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Biomedical subjects

Y Zhang

Publications and source records attributed to Y Zhang.

At least 343 records · Page 19Linked to original sources
PubMed2001

Melatonin reverses the profibrillogenic activity of apolipoprotein E4 on the Alzheimer amyloid Abeta peptide.

Inheritance of apoE4 is a strong risk factor for the development of late-onset sporadic Alzheimer's disease (AD). Several lines of evidence suggest that apoE4 binds to the Alzheimer Abeta protein and, under certain experimental conditions, promotes formation of beta-sheet structures and amyloid fibrils. Deposition of amyloid fibrils is a critical step in the development of AD. We report here that addition of melatonin to Abeta in the presence of apoE resulted in a potent isoform-specific inhibition of fibril formation, the extent of which was far greater than that of the inhibition produced by melatonin alone. This effect was structure-dependent and unrelated to the antioxidant properties of melatonin, since it could be reproduced neither with the structurally related indole N-acetyl-5-hydroxytryptamine nor with the antioxidants ascorbate, alpha-tocophenol, and PBN. The enhanced inhibitory effects of melatonin and apoE were lost when bovine serum albumin was substituted for apoE. In addition, Abeta in combination with apoE was highly neurotoxic (apoE4 > apoE3) to neuronal cells in culture, and this activity was also prevented by melatonin. These findings suggest that reductions in brain melatonin, which occur during aging, may contribute to a proamyloidogenic microenvironment in the aging brain.

Alzheimer Disease↗
PubMed2001

Molecular scaffold of a new pokeweed antifungal peptide deduced by 1H nuclear magnetic resonance.

The antifungal peptide from seeds of Phytolacca americana (Pokeweed), designated PAFP-S hereinafter, is a recently found cationic peptide which consists of 38 amino acid residues and exhibits a broad spectrum of antifungal activity, including inhibition of certain saprophytic fungi and some plant pathogens. The secondary structure and three cysteine pairings have been investigated by 1H NMR analysis. The results show that the molecular scaffold of PAFP-S features a triple-stranded antiparallel beta-sheet knotted by a typical disulfide bridge motif, which characterizes the knottin fold. CD spectroscopy indicates a high stability of the molecule in solution. Therefore, PAFP-S should be a new member of the knottin structural family and the first antifungal peptide that adopts the knottin-like fold.

Amino Acid Motifs↗
PubMed2001

Nuclear translocation of PDCD5 (TFAR19): an early signal for apoptosis?

The programmed cell death 5 (PDCD5) protein is a novel protein related to regulation of cell apoptosis. In this report, we demonstrate that the level of PDCD5 protein expressed in cells undergoing apoptosis is significantly increased compared with normal cells, then the protein translocates rapidly from the cytoplasm to the nucleus of cells. The appearance of PDCD5 in the nuclei of apoptotic cells precedes the externalization of phosphatidylserine and fragmentation of chromosome DNA. This phenomenon is parallel to the loss of mitochondrial membrane potential, independent of the feature of apoptosis-inducing stimuli and also independent of the cell types and the apoptosis modality. In conclusion, the nuclear translocation of PDCD5 is a universal earlier event of the apoptotic process, and may be a novel early marker for apoptosis.

Active Transport, Cell Nucleus↗
PubMed2001

1-acetyl-3-[benzoyl(4-methoxyphenyl)methylene]-2,3-dihydro-1H-indol-2-one.

In the title compound, C25H19NO4, the indole moiety is not completely planar, the heterocyclic ring being distorted very slightly towards a half-chair conformation. The benzoyl and 4-methoxyphenyl substituents are individually almost planar and are in a bisecting and nearly perpendicular configuration, respectively, with respect to the plane of the indole moiety. The molecular and packing structures in the crystal are stabilized by intramolecular and intermolecular C-H...O interactions.

