Short and convergent synthesis of asterriquinone B1 and demethylasterriquinone B1.
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Biochemistry↗
Biomedical subjects
H Mukai
Publications and source records attributed to H Mukai.
Effective plasma concentration of a novel Na+/Ca2+ channel blocker NS-7 for its cerebroprotective actions in rats with a transient middle cerebral artery occlusion.
The effect of a novel Na+/Ca2+ channel blocker NS-7 [4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy) pyrimidine hydrochloride] on the cerebral infarction, edema, and mortality was examined in rats with a transient middle cerebral artery occlusion (MCAO), and the effective plasma concentration of this compound for producing the cerebroprotective action was subsequently determined. MCA was occluded by inserting a thread through internal carotid artery for 2 h, and then recirculated for 6 h. NS-7 (0.125-1 mg/kg), when injected i.v. immediately after recirculation, significantly reduced the infarct volume as well as the cerebral edema. Delayed treatment with NS-7 at 1 h after recirculation produced an equivalent inhibition of the infarction, and was still effective, although to a lesser extent, when injected at 2 h but not 3 h after recirculation. Glycerol (4 g/kg) suppressed the cerebral edema but did not reduce the size of cerebral infarction in the cerebral cortex or striatum. Therefore, it is likely that the suppression of brain edema does not always lead to the reduction of the infarct size. NS-7 treated in combination with glycerol further decreased the water content in the occluded brain. Moreover, NS-7 significantly lowered the mortality observed up to 10 days after a transient MCAO. From these data, it is suggested that the presence of NS-7 in plasma during 1 to 3 h after recirculation is important for producing the neuroprotective action. To determine the pharmacologically effective plasma concentration of NS-7, the effect of continuous infusion of this compound on the cerebral infarction was examined. Infusion of NS-7 at 0.3 mg/kg over 2 h, starting immediately after recirculation, significantly reduced the infarct size. Its plasma concentration during 1 to 3 h was 14.5 to 28.5 ng/ml (36.9-72.3 nM). From these finding it is suggested that NS-7 has a potent anti-infarct action in addition to antiedema action in the rat transient MCAO model. Moreover, its effective plasma concentration was assumed to be 36.9 to 72.3 nM.
Animals↗
[Mastoparan as a G protein activator].
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Amino Acid Sequence↗
Elastofibroma in shoulder osteoarthritis: a theoretical concept of the etiology.
A case of unilateral, subscapular elastofibroma dorsi secondary to degenerative osteoarthritis in the ipsilateral glenohumeral joint is presented. A 69-year-old woman had experienced symptoms of osteoarthritis in the right shoulder since contracting septic arthritis when she was 7 years old. The patient noticed a soft tissue mass in the right subscapular region when she was 65 years old. The range of motion of the glenohumeral joint was severely restricted. Histopathologic examination of the excised mass revealed elastofibroma. The authors think the excessive scapulothoracic motion was important in formation of the lesion. This case indicates that elastofibroma is not a true neoplasm but a reactive lesion formed by repetitive minor trauma.
Aged↗
[Two cases successfully treated with long-term administration of low-dosage azithromycin].
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Aged↗
[Case of pulmonary MALT lymphoma successfully treated with clarithromycin].
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Aged↗
Phosphorylation of tau is regulated by PKN.
For the phosphorylation state of microtubule-associated protein, tau plays a pivotal role in regulating microtubule networks in neurons. Tau promotes the assembly and stabilization of microtubules. The potential for tau to bind to microtubules is down-regulated after local phosphorylation. When we investigated the effects of PKN activation on tau phosphorylation, we found that PKN triggers disruption of the microtubule array both in vitro and in vivo and predominantly phosphorylates tau in microtubule binding domains (MBDs). PKN has a catalytic domain highly homologous to protein kinase C (PKC), a kinase that phosphorylates Ser-313 (= Ser-324, the number used in this study) in MBDs. Thus, we identified the phosphorylation sites of PKN and PKC subtypes (PKC-alpha, -betaI, -betaII, -gamma, -delta, -epsilon, -zeta, and -lambda) in MBDs. PKN phosphorylates Ser-258, Ser-320, and Ser-352, although all PKC subtypes phosphorylate Ser-258, Ser-293, Ser-324, and Ser-352. There is a PKN-specific phosphorylation site, Ser-320, in MBDs. HIA3, a novel phosphorylation-dependent antibody recognizing phosphorylated tau at Ser-320, showed immunoreactivity in Chinese hamster ovary cells expressing tau and the active form of PKN, but not in Chinese hamster ovary cells expressing tau and the inactive form of PKN. The immunoreactivity for phosphorylated tau at Ser-320 increased in the presence of a phosphatase inhibitor, FK506 treatment, which means that calcineurin (protein phosphatase 2B) may be involved in dephosphorylating tau at Ser-320 site. We also noted that PKN reduces the phosphorylation recognized by the phosphorylation-dependent antibodies AT8, AT180, and AT270 in vivo. Thus PKN serves as a regulator of microtubules by specific phosphorylation of tau, which leads to disruption of tubulin assembly.
