PubMed Health⌕ Search

Biomedical subjects

Jing Wang

Publications and source records attributed to Jing Wang.

At least 55 records · Page 3Linked to original sources
PubMed2007

Novel Bcl-2 inhibitors: Discovery and mechanism study of small organic apoptosis-inducing agents.

Apoptosis as a novel target for cancer chemotherapy has generated an intense demand for new apoptosis-inducing agents. The newly revealed role of protein families involved in the apoptosis pathway, and resistance to cytotoxic therapies have opened new avenues for the development of novel anticancer strategies. We have established a novel strategy to rapidly obtain protein-targeted, instead of conventional DNA-targeted, apoptosis inducers as antitumor leads. First, a novel organic non-DNA intercalative compound S1 (8-oxo-3-thiomorpholin-4-yl-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile, M(W) = 331) was found with an IC50 of 10(-7)-10(-8) microM against diverse cancer cell lines. Further biological evaluation demonstrated that it was an apoptosis-inducer both in vivo and in vitro. The treatment of hydroperitoneum hepatoma cells (H22 cell line) with S1 at various concentrations (from 0.01 to 10 microM) for 24 h triggered these cells to enter the apoptosis process. The antitumor efficiency was also tested in the H22 xenotransplant models in mice. At a dosage of 0.3 mg kg(-1), S1 exhibited significant antitumor activity with a much longer survival time, a decrease in tumor size, and increased apoptosis cells in tumor tissue. More importantly, studies of the molecular mechanism of apoptosis induction by S1 revealed that S1 inactivated the Bcl-2 protein by binding to it, depolarizing the mitochondrial membrane, and then activating caspase 9, followed by caspase 3. Finally, structure-based virtual modification was performed by computer modeling. As a result, a derivative, S2 (8-oxo-3-[(thienylmethyl)amino]-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile, M(W) = 341) was identified that possessed a lower binding energy to Bcl-2, and demonstrated better antitumor potency, even on the Bcl-2-overexpressing human acute myeloid leukemia (HL-60) cells (IC50 = 1.3 microM) in vitro. S1 and S2 are the well-defined Bcl-2 inhibitors that give us a promising platform for the development of new therapeutic agents.

Acenaphthenes↗
PubMed2006

Interaction of heparin with two synthetic peptides that neutralize the anticoagulant activity of heparin.

Two synthetic analogues of the heparin-binding domain of heparin/heparan sulfate-interacting protein (Ac-SRGKAKVKAKVKDQTK-NH2) and the all-d-amino acid version of the same peptide (l-HIPAP and d-HIPAP, respectively) were synthesized, and their efficacy as agents for neutralization of the anticoagulant activity of heparin was assayed. The two analogue peptides were found to be equally effective for neutralization of the anticoagulant activity of heparin, as measured by restoration of the activity of serine protease factor Xa by the Coatest heparin method. The finding that l-HIPAP and d-HIPAP are equally effective suggests that d-amino acid peptides show promise as proteolytically stable therapeutic agents for neutralization of the anticoagulant activity of heparin. The interaction of l-HIPAP and d-HIPAP with heparin was characterized by 1H NMR, isothermal titration calorimetry (ITC), and heparin affinity chromatography. The two peptides were found to interact identically with heparin. Analysis of the dependence of heparin-peptide binding constants on Na+ concentration by counterion condensation theory indicates that, on average, 2.35 Na+ ions are displaced from heparin per peptide molecule bound and one peptide molecule binds per hexasaccharide segment of heparin. The analysis also indicates that both ionic and nonionic interactions contribute to the binding constant, with the ionic contribution decreasing as the Na+ concentration increases.

Amino Acid Sequence↗
PubMed2006

Inhibition of the c-Jun N-terminal kinase-mediated mitochondrial cell death pathway restores auditory function in sound-exposed animals.