Journal Article↗
PubMed2001

Phospholipid metabolite 1-palmitoyl-lysophosphatidylcholine enhances human ether-a-go-go-related gene (HERG) K(+) channel function.

BACKGROUND: Lysophosphatidylcholine (LPC), a naturally occurring phospholipid metabolite, accumulates in the ischemic heart and causes extracellular K(+) accumulation and action potential shortening. LPC has been incriminated as a biochemical trigger of lethal cardiac arrhythmias, but the underlying mechanisms remain poorly understood. METHODS AND RESULTS: We studied the effect of 1-palmitoyl-LPC (Pal-LPC) on currents resulting from human ether-a-go-go-related gene (HERG) expression in human embryonic kidney (HEK) cells using whole-cell patch-clamp techniques. Bath application of Pal-LPC consistently and reversibly increased HERG current (I(HERG)). The effects of Pal-LPC were apparent as early as 3 minutes after application of the drug, reached maximum within 10 minutes, and were reversible on washout. Pal-LPC increased I(HERG) at voltages between -20 and +30 mV, with greater effects at stronger depolarization. However, Pal-LPC did not affect the voltage-dependence of I(HERG) activation. In contrast, Pal-LPC significantly shifted the inactivation curve toward more positive potentials, causing a mean 20.0+/-2.2 mV shift in half-inactivation voltage relative to control. CONCLUSIONS: Our results indicate that apart from being a well-recognized target for drug inhibition, I(HERG) can also be enhanced by natural substances. An increase in I(HERG) by Pal-LPC may contribute to K(+) loss, abnormal electrophysiology, and arrhythmia occurrence in the ischemic heart.

Arrhythmias, Cardiac↗
PubMed2001

Analysis of the expression pattern of Ebp1, an ErbB-3-binding protein.

Ebp1, a member of the PA2G4 family, was isolated as an ErbB-3-binding protein in our laboratory using yeast two hybrid analysis. Although Ebp1 mRNA is ubiquitously expressed, little is known about either the expression of Ebp1 protein in vivo or its translation initiation site. Western blotting analysis of a wide range of cell lines and primary tissue indicated that in the majority of cases Ebp1 is expressed as a single protein which migrates at 48 kDa in SDS-polyacrylamide gels. We show using epitope-tagged expression constructs that the second, not the first, in-frame ATG is used for the initiation of translation of the endogenous protein, encoding a protein predicted to be 41.5 kDa. The molecular mass of endogenous Ebp1 protein derived from mouse liver and brain was determined by mass spectrometry and the data confirm that translation of endogenous Ebp1 in tissues is initiated from the second in-frame ATG.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Conformational and functional significance of residue proline 17 in chicken muscle adenylate kinase.

The effect of mutation proline 17 on the multiple conformations and catalytic function in chicken muscle adenylate kinase (AK) has been studied. The substitution of proline 17 with glycine or valine altered the distribution of multiple conformations. Compared with the wild-type enzyme, the P17G and P17V mutants contained decreased fraction of minor conformer from 18% to 9% and 11%, respectively. Due to the mutation, the enzyme showed lower secondary structural content, poorer affinity to substrates or substrate analogues, and reduced catalytic efficiency. The results revealed the significance of proline 17 in the conformation and function of AK.

Adenosine Diphosphate↗
PubMed2001

Minocycline blocks nitric oxide-induced neurotoxicity by inhibition p38 MAP kinase in rat cerebellar granule neurons.