Amino Acid Sequence↗
Association of immature hypophosphorylated protein kinase cepsilon with an anchoring protein CG-NAP.
Protein kinase C (PKC) family requires phosphorylation of itself to become competent for responding to second messengers. Much attention has been focused on elucidating the role of phosphorylation in PKC activity; however, it remains unknown where this modification takes place in the cells. This study examines whether anchoring protein is involved in the regulation of PKC phosphorylation. A certain population of PKC epsilon in rat brain extracts as well as that expressed in COS7 cells was associated with an endogenous anchoring protein CG-NAP (centrosome and Golgi localized PKN- associated protein). Pulse chase experiments revealed that the associated PKC epsilon was an immature species at the hypophosphorylated state. In vitro binding studies confirmed that non- or hypophosphorylated PKC epsilon directly bound to CG-NAP via its catalytic domain, whereas sufficiently phosphorylated PKC epsilon did not. PKC epsilon mutant at a potential phosphorylation site of Thr-566 or Ser-729 to Ala, possessing almost no catalytic activity, was associated and co-localized with CG-NAP at Golgi/centrosome area. On the other hand, wild type and a phosphorylation-mimicking mutant at Thr-566 were mainly distributed in cytosol and represented second messenger-dependent catalytic activation. These results suggest that CG-NAP anchors hypophosphorylated PKCepsilon at the Golgi/centrosome area during maturation and serves as a scaffold for the phosphorylation reaction.
A Kinase Anchor Proteins↗
Dual effects of PKNalpha and protein kinase C on phosphorylation of tau protein by glycogen synthase kinase-3beta.
We analyzed the effects of PKNalpha and protein kinase C (PKC) on phosphorylation of tau protein by glycogen synthase kinase (GSK)-3beta using monoclonal antibodies (AT8, AT180, and AT270). These antibodies are highly specific for phosphorylated tau in Alzheimer paired helical filaments, and recognize phosphorylated Ser202/Thr205, Thr231, and Thr181 of tau protein, respectively. Immunoblot analysis demonstrated that PKNalpha and PKC did not directly phosphorylate their sites, whereas GSK-3beta efficiently did so. Incubating GSK-3beta with PKNalpha or PKC subtypes inhibited subsequent GSK-3beta-induced AT8 and AT270 immunoreactivity. However, the constitutive active form of the GSK-3beta(S9A) mutant was almost totally inert to each enzyme. Incubating tau with PKNalpha increased the GSK-3beta-induced AT180 immunoreactivity, which was further enhanced when the S9A mutant was used instead of the wild type GSK-3beta. These results suggest that PKNalpha and PKC directly inhibit GSK-3beta activity at least in part by phosphorylating Ser9 of GSK-3beta, and that they indirectly suppress GSK-3beta-stimulated phosphorylation of tau at amino acids Ser202/Thr205 and Thr181, but enhanced phosphorylation at Thr231 through phosphorylation at other sites of tau.
Amino Acid Sequence↗
PKN binds and phosphorylates human papillomavirus E6 oncoprotein.
The high risk human papillomaviruses (HPVs) are associated with carcinomas of cervix and other genital tumors. Previous studies have identified two viral oncoproteins E6 and E7, which are expressed in the majority of HPV-associated carcinomas. The ability of high risk HPV E6 protein to immortalize human mammary epithelial cells has provided a single gene model to study the mechanisms of E6-induced oncogenic transformation. In recent years, it has become clear that in addition to E6-induced degradation of p53 tumor suppressor protein, other targets of E6 are required for mammary epithelial cells immortalization. Using the yeast two-hybrid system, we have identified a novel interaction of HPV16 E6 with protein kinase PKN, a fatty acid- and Rho small G protein-activated serine/threonine kinase with a catalytic domain highly homologous to protein kinase C. We demonstrate direct binding of high risk HPV E6 proteins to PKN in wheat-germ lysate in vitro and in 293T cells in vivo. Importantly, E6 proteins of high risk HPVs but not low risk HPVs were able to bind PKN. Furthermore, all the immortalization-competent and many immortalization-non-competent E6 mutants bind PKN. These data suggest that binding to PKN may be required but not sufficient for immortalizing normal mammary epithelial cells. Finally, we show that PKN phosphorylates E6, demonstrating for the first time that HPV E6 is a phosphoprotein. Our finding suggests a novel link between HPV E6 mediated oncogenesis and regulation of a well known phosphorylation cascade.
