A new type of potent inhibitors of HIV-1 TAR RNA-Tat peptide binding by zinc(II)-macrocyclic tetraamine complexes.
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ATPases Associated with Diverse Cellular Activitie↗
Biomedical subjects
S Aoki
Publications and source records attributed to S Aoki.
Reversal of drug resistance mediated by multidrug resistance protein (MRP) 1 by dual effects of agosterol A on MRP1 function.
We previously isolated agosterol A (AG-A) from a marine Spongia sp. and found that it completely reversed colchicine resistance in P-glycoprotein (Pgp)-over-expressing KB-C2 cells and vincristine resistance in multidrug-resistance protein (MRP)1-over-expressing CV60 cells. However, a tri-deacetylated derivative of AG-A (IAG-A) showed almost no activity in reversing Pgp- or MRP1-mediated drug resistance. In this study, we examined the mechanisms by which AG-A reverses MRP1-mediated drug resistance by investigating the interaction between agosterols and MRP1 in MRP1-over-expressing human KB carcinoma (KB/MRP) cells. [3H]-Leukotriene C4 (LTC4), [3H]-2,4-dinitrophenyl-S-glutathione uptake into membrane vesicles prepared from KB/MRP cells and intracellular [3H]-vincristine accumulation and efflux in KB/MRP cells were measured with or without AG-A and/or inactive IAG-A. AG-A reduced MRP1-mediated [3H]-LTC4 transport in a dose-dependent manner, but IAG-A did not. Inhibition by AG-A was competitive, with a K(i) value of 31 microM. AG-A at 10 microM enhanced the accumulation of [3H]-vincristine in KB/MRP cells to the level of that in control cells in the absence of the agent. Likewise, ATP-dependent efflux of [3H]-vincristine from KB/MRP cells was enhanced compared with KB-3-1 cells and inhibited by AG-A. In addition, AG-A reduced intracellular levels of glutathione, a compound required for MRP1-mediated transport of some anti-cancer drugs. These findings suggest that AG-A reverses MRP1-mediated drug resistance by directly inhibiting the capacity of MRP1 to transport drugs. In addition, the capacity of AG-A to reduce cellular glutathione levels may contribute to the modulating activity of MRP1.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Characterization of two genes, Sig1 and Sig2, encoding distinct plastid sigma factors(1) in the moss Physcomitrella patens: phylogenetic relationships to plastid sigma factors in higher plants.
We isolated the cDNA for a sigma factor from the moss Physcomitrella patens, which possesses unusually large N-terminal extension and the conserved subdomains 1.2-4.2. Phylogenetic analyses indicated that this novel sigma factor and PpSIG1*(2), a plastid sigma factor previously identified from Physcomitrella, were classified into SigA and SigB groups, two major classes of higher plant plastid sigma factors, respectively. According to the nomenclature recently proposed, we renamed PpSIG1* into PpSIG2, and named the novel sigma factor PpSIG1. A transient expression assay using a green fluorescent protein showed that the N-terminal region of PpSIG1 acts as a chloroplast-targeting signal. Reverse transcription-PCR experiments showed that light induces the expression of the Sig1 and Sig2 genes encoding PpSIG1 and PpSIG2, respectively. Thus, PpSIG1 and PpSIG2 are likely plastid sigma factors regulating plastid gene expression in response to light signals.
Amino Acid Sequence↗
Cloning, expression, and mapping of a mouse gene, Uchl4, highly homologous to human and mouse Uchl3.
Ubiquitin carboxyl-terminal hydrolases (UCHs) are implicated in the proteolytic processing of polymeric ubiquitin. We have isolated a novel mouse gene for ubiquitin carboxyl-terminal hydrolase isozyme L4. The gene named Uchl4 encodes a novel member of the family of ubiquitin carboxyl-terminal hydrolases (UCHs) whose predicted amino acid sequence shows 95% identity to mouse UCH-L3 and 94% identity to human UCH-L3. Genomic structure, chromosome localization, and expression pattern of Uchl3 and Uchl4 were characterized in the mouse. Both Uchl3 and Uchl4 were expressed in various tissues examined; however, expression level was quite lower in Uchl4. While Uchl3 consists of at least 9 exons spanning about 12 kb, Uchl4 was an intronless gene with a size of about 2 kb. By PCR-based analysis with T31 radiation hybrid mapping panel, Uchl3 and Uchl4 were mapped on mouse chromosome 9 and 14, respectively.
