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Biomedical subjects

Y Shigeta

Publications and source records attributed to Y Shigeta.

At least 55 records · Page 3Linked to original sources
PubMed1995

Effects of an HMG-CoA reductase inhibitor, pravastatin, and bile sequestering resin, cholestyramine, on plasma plant sterol levels in hypercholesterolemic subjects.

To study exogenous sterol metabolism during the suppression or stimulation of cholesterol biosynthesis induced by treatments for hyperlipidemia, we determined plasma plant sterol concentrations before and after administration of an HMG-CoA reductase inhibitor, pravastatin, and compared these with changes in these plasma sterol levels by the bile-sequestrating resin, cholestyramine. The effects of the drugs were also studied in a sitosterolemic patient who has had increased plasma levels of plant sterols. Plasma cholesterol levels determined by the HPLC method were decreased significantly after administration of pravastatin. Plasma plant sterol (sitosterol and campesterol) as well as cholestanol concentrations were also significantly reduced. Cholestyramine administration decreased plasma levels of cholesterol, but did not change those of plant sterols in the hypercholesterolemic subjects. Pravastatin had little effect in a sitosterolemic patient on plasma levels of sterols, where cholestyramine decreased the plasma levels of both cholesterol and cholestanol. These results indicate that treatment with the HMG-CoA reductase inhibitor decreases plasma plant sterol concentrations, and suggest that the increased plasma plant sterol levels in sitosterolemia might not be due to the decreased cholesterol biosynthesis in vivo.

Acyl Coenzyme A↗
PubMed1995

[MAP kinase cascade in cultured rat mesangial cells].

In order to evaluate the intracellular signaling pathway of endothelin 1 (ET-1), we examined mitogen-activated protein kinase (MAPK) cascade in cultured rat glomerular mesangial cells. Treatment of quiescent mesangial cells with ET-1 increased kinase activities toward bovine myelin basic protein (MBP). Maximal activation was at 10 min and ED50 was about 5 nM. The 44- and 42-kDa kinases were activated in MBP containing gel kinase assay. These kinases were identified as extracellular signal regulated kinase (ERK) 1 and ERK2 with immunoblotting, respectively. MAPK or ERK kinase (MEK), one of the MAPK kinases, was present in rat mesangial cells and ET-1 also activated this MAPK kinase. These results indicate that MAPK kinase and MAP kinase are rapidly activated by ET-1 and may modulate cellular functions in rat mesangial cells.

Animals↗
PubMed1994

[A case of pulmonary sarcoidosis associated with severe hypercalcemia].

A 71-year-old man with a history of sarcoidosis was admitted to our hospital because of polyuria and polydipsia. On admission, the serum calcium concentration was elevated to 12.7mg/dl, and the creatinine clearance was 28.3ml/min. The initial serum 1,25-dihydroxyvitamin D concentration was 55.0pg/ml, while angiotensin-converting enzyme activity and serum PTH-rP concentration were within the normal range. Radiological studies revealed enlargement of bilateral hilar lymph nodes and a nodular lesion in the right lower lung field. Transbronchial lung biopsy showed noncaseous granuloma consistent with pulmonary sarcoidosis. After oral administration of 20mg prednisolone daily, the serum calcium and 1,25-dihydroxyvitamin D concentration returned to normal, and creatinine clearance was raised to 55ml/min. In conclusion, low dose glucocorticoid administration successfully reduced serum 1,25-dihydroxyvitamin D level with a prompt decrease in serum calcium level in a patient with sarcoidosis.

Aged↗
PubMed1994

High glucose condition activates protein tyrosine phosphatases and deactivates insulin receptor function in insulin-sensitive rat 1 fibroblasts.

To investigate the mechanism for the impairment of insulin receptor kinase activity induced by high glucose (HG) in Rat 1 fibroblasts that expressed human insulin receptors (HIRc), we measured protein tyrosine phosphatase (PTPase) activity in HG cells. Incubating HIRc cells for 4 days in 27 mM D-glucose (HG) stimulated cytosolic PTPase activities, but not particulate PTPase activity as determined by two methods using the dephosphorylation of insulin receptors. Furthermore, PTP1B, a major non-transmembrane PTPase in the cytosolic fraction, was increased in HG cells according to Western blots. These results indicate that desensitization of insulin receptor function by a high glucose condition is associated with the activation of PTPase activity.

Animals↗
PubMed1994

Insulin receptor kinase phosphorylates protein tyrosine phosphatase containing Src homology 2 regions and modulates its PTPase activity in vitro.

