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X Sun

Publications and source records attributed to X Sun.

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

Fractal and chaotic behavior of circular cellular automata.

A new type of circular cellular automata (CCA) has been introduced. The evolutions of the CCA obtained by the clockwise, anticlockwise, and scanning line-by-line site sequence in the successively growing rings divided from a square lattice are studied. The evolution seems to form a twisty fishnet when the CCA are grown by the first two sequences. Sierpinski triangle gasket or the modulated ones are formed in the fourth quadrant of the CCA grown by the line scanning sequence. Fractal analysis is used to characterize the relationships between the pattern formed and the initial position of the growing ring and it is found that the pattern is very sensitive to the initial growth condition, showing the chaotic behavior.

Journal Article↗
PubMed2001

Synthesis and evaluation of oxodioxolenylmethyl carbamate prodrugs of pseudomycins.

With the aim of increasing therapeutic indexes of novel cyclic depsinonapeptide pseudomycins, we synthesized and evaluated a series of mono-, di-, and trioxodioxolenylmethyl carbamate prodrugs (2 and 4) of pseudomycin B 1 and pseudomycin C' 3. It is rather encouraging to note that several members of the newly synthesized prodrugs described herein (e.g., 2a, 2e, and 4e) exhibited comparable in vivo efficacy to that achieved by the parent compounds, yet free of tail vein irritation and histamine induced toxicity in vivo.

Animals↗
PubMed2001

Re-expression of estrogen receptor alpha in estrogen receptor alpha-negative MCF-7 cells restores both estrogen and insulin-like growth factor-mediated signaling and growth.

Estrogen can increase insulin-like growth factor-I receptor (IGF-IR) and insulin receptor substrate-1 (IRS-1) expression, two key components of IGF-I-mediated signaling. The result is sensitization of breast cancer cells to IGF-I and synergistic growth in the presence of estrogen and IGF-I. We hypothesized that loss of estrogen receptor alpha (ERalpha) would result in reduced IGF-mediated signaling and growth. To test this hypothesis, we examined IGF-I effects in MCF-7 breast cancer cell sublines that have been selected for loss of ERalpha (C4 and C4-12 cells are ERalpha-negative) by long-term estrogen withdrawal. C4 and C4-12 cells had reduced IGF-IR and IRS-1 mRNA and protein expression (compared with MCF-7 cells) that was not inducible by estrogen. Furthermore, C4 and C4-12 cells showed reduced IGF-I signaling and failed to show any growth response to either estrogen or IGF-I. To prove that loss of IGF and estrogen-mediated signaling and growth was a consequence of loss of ERalpha, we re-expressed ERalpha in C4-12 cells by stable transfection with HA-tagged ERalpha. Three independent C4-12 ERalpha-HA clones expressed a functional ERalpha that (a) was down-regulated by estrogen, (b) conferred estrogen-induction of cyclin D1 expression, and (c) caused estrogen-mediated increase in the number of cells in S phase. All of the effects were completely blocked by antiestrogens. Interestingly, ERalpha-HA expression in C4-12 cells did not restore estrogen induction of progesterone receptor expression. However, ERalpha-positive C4-12 cells now exhibited estrogen-induction of IGF-IR and IRS-1 levels and responded mitogenically to both estrogen and IGF-I. These data show that ERalpha is a critical requirement for IGF signaling, and to our knowledge this is the first report of functional ERalpha expression that confers estrogen-mediated growth of an ER-negative breast cancer cell line.

Breast Neoplasms↗
PubMed2001

Folate-binding triggers the activation of folylpolyglutamate synthetase.