Amino Acid Sequence↗
Glutathione-dependent binding of a photoaffinity analog of agosterol A to the C-terminal half of human multidrug resistance protein.
MRP1 is a 190-kDa membrane glycoprotein that confers multidrug resistance (MDR) to tumor cells. MRP1 is characterized by an N-terminal transmembrane domain (TMD(0)), which is connected to a P-glycoprotein-like core region (DeltaMRP) by a cytoplasmic linker domain zero (L(0)). It has been demonstrated that GSH plays an important role in MRP1-mediated MDR. However, the mechanism by which GSH mediates MDR and the precise roles of TMD(0) and L(0) are not known. We synthesized [(125)I]11-azidophenyl agosterol A ([(125)I]azidoAG-A), a photoaffinity analog of the MDR-reversing agent, agosterol A (AG-A), to photolabel MRP1, and found that the analog photolabeled the C-proximal molecule of MRP1 (C(932-1531)) in a manner that was GSH-dependent. The photolabeling was inhibited by anticancer agents, reversing agents and leukotriene C(4). Based on photolabeling studies in the presence and absence of GSH using membrane vesicles expressing various truncated, co-expressed, and mutated MRP1s, we found that L(0) is the site on MRP1 that interacts with GSH. This study demonstrated that GSH is required for the binding of an unconjugated agent to MRP1 and suggested that GSH interacts with L(0) of MRP1. The photoanalog of AG-A will be useful for identifying the drug binding site within MRP1, and the role of GSH in transporting substrates by MRP1.
Base Sequence↗
Differentiation in chronic myelogenous leukemia cell K562 by spongean sesterterpene.
Scalarane-type sesterterpenes, PHC-1-PHC-7, which have been isolated from a marine sponge, increased hemoglobin production in human chronic myelogenous leukemia cell line K562 at the concentration of 0.1-5 microg/ml. PHC-1, the major constituent, induced the expression of glycophorin A and the enucleation for K562 cells. These sesterterpenes were found to induce erythroid differentiation in K562 cells. In addition, PHC-1 induced G1 arrest of the cell cycle of K562 cells.
Animals↗
Molecular cloning and characterization of Kremen, a novel kringle-containing transmembrane protein.
Kringle domain, a triple-disulfide-linked domain, is conserved in diverse proteins which play important roles in various biological processes. We cloned Kremen, a novel member of kringle-containing proteins, using a newly developed unique strategy, 'Kringle-SAGE (serial analysis of gene expression)', which enables comprehensive analysis of kringle-containing proteins. Kremen is likely to be a type-I transmembrane protein composed of 473 amino acid residues. Kremen has a kringle domain, a WSC domain, and CUB domains in the extracellular region, while the intracellular region has no conserved motif involved in signal transduction. In the mouse embryo, the Kremen mRNA level, which was increased during embryonic development, was localized in the apical ectodermal ridge of limb buds, myotome, and sensory organs (e.g. optic vesicle, otic vesicle, nasal pit). In the adult mouse, Kremen mRNA was expressed in a variety of tissues with a relatively strong expression in the lung, heart, and skeletal muscle. Kremen mRNA expression in C2C12 and NIE-115 cells increased during respective differentiation into muscular and neural cells. These results suggest a potential role for Kremen in the regulation of cellular responses upon extracellular stimulus or cell-cell interaction in neuronal and/or muscle cells. Kringle-SAGE is expected to facilitate further elucidation of structure and functions of kringle proteins.
Amino Acid Sequence↗
Serum nm23-H1 protein as a prognostic factor in aggressive non-Hodgkin lymphoma.
