Search tips
Search criteria

Results 1-8 (8)

Clipboard (0)

Select a Filter Below

Year of Publication
Document Types
author:("Wang, dahuang")
1.  Human PDE4A8, a novel brain-expressed PDE4 cAMP-specific phosphodiesterase that has undergone rapid evolutionary change 
The Biochemical journal  2008;411(2):361-369.
We have isolated cDNAs encoding PDE4A8 (phosphodiesterase 4 isoform A8), a new human cAMP-specific PDE4 isoform encoded by the PDE4A gene. PDE4A8 has a novel N-terminal region of 85 amino acids that differs from those of the related ‘long’ PDE4A4, PDE4A10 and PDE4A11 isoforms. The human PDE4A8 N-terminal region has diverged substantially from the corresponding isoforms in the rat and other mammals, consistent with rapid evolutionary change in this region of the protein. When expressed in COS-7 cells, PDE4A8 localized predominantly in the cytosol, but approx. 20% of the enzyme was associated with membrane fractions. Cytosolic PDE4A8 was exquisitely sensitive to inhibition by the prototypical PDE4 inhibitor rolipram (IC50 of 11 ± 1 nM compared with 1600 nM for PDE4A4), but was less sensitive to inhibition by cilomilast (IC50 of 101 ± 7 nM compared with 61 nM for PDE4A4). PDE4A8 mRNA was found to be expressed predominantly in skeletal muscle and brain, a pattern that differs from the tissue expression of other human PDE4 isoforms and also from that of rat PDE4A8. Immunohistochemical analysis showed that PDE4A8 could be detected in discrete regions of human brain, including the cerebellum, spinal cord and cerebral cortex. The unique tissue distribution of PDE4A8, combined with the evolutionary divergence of its N-terminus, suggest that this isoform may have a specific function in regulating cAMP levels in human skeletal muscle and brain.
PMCID: PMC4337886  PMID: 18095939
alternative mRNA splicing; cAMP; cilomilast; phosphodiesterase 4 isoform A (PDE4A); phosphoric diester hydrolyase; rolipram
2.  Poly[[(μ2-benzene-1,3-di­carboxyl­ato){μ2-1,4-bis­[(1H-imidazol-1-yl)meth­yl]benzene}­cadmium] di­methyl­formamide monosolvate] 
The title coordination polymer, {[Cd(C8H4O4)(C14H14N4)]·C3H7NO}n, was synthesized by solvothermal reaction of metallic cadmium with the semi-rigid neutral ligand 1,4-bis­[(1H-imidazol-1-yl)meth­yl]benzene (bix) and the V-shaped benzene-1,3-di­carb­oxy­lic acid (m-H2bdc). The structure exhibits a pseudo-C-centring which is almost fulfilled by the polymeric metal complex but not by the solvent dimethylform­amide (DMF) mol­ecules. The asymmetric unit contains two independent CdII ions, two m-bdc2− ligands, one and two half bix ligands, and two solvent DMF mol­ecules. The CdII ions are both five-coordinated by three O atoms from two different m-bdc2− ligands and two N atoms from two different bix ligands in a distorted square-pyramidal geometry. The m-bdc2− ligands adopt a chelate-monodentate coordination mode, connecting neighboring CdII ions into a zigzag chain parallel to [110]. Adjacent chains are further cross-linked by bix ligands, giving rise to a puckered sheet nearly perpendicular to the chain direction. Thus, each CdII ion is connected to four neighboring CdII ions through two m-bdc2− anions and two bix ligands, giving rise to the final non-inter­penetrating uninodal layer with sql (4,4) topology.
PMCID: PMC3884267  PMID: 24454043
3.  Optimization of the method for the culture of melanocyte precursors from hair follicles and their activation by 1,25-dihydroxyvitamin D3 
The melanocytes in vitiligo repigmentation are derived predominantly from melanocyte precursors (MPs) present in the outer root sheath (ORS) of hair follicles. The methods currently used for culturing MPs are unstable, and the cultured cells have the capacity to produce melanin. These factors are problematic when conducting in vitro studies to investigate the mechanism of repigmentation. Although 1,25-dihydroxyvitamin D3 (VID) has been demonstrated to be highly effective in the treatment of vitiligo in the clinic, its precise mode of action has yet to be elucidated. In the present study, the method for the culture of MPs from the ORS of hair follicles was optimized and the ability of VID to activate MPs was