Folic acid is an essential vitamin for normal cell growth, primarily through its central role in one-carbon metabolism. Folate analogs (antifolates) are targeted at the same reactions and are widely used as therapeutic drugs for cancer and bacterial infections. Effective retention of folates in cells and the efficacy of antifolate drugs both depend upon the addition of a polyglutamate tail to the folate or antifolate molecule by the enzyme folylpolyglutamate synthetase (FPGS). The reaction mechanism involves the ATP-dependent activation of the free carboxylate group on the folate molecule to give an acyl phosphate intermediate, followed by attack by the incoming L-glutamate substrate. FPGS shares a number of structural and mechanistic details with the bacterial cell wall ligases MurD, MurE and MurF, and these enzymes, along with FPGS, form a subfamily of the ADP-forming amide bond ligase family. High-resolution crystallographic analyses of binary and ternary complexes of Lactobacillus casei FPGS reveal that binding of the first substrate (ATP) is not sufficient to generate an active enzyme. However, binding of folate as the second substrate triggers a large conformational change that activates FPGS and allows the enzyme to adopt a form that is then able to bind the third substrate, L-glutamate, and effect the addition of a polyglutamate tail to the folate.

Adenosine Triphosphate↗
PubMed2001

N-acyloxymethyl carbamate linked prodrugs of pseudomycins are novel antifungal agents.

We describe herein the synthesis, bioconversion, antifungal activity, and preliminary toxicology evaluation of a series of N-acyloxymethyl carbamate linked triprodrugs of pseudomycins. The syntheses of these prodrugs (3-6) were achieved via simple N-acylation of PSB (1) or PSC' (2) with various prodrug linkers (7-9). As expected, upon incubation with mouse and/or human plasma, many of these prodrugs (3, 5, and 6) were converted to the parent compound within a few hours. Of particular significance, two pseudomycin triprodrugs (5 and 6) showed excellent in vivo efficacy against systemic Candidiasis without tail vein irritation being observed.

Animals↗
PubMed2001

Prodrugs of 3-amido bearing pseudomycin analogues: novel antifungal agents.

With the aim of identifying safer pseudomycin derivatives, we synthesized and evaluated a number of N-acyloxymethyl carbamate linked prodrugs of 3-amido pseudomycin analogues. To our satisfaction, all of the prodrug-amide combinations prepared exhibited good in vivo efficacy against murine Candidiasis. When evaluated in a dose elevation study, all of the newly synthesized combinations (e.g., 4A, 6A, 8A, and 8B) demonstrated improved toxicity profiles in comparison to their corresponding 3-amides as well as the parent pseudomycin B.

Amides↗
PubMed2001

[Epidermal growth factor induce the epithelial stem cell island formation in the regenerated epidermis].

OBJECTIVE: To explore the cell reversion and epithelial stem cell distribution in skins from different developed stages and regenerated epidermis treated with rhEGF. METHODS: Tissue biopsies from 8 regenerated ulcer skins treated with recombinant human epidermal growth factor (rhEGF) were used to evaluate the cell reversion and stem cell distribution in epidermis. The expression of beta1 integrin, keratin 19 (K19), keratin 14 (K14) and keratin 10 (K10) in skin was detected with Streptavidin/Peroxidase (SP) immunohistochemical methods. Another 15 biopsies including 7 cases from the regenerated epidermis treated with SD-Ag, 3 cases from fetus (24 weeks), 3 cases from children and 2 cases from adults were used as the controls. RESULTS: Immunohistochemical stain from beta1 integrin and keratin 19 showed that there were some stem cell islands in epidermis treated with rhEGF. These cells were small and exhibiting positive expression with beta1 integrin and K19 stain. They were isolated, bearing no anatomic relation with the epithelial stem cells in the basal layer. The serial identification experiments indicated that there were no similar stem cell islands in skins from normal adult skin, fetus or child's skin and the regenerated epidermis treated with SD-Ag. All of these results supported that these beta1 integrin and K19 positive stain cells were the stem cells. CONCLUSIONS: The results indicated that these stem cell islands were the specific and individual cell structures in rhEGF treated wounds. There is a possibility that these cells come from the cell reversion from differentiated cells to undifferentiated stem cells.

Epidermal Growth Factor↗
PubMed2001

New insights on how metals disrupt amyloid beta-aggregation and their effects on amyloid-beta cytotoxicity.