Advances in chemotherapy have led to a favorable long-term prognosis in approximately 50% of patients with aggressive non-Hodgkin lymphoma (NHL). However, the remaining patients do not enjoy such prolonged survival after standard treatment. New prognostic factors are needed to define this poor-prognosis group and to plan an appropriate treatment strategy. It has been reported that serum nm23-H1 protein may be a new prognostic factor for aggressive NHL. In the present study involving multiple institutions and a large number of patients, the level of nm23-H1 protein was compared among different types of lymphoma; it was lowest for indolent lymphoma, followed by aggressive lymphoma and then highly aggressive lymphoma. In addition, patients with aggressive NHL and higher nm23-H1 levels had worse overall and progression-free survival rates than those with lower nm23-H1 levels. The nm23-H1 level was also compared between patients with diffuse large B-cell lymphoma and patients with peripheral T-cell lymphoma. The results suggest that the level of nm23-H1 could serve as a prognostic factor in both groups. Moreover, the prognosis of lymphoma patients could be ascertained even more precisely by combining soluble interleukin-2 receptor or soluble CD44 and nm23-H1 levels. A multivariate analysis confirmed that the nm23-H1 level is an independent and important prognostic factor in aggressive NHL. Therefore, it may provide useful information for clinicians to determine the appropriate therapy for each type of lymphoma.
Actuarial Analysis↗
A double-functionalized cyclen with carbamoyl and dansyl groups (cyclen = 1,4,7,10-tetraazacyclododecane): a selective fluorescent probe for Y(3+) and La(3+).
A cyclen (=1,4,7,10-tetraazacyclododecane) doubly functionalized with three carbamoylmethyl groups and one dansylaminoethyl (dansyl = 2-(5-(dimethylamino)-1-naphthalenesulfonyl) group (L(2) = 1-(2-(5-(dimethylamino)-1-naphthalenesulfonylamido)ethyl)-4,7,10-tris(carbamoylmethyl)-cyclen) was synthesized and characterized. Potentiometrtic pH titration and UV spectrophotometric titration of L(2) served to determine deprotonation of the pendant dansylamide (L(2) --> H(-1)L(2)) with a pK(a) value of 10.6, while the fluorometric titration disclosed a pK(a) value of 8.8 +/- 0.2, which was assigned to the dansyl deprotonation in the excited state. The 1:1 M(3+)-H(-1)L(2) complexation constants (log K(app) = 6.0 for Y(3+) and 5.2 for La(3+), where K(app)(M-H(-1)L(2)) = [M(3+)-H(-1)L(2)]/[M(3+)](free)[L(2)](free) (M(-1)) at pH 7.4) were determined by potentiometric pH titration and UV and fluorescence spectrophotometric titrations (excitation at 335 nm and emission at 520 nm) in aqueous solution (with I = 0.1 (NaNO(3))) and 25 degrees C. The X-ray structure analysis of the Y(3+)-H(-1)L complex showed nine-coordinated Y(3+) with four nitrogens of cyclen, three carbamoyl oxygens, and the deprotonated nitrogen and a sulfonyl oxygen of the dansylamide. The crystal data are as follow: formula C(28)H(49)N(11)O(13.5)SY (Y(3+)-H(-1)L(2) x 2(NO(3)(-)) x 2.5H(2)O), M(r) = 876.73, monoclinic, space group P2(1)/n (No. 14), a = 18.912(3) A, b = 17.042(3) A, c = 24.318(4) A, beta = 95.99(1) degrees, V = 7794(2) A(3), Z = 8, R1 = 0.099. Upon M(3+)-H(-1)L(2) complexation, the dansyl fluorescence greatly increased (8.6 and 3.8 times for Y(3+) and La(3+), respectively) in aqueous solution at pH 7.4. Other lanthanide ions also yielded Ln(3+)-H(-1)L(2) complexes with similar K(app) values, although all the dansyl fluorescences were weakly quenched. On the other hand, zinc(II) formed only a 1:1 Zn(2+)-L(2) complex at neutral pH with negligible fluorescence change. The X-ray crystal structure of the Zn(2+)-L(2) complex confirmed the pendant dansylamide being noncoordinating. The crystal data are as follow: formula C(28)H(51)N(11)O(14)SZn (Zn(2+)-L(2) x 2(NO(3)(-)) x 3H(2)O), M(r) = 863.22, monoclinic, space group C2/n (No. 15), a = 35.361(1) A, b = 13.7298(5) A, c = 18.5998(6) A, beta = 119.073(2) degrees, V = 7892.3(5) A(3), Z = 8, R1 = 0.084. Other divalent metal ions did not interact with L(2) at all (e.g., Mg(2+) and Ca(2+)) or interacted with L(2) with the dansyl fluorescence quenched (e.g., Cu(2+)).
