Significance of vascular natriuretic peptide system in vascular remodeling in humans and its application to gene therapy.
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Animals↗
Biomedical subjects
K Doi
Publications and source records attributed to K Doi.
Down regulation of epidermal growth factor receptors in rat hepatocytes treated with clofibric acid.
The effect of clofibric acid (CA), a peroxisome proliferator and a non-genotoxic hepatocarcinogen was investigated on epidermal growth factor (EGF) receptors in hepatocytes of female Sprague-Dawley rats treated at a dose of 9000 ppm in a diet for up to 13 weeks. Hepatocyte plasma membranes were isolated in Weeks 1 and 13, and assayed with [125I]EGF. The binding of EGF to the hepatocyte plasma membranes was reduced in Week 1 as a result of decreased number of low-affinity receptors. The fall of binding capacity was further evident in Week 13, which was associated with decreased numbers of both high- and low-affinity receptors. The equilibrium dissociation constant remained unchanged either in Week 1 or 13. These results were in agreement with previous observations of a decreased hepatocyte response to mitogens after prolonged treatment with CA. This suggested that the CA-associated liver tumor promoting effect is related to its ability to decrease the number of EGF receptors and the resultant aberrant growth environment.
Administration, Oral↗
Enhanced vascularization in a microporous polyurethane graft impregnated with basic fibroblast growth factor and heparin.
Rapid and controlled neoarterial regeneration via perianastomotic as well as transmural tissue ingrowth is critical to patency of implanted small-caliber artificial vascular grafts. Microporous polyurethane (PU) grafts (inner diameter, 1.5 mm; wall thickness, 100 microns; length, 20 mm; pore size, 100 microns), fabricated using an excimer laser ablation technique, were coated with a mixed solution of photoreactive gelatin, basic fibroblast factor (bFGF), and heparin, and were photocured by ultraviolet irradiation. Control grafts were treated with only photoreactive gelatin. An in vitro study showed that coimmobilization of bFGF and heparin (bFGF/heparin) in a crosslinked gelatin gel significantly enhances proliferation of endothelial cells. The bFGF/heparin-impregnated grafts (n = 6) and nonimpregnated (control) grafts (n = 9) were implanted in aortas of rats for 4 weeks. All the implanted grafts were patent, but there was a marked difference in the extent of neoarterial regeneration between the two groups. Irrespective of group, endothelialization proceeded from anastomotic sites and little occurrence of transmural capillary ingrowth was observed. The extent of endothelialization was much greater for bFGF/heparin-immobilized grafts than that for controls. In subendothelial tissues for the impregnated group, a significantly profound peripheral transmural tissue ingrowth including recruits of smooth muscle cells and fibroblasts from adjacent native tissue was observed near anastomotic sites; subendothelial tissue regeneration was noticed at the midportions of the grafts. However, only a fibrin layer was formed on control grafts. Thus, coimmobilization of bFGF and heparin significantly accelerated neoarterial regeneration via both perianastomotic and transmural tissue ingrowth. The former was more extensive than the latter.
Animals↗
Aging-related changes in calcium oscillations in fertilized mouse oocytes.
Aging of oocytes, being not fertilized after ovulation for a prolonged time, considerably affects normal development of the fertilized oocyte. We examined effects of the aging on a series of highly repetitive Ca2+ transients commonly seen in fertilized mouse oocytes (Ca2+ oscillations). Frequency of Ca2+ oscillations in the aged oocyte [20 hrs after induction of superovulation by i.p. human chorionic gonadotropin (hCG)] was significantly higher (34.1 +/- 5.8 l/hr) than the fresh oocyte (14 hr post-hCG, 21.8 +/- 7.9 l/hr). Rates of rise and fall of individual Ca2+ transient in the aged oocyte were significantly slower than the fresh oocyte, whereas durations of individual Ca2+ transients were similar. When extracellular Ca2+ was raised from 2.04 mM to 5.00 mM, aged oocytes showed significant prolongation of the duration of individual Ca2+ transient, that resulted in a sustained elevation of intracellular Ca2+ ([Ca2+]i) in 33% of the aged oocyte. Transient increase in [Ca2+]i by photolysis of a caged Ca2+, Nitr-5, injected into cytoplasm was completely restored in the fresh oocyte [fluorescence intensity of [Ca2+]i indicator dye Fluo-3 (F480) returned to 97 +/- 2% of the control level, time constant = 37 +/- 9 sec]. In contrast, in the aged oocyte, restoration of F480 following Nitr-5 photolysis was incomplete (115 +/- 12% of the control) and slow (time constant = 64 +/- 23 sec). Because inhibition of the Ca2+ pump of the endoplasmic reticulum (ER) by 5 microM thapsigargin almost completely inhibited restoration of F480 following Nitr-5 photolysis in the fresh oocyte, we conclude that the aging-related changes in Ca2+ oscillations may be accounted for by dysfunction of intracellular Ca2+ regulation, presumably of the Ca2+ pump of the ER.
