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Biomedical subjects

J Shin

Publications and source records attributed to J Shin.

At least 37 records · Page 2Linked to original sources
PubMed2001

New lactone-containing metabolites from a marine-derived bacterium of the genus Streptomyces.

Six novel metabolites containing a lactone moiety as a common structural feature, along with the previously described (-)-blastmycinolactol, have been isolated from the cultivation broth of a bacterium of the genus Streptomyces isolated from marine sediment. On the basis of the results of combined spectroscopic analysis, the structures of the new compounds have been determined as butenolides and 3-hydroxy-gamma-butyrolactones.

Antifungal Agents↗
PubMed2001

New triterpenoid saponins from the sponge Erylus nobilis.

Erylosides G--J (1--4), four new triterpenoid saponins, were isolated from the sponge Erylus nobilis collected from Jaeju Island, Korea. On the basis of the results of combined chemical and spectral analyses, the structures of the aglycones were determined to be lanostane-based, modified penasterols. The oligosaccharide portions were composed of one unit each of L-arabinose, D-galactose, and 2-N-acetyl-D-glucosamine (1 and 3) or two units of L-arabinose and one unit of 2-N-acetyl-D-glucosamine (2 and 4). These compounds exhibited moderate cytotoxicty against a human leukemia cell line.

Animals↗
PubMed2001

New steroidal alkaloids from an undescribed sponge of the genus Corticium.

Two new steroidal alkaloids, along with a previously reported one of the plakinamine class, were isolated from the sponge Corticium sp. collected from Guam. The structures of the new compounds were determined by combined spectroscopic methods. These compounds exhibited moderate cytotoxicity and antifungal activity as well as DNA- and RNA-cleaving activities.

Alkaloids↗
PubMed2001

Treatment of vitamin K deficiency in cystic fibrosis: Effectiveness of a daily fat-soluble vitamin combination.

OBJECTIVE: Patients with cystic fibrosis (CF) and pancreatic insufficiency (PI) commonly have vitamin K deficiency, and those with CF-associated liver disease (CFLD) have universal vitamin K deficiency. We evaluated the effectiveness of an oral fat-soluble vitamin combination (ADEKs) to treat patients with vitamin K deficiency. STUDY DESIGN: Patients with PI and CF (mean age, 15 years; range, 0.6 to 46 years) including 6 with advanced CFLD were prospectively enrolled in a study of a fat-soluble vitamin combination taken on a daily basis. None had received vitamin K supplementation for at least 4 months before the study. Fat-soluble vitamin combination supplementation was given for a minimum of 4 months; the mean vitamin K intake was 0.18 mg/d (SD = 0.1, range, 0 to 0.3). The primary outcome was change in plasma PIVKA-II (prothrombin in vitamin K absence). RESULTS: Before supplementation 58 (81%) of 72 patients had abnormal PIVKA-II levels (>2.9 ng/mL). After supplementation 29 (40%) had abnormal PIVKA-II levels (P =.001). All 6 patients with advanced CFLD had abnormal PIVKA-II levels (median, range of 20.8, 5.5 to 55 ng/mL) before treatment, which corrected to normal in 50% (4.1, 2.1 to 65 ng/mL). Four patients, 2 with CFLD, had a prolonged prothrombin time (>13.5 seconds) at both time periods. CONCLUSIONS: An oral fat-soluble vitamin combination with a modest amount of vitamin K can, as a daily supplement, improve the PIVKA-II levels in patients with PI and CF.

Adolescent↗
PubMed2001

Solution structure of p21(Waf1/Cip1/Sdi1) C-terminal domain bound to Cdk4.

Cyclin-dependent kinase (Cdk) inhibitor p21(Waf1/Cip1/Sdi1), a multifunctional protein, has a major role as tumor suppressor, mediating G1/S arrest through inhibition of Cdks. Recent biological studies of Cyclin D1/Cdk4 have proposed that p21 C-terminal domain (p21(CT)) plays a key role as a potent Cdk4 inhibitor. We report here solution structures of p21(CT) for both the free and Cdk4-bound forms using 2D transferred NOE spectroscopy and dynamical simulated annealing calculations. Even though p21(CT) peptide is very flexible in the free state, when it bound to Cdk4, the structure becomes well structured in the binding domain. Therefore we propose that p21(CT) experiences an extensive conformational change upon Cdk4 binding. This structural change of p21(CT) may suggest the molecular mechanism of p21 for specificity and inhibition mode to assemble different cyclin-Cdk complexes. Especially, our data suggests that the D(149)FYHSKRR(156) region of p21 is critical for Cdk4 binding, indicating that the major driving force for complex originates from hydrophobic interaction between p21 and Cdk4.

