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Biomedical subjects

Yong Zhang

Publications and source records attributed to Yong Zhang.

At least 145 records · Page 8Linked to original sources
PubMed2005

Vascular hypertrophy in angiotensin II-induced hypertension is mediated by vascular smooth muscle cell-derived H2O2.

Angiotensin II induces the development of vascular hypertrophy and hypertension. An increasing number of studies have demonstrated that reactive oxygen species are involved in many of the vascular responses to angiotensin II. However, the role of specific cell types and the precise identity of the functionally relevant reactive oxygen species remain unclear. In this study, we established a line of transgenic mice with vascular smooth muscle cell (SMC)-specific overexpression of the human catalase gene to explicitly test the functional role of vascular smooth muscle-derived hydrogen peroxide in the hypertensive and hypertrophic responses to angiotensin II in vivo. Catalase overexpression was confirmed by increased expression of catalase mRNA and protein, as well as by an increase in catalase enzymatic activity. The catalase transgenic mice were viable, had no change in basal hydrogen peroxide release (0.36+/-0.03 versus 0.37+/-0.14 micromol/L), and showed no overt developmental abnormality. In response to angiotensin II treatment, catalase transgenic mice exhibited lower hydrogen peroxide release compared with control animals. There was no effect on the hypertensive response to angiotensin II (147+/-10 versus 148+/-12 mm Hg). However, angiotensin II-induced aortic wall hypertrophy was dramatically attenuated in the catalase transgenic mice (wall thickness 32.4+/-2.0 versus 43.2+/-7.6 microm; P<0.001). These results demonstrate that vascular SMC-derived hydrogen peroxide plays an important role in angiotensin II-induced hypertrophy of the arterial wall.

Angiotensin II↗
PubMed2005

A solid state 13C NMR, crystallographic, and quantum chemical investigation of chemical shifts and hydrogen bonding in histidine dipeptides.

We report the first solid-state NMR, crystallographic, and quantum chemical investigation of the origins of the 13C NMR chemical shifts of the imidazole group in histidine-containing dipeptides. The chemical shift ranges for Cgamma and Cdelta2 seen in eight crystalline dipeptides were very large (12.7-13.8 ppm); the shifts were highly correlated (R2= 0.90) and were dominated by ring tautomer effects and intermolecular interactions. A similar correlation was found in proteins, but only for buried residues. The imidazole 13C NMR chemical shifts were predicted with an overall rms error of 1.6-1.9 ppm over a 26 ppm range, by using quantum chemical methods. Incorporation of hydrogen bond partner molecules was found to be essential in order to reproduce the chemical shifts seen experimentally. Using AIM (atoms in molecules) theory we found that essentially all interactions were of a closed shell nature and the hydrogen bond critical point properties were highly correlated with the N...H...O (average R2= 0.93) and Nepsilon2...H...N (average R2= 0.98) hydrogen bond lengths. For Cepsilon1, the 13C chemical shifts were also highly correlated with each of these properties (at the Nepsilon2 site), indicating the dominance of intermolecular interactions for Cepsilon1. These results open up the way to analyzing 13C NMR chemical shifts, tautomer states (from Cdelta2, Cepsilon1 shifts), and hydrogen bond properties (from Cepsilon1 shifts) of histidine residue in proteins and should be applicable to imidazole-containing drug molecules bound to proteins, as well.

Carbon Isotopes↗
PubMed2005

Novel 2,3-dihydrobenzofuran-2-carboxylic acids: highly potent and subtype-selective PPARalpha agonists with potent hypolipidemic activity.

The design and synthesis of a novel class of 2,3-dihydrobenzofuran-2-carboxylic acids as highly potent and subtype-selective PPARalpha agonists are reported. Systematic study of structure-activity relationships has identified several key structural elements within this class for maintaining the potency and subtype selectivity. Select compounds were evaluated in animal models of dyslipidemia using Syrian hamsters and male Beagle dogs, and all these compounds displayed excellent cholesterol- and triglyceride-lowering activity at dose levels that were much lower than the marketed weak PPARalpha agonist fenofibrate.

Animals↗
PubMed2005

Modification of the Stat1 SH2 domain broadly improves interferon efficacy in proportion to p300/CREB-binding protein coactivator recruitment.