Amino Acid Substitution↗
Phosphorylation of protein kinase N by phosphoinositide-dependent protein kinase-1 mediates insulin signals to the actin cytoskeleton.
Growth factors such as insulin regulate phosphatidylinositol 3-kinase-dependent actin cytoskeleton rearrangement in many types of cells. However, the mechanism by which the insulin signal is transmitted to the actin cytoskeleton remains largely unknown. Yeast two-hybrid screening revealed that the phosphatidylinositol 3-kinase downstream effector phosphoinositide-dependent protein kinase-1 (PDK1) interacted with protein kinase N (PKN), a Rho-binding Ser/Thr protein kinase potentially implicated in a variety of cellular events, including phosphorylation of cytoskeletal components. PDK1 and PKN interacted in vitro and in intact cells, and this interaction was mediated by the kinase domain of PDK1 and the carboxyl terminus of PKN. In addition to a direct interaction, PDK1 also phosphorylated Thr(774) in the activation loop and activated PKN. Insulin treatment or ectopic expression of the wild-type PDK1 or PKN, but not protein kinase Czeta, induced actin cytoskeleton reorganization and membrane ruffling in 3T3-L1 fibroblasts and Rat1 cells that stably express the insulin receptor (Rat1-IR). However, the insulin-stimulated actin cytoskeleton reorganization in Rat1-IR cells was prevented by expression of kinase-defective PDK1 or PDK1-phosphorylation site-mutated PKN. Thus, phosphorylation by PDK1 appears to be necessary for PKN to transduce signals from the insulin receptor to the actin cytoskeleton.
3-Phosphoinositide-Dependent Protein Kinases↗
Effects of neurosteroids on Ca(2+) signaling mediated by recombinant N-methyl-D-aspartate receptor expressed in Chinese hamster ovary cells.
Pregnenolone sulfate (PREGS) potentiates the N-methyl-D-aspartate (NMDA) receptor-mediated Ca(2+)-signals in cultured hippocampal neurons. The NMDA receptor family has several different subunits whose expression in neurons has distinct spatial and temporal patterns. To examine subunit specificity of the PREGS action, we have investigated the effect of PREGS on recombinant GluR epsilon2/zeta1 (NR2B/NR1) type NMDA receptors stabley expressed in Chinese hamster ovary cells using heat shock promoters. PREGS enhanced the Ca(2+) influx through the GluR epsilon2/zeta1 receptors in a dose-dependent manner. The EC(50) of PREGS for the GluR epsilon2/zeta1 receptors was 8.6 microM. Other sulfated neurosteroids, dehydroepiandrosterone sulfate (DHEAS), 17beta-estradiol sulfate and 3alpha-ol-5beta-pregnan-20-one sulfate (3alpha5betaS), inhibited the positive modulatory effect of PREGS on the GluR epsilon2/zeta1 NMDA receptors. Ifenprodil, a specific inhibitor of GluR epsilon2 subunit, abolished the NMDA-induced Ca(2+) influx even in the presence of PREGS. These results imply that PREGS positively modulates the Ca(2+) influx through the GluR epsilon2/zeta1 receptors which are expressed from the embryonic period.
Action Potentials↗
Case report. A case of chromoblastomycosis effectively treated with terbinafine. Characteristics of chromoblastomycosis in the Kitasato region, Japan.
A 38-year-old male with history of trauma in the left gluteal region 20 years ago presented with a dark red skin eruption at the traumatized area. It gradually grew to form an erythematous plaque with a well-defined border. Clinical findings and mycological cultures resulted in the diagnosis of chromoblastomycosis due to Fonsecaea pedrosoi. After initial administration of 5-fluorocytosine and local heat an almost complete cure was achieved with terbinafine combined with local heat therapy. A review is given on the chromoblastomycosis cases observed in the Kitasato region in Japan.
Adult↗
Isolation of two novel genes, down-regulated in gastric cancer.
Using a differential display technique, we identified two genes that are down-regulated in human gastric cancer tissue as compared to normal gastric mucosa. The down-regulated expression of these genes in gastric cancer tissue was confirmed by northern blotting analysis and RT-PCR. One, CA11, was a novel gene expressed predominantly in the stomach and was depleted in all of the gastric cancer cell lines examined. The other gene, GC36, was homologous to the digestive tract-specific calpain gene, nCL-4. The expression of both GC36 and nCL-4 was suppressed or depleted in gastric cancer cell lines of differentiated and poorly differentiated types. This is the first report of genes, the expression of which is down-regulated with considerable frequency in gastric cancer.
