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H Hidaka

Publications and source records attributed to H Hidaka.

At least 145 records · Page 8Linked to original sources
PubMed1997

Functional analyses of mammalian protein kinase C isozymes in budding yeast and mammalian fibroblasts.

BACKGROUND: The PKC1 gene of Saccharomyces cerevisiae encodes a homologue of mammalian protein kinase C (PKC) that is required for yeast cell growth. Pkc1 has been proposed to regulate a protein kinase cascade which includes the Bck1, Mkk1/Mkk2 and Mpk1 kinases. The functional relationship between Pkc1 and mammalian PKCs is unknown. Another signal transduction in Saccharomyces cerevisiae, the mating pheromone signalling pathway, is mediated by a heterotrimeric G protein, and causes cell cycle arrest in the G1 interval. It is not clear whether PKC is involved in this pathway. The effects of overexpression of PKCs in mammalian cells have been widely studied to analyse the function of PKCs in vivo. RESULTS: We isolated a human cDNA which encodes a protein kinase C type eta (PKC-eta) by complementation of pkc1 mutations in Saccharomyces cerevisiae. The human PKC-eta was able to complement the growth defect caused by the deletion of PKC1, whereas PKC-eta was unable to suppress the defect caused by deletion of BCK1. We also isolated human cDNAs that can suppress the adaptation defect of sst2. One of them encodes a protein kinase C type delta (PKC-delta). Expression of this gene in yeast stimulated an adaptation to the pheromone response. Human PKC-delta suppressed the adaptation defect of a pheromone receptor mutation lacking its C-terminal domain, but not that of a G protein beta-subunit mutation eliminating signal-induced phosphorylation, and not the lethality of the gpa1 null mutation. Moreover, overexpression of PKC-eta in NIH3T3 cells induced anchorage-independent growth. CONCLUSIONS: PKC-eta has a biological activity which is closely related to Pkc1, and PKC-eta activates the Pkc1-mediated pathway through an activation of the Bck1 kinase that is a homologue of MAP kinase kinase kinase. PKC-eta appears to play a critical role in growth control of yeast and mammalian cells. Suppression experiments with PKC-delta suggest that PKC-delta desensitizes the pathway by regulating an aspect of G protein function.

Adaptation, Biological↗
PubMed1997

Cilostazol, a cAMP phosphodiesterase inhibitor, attenuates the production of monocyte chemoattractant protein-1 in response to tumor necrosis factor-alpha in vascular endothelial cells.

The induction of monocyte chemoattractant protein-1 (MCP-1) in vascular endothelial cells is thought to be an initial event in the development of atherosclerotic lesions. Therefore, inhibition of MCP-1 production may exhibit some effects in preventing atherosclerosis. In the present study, we found that 10 microM cilostazol, a cAMP phosphodiesterase inhibitor, increased the intracellular cAMP content by a twenty-five times of the basal level and resulted in the reduction of basal MCP-1 release by 41% from 168 +/- 11 ng/24 hr/mg protein to 99 +/- 14 ng/24 hr/mg protein (P < 0.001) from cultured human umbilical vein endothelial cells. Furthermore, 10 microM cilostazol also significantly attenuated the dose-dependent increment of MCP-1 production by tumor necrosis factor-alpha. The inhibition was consistent with the reduction of MCP-1 mRNA level, possibly through reduced activation of transcription factor NF-kappa B level. Similarly, 1 mM dibutyryl cAMP inhibited MCP-1 production in endothelial cells. These data suggest that cilostazol inhibits MCP-1 production through increased intracellular cAMP levels and modulation of its expression in vascular endothelial cells.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1997

Myosin light-chain phosphorylation controls insulin secretion at a proximal step in the secretory cascade.