investigated. The results suggested that the MPs cultured using the optimized method mainly exhibited bipolar morphology. The cells proliferated well and were negative for 3,4-dihydroxy-L-phenylalanine (DOPA) staining. Transmission electron microscopy revealed that the cytoplasm of the MPs contained numerous stage I and stage II melanosomes; however, stage III and IV melanosomes were not observed. Following VID treatment, the MPs showed increased dendritic morphology, the cells stained positive for DOPA and stage III and IV melanosomes appeared in the cells. Western blotting revealed that microphthalmia-associated transcription factor (MITF), tyrosinase (TYR), tyrosinase-related protein-1 (TRP-1) and TRP-2 were expressed in the MPs and that VID increased the expression levels of MITF, TYR and TRP-1. However, the levels of MITF, TYR and TRP-1 in the MPs prior to and following VID treatment were significantly lower compared with those in cultured epidermal melanocytes, while the levels of TRP-2 in these three groups were not significantly different. Subsequent to VID treatment, the TYR activity in the MPs increased significantly, as did the corresponding melanin levels. In conclusion, the present study successfully optimized the method for MP culture. The MPs demonstrated no significant TYR activity or melanin synthesis; therefore, the MP cultures exhibited the features of MPs in vivo. In addition, VID significantly promoted the differentiation of MPs.
PMCID: PMC3797309  PMID: 24137299
melanocyte precursors; culture; 1,25 dihydroxyvitamin D3; activation
4.  Poly[[diaqua­bis­{μ-4-[6-(4-carb­oxy­phen­yl)-4,4′-bipyridin-2-yl]benzoato-κ2 O:N 1′}copper(II)] dimethyl­formamide tetra­solvate] 
In the title compound, {[Cu(C24H15N2O4)2(H2O)2]·4C3H7NO}n, the CuII ion, lying on an inversion center, is six-coordinated by two N atoms from two 4-[6-(4-carb­oxy­phen­yl)-4,4′-bipyridin-2-yl]benzoate (L) ligands, two deprotonated carboxyl­ate O atoms from two other symmetry-related L ligands and two water mol­ecules in a slightly distorted octa­hedral geometry. The CuII atoms are linked by the bridging ligands into a layer parallel to (101). The presence of intra­layer O—H⋯O hydrogen bonds and π–π inter­actions between the pyridine and benzene rings [centroid–centroid distances = 3.808 (2) and 3.927 (2) Å] stabilizes the layer. Further O—H⋯O hydrogen bonds link the layers and the dimethyl­formamide solvent mol­ecules.
PMCID: PMC3629482  PMID: 23634000
5.  Chemistry and Behavioral Studies Identify Chiral Cyclopropanes as Selective α4β2-Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting an Antidepressant Profile 
Journal of Medicinal Chemistry  2012;55(2):717-724.
Despite their discovery in the early 20th century and intensive study over the last twenty years, nicotinic acetylcholine receptors (nAChRs) are still far from being well understood. Only a few chemical entities targeting nAChRs are currently undergoing clinical trials, and even fewer have reached the marketplace. In our efforts to discover novel and truly selective nAChR ligands, we designed and synthesized a series of chiral cyclopropane-containing α4β2-specific ligands that display low nanomolar binding affinities and excellent subtype selectivity, while acting as partial agonists at α4β2-nAChRs. Their favorable antidepressant-like properties were demonstrated in the classical mouse forced swim test. Preliminary ADMET studies and broad screening towards other common neurotransmitter receptors were also carried out to further evaluate their safety profile and eliminate their potential off-target activity. These highly potent cyclopropane ligands possess superior subtype selectivity compared to other α4β2-nAChR agonists reported to date, including the marketed drug varenicline, and therefore may fully satisfy the crucial prerequisite for avoiding adverse side effects. These novel chemical entities could potentially be advanced to the clinic as new drug candidates for treating depression.
PMCID: PMC3292870  PMID: 22171543
6.  Discovery of Isoxazole Analogs of Sazetidine-A as Selective α4β2-Nicotinic Acetylcholine Receptor (nAChR) Partial Agonists for the Treatment of Depression 