Amyloid-beta protein (A beta) aggregates in the brain to form senile plaques. By using thioflavin T, a dye that specifically binds to fibrillar structures, we found that metals such as Zn(II) and Cu(II) normally inhibit amyloid beta-aggregation. Another method for detecting A beta, which does not distinguish the types of aggregates, showed that these metals induce a non-beta-sheeted aggregation, as reported previously. Secondary structural analysis and microscopic studies revealed that metals induced A beta to make non-fibrillar aggregates by disrupting beta-sheet formation. These non-fibrillar A beta aggregates displayed much weaker Congo Red birefringence, and in separate cell culture experiments, were less toxic than self beta-aggregates, as demonstrated by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. The toxicity of soluble A beta was enhanced in the presence of Cu(II), which suggests the previously hypothesized role of A beta in generating oxidative stress. Finally, under an acidic condition, similar to that in the inflammation associated with senile plaques, beta-aggregation was robustly facilitated at one specific concentration of Zn(II) in the presence of heparin. However, because a higher concentration of Zn(II) virtually abolished this abnormal phenomenon, and at normal pH any concentrations strongly inhibit beta-aggregation and its associated cytotoxicity, including its anti-oxidative nature we suggest that Zn(II) has an overall protective effect against beta-amyloid toxicity.

Amyloid beta-Peptides↗
PubMed2001

Niemann-Pick C variant detection by altered sphingolipid trafficking and correlation with mutations within a specific domain of NPC1.

Niemann-Pick disease type C (NPC) is a fatal, autosomal recessive lipidosis characterized by lysosomal accumulation of unesterified cholesterol and multiple neurological symptoms, such as vertical supranuclear ophthalmoplegia, progressive ataxia, and dementia. More than 90% of cases of NPC are due to a defect in Niemann-Pick C1 (NPC1), a late endosomal, integral membrane protein that plays a role in cholesterol transport or homeostasis. Biochemical diagnosis of NPC has relied on the use of patient skin fibroblasts in an assay to demonstrate delayed low-density lipoprotein (LDL)-derived cholesterol esterification and a cytological technique-filipin staining-to demonstrate the intracellular accumulation of cholesterol. A small percentage of patients, referred to as "NPC variants," present with clinical symptoms of NPC but show near-normal results of these biochemical tests, making laboratory confirmation of NPC disease problematic. Here, we demonstrate that NPC-variant fibroblast samples can be detected as sphingolipid storage disease cells, using a fluorescent sphingolipid analog, BODIPY-lactosylceramide. This lipid accumulated in endosomes/lysosomes in variant cells preincubated with LDL cholesterol but targeted to the Golgi complex in normal cells under these conditions. The reproducibility of this technique was validated in a blinded study. In addition, we performed mutation analysis of the NPC1 gene in NPC variant and "classical" NPC cell samples and found a high incidence of specific mutations within the cysteine-rich region of NPC1 in variants. We also found that 5 of the 12 variant cell samples had no apparent defect in NPC1 but were otherwise indistinguishable from other variant cells. This is a surprising result, since, in general, approximately 90% of patients with NPC possess defects in NPC1. Our findings should be useful for the detection of NPC variants and also may provide significant new insight regarding NPC1 genotype/phenotype correlations.

Alleles↗
PubMed2001

HSP22, a new member of the small heat shock protein superfamily, interacts with mimic of phosphorylated HSP27 ((3D)HSP27).

Most of the members of the superfamily of mammalian small heat shock or stress proteins are abundant in muscles where they play a role in muscle function and maintenance of muscle integrity. One member of this protein superfamily, human HSP27, is rapidly phosphorylated on three serine residues (Ser(15), Ser(78), and Ser(82)) during cellular response to a number of extracellular factors. To understand better the role of HSP27, we performed a yeast two-hybrid screen of a human heart cDNA library for HSP27-interacting proteins. By using the triple aspartate mutant, a mimic of phosphorylated HSP27, as "bait" construct, a protein with a molecular mass of 21.6 kDa was identified as an HSP27-binding protein. Sequence analysis revealed that this new protein shares an overall sequence identity of 33% with human HSP27. This protein also contains the alpha-crystallin domain in its C-terminal half, a hallmark of the superfamily of small stress proteins. Thus, the new protein itself is a member of this protein superfamily, and consequently we designated it HSP22. According to the two-hybrid data, HSP22 interacts preferentially with the triple aspartate form of HSP27 as compared with wild-type HSP27. HSP22 is expressed predominantly in muscles. In vitro, HSP22 is phosphorylated by protein kinase C (at residues Ser(14) and Thr(63)) and by p44 mitogen-activated protein kinase (at residues Ser(27) and Thr(87)) but not by MAPKAPK-2.

