreous levels of angiopoietin 2 and vascular endothelial growth factor in patients with proliferative diabetic retinopathy.

PURPOSE: To investigate the levels of angiopoietin-2 (Ang2) and vascular endothelial growth factor (VEGF) in the vitreous fluids of patients with proliferative diabetic retinopathy (PDR) and to ascertain their involvement, if any, in angiogenesis of PDR. DESIGN: Retrospective case-control study. METHODS: Forty-one eyes of 41 patients with proliferative diabetic retinopathy and 18 eyes of 18 patients with nondiabetic ocular diseases (control group). Nondiabetic control eyes included 11 with idiopathic macular hole and 7 with idiopathic epiretinal membrane. Vitreous fluid samples were obtained at vitrectomy, and the levels of Ang2 and VEGF were measured by enzyme-linked immunosorbent assay. RESULTS: Vitreous level (mean +/- SD) of Ang2 was significantly higher in patients with PDR (1,753 +/- 3,213 pg/ml) than in control patients (112 +/- 113 pg/ml) (P < .0001). The vitreous concentration of VEGF was also significantly higher in patients with PDR (812 +/- 1,108 pg/ml) than in control patients (1.7 +/- 4.4 pg/ml) (P < .0001). Both Ang2 and VEGF levels in eyes with active PDR were significantly higher than in those with inactive PDR. The vitreous concentration of Ang2 correlated significantly with that of VEGF in eyes with proliferative diabetic retinopathy ([correlation coefficient] rho = 0.497, P = .001). CONCLUSIONS: These data demonstrate an increase of Ang2 in the vitreous fluid of patients with PDR and suggest an association of Ang2 and VEGF with angiogenic activity in PDR.

Angiopoietin-2↗
PubMed2005

Efficacy of surgical removal of the internal limiting membrane in diabetic cystoid macular edema.

PURPOSE: To evaluate the efficacy of surgical removal of the internal limiting membrane (ILM) in diabetic cystoid macular edema (CME). METHODS: Prospective, noncomparative, interventional case series including 21 eyes of 18 consecutive patients with diabetic CME. Vitrectomy with separation of the posterior hyaloid and induction of posterior vitreous detachment had been performed previously on nine eyes. Pars plana vitrectomy for removal of the ILM was performed. RESULTS: CME resolved in eyes that underwent initial vitrectomy and in those with long-standing (>1 year) CME after previous vitrectomy. Postoperative best-corrected visual acuity improved by >/=2 lines of a Snellen equivalent in 14 eyes (67%) (P < 0.01). The mean foveal thickness (distance between the inner retinal surface and the retinal pigment epithelium) decreased from 553 microm to 221 microm at 4 weeks (P < 0.001). No recurrences or deterioration of CME was observed during the entire follow-up period (mean, 17.8 months; range, 8-34 months). CONCLUSION: Surgical removal of the ILM might be an effective procedure for reducing CME in patients with diabetes. A prospective, randomized, controlled study is necessary to further evaluate the efficacy of the procedure.

Adult↗