Minocycline, a semisynthetic second-generation tetracycline, was reported to have neuroprotective effects in models of global and focal cerebral ischemia, the R6/2 mouse model of Huntington disease, as well as glutamate-induced neurotoxicity in mixed neuronal/glial cultures. It was suggested that neuroprotective effects of minocycline resulted from inhibition of microglial/astroglial activation 'Proc. Natl. Acad. Sci. USA 95 1998 15769'. To determine whether or not minocycline is able to directly protect neurons against injury insults and to delineate its neuroprotective mechanism(s), we treated cultured rat cerebellar granule neurons (CGN) with nitric oxide (NO) in the presence or absence of minocycline. We found that minocycline protected neurons against NO-induced neuronal death in a concentration-dependent fashion. Consistent to other reports, NO was able to induce p38 MAP kinase phosphorylation at 3-6 h and such an induction could be significantly inhibited by minocycline. Furthermore, SB 203580, a p38 MAP kinase inhibitor, almost completely attenuated NO-induced neuronal death of CGN as well. These results suggest that minocycline is able to block NO-induced neurotoxicity in CGN by inhibiting NO-induced phosphorylation of p38 MAP kinase. Our finding may explain the neuroprotective mechanism of minocycline in those neurodegenerative models.

Animals↗
PubMed2001

Generation of three selenium-containing catalytic antibodies with high catalytic efficiency using a novel hapten design method.

A novel strategy for design of haptens that were used to produce catalytic antibodies was developed and three monoclonal antibodies, 3G5, 2F3, and 5C9, were generated using this strategy. These monoclonal antibodies were converted into selenium-containing abzymes by chemically modifying the hydroxyl group of serines followed by sodium hydrogen selenide displacement. These selenium-containing abzymes exhibited remarkable glutathione peroxidase activity, which surpasses the activity of some native glutathione peroxidases. The activities of the selenium-containing abzymes Se-3G5, Se-2F3, and Se-5C9 which catalyzed reduction of hydroperoxides by glutathione were 2.23, 4.20, and 3.79 times that of rabbit liver glutathione peroxidase, respectively. Detailed steady-state kinetics study on Se-2F3 was carried out and the value of k(cat)/K(m) (H(2)O(2)) was found to be 2.11 x 10(7) M(-1) min(-1) which was supposed to be one of the highest among the known catalytic antibodies. The data of association constants and glutathione peroxidase activities of these catalytic antibodies and the steady-state kinetics of Se-2F3 showed that the method might be a remarkably efficient one for generating catalytic antibodies with glutathione peroxidase activity.

Amino Acid Sequence↗
PubMed2001

Laboratory and field evaluation of Schistosoma japonicum DNA vaccines in sheep and water buffalo in China.

Vaccines are needed to control zoonotic Schistosoma japonicum infection and several vaccine candidates have now been identified. Two of these (Sj28GST and Sj23) have shown particular promise in sheep when injected with Freund's adjuvants. The objective of the present work was to find a vaccine formulation which may have potential for widespread use in the field. DNA vaccine formulations of these antigens were produced and tested first in sheep under laboratory conditions and then in both the laboratory and the field in water buffalo. In both host species partial protection as evidenced by a reduction in parasite counts in vaccinated compared with control animals was induced by both vaccines, and in water buffalo the vaccines were shown to be partially protective in the field as well as in the laboratory. These results suggest that the two DNA vaccines tested here may have potential for large-scale field use.

Animals↗
PubMed2001

Synthesis and biological evaluation of tropane-like 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909) analogues.

We have prepared azabicyclo[3.2.1] derivatives (C-3-substituted tropanes) that bind with high affinity to the dopamine transporter and inhibit dopamine reuptake. Within the series, 3-[2-[bis-(4-fluorophenyl)methoxy]ethylidene]-8-methyl-8-azabicyclo[3.2.1]octane (8) was found to have the highest affinity and selectivity for the dopamine transporter. These azabicyclo[3.2.1] (bridged piperidine) series of compounds differ from the well-known benztropines by a 2-carbon spacer between C-3 and a diarylmethoxy moiety. Interestingly, these new compounds demonstrated a much lower affinity for the muscarinic-1 site, at least a 100-fold decrease compared to benztropine. Replacing N-methyl with N-phenylpropyl in two of the compounds resulted in a 3-10-fold increase in binding affinity for the dopamine transporter. However, those compounds lost selectivity for the dopamine transporter over the serotonin transporter. Replacement of the ether oxygen in the diarylmethoxy moiety with a nitrogen atom gave relatively inactive amines, indicating the important role which is played by the ether oxygen in transporter binding. Reduction of the C-3 double bond in 8 gave 3 alpha-substituted tropanes, as shown by X-ray crystallographic analyses of 11, 12, and 19. The 3 alpha-substituted tropanes had lower affinity and less selectivity than the comparable unsaturated ligands.