Amino Acid Sequence↗
PubMed2001

Attenuation of doxorubicin chronic toxicity in metallothionein-overexpressing transgenic mouse heart.

Previous studies have shown that cardiac-specific metallothionein (MT)-overexpressing transgenic mice are highly resistant to acute cardiotoxicity induced by doxorubicin (DOX), a most effective anticancer agent. However, cumulative dose-dependent chronic cardiotoxicity attributable to long-term administration of DOX is a significant clinical problem. Because MT is a potent antioxidant and oxidative stress is critically involved in DOX-induced heart injury, the present study was undertaken to test the hypothesis that MT also provides protection against DOX chronic cardiotoxicity. Transgenic mice containing high levels of cardiac MT and nontransgenic controls were treated with a cumulative dose of 40 mg/kg of DOX in 10 equal i.v. injections over a period of 7 weeks. Three weeks after the last injection, the mice were killed for an analysis of cardiotoxicity. As compared with nontransgenic controls, DOX-induced cardiac hypertrophy was significantly inhibited in the transgenic mice. Light microscopic examination revealed that DOX-induced myocardial morphological changes were markedly suppressed or almost eliminated in the transgenic mice. Under electron microscopy, extensive sarcoplasmic vacuolization and severe disruption of mitochondrial fine structure were observed in nontransgenic cardiomyocytes, but almost no sarcoplasmic vacuolization was observed, and the mitochondrial structural changes were almost completely prevented in the transgenic cardiomyocytes. The results thus indicate that MT elevation is a highly effective approach to prevent chronic cardiomyopathy attributable to DOX. This study also suggests that oxidative stress is critically involved in the DOX-induced chronic cardiotoxicity.

Animals↗
PubMed2001

Syntheses and antifungal activities of novel 3-amido bearing pseudomycin analogues.

As a result of our core SAR effort, we discovered a large number of 3-amido pseudomycin B (PSB) analogues (e.g., 4e LY448212 and 5b LY448731) that retain good in vitro and in vivo (IP) activities against Candida and Cryptococcus without inherent tail vein irritation. Several dimethylamino termini bearing 3-amides (e.g., 5b) also exhibited improved potency against Aspergillus in vitro. When evaluated in a two-week rat toxicology study, it was found that all animals receiving 4e (up to 75 mg/kg) were found to be normal. On the basis of these observations, we are convinced that it is possible to broaden the antifungal spectrum and improve the safety profile of pseudomycin analogues at the same time.

Amides↗
PubMed2001

Comparison of effects of the tyrosine kinase inhibitors AG957, AG490, and STI571 on BCR-ABL--expressing cells, demonstrating synergy between AG490 and STI571.

STI571 (formerly CGP57148) and AG957 are small molecule inhibitors of the protein tyrosine kinase (PTK) p145(abl) and its oncogenic derivative p210(bcr-abl). AG490 is an inhibitor of the PTK Janus kinase 2 (JAK2). No direct comparison of these inhibitors has previously been reported, so this study compared their effects on factor-dependent FDC-P1, 32D, and MO7e cells and their p210(bcr-abl)-expressing factor-independent derivatives. STI571 was a more potent inhibitor of (3)H-thymidine incorporation in p210(bcr-abl)-expressing cells than was AG957, and it showed superior discrimination between inhibitory effects on parental cell lines and effects on their p210(bcr-abl)-expressing derivatives. Assays performed with and without growth factor demonstrated that STI571 but not AG957 reversed the p210(bcr-abl)-driven factor independence of cell lines. p210(bcr-abl)-expressing cells were less sensitive to AG490 than to AG957 or STI571. However, for p210(bcr-abl)-expressing clones from all 3 cell lines, synergistic inhibition was demonstrated between STI571 and concentrations of AG490 with no independent inhibitory effect. Inhibition of nucleic acid synthesis with AG957 treatment was associated with reduced cell numbers, reduced viability, and small pyknotic apoptotic cells. At concentrations of STI571 that reversed the p210(bcr-abl) factor-independent phenotype, STI571 treatment and growth factor deprivation together were sufficient to induce apoptosis. This study concludes that, for the cell lines studied, (1) STI571 is a more potent and more selective inhibitor of a p210(bcr-abl)-dependent phenotype than AG957; (2) AG490 synergizes with STI571 to enhance its inhibitory effect on p210(bcr-abl)-driven proliferation; and (3) the combination of p210(bcr-abl)-tyrosine kinase inhibition and growth factor signal withdrawal can be sufficient to induce apoptotic death of transformed cells. (Blood. 2001;97:2008-2015)