Aging↗
Oxygen transport to ischemic cardiac myocytes.
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Adenosine Triphosphate↗
Classification of normal and abnormal lungs with interstitial diseases by rule-based method and artificial neural networks.
We devised an automated classification scheme by using the rule-based method plus artificial neural networks (ANN) for distinction between normal and abnormal lungs with interstitial disease in digital chest radiographs. Four measures used in the classification scheme are determined from the texture and geometric-pattern feature analyses. The rms variation and the first moment of the power spectrum of lung patterns are determined as measures for the texture analysis. In addition, the total area of nodular opacities and the total length of linear opacities are determined as measures for the geometric-pattern feature analysis. In our classification scheme with these measures, we identify obviously normal and abnormal cases first by the rule-based method and then ANN is applied for the remaining difficult cases. The rule-based plus ANN method provided a sensitivity of 0.926 at the specificity of 0.900, which was considerably improved compared to performance of either the rule-based method alone or ANNs alone.
Diagnosis, Computer-Assisted↗
Deposition of amyloid beta protein (A beta) subtypes [A beta 40 and A beta 42(43)] in canine senile plaques and cerebral amyloid angiopathy.
To clarify the immunohistochemical features of canine senile plaques (SPs) and cerebral amyloid angiopathy (CAA), the distribution of the amyloid beta protein (A beta) subtypes A beta 40 and A beta 42(43), A beta precursor protein (APP), and glial cell reaction were examined in the brains of seven aged dogs (12-18 years). A beta 42(43) was found to be deposited in all types of SPs, whereas A beta 40 was deposited only in mature (classical and primitive) plaques. CAA, which was located along parenchymal and meningeal arterioles and capillaries, consisted of both subtypes of A beta. APP was exhibited in normal and degenerative neurons and swollen neurites of mature plaques. It was, therefore, considered that A beta 42(43) in diffuse plaques might be derived from APP in neurons, while A beta 40 and A beta 42(43) in mature plaques might be generated from APP in swollen neurites in the plaque. In contrast to the case in humans, in whom deposition of A beta 40 and A beta 42(43) in the mature plaques is predominantly associated with microglial reaction, in dogs we found that it was closely associated with astroglial reaction. The present findings showed characteristics of canine SPs which are different from those of humans.
Aging↗
One base change is sufficient for host range conversion of murine leukemia virus from B to NB tropism.
Comparison of the whole p30 (CA) sequence between B-tropic WN1802B murine leukemia virus and its NB-tropic derivative revealed a single base change at the 313th nucleotide. We constructed hybrid proviruses differing only at the 313th nucleotide of p30 along the whole genome, and examined the host range of the produced viruses. The single point mutation in p30 was found sufficient for the B to NB tropism conversion.
Animals↗
Decreased glucose effectiveness but not insulin resistance in glucose-tolerant offspring of Japanese non-insulin-dependent diabetic patients: a minimal-model analysis.
The aim of the study was to estimate insulin sensitivity (SI), insulin secretion, and glucose effectiveness (SG) in 10 subjects with normal glucose tolerance (eight men and two women) with a family history of non-insulin-dependent diabetes mellitus (NIDDM offspring). Ten glucose-tolerant subjects (eight men and two women) without a family history of NIDDM served as control subjects. All subjects were Japanese. They underwent a modified frequently sampled intravenous glucose tolerance test (FSIGT): glucose (300 mg/kg body weight) was administered, and insulin (20 mU/kg over 5 minutes) was infused from 20 to 25 minutes after glucose. SI and SG were estimated by Bergman's minimal-model method. No significant difference was observed in body mass index (22.6 +/- 1.5 v 21.5 +/- 0.6 kg/m2) and fasting glucose (5.1 +/- 0.1 v 5.2 +/- 0.1 mol/L) and insulin (40.7 +/- 6.3 v 42.6 +/- 6.7 pmol/L). SI was not different between the two groups (0.83 +/- 0.11 v 0.94 +/- 0.15 x 10(-1).min-1.pmol/ L-1, P > .05). The acute insulin response to glucose (AIRglucose) estimated by intravenous glucose tolerance testing was significantly lower in the offspring than in the normal controls (2,139 +/- 265 v 3,438 +/- 318 pmol/L.min, P < .05). The glucose disappearance rate (KG) and SG were significantly diminished in the offspring versus normal controls (KG, 1.50 +/- 0.22 v 2.10 +/- 0.15 min-1, P < .05; SG, 0.016 +/- 0.003 v 0.023 +/- 0.002 min-1, P < .05). Thus, glucose-tolerant Japanese NIDDM offspring with normal insulin sensitivity are characterized by a reduced AIRglucose and diminished SG. This is the first report that glucose resistance but not insulin resistance already exists in glucose-tolerant Japanese NIDDM offspring.