Alternative Splicing↗
Novel synthesis of natural pseudo-aminosugars, (+)-valienamine and (+)-validamine.
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Cyclohexenes↗
Selective stimulation of G-CSF gene expression in macrophages by a stimulatory monoclonal antibody as detected by a luciferase reporter gene assay.
We have identified a stimulatory monoclonal antibody (mAb) from autoimmune mice that selectively stimulates granulocyte colony-stimulating factor (G-CSF) gene expression in a mouse macrophage cell line. The induction was observed not only in the cell line, but also in normal peritoneal macrophages. This mAb bound to the monocyte/macrophage cell lines and pre-B leukemia cell lines, but also in normal peritoneal macrophages, whereas it did not bind to normal T and B cells in the spleen or fibroblastic cell lines. It could even bind to a human promyelocytic leukemia cell line, when they were differentiated into monocytic cells. On Western blotting, this mAb mainly recognized an approximately 30-kDa band and it was unique because there have been no reports of membrane-associated proteins with a similar molecular mass found in macrophages. These results suggest that there could be a specific gateway molecule to induce G-CSF in macrophages.
Animals↗
Clinical significance of cathepsin E in pancreatic juice in the diagnosis of pancreatic ductal adenocarcinoma.
BACKGROUND: It has been reported that cathepsin E (CTSE) is a non-secretory and intracellular aspartic proteinase found in the superficial epithelial cells of the stomach and that it is also expressed in pancreatic ductal adenocarcinoma. We evaluated the diagnostic value of CTSE in the pancreatic juice in the diagnosis of pancreatic ductal adenocarcinoma compared with that of CA19-9, carcinoembryonic antigen (CEA) and K-ras mutations. METHODS: One hundred and one patients (25 with pancreatic ductal adenocarcinoma and 76 with chronic pancreatitis) were examined for the diagnostic significance of CTSE in the pancreatic juice in the diagnosis of pancreatic ductal adenocarcinoma. Forty of 101 patients (15 with pancreatic ductal adenocarcinoma and 25 with chronic pancreatitis) were examined to compare the diagnostic value of various tumor markers in the pancreatic juice, namely CA19-9, CEA, K-ras mutations and CTSE. RESULTS: The detection frequency of CTSE was significantly higher in patients with pancreatic ductal adenocarcinoma (64.0%) than in patients with chronic pancreatitis (7.9%; chi2 = 34.76; P < 0.0001). The sensitivity, specificity and diagnostic accuracy of CTSE in the pancreatic juice for pancreatic ductal adenocarcinoma was 66.7, 92.0 and 82.5%, respectively. These values were more efficient in comparison with those of CA19-9, CEA and K-ras mutations. The main cause of the detection failure of CTSE in pancreatic ductal adenocarcinoma was obstruction of the main pancreatic duct. Sensitivity was 85.7% in patients without obstruction of the main pancreatic duct. CONCLUSIONS: Cathepsin E in the pancreatic juice is a novel marker for a definitive diagnosis of pancreatic ductal adenocarcinoma.
Adult↗
Usefulness of 1% terbinafine HCl (Lamisil) cream for hyperkeratotic-type tinea pedis and its transfer into the horny layer.
The usefulness of 1% terbinafine HCl (Lamisil) cream for hyperkeratotic-type tinea pedis and its transfer into the horny layer were evaluated. Of the 36 patients enrolled in the study, 35 were retained for analysis and one was excluded due to inappropriate drug application. Hyperkeratotic-type tinea pedis was classified into three types: true hyperkeratotic-type, partial hyperkeratotic-type, and quasi-hyperkeratotic type. The overall clinical improvement rate was 95.5% (100% for true-, 80% for partial- and 96.2% for quasi-hyperkeratotic type). The overall fungal eradication rate was 88.6% (75% for true-, 100% for partial- and 88.5% for quasi-hyperkeratotic type). The overall efficacy rate was 88.6% (75% for true-, 100% for partial- and 88.5% for quasi-hyperkeratotic type). No adverse reactions were reported. Drug concentrations in the horny layer were 170.3, 228.5 and 249.2 ng mg-1, respectively, 2, 4 and 12 weeks after starting the treatment. These concentrations are more than 50,000 times higher than the minimum inhibitory concentrations of terbinafine for dermatophytes. These findings indicate that terbinafine HCl (Lamisil) cream is very useful for refractory hyperkeratotic-type tinea pedis when administered alone. The pharmacokinetic data also support the clinical and mycological findings.
Administration, Topical↗