To clarify the role of protein tyrosine phosphatase (PTPase) containing a pair of Src homology 2 (SH2) regions upon insulin signaling, we studied the interactions between the insulin receptor and SH-PTP2 coupled to glutathione-S-transferase. A full length SH-PTP2 was phosphorylated by insulin receptor kinase and associated with the insulin receptor in vitro. The N-terminal SH2 domain was more phosphorylated than the other SH2 domain of SH-PTP2. However, both SH2 domains of SH-PTP2 were necessary for association with insulin receptors. Phosphorylation of the SH2 domains of SH-PTP2 resulted in decreased PTPase activities toward the phosphorylated insulin receptor. These results indicate that the insulin receptor can negatively regulate SH-PTP2 activity by means of phosphorylating the SH2 domains.

Cell Line↗
PubMed1994

Src homology 2 domains of protein tyrosine phosphatase are associated in vitro with both the insulin receptor and insulin receptor substrate-1 via different phosphotyrosine motifs.

To clarify the role of protein tyrosine phosphatase containing Src homology 2 (SH2) regions on insulin signaling, we investigated the interactions among the insulin receptor, a pair of SH2 domains of SH-PTP2 coupled to glutathione-S-transferase (GST) and insulin receptor substrate-1 (IRS-1)-GST fusion protein (amino-portion, IRS-IN; carboxyl portion, IRS-1C). GST-SH2 protein of SH-PTP2 bound to the wild type insulin receptor, but not to that with a carboxyl-terminal mutation (Y/F2). Furthermore, even though Y/F2 receptors were used, the SH2 protein was also co-immunoprecipitated with IRS-IC, but not with IRS-IN. These results indicate that SH2 domains of SH-PTP2 can directly associate with the Y1322TXM motif on the carboxyl terminus of insulin receptors and also may bind to the carboxyl portion of IRS-1, possibly via the Y1172IDL motif in vitro.

Binding Sites↗
PubMed1994

Abnormal glutathione metabolism and increased cytotoxicity caused by H2O2 in human umbilical vein endothelial cells cultured in high glucose medium.

To determine whether increased oxidative stress in diabetes mellitus is due to an impaired free-radical scavenger function in endothelial cells, GSH-dependent H2O2 degradation in human umbilical vein endothelial cells was studied. The GSH-dependent, NaN3-uninhibitable H2O2-degradation in endothelial cells was reduced by 48% (p < 0.001) when the cells were exposed to 33 mmol/l D-glucose vs 5.5 mmol/l D-glucose. This impairment was dependent not only on the D-glucose concentration in the medium but also on D-glucose specific metabolism, since neither 27.5 mmol/l L-glucose nor 27.5 mmol/l D-raffinose had any effect on the peroxide degradation activity. Activation of the glutathione redox cycle by H2O2 in cells exposed to high glucose concentrations was attenuated as compared with 5.5 mmol/l D-glucose because of: 1) a 42% decrease (p < 0.001) in intracellular NADPH content, and 2) a 34% reduction (p < 0.01) in glutathione release into the media. This results in an accumulation of GSSG in the cells following exposure to H2O2. Both H2O2-evoked 51Cr-release and H2O2-induced endothelial cell damage were significantly (p < 0.01) greater in the 33 mmol/l D-glucose group than in the 5.5 mmol/l D-glucose group. These results indicate that the abnormal glutathione redox cycle observed in endothelial cells is induced by high glucose concentrations in the medium, resulting in an impairment of reduced GSH-dependent H2O2-degradation. These abnormalities may associate with the increased cellular damage following an exogenous exposure to H2O2.

Cell Death↗
PubMed1994

Translocation of protein kinase C alpha and zeta in rat glomerular mesangial cells cultured under high glucose conditions.

The activities and expression of protein kinase C isoenzymes were examined in glomerular mesangial cells cultured under high glucose conditions. Exposure of cells to high glucose concentrations (27.8 mmol/l) for more than 3 days resulted in a significant elevation of protein kinase C activities in the membrane fraction. Of the protein kinase C isoenzymes, the levels of protein kinase C alpha significantly increased in the membrane fraction after 3 days of exposure to glucose, and protein kinase C zeta increased after 5 days of exposure. Levels of protein kinase C delta and epsilon remained unchanged and protein kinase, C beta and gamma were not detected. These results indicate that protein kinase C alpha and zeta are translocated under high glucose conditions possibly through different mechanisms.

Animals↗
PubMed1994

Metabolic effect of PGE1 analogue 01206.alpha CD on nerve Na(+)-K(+)-ATPase activity of rats with streptozocin-induced diabetes is mediated via cAMP: possible role of cAMP in diabetic neuropathy.