Journal Article↗
Identity of dimeric dihydrodiol dehydrogenase as NADP(+)-dependent D-xylose dehydrogenase in pig liver.
Dimeric dihydrodiol dehydrogenases (DDs, EC 1.3.1.20), which oxidize trans-dihydrodiols of aromatic hydrocarbons to the corresponding catechols, have been molecularly cloned from human intestine, monkey kidney, pig liver, dog liver, and rabbit lens. A comparison of the sequences with the DNA sequences in databases suggested that dimeric DDs constitute a novel protein family with 20 gene products. In addition, it was found that dimeric DD oxidizes several pentoses and hexoses, and the specificity resembles that of NADP(+)-dependent D-xylose dehydrogenase (EC 1.1.1.179) of pig liver. The inhibition of D-xylose dehydrogenase activity in the extracts of monkey kidney, dog liver and pig liver, its co-purification with dimeric DD activity from pig liver, and kinetic analysis of the D-xylose reduction by pig dimeric DD indicated that the two enzymes are the same protein.
Alcohol Oxidoreductases↗
Cloning and characterization of the cDNA for a plastid sigma factor from the moss Physcomitrella patens.
We isolated a cDNA PpSig1 encoding a plastid sigma factor from the moss Physcomitrella patens. The PpSIG1 protein is composed of the conserved subdomains for recognition of -10 and -35 promoter elements, core complex binding and DNA melting. Southern blot analysis showed that the moss sig1 gene is likely a member of a small gene family. Transient expression assay using green fluorescent protein demonstrated that the N-terminal region of PpSIG1 functions as a chloroplast-targeting signal peptide. These observations suggest that multiple nuclear-encoded sigma factors regulate chloroplast gene expression in P. patens.
Amino Acid Sequence↗
Genetically distinct populations in an Asian soldier-producing aphid, Pseudoregma bambucicola (Homoptera: Aphididae), identified by DNA fingerprinting and molecular phylogenetic analysis.
To estimate genetic structure of a soldier-producing aphid, Pseudoregma bambucicola, samples from natural populations throughout southeastern Asia were analyzed by a DNA fingerprinting technique. We unexpectedly found that P. bambucicola comprises two geographic groups, the northern group and the southern group, which are genetically distinct from each other but morphologically almost indistinguishable. Molecular phylogenetic and statistical analyses based on mitochondrial ribosomal DNA sequences demonstrated that the northern and southern groups of P. bambucicola are not closely related but constitute distinct lineages in the genus Pseudoregma. Detailed morphological reexamination revealed that the two groups could be distinguished by the number of setae on the 8th abdominal tergite of 1st instar nymphs and soldiers. From these results, it was suggested that P. bambucicola should be divided into two species. The northern group from Japan, Taiwan, Hong Kong, and northern Vietnam retains the name P. bambucicola, whereas we suggest that the name P. carolinensis (R. Takahashi, 1941, Tenthredo 3, 208-220) should be used for the southern group from Thailand, Malay Peninsula, Java, Irian Jaya, and Micronesia. The morphological resemblance between P. bambucicola and P. carolinensis might be due to shared ancestral characters of the genus Pseudoregma.
Animals↗
Myelodysplastic syndrome progresses rapidly into erythroleukemia associated with synchronous double cancers of the stomach and the papilla of Vater.