The aim of this study was to investigate how insulin secretion is controlled by phosphorylation of the myosin light chain (MLC). Ca2+-evoked insulin release from pancreatic islets permeabilized with streptolysin O was inhibited by different monoclonal antibodies against myosin light-chain kinase (MLCK) to an extent parallel to their inhibition of purified MLCK. Anti-MLCK antibody also inhibited insulin release caused by the stable GTP analog guanosine 5'-O-(3-thiodiphosphate), even at a substimulatory concentration (0.1 microM) of Ca2+. Free Ca2+ increased MLC peptide phosphorylation by beta-cell extracts in vitro. In contrast to the phosphorylation by purified MLCK or by calmodulin (CaM) kinase II, the activity partially remained with the beta-cell under nonstimulatory Ca2+ (0.1 microM) conditions. The MLCK inhibitor ML-9 inhibited the activity in the beta-cell with both substimulatory and stimulatory Ca2+, whereas KN-62, an inhibitor of CaM kinase II, only exerted an influence in the latter case. ML-9 decreased intracellular granule movement in MIN6 cells under basal and acetylcholine-stimulated conditions. We propose that MLC phosphorylation may modulate translocation of secretory granules, resulting in enhanced insulin secretion.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1997

An early insulin intervention accelerates pancreatic beta-cell dysfunction in young Goto-Kakizaki rats, a model of naturally occurring noninsulin-dependent diabetes.

This study was designed to delineate the nature of beta-cell dysfunction in a model of genetically determined nonobese diabetes, the Goto-Kakizaki (GK) rat. Pancreatic beta-cell function was analyzed immediately after weaning and 5 weeks thereafter, comparing animals with or without insulin treatment during the interval. In 3.5-week-old GK rats, fasting plasma glucose was mildly elevated with normoinsulinemia, and the islet insulin content was reduced by 33%. When incubated with 3-30 mM glucose in vitro, the GK rat islets showed reduced glucose sensitivity, i.e. the EC50 values were 19.5 and 15.9 mM, and the Hill constants for the positive cooperativity 2.1 and 4.2 in the islets of GK and the control rats, respectively. On the other hand, the maximum response to glucose was not attenuated when reduced islet insulin content was considered. In 8.5-week-old GK rats hyperglycemia worsened and glucose-stimulated insulin release by the islets more severely impaired. A daily insulin injection from the 3.5-8.5 weeks of age significantly lowered plasma glucose in the GK rat, accompanied by a marked suppression of both basal (with 3 mM glucose) and glucose (6-30 mM)-stimulated insulin release by the islets. In the GK rat, beta-cell dysfunction develops by the age of 3.5 weeks, and insulin treatment during the subsequent 5 weeks accelerates its progression.

Animals↗
PubMed1997

Studies on cardiac ingredients of plants. XIII: Chemical modification of gitoxin to cardiotonic compounds without vascular effect.

Nitrated gitoxins (4) and bufotoxin homologues with various lengths of alkyl chain at C-3 of the steroid nucleus (10) were prepared from gitoxin (1). The pharmacological activities of the resulting compounds (4 and 10) were evaluated by measurement of inhibitory effect on NA+, K(+)-adenosine triphosphatase (ATPase) prepared from dog kidney, positive inotropic effect (PIE) on isolated guinea-pig papillary muscle preparations, and the effect on smooth muscle using the mesenteric artery from spontaneously hypertensive rats. Most of the compounds showed a smaller contractile effect on the arterial muscle. Among these compounds, gitoxin 3"-nitrate (4g) exhibited the most desirable biological activities, such as PIE comparable to that of 1, 1.25 times wider concentration-dependent range than 1, and lack of contractile activity on vascular muscle.

Animals↗
PubMed1997

Studies on chemical modification of monensin. VI. Preparation of C-7 modified monensins via protected 7-oxomonensin and evaluation of their ion transport activity.

7-Carboxymethylmonensin (3), 7-aminomonensin (4), and 7-oxomonensin (5) were synthesized via protected 7-oxomonensin (2), which is expected to be a useful intermediate for the preparation of various monensin derivatives. intermediate for the preparation of various monensin derivatives. Compounds 3-5 exhibited smaller ion transport activity than monensin (1).

Calcium↗
PubMed1997

Modulation of tyrosine kinase activity has multiple actions on insulin release from the pancreatic beta-cell: studies with lavendustin A.

We investigated the role of tyrosine kinases in the regulation of insulin release from a hamster beta-cell line, HIT T15, using selective tyrosine kinase inhibitors. Genistein increased the insulin release induced by glucose, but herbimycin A, tyrphostins and the erbstatin analogue failed to change the release. Lavendustin A at 0.1 nM-1 microM caused a concave-shaped inhibition of the insulin release stimulated by 7 mM glucose. The inhibitory effect of lavendustin A was overcome by higher concentrations of glucose. Lavendustin B, the negative control analogue, had no effect on the release. Lavendustin A at a nanomolar range progressively inhibited insulin release by high K+ (50 mM)-depolarization, whereas the inhibitor did not change the insulin release by Ca2+ ionophore (A23187). On the contrary, lavendustin A at 10 nM significantly increased insulin release when glucose-induced insulin release was enhanced by either 5 microM forskolin or 162 nM 12-O-tetradecanoylphorbol 13-acetate. Lavendustin A failed to influence the Ca(2+)-induced insulin release from HIT cells permeabilized with streptolysin-O. These findings suggest that tyrosine kinases may play versatile roles in the control of insulin release from the pancreatic beta-cell.