Journal of medicinal chemistry  2011;54(20):7280-7288.
Depression, a common neurological condition, is one of the leading causes of disability and suicide worldwide. Standard treatment targeting monoamine transporters selective for the neurotransmitters serotonin and noradrenalin are not able to help many patients that are poor responders. This study advances the development of sazetidine-A analogs that interact with α4β2-nAChR as partial agonists and that possess favorable antidepressant profiles. The resulting compounds that are highly selective for the α4β2 subtype of nAChR over α3β4-nAChRs are partial agonists at the α4β2 subtype and have excellent antidepressant behavioral profiles as measured by the mouse forced swim test. Preliminary ADMET studies for one promising ligand revealed an excellent plasma protein binding (PPB) profile, low CYP450 related metabolism, and low cardiovascular toxicity, suggesting it is a promising lead as well as a drug candidate to be advanced through the drug discovery pipeline.
PMCID: PMC3197876  PMID: 21905669
7.  Dissociation between duration of action in the forced swim test and nicotinic acetylcholine receptor occupancy with sazetidine, varenicline, and 5-I-A85380 
Psychopharmacology  2011;217(2):199-210.
Nicotinic acetylcholine receptor (nAChR) agonists, partial agonists and antagonists have antidepressant-like effects in rodent models and reduce symptoms of depression in humans.
The aim of this study was to determine if the β2* partial agonist sazetidine-A (sazetidine) showed an antidepressant-like effect in the forced swim test that was mediated by β2* nAChRs activation or desensitization.
Sazetidine, the less selective β2* partial agonist varenicline and the full β2* agonist 5-I-A8350, exhibited acute antidepressant-like effects in the forced swim test. The role of β2* nAChRs was confirmed by results showing 1) reversal of sazetidine’s antidepressant-like effects in the forced swim test by nAChR antagonists mecamylamine and dihydro-β-erythroidine (DHβE); 2) no effect of sazetidine in mice lacking the β2 subunit of the nAChR; and 3) a high correspondence between behaviorally active doses of sazetidine and β2* receptor occupancy. β2* receptor occupancy following acute sazetidine, varenicline, and 5-I-A8350 extended beyond the duration of action in the forced swim test. The long lasting receptor occupancy of sazetidine did not diminish behavioral efficacy in the forced swim test following repeated dosing.
These results demonstrate that activation of β2* nAChRs mediate sazetidine’s antidepressant-like actions and suggest that ligands that activate β2* nAChRs would be promising targets for the development of a new class of antidepressant.
PMCID: PMC3266849  PMID: 21487659
nicotinic receptor; antidepressant; sazetidine-A; AMOP-H-OH; varenicline; 5-I-A85380; receptor occupancy; forced swim
8.  Hydrazide oligonucleotides: new chemical modification for chip array attachment and conjugation 
Nucleic Acids Research  2002;30(21):4793-4802.
We report the synthesis of new phosphoramidite building blocks and their use for the modification of oligonucleotides with hydrazides. The reaction of these hydrazide oligonucleotides with active esters and aldehydes is demonstrated for solution conjugation and immobilization. Compared with the established amino modified oligonucleotides, hydrazides show enhanced reactivity at neutral and acidic buffer conditions. One method to introduce hydrazides is using amidites with preformed, protected hydrazides. A completely novel approach is the generation of the hydrazide functionality during the oligonucleotide cleavage and deprotection with hydrazine. Therefore, building blocks for the introduction of esters as hydrazide precursors are described. For the enhanced attachment on surfaces branched modifier amidites, which introduce up to four reactive groups to the oligonucleotide, are applied. The efficiency of branched hydrazide oligonucleotides compared with standard amino modified oligonucleotides for the immobilization of DNA on active electronic Nanogen chips is demonstrated.
PMCID: PMC135808  PMID: 12409470

Results 1-8 (8)