We tested and characterized the therapeutic value of round window membrane-delivered (RWM) d-JNKI-1 peptide (Bonny et al., 2001) against sound trauma-induced hearing loss. Morphological characteristics of sound-damaged hair cell nuclei labeled by Hoechst staining show that apoptosis is the predominant mode of cell death after sound trauma. Analysis of the events occurring after sound trauma demonstrates that c-Jun N-terminal kinase (JNK)/stress-activated protein kinase activates a mitochondrial cell death pathway (i.e., activation of Bax, release of cytochrome c, activation of procaspases, and cleavage of fodrin). Fluorescein isothiocyanate (FITC)-conjugated d-JNKI-1 peptide applied onto an intact cochlear RWM diffuses through this membrane and penetrates cochlear tissues with the exception of the stria vascularis. A time sequence of fluorescence measurements demonstrates that FITC-labeled d-JNKI-1 remains in cochlear tissues for as long as 3 weeks. In addition to blocking JNK-mediated activation of a mitochondrial cell death pathway, RWM-delivered d-JNKI-1 prevents hair cell death and development of a permanent shift in hearing threshold that is caused by sound trauma in a dose-dependent manner (EC50 = 2.05 microM). The therapeutic window for protection of the cochlea from sound trauma with RWM delivery of d-JNKI-1 extended out to 12 h after sound exposure. These results show that the mitogen-activated protein kinase/JNK signaling pathway plays a crucial role in sound trauma-initiated hair cell death. Blocking this signaling pathway with RWM delivery of d-JNKI-1 may have significant therapeutic value as a therapeutic intervention to protect the human cochlea from the effects of sound trauma.

Animals↗
PubMed2006

Effect of acid on the aggregation of poly(ethylene xide)-poly(propylene oxide)-poly(ethylene oxide) block copolymers.

The acid effect on the aggregation of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) block copolymers EO(20)PO(70)EO(20) has been investigated by transmission electron microscopy (TEM), particle size analyzer (PSA), Fourier transformed infrared, and fluorescence spectroscopy. The critical micellization temperature for Pluronic P123 in different HCl aqueous solutions increases with the increase of acid concentration. Additionally, the hydrolysis degradation of PEO blocks is observed in strong acid concentrations at higher temperatures. When the acid concentration is low, TEM and PSA show the increase of the micelle mean diameter and the decrease of the micelle polydispersity at room temperature, which demonstrate the extension of EO corona and tendency of uniform micelle size because of the charge repulsion. When under strong acid conditions, the aggregation of micelles through the protonated water bridges was observed.

Epoxy Compounds↗
PubMed2006

IKK antagonizes CD95 ligation-mediated apoptosis by regulating NF-kappaB activity.

The CD95 (Apo1/Fas)/CD95 ligand system plays pivotal roles in various aspects of immune regulation and function by triggering apoptosis. Besides the apoptosis signaling pathway, CD95 ligation also induces the activation of NF-kappaB. Previous studies suggest that IkappaB kinase (IKK) may be a key player in cell survival by mediating NF-kappaB activation. However, the roles of IKK in CD95 ligation-mediated apoptosis and NF-kappaB activation are still not clear. In this report, we show that expression of the caspase-resistant uncleavable IKKbeta (UCIKKbeta) mutant suppressed CD95 ligation-mediated cell death in HeLa cells. Furthermore, CD95 ligation induced much more cell death in IKKbeta-/- murine embryonic fibroblasts (MEFs) than in wild type MEFs, despite that IKK was only marginally activated upon CD95 ligation. Pretreatment of HeLa cells with a specific IKK inhibitor NEMO-binding domain (NBD) peptide blocked CD95 ligation-induced NF-kappaB transcriptional activity. And UCIKKbeta enhanced the basal NF-kappaB activity, and consequently led to higher NF-kappaB activity upon CD95 ligation in HeLa cells. Therefore, IKK antagonizes CD95 ligation-mediated apoptosis by regulating NF-kappaB activity.

Animals↗
PubMed2006

Blocking c-Jun-N-terminal kinase signaling can prevent hearing loss induced by both electrode insertion trauma and neomycin ototoxicity.