We investigated the dose-dependent effects of prostaglandin E1 (PGE1) analogue, OP1206.alpha CD (OP), on motor nerve conduction velocity (MNCV), nerve blood flow (NBF) and Na(+)-K(+)-ATPase (ATPase) activity in streptozocin-induced diabetic rats. At 10 micrograms/kg/day, OP ameliorated MNCV and NBF, but no ATPase activity, whereas at 30 micrograms/kg/day it increased MNCV and ATPase activity, but not NBF. These results suggested a possible direct metabolic effect of OP, at least at a certain dose, on ATPase activity independent of NBF. Since PGE1 exerts an effect on nerve cAMP content, we conducted an in vitro study to clarify the relationship of cAMP to the modulation of ATPase activity in diabetic nerves. We studied sciatic nerves isolated from 53 rats with streptozocin-induced diabetes that had exhibited hyperglycemia for 6 wk. OP increased the activity of ATPase and the accumulation of cAMP in a dose-dependent manner. Dibutyryl cAMP, a cAMP analogue, and aminophyline, which increases nerve cAMP content, enhanced ATPase activity in a dose-dependent manner. In addition, the increased activity of ATPase in diabetic nerves produced by OP was suppressed by a protein kinase inhibitor, H8. These results suggest that ATPase activity in diabetic nerves might be regulated or modified by cAMP and, possibly, by protein kinase A, a finding that is important for clarifying the pathogenesis of diabetic neuropathy and for developing new approaches to treatment.

Alprostadil↗
PubMed1994

The effect of an aldose reductase inhibitor (Epalrestat) on diabetic nephropathy in rats.

In order to clarify the possible contribution of the abnormal polyol pathway to the development of diabetic nephropathy, the effect of aldose reductase inhibitor on renal function and morphology was examined in streptozotocin (STZ)-induced diabetic rats. Six months after STZ injection, glomerular filtration rate and renal plasma flow showed marked decline with significant increase in nuclear-free mesangial area (MA) and relative mesangial area (RMA; MA per glomerular area) in diabetic rats. Oral administration of an aldose reductase inhibitor, Epalrestat, prevented renal hypofunction and mesangial expansion in diabetic rats without influencing the levels of blood glucose. These results suggest that the abnormal polyol pathway in diabetic rats is closely related to the development of mesangial expansion, a morphologic representative of diabetic glomerulopathy, and renal hypofunction.

Albuminuria↗
PubMed1994

Diabetic nephropathy in Japan.

According to a nation-wide survey of dialysis patients in Japan the number of diabetic patients with end-stage renal failure introduced to dialysis therapy has been increasing year by year, exceeding 6000 cases (28% of total cases) in 1991. A six-fold increase in numbers and a three-fold increase in percentages (DM/total) were observed in the past ten years. Although the medical technology and regimen in dialysis therapy have been greatly improved, the prognosis of those diabetic patients on maintenance dialysis has remained unsatisfactory. Their quality of life has been severely damaged mostly because of the impairment of visual acuity. The early detection and early introduction of effective therapy for diabetic nephropathy, therefore, may be the most imminent tasks necessary to prevent the various problems afflicting diabetic patients on end-stage renal failure.

Diabetes Mellitus, Type 1↗
PubMed1994

A case of lipoprotein glomerulopathy successfully treated with probucol.

A 54-year-old woman presented proteinuria and severe hyperlipoproteinemia, She had type III hyperlipoproteinemia with the phenotype E2/2. Renal biopsy specimen revealed lipoprotein thrombi within the glomerular capillary lumina without tubulointerstitial lesion and deposition of IgA in the mesangium and peripheral capillary loops, indicating lipoprotein glomerulopathy with IgA nephropathy. Treatment with probucol resulted in the improvement of both hyperlipoproteinemia and proteinuria with the disappearance of the lipoprotein thrombi in the glomerular capillary without any change in the mesangial IgA deposition. The data suggest that probucol may be effective against the early stage of lipoprotein glomerulopathy with less lipoprotein thrombi and without tubulointerstitial damage.

Female↗
PubMed1994

[A case of sarcoidosis with frequent recurrence of ophthalmoplegia].