Amino Acid Sequence↗
PubMed2001

New farnesylhydroquinone glycosides from the gorgonian Euplexaura anastomosans.

Euplexides F (3) and G (4), novel farnesylhydroquinone glycosides, have been isolated as minor constituents of the gorgonian Euplexaura anastomosans. The structures of these compounds have been determined by combined spectroscopic methods. These compounds exhibited moderate cytotoxicity and inhibitory activity against PLA2.

Animals↗
PubMed2001

Transient dissociation of polyribosomes and concurrent recruitment of calreticulin and calmodulin transcripts in gravistimulated maize pulvini.

The dynamics of polyribosome abundance were studied in gravistimulated maize (Zea mays) stem pulvini. During the initial 15 min of gravistimulation, the amount of large polyribosomes transiently decreased. The transient decrease in polyribosome levels was accompanied by a transient decrease in polyribosome-associated mRNA. After 30 min of gravistimulation, the levels of polyribosomes and the amount of polyribosome-associated mRNA gradually increased over 24 h up to 3- to 4-fold of the initial value. Within 15 min of gravistimulation, total levels of transcripts coding for calreticulin and calmodulin were elevated 5-fold in maize pulvinus total RNA. Transcripts coding for calreticulin and calmodulin were recruited into polyribosomes within 15 min of gravistimulation. Over 4 h of gravistimulation, a gradual increase in the association of calreticulin and calmodulin transcripts with polyribosomes was seen predominantly in the lower one-half of the maize pulvinus; the association of transcripts for vacuolar invertase with polyribosomes did not change over this period. Our results suggest that within 15 min of gravistimulation, the translation of the majority of transcripts associated with polyribosomes decreased, resembling a general stress response. Recruitment of calreticulin and calmodulin transcripts into polyribosomes occurred predominantly in the lower pulvinus one-half during the first 4 h when the presentation time for gravistimulation in the maize pulvinus is not yet complete.

Biological Transport↗
PubMed2000

Analysis of upstream elements in the HuC promoter leads to the establishment of transgenic zebrafish with fluorescent neurons.

HuC encodes an RNA binding protein homologous to Drosophila elav that serves as an excellent early marker for differentiating neurons. We have characterized the promoter of the zebrafish HuC gene by examining the ability of 5'-upstream fragments to drive expression of green fluorescent protein (GFP) in live embryos. We determined that 2.8 kb of the 5'-flanking sequence is sufficient to restrict GFP gene expression to neurons. The core promoter spans 251 base pairs and contains a CCAAT box and one SP1 sequence but no TATA box is present near the transcription start site. A putative MyT1 binding site and at least 17 E-box sequences are necessary to maintain the neuronal specificity of HuC expression. Interestingly, sequential removal of the putative MyT1 binding site and 14 distal E boxes does not appear to abolish neuronal expression; rather, it leads to a progressive expansion of GFP expression into muscle cells. Further removal of the three proximal E boxes eliminates neuronal and muscle specificity of GFP expression and leads to ubiquitous expression of GFP in the whole body. Identification of key components of the HuC promoter has led to the establishment of a stable zebrafish transgenic line (HuC-GFP) in which GFP is expressed specifically in neurons. We crossed mind bomb (mib) fish with this line to visualize their neurogenic phenotype in live mib(-/-) mutant embryos. This cross illustrates how HuC-GFP fish could be used in the future to identify and analyze zebrafish mutants with an aberrant pattern of early neurons.

Animals↗
PubMed2000

A novel anti-tumor cytokine contains an RNA binding motif present in aminoacyl-tRNA synthetases.

Endothelial monocyte-activating polypeptide II (EMAP II) is a novel pro-apoptotic cytokine that shares sequence homology with the C-terminal regions of several tRNA synthetases. Pro-EMAP II, the precursor of EMAP II, is associated with the multi-tRNA synthetase complex and facilitates aminoacylation activity. The structure of human EMAP II, solved at 1.8 A resolution, revealed the oligomer-binding fold for binding different tRNAs and a domain that is structurally homologous to other chemokines. The similar structures to the RNA binding motif of EMAP II was previously observed in the anticodon binding domain of yeast Asp-tRNA synthetase (AspRSSC) and the B2 domain of Thermus thermophilus Phe-tRNA synthetase. The RNA binding pattern of EMAP II is likely to be nonspecific, in contrast to the AspRSSC. The peptide sequence that is responsible for cytokine activity is located, for the most part, in the beta1 strand. It is divided into two regions by a neighboring loop.