Blood Glucose↗
Intravenous glucose tolerance test-derived glucose effectiveness in bulimia nervosa.
The aim of the present study was to estimate insulin secretion, insulin sensitivity (SI), and glucose effectiveness at basal insulin (SG) in subjects with bulimia nervosa. Eight bulimic patients and eight age-, body mass index-, and sex-matched healthy control subjects without a family history of diabetes were studied. The subjects all had normal glucose tolerance. They underwent a modified frequently sampled intravenous glucose tolerance test; glucose (300 mg/kg body weight) was administered, and insulin (4 mU/kg body weight/min) was infused from 20 to 25 minutes after administration of glucose. SI and SG were estimated by Bergman's minimal model method. Basal insulin (27 +/- 3 v 45 +/- 3 pmol/L) was significantly lower in bulimic patients than in normal controls (P < .05), but basal glucose was similar between the two groups (4.5 +/- 0.1 v 4.9 +/- 0.1 mmol/L, P > .05). The glucose disappearance rate (KG) and acute insulin response to glucose estimated by the intravenous glucose tolerance test (AIR(glucose)) were similar between the two groups (KG, 1.35 +/- 0.29 v 2.20 +/- 0.21 min(-1), P > .05; AIR(glucose), 2,920 +/- 547 v 2,368 +/- 367 pmol/L x min, P > .05). No significant difference was observed in SI between the two groups (1.34 +/- 0.18 v 1.25 +/- 0.20 x 10(-4) x min(-1) x pmol/L(-1), P > .05). On the other hand, glucose effectiveness at basal (SG) and zero (GEZI) insulin was significantly diminished in comparison to normal controls (SG, 0.011 +/- 0.002 v 0.024 +/- 0.002 min(-1), P < .01; GEZI, 0.008 +/- 0.002 v 0.017 +/- 0.003 min(-1), P < .01). Thus, bulimic patients with normal glucose tolerance without a family history of diabetes were characterized by normal insulin secretion, normal SI, and reduced SG and GEZI.
Adult↗
5-Azacytidine induces toxicity in PC12 cells by apoptosis.
5-Azacytidine (5 Az)is a potent inhibitor of DNA methylation, and it may allow inactive genes to become expressed. In a previous study, we demonstrated that 5 Az administered to the dam induced apoptosis in the brains of fetal mice. In this study, the 5 Az-induced apoptosis was further characterized in differentiated PC 12 cells as a model for neuronal apoptosis. Cell death, determined by the activity of released lactate dehydrogenase (LDH) into the medium, occurred from 24 to 48 hrs after 5 Az treatment. Toxicity for differentiated PC 12 cells was observed on treatment with more than 10(-1) micrograms/ml of 5 Az, and it reached the maximal level at 10 micrograms/ml. Cycloheximide, an inhibitor of protein synthesis, prevented 5 Az toxicity, suggesting that this cell death required protein synthesis which could be related to the activation of a dormant gene(s). Electrophoresis of DNA from 5 Az-treated cells evoked ladder formation, indicating the cleavage of DNA into nucleosomes. Scanning electron microscopy demonstrated bleb formation, the so-called apoptotic bodies on the cell surface. The biochemical and morphological findings indicated that 5 Az-induced cell death occurred in the form of apoptosis. 5 Az-induced cell death was prevented by treatment with cAMP but not by treatment with high K+ or deoxycytidine. These results suggest that a cAMP-sensitive mechanism is involved in 5 Az-induced cell death. PC 12 cells should be of value in elucidating the molecular mechanism of 5 Az-induced neuronal apoptosis.
Animals↗
Effects of fructose-induced hypertriglyceridemia on hepatorenal toxicity of acetaminophen in rats: role of pharmacokinetics and metabolism of acetaminophen.