Animals↗
PubMed2001

Protective effects of nitroglycerin-induced preconditioning mediated by calcitonin gene-related peptide in rat small intestine.

Previous studies of myocardium have shown that ischemic preconditioning could be mimicked by nitroglycerin through stimulating the release of calcitonin gene-related peptide (CGRP). The present study examined whether nitroglycerin could also provide a preconditioning stimulus in the peripheral vascular bed (the anse intestinalis of rat), and whether endogenous CGRP is involved in this process. The model of in situ perfusion was prepared with rat small intestine. One hour of ischemia and 15 min of reperfusion caused a significant impairment of intestinal morphology and an increase in the release of both lactate dehydrogenase and malondialdehyde. Pretreatment with nitroglycerin, 10(-7), 3 x 10(-7), 10(-6) M for 5 min produced a significant improvement of intestinal tissue morphology and a decrease in the release of both lactate dehydrogenase and malondialdehyde. However, the protection afforded by nitroglycerin was abolished by CGRP-(8-37), a selective CGRP acceptor antagonist. Pretreatment with capsaicin, which specifically depletes the transmitter content of sensory nerves, also abolished the protection by nitroglycerin. In addition, the content of CGRP-like immunoreactivity in the effluent was increased during nitroglycerin perfusion. On the other hand, the results from the in vivo experiment showed that nitroglycerin (i.v. 0.13 mg/kg) injected 5 min before prolonged ischemia could provide significant protection against the injury caused by 30-min ischemia and 1-h reperfusion in the rat small intestine, but would also cause a significant increase in the levels of CGRP in the plasma. All these findings suggest that nitroglycerin-induced preconditioning is related to stimulation of CGRP release in the rat small intestine.

Animals↗
PubMed2001

Analysis of the proliferative responses to peptides in individuals with vigorous Gag protein-specific proliferation.

Proliferative responses to recombinant HIV proteins in infected individuals may represent a correlate of protection from disease progression. In this study, the proliferative responses to HIV p24, p55 and gp120 were evaluated in infected subjects. Whereas, vigorous proliferative responses directed at the Gag proteins were detected in several individuals, Env-specific proliferation was observed in only one subject. Epitope mapping using overlapping peptides demonstrated proliferative responses of PBMC to Gag peptides. Responses were broadly directed at multiple peptides in some subjects. Although several of the peptides that induced proliferative responses also contain CTL epitopes potentially relevant in the particular individuals, many additional Gag T cell epitopes were present in each subject. This finding may be relevant for the design and testing of HIV candidate vaccines.

AIDS Vaccines↗
PubMed2001

Bone mineral density and verbal memory impairment: Third National Health and Nutrition Examination Survey.

Previous studies have examined the relation of endogenous estrogen levels or estrogen replacement therapy to the risk of poor cognitive function, but results have been inconclusive. Bone mineral density has been proposed as a marker for cumulative estrogen exposure. The authors studied the relation of bone mineral density to the prevalence of verbal memory impairment among 4,304 elderly subjects in the Third National Health and Nutrition Examination Survey (1988-1994). Bone mineral density was measured in five regions of the proximal femur with dual-energy x-ray absorptiometry. Verbal memory was assessed using delayed recall of a three-item word list and a six-item story. Verbal memory impairment was defined as a combined score of <4. The prevalence of verbal memory impairment for each increasing bone mineral density quintile at the femoral neck was 8.35, 5.74, 5.22, 5.00, and 3.38% in women and 11.54, 7.27, 8.47, 6.29, and 5.89% in men, respectively. With adjustment for age, sex, and other covariates, the prevalence ratios of verbal memory impairment for each increased bone mineral density quintile were 1.00, 0.64, 0.65, 0.55, and 0.44, respectively (p for trend < 0.001). These results suggest that bone mineral density in the elderly is associated with verbal memory impairment. The mechanisms underlying this relation are not understood, but cumulative exposure to estrogen may play a role.