A 72-year-old woman was admitted to our hospital with the complaint of recurrent ophthalmoplegia. During three months before her first consultation, she had experienced five episodes of ptosis and diplopia, which had lasted for about 1 month. No significant abnormality was shown with computed tomography (CT), magnetic resonance imaging (MRI) and MR-angiography on her brain. Cerebrospinal fluid was normal. Serum angiotensin converting enzyme (ACE) level was mildly elevated. The enlargement of hilar lymph nodes which showed non-caseating epitheloid granuloma suggestive of sarcoidosis was seen with chest X-ray and CT. A few days after the treatment of 60 mg of prednisolone every other day, ophthalmoplegia disappeared and no recurrence has been observed. Cranial nerve involvement tends to be seen commonly in neurosarcoidosis. By contrast, the nerves innervating the extraocular muscles are rarely involved. Although relapsing course of neurosarcoidosis is well known, no case with frequent recurrence of ophthalmoplegia during a few months has been reported.

Aged↗
PubMed1993

Pioglitazone ameliorates high glucose induced desensitization of insulin receptor kinase in Rat 1 fibroblasts in culture.

A new oral agent, pioglitazone, increases insulin sensitivity by activating receptor kinase in insulin-resistant rats. To clarify the mechanism, we studied in vitro effects of glucose and pioglitazone on the insulin receptor function using Rat 1 fibroblasts which expressed human insulin receptors. Insulin receptor kinase activity was impaired by incubating cells for 4 days in the presence of 27mM D-glucose. The glucose effect was time- and dose-dependent and also specific for D-glucose, since D-raffinose incubation had no effect. Pioglitazone treatment did not have any effect on intact receptor kinase. However, exposure of both 27mM D-glucose and 0.1 microM pioglitazone to the cells completely prevented the glucose-induced impairment of insulin receptor kinase activity, suggesting that pioglitazone might reverse the processes which are critical for the glucose-induced desensitization of insulin receptor kinase.

Animals↗
PubMed1993

Co-expression of mutant and normal human insulin receptors in COS 7 cells.

In order to assess the interference of the mutant insulin proreceptor on normal receptor function and formation of proreceptor-receptor heterotrimers (alpha beta-proreceptor), COS 7 cells were transfected with the same amount of expression plasmid (pGEM3SV) containing wild-type, a mutant proreceptor cDNA and both, using the DEAE-dextran method. Scatchard analysis of insulin binding data revealed that there was an approx. 50-fold higher receptor concentration in the transfected cells than in untransfected cells. After 0.025% trypsin treatment, insulin binding to the cells expressed with wild-type, proreceptor and both increased by 1-fold, 2.9-fold and 1.5-fold of the untreated cells, respectively. In the presence of 167 nM insulin, the amounts of phosphate incorporated into the 95 kDa protein beta-subunits and 210 kDa proreceptors from co-transfected cells, were identical to those of an in vitro mixture of the wild-type and the mutant receptors. At 10 nM insulin, the proreceptors from co-transfected cells normally autophosphorylated by insulin stimulation, whereas those mixed in vitro did not (73.3 +/- 9.3 vs. 29.6 +/- 2.6% of the maximal effect, n = 4, P < 0.01). However, at a similar concentration of insulin, the phosphate incorporation into Glu-80/Tyr-20 polymers by receptors from co-transfected cells was decreased when compared with a in vitro mixture (9.0 +/- 2.6 vs. 22.5 +/- 6.7% of the maximal effect at 4 nM, n = 6, P < 0.01), although the basal and maximally stimulated phosphate incorporation were comparable among these groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1993

An animal model of chronic ischemic neuropathy with proliferative changes of nerve microvessel wall.

In order to produce a model of ischemic neuropathy with neural microvascular alterations, sodium laurate was injected into a femoral artery and saline into the contralateral artery at the mid-thigh level in Sprague-Dawley rats aged 11 weeks. In view of the dose-related findings, 0.3 mg sodium laurate dissolved in 0.1 ml saline was used for the main experiment. The laurate-injected leg showed paresis during the experimental period. On day 1-7, various stages of Wallerian degeneration and acute microvascular changes were found. At 1 month, regenerating myelinated nerve fibers (MNFs) were found at the central or total fascicular area mainly in the distal tibial nerve. Morphometric analyses suggested that MNFs other than regenerating fibers are atrophic ones. The proliferative changes of nutrient microvascular walls were striking. The percent of closed epineurial microvessels was significantly larger on the laurate-injected sides and inversely associated with the diameter of MNFs. At 7 months, the attenuation of MNFs was more prominent and microvascular alterations were persistently observed. These pathological findings resemble those of chronic ischemic neuropathy including diabetic neuropathy, suggesting that this neuropathy model might provide some valuable and useful clues for clarifying the pathogenesis of chronic ischemic neuropathy.

Animals↗