Fructose-induced hypertriglyceridemic rats become resistant to hepatotoxicity and susceptible to nephrotoxicity of acetaminophen (APAP), as compared with normal ones. The present study was designed to test the hypothesis that alterations in the distribution of APAP and in the intrinsic susceptibility to toxicants are responsible for the alteration in hepatorenal toxicity of APAP in fructose-induced hypertriglyceridemic rats. Following APAP-administration (750 mg/kg, i.p.), fructose-pretreated rats (25% fructose in drinking water for 5 weeks) showed nephrotoxicity of APAP more promptly and more severely than normal ones. Renal APAP-concentrations at the early phase (15 and 30 min. after APAP-administration) were significantly greater in fructose-pretreated rats than those in normal ones. Plasma and hepatic APAP concentrations in fructose-pretreated rats were greater than those in normal ones only at the later phase (plasma; 6 hr, liver; 6 and 12 hr after APAP-administration). There were no significant differences in the APAP-induced depletion of hepatic and renal glutathione and in the basal hepatic and renal cytochrome P-450 contents between these rats. Fructose-pretreated rats were also more susceptible to p-aminophenol (PAP), a nephrotoxic metabolite of APAP, than normal rats. Therefore, enhanced susceptibility to APAP-nephrotoxicity in fructose-pretreated rats may be due, at least in part, to increased renal APAP concentration and increased intrinsic susceptibility to the metabolic nephrotoxicant.
Acetaminophen↗
Histopathological study on bone changes induced by recombinant granulocyte colony-stimulating factor in rats.
Histopathological bone changes were examined in growing rats intravenously administered with high doses (100 and 1000 micrograms/kg/day) of recombinant human granulocyte colony-stimulating factor (rG-CSF) for 28 days. The changes were observed in the region where physiological bone resorption actively occurs in the growth phase, that is the trabeculae of metaphyseal spongy bone and the endosteum region of diaphyseal compact bone. Histologically, the changes involved accelerated osteoclastic bone resorption and osteogenesis due to intramembranous ossification. While osteoclastic bone resorption was observed in almost all lesions, about half of which were accompanied by osteogenesis. Bone changes which appeared after administration of rG-CSF were characterized by frequent occurrence at the site of highly osteoclastic activity and by initial osteoclastic resorption followed by osteogenesis due to intramembranous ossification. These results suggest that the main action of rG-CSF on bone may be an acceleration of osteoclastic bone resorption.
Animals↗
Morphologic changes in hepatocyte nuclei of streptozotocin (SZ)-induced diabetic mice.
Morphological examinations were carried out on hepatocyte nuclei of streptozotocin (SZ)-induced diabetic mice. The area of hepatocyte nuclei in diabetic mice was about two times larger than that in control mice, and the incidence of hepatocytes with intranuclear inclusions was 3.4 +/- 0.2% in diabetic mice and 0% in control mice, respectively. Although the incidence of binuclear hepatocytes was not significantly different between diabetic (14.5 +/- 4.6%) and control mice (16.4 +/- 4.4%), the morphology of the nuclei of binuclear hepatocytes was apparently different between diabetic and control mice. Namely, the nuclei of binuclear hepatocytes of control mice were round and identical in ultrastructural appearance, and they did not differ from those of mononuclear diploid hepatocytes. On the other hand, the nuclei of binuclear hepatocytes of diabetic mice were not identical in distribution pattern of chromatin granules, and they frequently varied in size and showed irregular contours.
Animals↗
Galactosamine-induced apoptosis in the primary mouse hepatocyte cultures.
Galactosamine (GalN)-induced apoptosis was investigated in cultured hepatocytes from mice. The percentage of fragmented DNA measured by the ELISA method increased in a concentration-dependent manner from the very early stage, i.e. 0.5 hrs, after GalN-exposure. In addition, a ladder-like fragmentation pattern by agarose gel electrophoresis appeared first at 3 hr-exposure to 20 mM GalN, at 6 hr-exposure to 10 mM GalN and at 12 hr-exposure to 5 mM GalN, respectively. On the other hand, cytotoxicity indicated by leakage of lactate dehydrogenase from cultured hepatocytes to culture medium was first detected at 24 hrs after GalN-treatment. Morphologically, formation of blebs and apoptotic bodies was observed from 12 hr-exposure to 20 mM GalN and from 24 hr-exposure to 10 mM GalN, respectively. Thus GalN could induce apoptosis in primary hepatocyte cultures from mice.
Animals↗
Effects of fructose-induced hypertriglyceridemia on hepatorenal toxicity of acetaminophen in rats. II. Role of enhancement of fructose metabolism and overproduction of triglyceride in the liver and kidney on hepatorenal toxicity of acetaminophen.