Amino Acid Sequence↗
PubMed2000

NMR studies on novel antitumor drug candidates, deoxoartemisinin and carboxypropyldeoxoartemisinin.

Artemisinin and its derivatives, which have been known as antimalarial drugs, have also demonstrated their cytotoxicity against tumor cells. It has been proposed that antitumor activity depends on the lipophilicity of functional group on artemisinin derivatives. Solution structures of two artemisinin derivatives as antitumor drug candidates, deoxoartemisinin and carboxypropyldeoxoartemisinin, were determined by NMR spectroscopy to elucidate structure-activity relationship. According to biological assay, antitumor efficiencies are not dependent upon lipophilicity. Instead, these compounds demonstrated their distinctive structural features of boat/chair conformation and capability to interact with receptors, as they have different efficiencies on antitumor activity. Especially, carboxypropyl moiety or carbonyl moiety in artemisinin derivatives influences the conformation and stability of ring structure. Although the detailed mechanism of antitumor activity by artemisinin derivatives has not been addressed, we suggest that antitumor activity is not determined only with lipophilicity and that artemisinin derivatives have specific target proteins in each type of cancer.

Animals↗
PubMed2000

Adhesion to target cells is disrupted by the killer cell inhibitory receptor.

Killer cell immunoglobulin-like receptors (KIR) inhibit the cytotoxic activity of natural killer (NK) cells by recruitment of the tyrosine phosphatase SHP-1 to immunoreceptor tyrosine-based inhibition motif (ITIM) sequences in the KIR cytoplasmic tail [1]. The precise steps in the NK activation pathway that are inhibited by KIR are yet to be defined. Here, we have studied whether the initial step of adhesion molecule LFA-1-dependent adhesion to target cells was altered by the inhibitory signal. Using stable expression of an HLA-C-specific KIR in the NK cell line YTS [2] and a two-color flow cytometry assay for conjugate formation, we show that adhesion to a target cell expressing cognate HLA-C was disrupted by KIR engagement. Conjugate formation was abruptly interrupted by KIR within less than 5 minutes. Inhibition of adhesion to target cells was mediated by a chimeric KIR molecule carrying catalytically active SHP-1 in place of its cytoplasmic tail. These results suggest that other ITIM-bearing receptors, many of which have no known function, may regulate adhesion in a wide variety of cell types.

Abatacept↗
PubMed2000

Substrate recognition through a PDZ domain in tail-specific protease.

Tail-specific protease (Tsp) is a periplasmic enzyme that selectively degrades proteins bearing a nonpolar C-terminus. Its substrate specificity suggests that Tsp may contain a substrate recognition domain, which selectively binds to the nonpolar C-termini of substrate proteins, separate from its catalytic site. In this work, we show that substrate recognition of Tsp is mediated by a PDZ domain, a small protein module that promotes protein-protein interactions by binding to internal or C-terminal sequences of their partner proteins. Partial proteolysis by V8 protease at a single peptide bond immediately N-terminal to the PDZ domain resulted in two distinct and relatively stable fragments and complete loss of catalytic activity. Photoaffinity labeling with a fluorescent nonpolar peptide caused the covalent attachment of the peptide to a single site on the Tsp protein. Systematic deletion mutagenesis of Tsp localized the binding site to amino acids 206-307, a region that completely encompasses the putative PDZ domain (217-301). The isolated PDZ domain (amino acids 206-334) is capable of folding into a well-behaved structure and binds to a nonpolar peptide with a dissociation constant (K(D)) of 1.9 microM, similar to that of the intact Tsp protein. Site-directed mutagenesis of a surface residue at the peptide binding site of the PDZ domain, valine 229, to Glu or Gln resulted in an increase in the K(M) value but had no effect on the k(cat) value. The use of a separate substrate recognition domain such as a PDZ domain may be a general mechanism for achieving selective protein degradation.

Binding Sites↗
PubMed2000

Segregation analysis in Shwachman-Diamond syndrome: evidence for recessive inheritance.