Neomycin ototoxicity and electrode insertion trauma both involve activation of the mitogen activated protein kinase (MAPK)/c-Jun-N-terminal kinase (JNK) cell death signal cascade. This article discusses mechanisms of cell death on a cell biology level (e.g. necrosis and apoptosis) and proposes the blocking of JNK signaling as a therapeutic approach for preventing the development of a permanent hearing loss that can be initiated by either neomycin ototoxicity or electrode insertion trauma. Blocking of JNK molecules incorporates the use of a peptide inhibitor (i.e. D-JNKI-1), which is specific for all three isoforms of JNK and has been demonstrated to prevent loss of hearing following either electrode insertion trauma or loss of both hearing and hair cells following exposure to an ototoxic level of neomycin. We present previously unpublished results that control for the effect of perfusate washout of aminoglycoside antibiotic by perfusion of the scala tympani with an inactive form of D-JNKI-1 peptide, i.e. JNKI-1(mut) peptide, which was not presented in the original J. Neurosci. article that tested locally delivered D-JNKI-1 peptide against both noise- and neomycin-induced hearing loss (i.e. Wang, J., Van De Water, T.R., Bonny, C., de Ribaupierre, F., Puel, J.L., Zine, A. 2003a. A peptide inhibitor of c-Jun N-terminal kinase protects against both aminoglycoside and acoustic trauma-induced auditory hair cell death and hearing loss. J. Neurosci. 23, 8596-8607). D-JNKI-1 is a cell permeable peptide that blocks JNK signaling at the level of the three JNK molecular isoforms, which when blocked prevents the increases in hearing thresholds and the loss of auditory hair cells. This unique therapeutic approach may have clinical application for preventing: (1) hearing loss caused by neomycin ototoxicity; and (2) the progressive component of electrode insertion trauma-induced hearing loss.

Animals↗
PubMed2006

Effect of hydrophobicity inside PEO-PPO-PEO block copolymer micelles on the stabilization of gold nanoparticles: experiments.

In this paper we present the effect of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) block copolymer micelles and their hydrophobicity on the stabilization of gold nanoparticles. Gold nanoparticles were prepared by a method developed by Sakai et al. (Sakai, T.; Alexandridis, P. Langmuir 2004, 20, 8426). An absorption centered at 300-400 nm in time-dependent UV spectra provided evidence that the very first step of the synthesis was to form primary gold clusters. Then the gold clusters grew in size and were stabilized by block copolymer micelles. The stabilization capacities of the micelles were modulated by tuning the block copolymer concentration and composition and by adding salts. With good stabilization, gold particles were spherical and uniform in size with a diameter of 5-10 nm. Otherwise they were aggregates with irregular shapes such as triangular, hexagonal, and rodlike. The presence of a small amount of NaF significantly increased the stabilization capacity of the micelles and consequently modified the quality of the gold particles. Using FTIR and 1H NMR spectroscopy, micellization of the block copolymers and hydrophobicity of the micelles were proven very important for the stabilization. A higher hydrophobicity of the micelle cores was expected to favor the entrapment of primary gold clusters and the stabilization of gold nanoparticles.

Colloids↗
PubMed2006

Physiology, pharmacology and plasticity at the inner hair cell synaptic complex.

This report summarizes recent neuropharmacological data at the IHC afferent/efferent synaptic complex: the type of Glu receptors and transporter involved and the modulation of this fast synaptic transmission by the lateral efferents. Neuropharmacological data were obtained by coupling the recording of cochlear potentials and single unit of the auditory nerve with intra-cochlear applications of drugs (multi-barrel pipette). We also describe the IHC afferent/efferent functioning in pathological conditions. After acoustic trauma or ischemia, acute disruption of IHC-auditory dendrite synapses are seen. However, a re-growth of the nerve fibres and a re-afferentation of the IHC were completely done 5 days after injury. During this synaptic repair, multiple presynaptic bodies were commonly found, either linked to the membrane or "floating" in ectopic positions. In the meantime, the lateral efferents directly contact the IHCs. The demonstration that NMDA receptors blockade delayed the re-growth of neurites suggests a neurotrophic role of NMDA receptors in pathological conditions.

Amino Acid Transport System X-AG↗
PubMed2006

Enrichment analysis in high-throughput genomics - accounting for dependency in the NULL.

Translating the overwhelming amount of data generated in high-throughput genomics experiments into biologically meaningful evidence, which may for example point to a series of biomarkers or hint at a relevant pathway, is a matter of great interest in bioinformatics these days. Genes showing similar experimental profiles, it is hypothesized, share biological mechanisms that if understood could provide clues to the molecular processes leading to pathological events. It is the topic of further study to learn if or how a priori information about the known genes may serve to explain coexpression. One popular method of knowledge discovery in high-throughput genomics experiments, enrichment analysis (EA), seeks to infer if an interesting collection of genes is 'enriched' for a Consortium particular set of a priori Gene Ontology Consortium (GO) classes. For the purposes of statistical testing, the conventional methods offered in EA software implicitly assume independence between the GO classes. Genes may be annotated for more than one biological classification, and therefore the resulting test statistics of enrichment between GO classes can be highly dependent if the overlapping gene sets are relatively large. There is a need to formally determine if conventional EA results are robust to the independence assumption. We derive the exact null distribution for testing enrichment of GO classes by relaxing the independence assumption using well-known statistical theory. In applications with publicly available data sets, our test results are similar to the conventional approach which assumes independence. We argue that the independence assumption is not detrimental.