A normal level of interferon (IFN) responsiveness via the Stat1 transcription factor is critical to the host, since decreased Stat1 signaling causes immune compromise and increased signaling is associated with inflammatory and neoplastic disease. Here we report how this balance may be influenced by novel alterations in the efficiency of Stat1 signaling. To enable disulfide-dependent and spontaneous formation of active Stat1 homodimer (as was done previously for Stat3), we engineered Stat1-CC with double-cysteine substitutions in the Src homology 2 (SH2)-homodimerization domain (at Ala-656 and Asn-658). In this case, however, mutant and wild-type Stat1 exhibited no difference inspontaneousdimerization. Moreover, Stat1-CC still required ligand-dependent Tyr-701 phosphorylation for function and exhibited hyperresponsiveness to IFN-beta (that depends on Stat1/Stat2 heterodimerization) as well as IFN-gamma (that depends on Stat1/Stat1 homodimerization). Hyperresponsivenss of Stat1-CC was accompanied by increased capacities for Tyr-701 phosphorylation and DNA binding, but these features were also found in a similarly substituted serine mutant (Stat1-SS) that showed no hyperresponsiveness to IFN-gamma. This finding raised the possibility that SH2 domain mutations also influence downstream transcriptional efficiency. Indeed, each of these mutations also enhanced recruitment of the normally rate-limiting p300/CREB-binding Protein (CBP) coactivator to the transcriptional complex in proportion to the level of IFN-driven transactivation and gene expression. Additional modifications indicated that the mutant residues in the SH2 domain appeared to cooperate with Ser-727 in the C-terminal domain to regulate p300/CBP interaction with Stat1. The profile of IFN responsiveness translated into the same progressive increase in the level of viral clearance from Stat1- to Stat1-SS- to Stat1-CC-expressing cells. Thus, SH2 domain determinants may be modified to direct better Stat1 phosphorylation, DNA binding, and coactivator recruitment to fully improve IFN efficacy.

Antineoplastic Agents↗
PubMed2005

AAA ATPases regulate membrane association of yeast oxysterol binding proteins and sterol metabolism.

The yeast genome encodes seven oxysterol binding protein homologs, Osh1p-Osh7p, which have been implicated in regulating intracellular lipid and vesicular transport. Here, we show that both Osh6p and Osh7p interact with Vps4p, a member of the AAA (ATPases associated with a variety of cellular activities) family. The coiled-coil domain of Osh7p was found to interact with Vps4p in a yeast two-hybrid screen and the interaction between Osh7p and Vps4p appears to be regulated by ergosterol. Deletion of VPS4 induced a dramatic increase in the membrane-associated pools of Osh6p and Osh7p and also caused a decrease in sterol esterification, which was suppressed by overexpression of OSH7. Lastly, overexpression of the coiled-coil domain of Osh7p (Osh7pCC) resulted in a multivesicular body sorting defect, suggesting a dominant negative role of Osh7pCC possibly through inhibiting Vps4p function. Our data suggest that a common mechanism may exist for AAA proteins to regulate the membrane association of yeast OSBP proteins and that these two protein families may function together to control subcellular lipid transport.

Adenosine Triphosphatases↗
PubMed2005

Nanoparticle-assisted micropatterning of active proteins on solid substrate.

Micropatterning of proteins on silica substrate was achieved using a new method. Proteins were first immobilized onto silica nanoparticles which were then dispensed into arrayed microwells on silicon. Atomic force microscopy (AFM), fluorescence microscopy and Fourier transform infrared (FTIR) spectroscopy were used to characterize the samples. The results showed that, compared to a planar surface, curved surfaces of nanoparticles provide more space for attaching proteins and thus increases the intensity of fluorescence signal. Furthermore, after attaching to silica nanoparticles, bovine serum albumin (BSA) maintains its major structure and the cytokine IFN-gamma maintains its ability to bind to its antibody. Use of this method can be extended to micropatterning of other biomolecules, such as DNA and enzymes.

Adsorption↗
PubMed2005

A global resource for computational chemistry.