Animals↗
PubMed1997

beta-Sitosterolemia with generalized eruptive xanthomatosis.

The clinical features of the first case of a patient with sitosterolemia and generalized eruptive xanthomatosis are described. A six-year-old girl with generalized eruption was referred to the lipid clinic because of the high plasma cholesterol levels determined by the enzymatic method. Neither clinical signs nor results of laboratory examinations appeared to be abnormal, except for the eruption and the increase in the plasma cholesterol concentration. A family survey revealed high plasma cholesterol concentrations in the mother and one of two other siblings. Histological examination showed the eruption to be a xanthoma. Plasma sterol analysis by high-performance liquid chromatography revealed a noticeable increase in plasma plant sterol as well as cholestanol concentrations in the proband and the hypercholesterolemic sibling. The other family members had slightly high plasma sterol concentrations. This is the first case of a sitosterolemic patient with eruptive xanthomatosis. The case indicates that the clinical features of the xanthoma in sitosterolemia are not only tuberous or tendon but also eruptive, and also suggests that sitosterolemia should be considered in the differential diagnosis of hypercholesterolemia in almost every case with tuberous or eruptive xanthoma. The diagnosis is clinically important, since the disease can be treated successfully by diet therapy and bile acid binding resins.

Child↗
PubMed1997

Diabetic lipemia with maturity-onset diabetes of the young.

A 19-year-old woman with diabetic lipemia and maturity-onset diabetes of the young (MODY) is reported. Though her insulin secretory activity was preserved, she fell into mild diabetic ketoacidosis (DKA) and showed type V hyperlipidemia. Post-heparin plasma activity of lipoprotein lipase (LPL) was decreased even 10 days after initiating insulin injection but not deficient. The abnormalities in lipid metabolism were improved by long-term insulin treatment. Though the contribution of the genetic background to the lipid abnormalities is not clear, the characteristics of MODY in this patient including insulin secretory capacity under stress conditions such as DKA might play a role in the development of diabetic lipemia.

Adult↗
PubMed1997

Pyruvate improves deleterious effects of high glucose on activation of pentose phosphate pathway and glutathione redox cycle in endothelial cells.

In our previous study (Diabetes 44:520-526, 1995), endothelial cells cultured in high glucose condition showed impairment of an oxidant-induced activation of the pentose phosphate pathway (PPP) and a reduced supply of NADPH to the glutathione redox cycle. To gain insight into the mechanisms of this impairment, the protective effect of pyruvate was studied in human umbilical vein endothelial cells cultured in either 5.5 mmol/l glucose (normal glucose [NG] condition) or 33 mmol/l glucose (high glucose [HG] condition). Through pretreatment of cells with 0.2 mmol/l pyruvate for 5-7 days in the HG condition, glucose oxidation through the PPP and total cellular NADPH content in the presence of 0.2 mmol/l H2O2 were increased by 54 (P < 0.05) and 34%, respectively, and glutathione-dependent degradation of H2O2 in HG cells was enhanced by 41% (P < 0.01), when compared with those cells to which pyruvate was not added. The addition of pyruvate significantly reduced the fructose 1,6-bisphosphate (FDP) content and free cytoplasmic NADH/NAD ratio, estimated by increased pyruvate/lactate ratio in NG and HG cells exposed to H2O2. Furthermore, the addition of pyruvate also showed a 46% reduction (P < 0.01) of endothelial cell damage induced by H2O2 in HG cells. These results indicate that abnormalities in PPP activation and glutathione redox cycle activity induced by H2O2 in HG cells are compensated, and that the accentuated reductive stress is improved by an addition of pyruvate. These pyruvate effects are associated with protection against an oxidant-induced endothelial cell injury in the high glucose condition.

Adenosine Triphosphate↗
PubMed1997

[Distribution of the apolipoprotein-E and -E-complexes in lipoproteins of human serum with the apolipoprotein-E4/E3 phenotype].