Patients with myelodysplastic syndrome (MDS) show a relatively high incidence of developing cancers. However, it is extremely rare that synchronous double cancers develop in an MDS patient. We report a case of MDS that progressed rapidly into erythroleukemia (M6 by French-American-British classification) complicated by gastric cancer and carcinoma of the papilla of Vater. A 66-year-old man was admitted because of pancytopenia with peripheral blasts. A diagnosis of MDS (with refractory anemia with excess of blasts in transformation [RAEB-T]) was made by bone marrow examination. Chromosome analysis revealed 46,XY. An early gastric cancer was also diagnosed by endoscopic examination. The peripheral blasts gradually proliferated and the disease progressed to M6. A chromosome abnormality 46,XY,del(1)(q42) was detected at the leukemic transformation. A CAG (low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor) regimen was started as a remission-induction therapy. However, obstructive jaundice developed and a marked dilatation of bile ducts was observed by abdominal computed tomography (CT). A carcinoma of the papilla of Vater was detected by endoscopy. As remission was achieved and the pancytopenia improved, the patient subsequently underwent a surgical jejuno-choledochostomy to manage the jaundice. However, the leukemia relapsed thereafter and additional chromosome abnormalities including der(5)t(5;10)(p15:q11) were observed.
Aclarubicin↗
Brain perfusion measured by flow-sensitive alternating inversion recovery (FAIR) and dynamic susceptibility contrast-enhanced magnetic resonance imaging: comparison with nuclear medicine technique.
The aim of this study was to compare cerebral perfusion images and regional cerebral blood flow (rCBF) of SPECT study with the images and regional intensity of relative cerebral blood flow (CBF) images acquired by contrast-enhanced perfusion MR imaging (pMRI) and flow-sensitive alternating inversion recovery (FAIR). Twelve patients with various cerebral diseases were underwent I-123-IMP SPECT, pMRI, and FAIR studies to measure rCBF. A total of 12 regions of interest (ROI) were created over cerebrum and cerebellum to acquire the corresponding rCBF from I-123-IMP study and regional average signal intensity from CBF images of pMRI and FAIR studies. Left-to-right (L/R) and cerebral-to-cerebellar (CCR) ratios were created from the rCBF of I-123-IMP and signal intensity of CBF images of pMRI and FAIR. Image quality of FAIR was the poorest among all; however, CBF images of pMRI and FAIR images show comparatively decreased intensity at the corresponding site of decreased perfusion on I-123-IMP images. Both FAIR and pMRI images showed high intensity along the sinuses, choroid plexus, and large vessels in sulci. No significant correlation was found among all imaging modalities. But L/R ratio of I-123-IMP showed significant correlation with those of pMRI and FAIR, but for CCR, significant correlation was observed only between I-123-IMP and FAIR. Perfusion images of both pMRI and FAIR may produce images comparable to SPECT study. But to calculate absolute CBF more easy-to-apply and accurate algorithms are needed to overcome the artifacts from large vessels.
Adult↗
Pharmacokinetic studies of Gln117 tissue-type plasminogen activator in rats.
Gln117 t-PA is a mutant type of tissue-type plasminogen activator (mt-PA), which is generated by the removal of a high mannose oligosaccharide resulting from the mutation of amino acid #117, from asparagine (Asn) to glutamine (Gln). The plasma concentration, distribution, metabolism and excretion of Gln117 t-PA were investigated after a single intravenous administration of 125I-Gln117 t-PA or Gln117 t-PA, comparing with wild-type t-PA (WT t-PA). The plasma concentration of Gln117 t-PA decreased more slowly than that of WT t-PA, plasma clearance (CL(p)), and that of Gln117 t-PA in rats was approximately 2.6 times lower than that of WT t-PA. The highest radioactivity was found in the liver at 5 min after intravenous administration of [125I]Gln117 t-PA to rats, but the radioactivity in the liver was lower than that after intravenous administration of [125I]WT t-PA in our previous paper. Within 288 h after intravenous administration of [125I]Gln117 t-PA to rats, 88.5 and 5.5% of administered radioactivity were excreted into urine and feces, respectively. In a gel-filtration chomatographic (GFC) analysis of plasma, Gln117 t-PA formed complexes with plasma proteins, similarly to WT t-PA. The hepatic clearance (CL(hep)) of both t-PAs was evaluated by comparing the plasma concentration after a constant intravenous infusion with that after a constant intraportal venous infusion. The CL(hep) of Gln117 t-PA was 6.5 times lower than that of WT t-PA. These results indicate that the low uptake of Gln117 t-PA to the liver reduces CL(p) compared with WT t-PA.