Shwachman-Diamond syndrome is a rare disorder of unknown cause. Reports have indicated the occurrence of affected siblings, but formal segregation analysis has not been performed. In families collected for genetic studies, the mean paternal age and mean difference in parental ages were found to be consistent with the general population. We determined estimates of segregation proportion in a cohort of 84 patients with complete sibship data under the assumption of complete ascertainment, using the Li and Mantel estimator, and of single ascertainment with the Davie modification. A third estimate was also computed with the expectation-maximization (EM) algorithm. All three estimates supported an autosomal recessive mode of inheritance, but complete ascertainment was found to be unlikely. Although there are no overt signs of disease in adult carriers (parents), the use of serum trypsinogen levels to indicate exocrine pancreatic dysfunction was evaluated as a potential measure for heterozygote expression. No consistent differences were found in levels between parents and a normal control population. Although genetic heterogeneity cannot be excluded, our results indicate that simulation and genetic analyses of Shwachman-Diamond syndrome should consider a recessive model of inheritance.

Abnormalities, Multiple↗
PubMed2000

Protease-catalyzed tripeptide (RGD) synthesis.

The tripeptide Bz-Arg-Gly-Asp(-OMe)-OH was synthesized by enzymatic method. Bz-Arg-Gly-OEt was synthesized by trypsin in ethanol containing 0.1 M Tris/HCl buffer (pH 8.0), and then H-Asp(-OMe)(2) was incorporated into the Bz-Arg-Gly-OEt using chymopapain in 0.25M CHES/NaOH buffer (pH = 9.0, EDTA 10 mM). The yield of Bz-Arg-Gly-OEt and Bz-Arg-Gly-Asp(-OMe)-OH were 80% and 70% using 1M Bz-Arg-OEt and 0.5M Bz-Arg-Gly-OEt, respectively. For Bz-Arg-Gly-OEt synthesis reaction at high concentrations of the substrates, the buffer content in ethanol was a key factor to determine the optimal reaction condition. In Bz-Arg-Gly-Asp(-OMe)-OH synthesis reaction, the yield was low in organic solvent due to various side products such as Bz-Arg-OH, Bz-Arg-Gly-OH, and Bz-Arg-Gly-Asp(-OMe)-Asp(-OMe)-OH, suggesting that chymopapain has a very broad substrate specificity of the S(1) site. The Bz-Arg-Gly-Asp(-OMe)-OH synthesis rate and its yield were dramatically elevated and the side reactions were reduced using only the CHES/NaOH buffer (pH = 9.0, EDTA 10 mM) as a reaction media. The final product Bz-Arg-Gly-Asp(-OMe)-OH was identified to be formed via C-terminal hydrolysis of Bz-Arg-Gly-Asp(-OMe)(2) after the nucleophile, H-Asp(-OMe)(2), was added.

Journal Article↗
PubMed2000

Direct interaction of the CD38 cytoplasmic tail and the Lck SH2 domain. Cd38 transduces T cell activation signals through associated Lck.

CD38 ligation has been shown to induce activation of intracellular signaling cascade in T lymphocytes through a Lck-dependent pathway. However, it is not clear how Lck initiates the CD38-mediated signaling process. In the present study, we showed that CD38 and Lck were physically associated through the cytoplasmic tail and the Src homology 2 domain, respectively. This was evidenced by coimmunoprecipitation of Lck with CD38 and Lck with isolated CD38 cytoplasmic domain from T cell lysate, cell lysate of COS-7 cells cotransfected with cDNAs of Lck and CD38, or a mixture of in vitro translated CD38 and Lck. Because the CD38 cytoplasmic domain does not contain any tyrosine residue, the interaction should be independent of phosphotyrosine. The interaction was further confirmed by in vitro interaction between a purified Lck Src homology 2 domain and a nonphosphosynthetic peptide corresponding to the membrane proximal region of the CD38 cytoplasmic domain. In addition, CD38 ligation resulted in an elevated tyrosine kinase activity of the CD38-associated Lck and ultimate activation of interleukin-2 gene transcription. Furthermore, expression of a kinase-deficient Lck mutant suppressed interleukin-2 gene activation in a dose-dependent manner. These results strongly suggested that CD38 ligation indeed tranduced signals for T cell activation using its associated Lck.

ADP-ribosyl Cyclase↗
PubMed2000

New xenicane diterpenoids from the gorgonian Acalycigorgia inermis.

Acalycixeniolides D-G [corrected] (1-4), four new diterpenoids of the xenicane class, have been isolated from the gorgonian Acalycigorgia inermis. The structures of these compounds have been determined by combined spectroscopic methods. These compounds exhibited cytotoxicity against a human leukemia cell-line.

Animals↗