Antineoplastic Agents↗
PubMed2001

Rational design and assembly of M(2)M'(3)L(6) supramolecular clusters with C(3h) symmetry by exploiting incommensurate symmetry numbers.

A rational approach to heterometallic cluster formation is described that uses incommensurate symmetry requirements at two different metals to control the stoichiometry of the assembly. Critical to this strategy is the proper design and synthesis of hybrid ligands with coordination sites selective toward each metal. The phosphino-catechol ligand 4-(diphenylphosphino)benzene-1,2-diol (H(2)L) possesses both hard catecholate and soft phosphine donor sites and serves such a role, using soft (C(2)-symmetric) and hard (C(3)-symmetric) metal centers. The ML(3) catecholate complexes (M = Fe(III), Ga(III), Ti(IV), Sn(IV)) have been prepared and characterized as C(3)-symmetry precursors for the stepwise assembly (aufbau) of heterometallic clusters. While the single-crystal X-ray structure of the Cs(2)[TiL(3)] salt shows a C(1) mer-configuration in the solid -state, room-temperature solution NMR data of this and related complexes are consistent with either exclusive formation of the C(3)-fac-isomer with all PPh(2) donor sites syn to each other or facile fac/mer isomerization. Coordination of these [ML(3)](2)(-) (M = Ti(IV), Sn(IV)) metallaligands via their soft P donor sites to C(2)-symmetric PdBr(2) units gives exclusively pentametallic [M(2)Pd(3)Br(6)L(6)](4)(-) (M = Ti, Sn) clusters. These clusters have been fully characterized by spectral and X-ray structural data as C(3h) mesocates with Cs(+) or protonated 1,4-diazabicyclo[2.2.2]octane (DABCO.H(+)) cations incorporated into deep molecular clefts. Exclusive formation of this type of supramolecular species is sensitive to the nature of the counterions. Alkali cations such as K(+), Rb(+), and Cs(+) give high-yield formation of the respective clusters while NEt(3)H(+) and NMe(4)(+) yield none of the desired products. Extension of the aufbau assembly to produce related [M(2)Pd(3)Cl(6)L(6)](4)(-), [M(2)Pd(3)I(6)L(6)](4)(-), and [M(2)Cr(3)(CO)(12)L(6)](4)(-) (M = Ti, Sn) clusters has also been realized. In addition to this aufbau approach, self-assembly of several of these [M(2)Pd(3)Br(6)L(6)](4)(-) clusters from all eleven components (two M(IV), three PdBr(2), six H(2)L) was also accomplished under appropriate reaction conditions.

Journal Article↗
PubMed2001

A novel multicomponent synthesis of polysubstituted 5-aminooxazole and its new scaffold-generating reaction to pyrrolo[3,4-b]pyridine.

A novel three-component synthesis of 5-amino oxazole (1) is reported. Its subsequent reaction with alpha,beta-unsaturated acyl chloride leads to polysubstituted pyrrolopyridine (2). A triple domino process, acylation/IMDA/retro-Michael cycloreversion, was involved in the latter process. The methodology allows the quick preparation, from simple and readily available inputs, of highly functionalized title compounds not easily accessed by other methods.

Journal Article↗