A modular distributable system has been built for high-throughput computation of molecular structures and properties. It has been used to process 250,000 compounds from the NCI database and to make the results searchable by structures and properties. The IUPAC/NIST InChI specification and algorithm has been used to index the structures and enforce integrity during computation. A number of novel features of the PM5 Hamiltonian were identified as a result of the high-throughput approach. The system and the data can be redistributed and reused and promote the value of computed data as a primary chemical resource.

Benzoquinones↗
PubMed2005

Carbon-bridged bis(phenolato)lanthanide alkoxides: syntheses, structures, and their application in the controlled polymerization of epsilon-caprolactone.

A convenient method for the synthesis of lanthanide alkoxo complexes supported by a carbon-bridged bis(phenolate) ligand 2,2'-methylenebis(6-tert-butyl-4-methylphenoxo) (MBMP2-) is described. The reaction of (C5H5)3Nd with MBMPH2 in a 1:1 molar ratio in THF gave the bis(phenolato)lanthanide complex (C5H5)Nd(MBMP)(THF)2 (1) in a nearly quantitative yield. Complex 1 further reacted with 1 equiv of 2-propanol in THF to yield the bis(phenolato)lanthanide isopropoxide [(MBMP)2Nd(mu-OPr(i))(THF)2]2 (2) in high yield. Complex 2 can also be synthesized by the direct reaction of (C5H5)3Nd with MBMPH2 in a 1:1 molar ratio and then with 1 equiv of 2-propanol in situ in THF. Thus, the analogue bis(phenolato)lanthanide alkoxides [(MBMP)2Ln(mu-OR)(THF)2]2 [R = Pr(i), Ln = Yb (3); R = Me, Ln = Nd (4), Yb (5); R = CH2Ph, Ln = Nd (6), Yb (7)] were obtained by the reactions of (C5H5)3Ln (Ln = Nd, Yb) with MBMPH2 and then with 2-propanol, methanol, or benzyl alcohol, respectively. The ytterbium complex {[(MBMP)2Yb(THF)2]2(mu-OCH2Ph)(mu-OH)} (8) was also isolated as a byproduct. The single-crystal structural analyses of complexes 1-3 and 8 revealed that the coordination geometry around lanthanide metal can be best described as a distorted tetrahedron in complex 1 and as a distorted octahedron in complexes 2, 3, and 8. A O-H...Yb agostic interaction was observed in complex 8. Complexes 2-7 were shown to be efficient catalysts for the controlled polymerization of epsilon-caprolactone.

Journal Article↗
PubMed2005

A novel three-dimensional copper(II) coordination polymer with 1,4-bis(1,2,4-triazol-1-ylmethyl)benzene and thiocyanate.

In the title complex, poly[copper(II)-di-2-thiocyanato-2-1,4-bis(1,2,4-triazol-1-ylmethyl)benzene], [Cu(NCS)2(C12H12N6)]n, the CuII atom lies on an inversion centre in a tetragonally distorted octahedral environment. Four N atoms from thiocyanate and 1,4-bis(1,2,4-triazol-1-ylmethyl)benzene (bbtz) ligands fill the equatorial positions, and S atoms from symmetry-related thiocyanate ligands fill the axial positions. The benzene ring of the bbtz ligand lies about an inversion centre. Single thiocyanate bridges link the CuII atoms into two-dimensional sheets containing an unprecedented 16-membered [Cu4(-NCS-N:S)4] ring. The bbtz ligands further link the two-dimensional sheets into a three-dimensional network.

Journal Article↗
PubMed2005

Protein micropatterning using surfaces modified by self-assembled polystyrene microspheres.

A technique for micropatterning of proteins on a nonplanar surface to improve the coverage and functionality of biomolecules is demonstrated. A nonplanar microstructure is created by the self-assembly of polystyrene microspheres into an array of microwells on a silicon wafer to allow the integration of a nonplanar spot on a planar chip. After the microspheres were deposited into the microwells, they were conjugated with proteins. The curve surfaces of the microspheres present more surface area for attaching biomolecules which will increase the density of biomolecules and, hence, the sensitivity for detection. Moreover, proteins immobilized on a curved surface can retain their native structures and function better than on a planar surface because of a smaller area of interaction between the protein and the substrate. Patterning of biomolecules was tested with two model fluorescent proteins. The results show that precise patterning of biomolecules on a nonplanar spot can be achieved with this technique.