Absorptiometry, Photon↗
PubMed2001

Cloning and characterization of a novel form of mouse fibroblast growth factor-1 (FGF-1) mRNA, FGF-1.G: differential expression of FGF-1 and FGF-1.G mRNAs during embryonic development and in postnatal tissues.

The fibroblast growth factor-1 (FGF-1) gene is characterized by the presence of different untranslated exons in its 5' end that direct the expression of alternatively spliced mRNA variants (1.A, 1.B and 1.C) that encode for FGF-1. We have previously isolated a new mouse FGF-1 upstream untranslated exon, which we termed -1G. Here we report on the cloning and characterization of the FGF-1 mRNA isoform arising from -1G. This newly identified FGF-1 mRNA species (FGF-1.G), whose transcription start site maps 295 bp upstream from the splice donor site, is predominantly expressed in young liver and kidney, where it comprises 40.2% and 30.7%, respectively, of the total FGF-1 mRNA. While the FGF-1 mRNA comprising all of the FGF-1 transcripts was present in distinct tissues at embryonic days E12.5 and E15.5, the FGF-1.G mRNA was not detected during murine embryogenesis; therefore the role of FGF-1 in embryonic development must be attributed to FGF-1 mRNAs arising from upstream untranslated exons other than -1G. On the other hand, the parallel decrease of both FGF-1 and FGF-1.G mRNA levels we observed in the aging mouse kidney and liver suggests a role of FGF-1.G in normal cellular maintenance and survival.

Aging↗
PubMed2001

A fast Newton method for entropy maximization in statistical phase estimation.

A fast Newton method is presented for solving the entropy maximization problem in the Bayesian statistical approach to phase estimation. The method requires only O(n log n) instead of standard O(n3) floating point operations per iteration, while converging in the same rate as the standard Newton method. The method is described and related computational issues are discussed. Numerical results on simple test cases are also presented to demonstrate the behavior of the method.

Journal Article↗
PubMed2001

UV-damaged DNA-binding proteins are targets of CUL-4A-mediated ubiquitination and degradation.

Cul-4A, which encodes a member of the cullin family subunit of ubiquitin-protein ligases, is expressed at abnormally high levels in many tumor cells. CUL-4A can physically associate with the damaged DNA-binding protein (DDB), which is composed of two subunits, p125 and p48. DDB binds specifically to UV-damaged DNA and is believed to play a role in DNA repair. We report here that CUL-4A stimulates degradation of p48 through the ubiquitin-proteasome pathway, resulting in an overall decrease in UV-damaged DNA binding activity. The R273H mutant of p48 identified from a xeroderma pigmentosium (group E) patient is not subjected to CUL-4A-mediated proteolysis, consistent with its inability to bind CUL-4A. p125 is also an unstable protein, and its ubiquitination is stimulated by CUL-4A. However, the abundance of p125 is not dramatically altered by Cul-4A overexpression. UV irradiation inhibits p125 degradation, which is temporally coupled to the UV-induced translocation of p125 from the cytoplasm into the nucleus. CUL-4A is localized primarily in the cytoplasm. These findings identify DDB subunits as the first substrates of the CUL-4A ubiquitination machinery and suggest that abnormal expression of Cul-4A results in reduced p48 levels, thus impairing the ability of DDB in lesion recognition and DNA repair in tumor cells.

Animals↗