Distribution of apolipoprotein(apo) E4 and E3 in lipoproteins of serum with apoE4/E3 phenotype was analyzed. ApoE was eluted in two major peaks by gel chromatography; peak 1 and 2 corresponding to very- and intermediate-low density lipoprotein (VLDL + IDL) and high density lipoprotein2 (HDL2), respectively. ApoE in peak 1 (VLDL + IDL) consisted of monomers of 34 kDa, complexes with a high molecular weight (apoEs) of 100 kDa and with a small amount of apoE-AII complexes weighing 43 kDa. In contrast, apoE in peak 2 (HDL2) was composed mainly of apoE-AII complexes and apoEs complexes, and a small amount of monomers. Both apoE3 and E4 isoforms were detected in these peaks; E4 was more predominant in peak 1 while E3 was more predominant in peak 2. These findings suggest that different distributions of apoE3 and E4 in lipoprotein particles.

Apolipoprotein A-II↗
PubMed1996

Cellular events involved in the sensitization of etoposide-resistant cells by inhibitors of calcium-calmodulin-dependent processes. Role for effects on apoptosis, DNA cleavable complex, and phosphorylation.

Inhibitors of calcium-calmodulin-dependent processes, 1-[N,O-bis(1,5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-piperazine KN-62 and trifluoperazine (TFP), at non-cytotoxic concentrations (2 and 5 microM, respectively) enhanced etoposide (VP-16) cytotoxicity in Adriamycin-resistant (HL-60/ADR0.05) cells (3- to > 50-fold). In contrast to TFP, the inhibitor KN-62 was able to reverse resistance in HL-60/ADR0.05 cells at VP-16 concentrations that produced equivalent cytotoxicity in sensitive (HL-60/S) cells. Unlike TFP, the cellular accumulation of VP-16 in the presence of KN-62 was enhanced 1.5- to 2-fold in HL-60/S (MDR1 -ve) and HL-60/ADR0.05 (MDR1 +ve) cells. To achieve equivalent cytotoxicity, levels of VP-16 in the resistant cells were > 4-fold lower in the presence of KN-62 compared with treatment with VP-16 alone. The sensitizing effects of both KN-62 and TFP were due to enhancement (2- to 4-fold) of VP-16-induced topoisomerase II (TOPO II)-mediated DNA cleavable complex formation, and depletion of the 170 kDa (alpha) TOPO II isoform. The DNA damage induced by VP-16 in the presence of KN-62 or TFP resulted in the rapid induction of apoptosis and depletion of cells in "S" phase of the cell cycle. Both 5 microM TFP and 2 microM KN-62 enhanced the phosphorylation of 170 kDa TOPO II 1.6-fold and 1.5-fold, respectively. Results suggest that the inhibitory effect of KN-62 or TFP on calcium-calmodulin-dependent processes may be mechanistically involved in sensitizing resistant cells to VP-16 by enhancing TOPO II-mediated DNA damage.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1996

Identification and purification of Ca2+/calmodulin-dependent protein kinase V from human gastric carcinoma.

We previously purified a novel Ca2+/calmodulin-dependent protein kinase (CaM kinase) V, which has proven to be a member of the CaM kinase I family. Immunohistochemical staining of surgically-resected specimens from human subjects using specific antibody which reacts with CaM kinases I and V demonstrated heterogeneous distribution of CaM kinase I/V in normal gastric mucosa. The kinase was located mainly at the bottom of foveoral epithelium and in the gastric gland (< 25% immunopositive). In contrast, this kinase was abundant in various types of gastric carcinomas (> 75%), but not in gastric adenomas. Preferential and consistent presence of this kinase was confirmed by immunoblot analysis of gastric carcinoma and human gastric cancer cell lines, Kato-III and MKN-45. CaM kinase I/V was co-purified with CaM kinase II from resected gastric carcinoma using anion-exchange chromatography followed by calmodulin-affinity chromatography. The two kinases were finally separated by HPLC-based gel filtration. Purified CaM kinase I/V from gastric carcinoma did not possess detectable autophosphorylating activity, in contrast to CaM kinase II. The findings suggest CaM kinase I/V may possess abnormal biochemical properties in human gastric carcinoma, and the kinase could participate in cell growth of the carcinoma.

Adenocarcinoma↗