Microscopy, Electron, Scanning↗
PubMed2005

Bm-TFF2, a trefoil factor protein with platelet activation activity from frog Bombina maxima skin secretions.

In mammals, trefoil factor family (TFF) proteins are involved in mucosal maintenance and repair, and they are also implicated in tumor suppression and cancer progression. A novel two domain TFF protein from frog Bombina maxima skin secretions (Bm-TFF2) has been purified and cloned. It activated human platelets in a dose-dependent manner and activation of integrin alpha(IIb)beta(3) was involved. Aspirin and apyrase did not largely reduce platelet response to Bm-TFF2 (a 30% inhibition), indicating that the aggregation is not substantially dependent on ADP and thromboxane A2 autocrine feedback. Elimination of external Ca(2+) with EGTA did not influence the platelet aggregation induced by Bm-TFF2, meanwhile a strong calcium signal (cytoplasmic Ca(2+) release) was detected, suggesting that activation of phospholipase C (PLC) is involved. Subsequent immunoblotting revealed that, unlike in platelets activated by stejnulxin (a glycoprotein VI agonist), PLCgamma2 was not phosphorylated in platelets activated by Bm-TFF2. FITC-labeled Bm-TFF2 bound to platelet membranes. Bm-TFF2 is the first TFF protein reported to possess human platelet activation activity.

Amino Acid Sequence↗
PubMed2005

Antibody responses to individual proteins of SARS coronavirus and their neutralization activities.

A novel coronavirus, the severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), was identified as the causative agent of SARS. The profile of specific antibodies to individual proteins of the virus is critical to the development of vaccine and diagnostic tools. In this study, 13 recombinant proteins associated with four structural proteins (S, E, M and N) and five putative uncharacterized proteins (3a, 3b, 6, 7a and 9b) of the SARS-CoV were prepared and used for screening and monitoring their specific IgG antibodies in SARS patient sera by protein microarray. Antibodies to proteins S, 3a, N and 9b were detected in the sera from convalescent-phase SARS patients, whereas those to proteins E, M, 3b, 6 and 7a were undetected. In the detectable specific antibodies, anti-S and anti-N were dominant and could persist in the sera of SARS patients until week 30. Among the rabbit antisera to recombinant proteins S3, N, 3a and 9b, only anti-S3 serum showed significant neutralizing activity to the SARS-CoV infection in Vero E6 cells. The results suggest (1) that anti-S and anti-N antibodies are diagnostic markers and in particular that S3 is immunogenic and therefore is a good candidate as a subunit vaccine antigen; and (2) that, from a virus structure viewpoint, the presence in some human sera of antibodies reacting with two recombinant polypeptides, 3a and 9b, supports the hypothesis that they are synthesized during the virus cycle.

Animals↗
PubMed2005

cAMP-mediated mechanisms for pain sensitization during opioid withdrawal.

Chronic opioid-induced drug dependence and withdrawal syndrome after opioid cessation remain a severe obstacle in clinical treatment of chronic pain and opioid drug addiction. One of the key symptoms during opioid withdrawal is a state of sensitized pain. The most significant molecular adaptation induced by chronic opioids in the brain is upregulation of the cAMP-signaling pathway. Although the cAMP system is known to have multiple effects on central neuron functions, how its upregulation mediates behavioral opioid dependence and withdrawal-induced pain in vivo remains unclear. In this study, we demonstrate that withdrawal from chronic morphine significantly upregulates the mRNA level of adenylyl cyclase (AC) VI and VIII isoforms and immunoreactivity of ACV/VI in the nucleus raphe magnus (NRM), a brainstem site critically involved in opioid modulation of pain. In cellular studies of NRM neurons containing mu-opioid receptors, we show that morphine withdrawal significantly increases glutamate synaptic transmission via a presynaptic mechanism mediated by an upregulated cAMP pathway. Morphine withdrawal also enhances the hyperpolarization-activated current in these neurons by increased intracellular cAMP. Both of the withdrawal-induced cAMP actions increase the excitability of these mu-receptor-containing neurons, which are thought to facilitate spinal pain transmission. Furthermore, in morphine-dependent rats in vivo, blocking the cAMP pathway significantly reduces withdrawal-induced pain sensitization. These results illustrate neurobiological mechanisms for the cAMP-mediated withdrawal pain and provide potential therapeutic targets for the treatment of opioid dependence and withdrawal-related problems.