Animals↗
Synthesis and evaluation of various layered octacalcium phosphates by wet-chemical processing.
Octacalcium phosphate was synthesized by hydrolysis of alpha-tricalcium phosphate through a wet-chemical processing. Using the same wet-chemical processing in presence of various succinate ions, the preparation of some complexed octacalcium phosphates was attempted. The products were examined by X-ray diffraction method. These complexed octacalcium phosphates intercalated with succinic acid, L-asparatic acid, and methyl succinic acid showed an expanded basal spacing in the octacalcium phosphate unit cell dimensions. The microstructure was observed by scanning and transmission electron microscopy.
Journal Article↗
Serum nm23-H1 protein as a prognostic factor for indolent non-Hodgkin's lymphoma.
Standard chemotherapy has been ineffective for improving the poor 10-year survival rate of patients with indolent lymphoma. However, a wider choice of therapeutic modalities has become recently available, including immunotherapy with monoclonal antibodies and allogeneic peripheral blood stem cell transplantation. Accordingly, a sensitive prognostic indicator is required to identify high-risk patients and to help design new therapeutic approaches for them. We previously reported that the serum nm23-H1 protein level was an independent prognostic factor for aggressive lymphoma. The present study was performed to assess the clinical implications of this protein on indolent lymphoma and whether it can be used to classify the aggressiveness of the disease in order to assist in the individualization of therapy. A total of 130 patients with indolent lymphoma were enrolled in this multicenter study. The serum nm23-H1 protein level was significantly higher in patients with indolent lymphoma than in a normal control group. In addition, indolent lymphoma patients with higher nm23-H1 levels had worse overall and progression-free survival rate than those with lower nm23-H1 levels. Therefore, nm23-H1 in serum may be useful for identifying a distinct group of patients at high risk.
Adolescent↗
Clinical study of transitional cell carcinoma of the prostate associated with bladder transitional cell carcinoma.
BACKGROUND: Transitional cell carcinoma of the prostate in patients with bladder cancer appears to influence the prognosis and affects the decision about therapeutic modality. Therefore, it is important to characterize transitional cell carcinoma associated with bladder cancer. METHODS: From April 1980 to December 1998, 81 male patients underwent total cystoprostatectomies for transitional cell carcinoma of the bladder. The 81 cystoprostatectomy specimens were examined to clarify the characteristics of prostatic involvement by transitional cell carcinoma. The extent, origin, mode of spread and risk factor of prostatic involvement as well as the prognosis were investigated. In 13 of 15 patients with prostatic involvement the prostate was examined by sequential step sections. RESULTS: Prostatic involvement was observed in 15 of 81 patients (18.5%). Prostatic urethral involvement, invasion to prostatic duct/acinus, prostatic stromal invasion and extraprostatic extension and/or seminal vesicle involvement were recognized in 12 (80%), 14 (93.3%), six (40%), and five (33.3%) of the 15 patients, respectively. Twelve of the 15 patients (80%) with prostatic involvement had papillary or non-papillary tumors (i.e. carcinoma in situ) both in the prostatic urethra and prostatic duct. In 10 of these 12 patients (88.3%), there was contiguity between prostatic urethral and ductal tumors. Seven of the 23 patients (30.4%) with carcinoma in situ of the bladder showed prostatic involvement, which increased to 50% in the presence of carcinoma in situ of the trigone or bladder neck. CONCLUSIONS: Eighty per cent of the patients with prostatic involvement showed papillary or non-papillary tumors both in the prostatic urethra and prostatic duct. There was a high level of contiguity between both tumors. Patients with carcinoma in situ of the trigone or bladder neck revealed significantly higher incidence of prostatic involvement.
Carcinoma in Situ↗