Fructose-induced hypertriglyceridemic rats are resistant to hepatoxicity and susceptible to nephrotoxicity of acetaminophen (APAP) as compared with normal ones. The present studied were designed to evaluate how fructose-treatment affects the developmental mode of hepatorenal toxicity of APAP. First, following fructose-pretreatment for various durations (1 day, 1 week or 3 weeks), 1-day-fructose-pretreatment induced hypertriglyceridemia and enhancement of APAP-nephrectoxicity simultaneously. However, it took at least 3 weeks for fructose-pretreatment to reduce APAP-hepatotoxicity. Second, following fructose, sucrose or glucose-pretreatment for 3 weeks, fructose-pretreated rats showed marked hypertriglyceridemia and modification of APAP-hepatorenal toxicity. Sucrose-pretreated rats showed less effects than fructose-pretreated rats. Glucose-pretreated rats showed no changes in plasma triglyceride and APAP-hepatorenal toxicity. Third, rats with hypertriglyceridemia induced by olive oil or Triton WR-1339 which did not produce enhanced metabolism and triglyceride-overproduction in the liver and kidney showed no modification of APAP-hepatorenal toxicity. Pretreatment of glycerol which was metabolized in liver and kidney and induced an overproduction of triglyceride resulted in an enhancement of APAP-nephrotoxicity. These results indicate that an enhancement of fructose metabolism and an overproduction of triglyceride in liver and kidney are responsible for the modification of APAP-hepatorenal toxicity in fructose-induced hypertriglyceridemic rats.
Acetaminophen↗
Enhanced nephrotoxicity of acetaminophen in fructose-induced hypertriglyceridemic rats: contribution of oxidation and deacetylation of acetaminophen to an enhancement of nephrotoxicity.
Fructose-induced hypertriglyceridemic Sprague-Dawley (SD) rats become resistant to hepatotoxicity and susceptible to nephrotoxicity of acetaminophen (APAP) as compared with normal SD rats. Fischer-344 rats, which are susceptible to APAP nephrotoxicity, have two toxic metabolic pathways involving cytochrome P450-dependent oxidation of APAP to N-acetyl-p-benzoquinone imine (NAPQI) and P450-independent deacetylation of APAP to p-aminophenol (PAP). SD rats, however, have only the former pathway. This study was undertaken to investigate whether alterations in the metabolic pathways of APAP and in the intrinsic susceptibility to toxic metabolites are responsible for an enhancement of APAP nephrotoxicity in the fructose-pretreated SD-rats. In the non-pretreated rats, the inhibition of APAP oxidation by the MFO inhibitor, piperonyl butoxide, and deacetylation by carboxyesterase inhibitor, bis(p-nitrophenyl)phosphate, did not alter APAP-induced renal lesions. In contrast, these inhibitors protected the fructose-pretreated rats from APAP-induced renal lesions. Since there were no differences in the severity of gentamicin-, chloroform, and 45 min-ischemia/reperfusion-induced renal lesions between the non-pretreated and the fructose-pretreated rats, it is unlikely that the increased intrinsic susceptibility to chemicals and their metabolites in the fructose-pretreated rats is a major factor in the enhancement of APAP nephrotoxicity. These results indicate that the enhancement of APAP nephrotoxicity in the fructose-pretreated rats is due, at least in part, to an alteration in metabolic pathways of APAP.
Acetaminophen↗
Enhanced nephrotoxicity of acetaminophen in fructose-induced hypertriglyceridemic rats: effect of partial hepatectomy.
Fructose-induced hypertriglyceridemic rats become resistant to hepatotoxicity and susceptible to nephrotoxicity of acetaminophen (APAP). Enhanced susceptibility to APAP nephrotoxicity in fructose-pretreated rats is due, at least in part, to increased renal APAP concentration at the early phase (15 and 30 min after APAP administration). However, the mechanism of an increase in renal APAP concentration is still obscure. The present study was designed to test the hypothesis that a decrease in capacity of hepatic APAP metabolism is responsible for an increase in renal APAP concentration in fructose-pretreated rats. Non-pretreated rats and fructose-pretreated rats (25% fructose in drinking water for 3 weeks) received 70% or 90% partial hepatectomy (PH) or sham operation at 1 hr before APAP administration (600 or 750 mg/kg, i.p.). PH did not potentiate APAP nephrotoxicity and renal APAP concentration, and fructose-pretreated rats showed server renal lesions and greater renal APAP concentration than non-pretreated rats irrespective of PH. The result indicates that an increase in renal APAP concentration in the fructose-pretreated rats has no relation to an alteration in hepatic metabolic capacity of APAP.
Acetaminophen↗