2-Amino-5-phosphonovalerate↗
PubMed2005

Solid-state NMR fermi contact and dipolar shifts in organometallic complexes and metalloporphyrins.

We have used density functional theory methods to investigate the solid-state "magic-angle" spinning (MAS) NMR and single-crystal NMR/ENDOR spectra of paramagnetic organometallic complexes and metalloporphyrins. The solid-state MAS NMR chemical shifts (including both diamagnetic and hyperfine contributions) are predicted with a slope of 1.007 and an R2 = 0.967, corresponding to a 28 ppm (or 6.3%) error over the entire 442 ppm range. Single-crystal ENDOR hyperfine values, including both isotropic Fermi contact and dipolar couplings, are predicted with a slope of 1.009 and an R2 = 0.998, corresponding to a 0.93 MHz (or 1.2%) error over the entire 78.37 MHz range. In addition, single-crystal NMR shifts (including both hyperfine terms) are predicted with an R2 = 0.961. The ability to compute solid-state MAS NMR and single-crystal NMR/ENDOR data should facilitate the use of these techniques in investigating paramagnetic metal complexes and should be of particular use in studying paramagnetic metalloproteins, where structures are less accurately known.

Electron Spin Resonance Spectroscopy↗
PubMed2005

Supramolecular isomers in the same crystal: a new type of entanglement involving ribbons of rings and 2D (4,4) networks polycatenated in a 3D architecture.

The reaction of corresponding cadmium salts with the flexible ligand 1,4-bis(1,2,4-triazol-1-ylmethyl)benzene (bbtz) affords the 3D coordination network [Cd3(bbtz)6(H2O)6](BF4)(6.1.75H2O (1), containing ribbons of rings and planar 2D (4,4) networks polycatenated with each other, the undulating 2D (4,4) network [Cd(bbtz)2(H2O)2](ClO4)2.2H2O (2), and ribbons of rings [Cd(bbtz)2(H2O)2](BF4)2.3DMF (3) and [Cd(bbtz)2(H2O)2](ClO4)2.3DMF (4).

Journal Article↗
PubMed2005

Surface modification of monodisperse magnetite nanoparticles for improved intracellular uptake to breast cancer cells.

Nanoparticles have been widely used for a variety of biomedical applications and there is a growing need for highly specific and efficient uptake of the nanoparticles into target cells. Poly(ethylene glycol) (PEG), folic acid (FA), and their conjugate PEG-FA were attached to magnetite nanoparticles to compare their effects on the improvement of intracellular uptake of the nanoparticles to human breast cancer cells, BT-20. AFM and TEM results indicated that the nanoparticles after surface modification were monodisperse, with coatings on individual nanoparticles. The cell culture experiments showed that the PEG-FA coated nanoparticles were internalized into BT-20 cancer cells and exhibited higher efficiency of intracellular uptake than only PEG- or FA-coated nanoparticles. The surface modification protocols can also be used to modify the surfaces of other nanoparticles for targeting intracellular delivery.

Breast Neoplasms↗
PubMed2005

(67)Zn NMR chemical shifts and electric field gradients in zinc complexes: a quantum chemical investigation.

We have used quantum chemical methods to predict 67Zn NMR chemical shifts as well as quadrupole coupling constants (CQ) in a series of biomimetic and inorganic zinc complexes. The 67Zn chemical shifts are predicted with an R2 = 0.975, corresponding to a 24.3 ppm or 6.7% error over the entire 365 ppm 67Zn chemical shift range. The 67Zn CQ values are predicted with an R2 = 0.991, corresponding to a 1.17 MHz or 3.0% error over the entire 38.75 MHz range. The 67Zn NMR shifts in a series of complexes containing N,O ligands are, in general, highly correlated with the number of oxygen ligands. The ability to compute 67Zn NMR shifts as well as CQ values opens up the possibility of using both of these properties in structure determination or refinement in proteins.

Imidazoles↗