Data Interpretation, Statistical↗
PubMed2006

Influenza Virus Database (IVDB): an integrated information resource and analysis platform for influenza virus research.

Frequent outbreaks of highly pathogenic avian influenza and the increasing data available for comparative analysis require a central database specialized in influenza viruses (IVs). We have established the Influenza Virus Database (IVDB) to integrate information and create an analysis platform for genetic, genomic, and phylogenetic studies of the virus. IVDB hosts complete genome sequences of influenza A virus generated by Beijing Institute of Genomics (BIG) and curates all other published IV sequences after expert annotation. Our Q-Filter system classifies and ranks all nucleotide sequences into seven categories according to sequence content and integrity. IVDB provides a series of tools and viewers for comparative analysis of the viral genomes, genes, genetic polymorphisms and phylogenetic relationships. A search system has been developed for users to retrieve a combination of different data types by setting search options. To facilitate analysis of global viral transmission and evolution, the IV Sequence Distribution Tool (IVDT) has been developed to display the worldwide geographic distribution of chosen viral genotypes and to couple genomic data with epidemiological data. The BLAST, multiple sequence alignment and phylogenetic analysis tools were integrated for online data analysis. Furthermore, IVDB offers instant access to pre-computed alignments and polymorphisms of IV genes and proteins, and presents the results as SNP distribution plots and minor allele distributions. IVDB is publicly available at http://influenza.genomics.org.cn.

Databases, Genetic↗
PubMed2006

Neurons containing tuberoinfundibular peptide of 39 residues are activated following male sexual behavior.

Tuberoinfundibular peptide of 39 residues (TIP39)-immunoreactive (IR) neurons are present in the medial subdivision of the parvocellular subparafascicular thalamic nucleus (mSPFp) where ejaculation-specific Fos expression is localized. The mSPFp is reciprocally connected to the medial preoptic area (MPOA), bed nucleus of the stria terminalis (BNST) and the medial nucleus of the amygdala (Me), all of which are critical for the regulation of male sexual behavior. The mSPFp also receives galanin and enkephalin containing projections from a region in the lumbar spinal cord, thought to be a central ejaculation center. Therefore, we hypothesized that TIP39 neurons in the mSPFp may be part of the neuronal circuitry activated by male sexual behavior. To test this hypothesis, we examined induction of Fos in TIP39 containing neurons in the mSPFp following male sexual behavior. Mating-induced Fos expression was evaluated in sexually experienced male rats under four experimental conditions: animals that (1) remained in their home cage without any interaction with females, (2) interacted with stimulus females and displayed intromission without ejaculation, (3) displayed one ejaculation, or (4) displayed 2 ejaculations. We found that Fos was induced in TIP39-IR neurons in the mSPFp in male rats following ejaculation but much less so following intromission without ejaculation. This suggests that TIP39-IR neurons in the mSPFp are part of the afferent circuits that process genital-somatosensory information related to ejaculation, and which contribute to mating and mating-induced changes in reproductive behavior.

Amygdala↗
PubMed2006

[Genetic advances in hydatidiform mole].

Hydatidiform mole is the most common gestational trophoblastic disease and is characterized by gross trophoblastic hyperplasia resulting from abnormal fertilization of the oocyte. It is of great interest to researchers because of its propensity for local invasion and spreading. Using cytogenetic and molecular genetic techniques researchers have performed various studies on hydatidiform mole. There are advances in the understanding of karyotype, DNA ploidy, fertilization types, expression of imprinted genes, the differences between genetic classification and pathologic classification, and the correlation to its invasion and spreading.

Female↗
PubMed2006

Postnatal development and gender-dependent expression of TIP39 in the rat brain.

Tuberoinfundibular peptide of 39 residues (TIP39) is a selective agonist of the parathyroid hormone 2 (PTH2) receptor. The topographical distributions of TIP39 and the PTH2 receptor in the brain, described for young male rats, suggested that TIP39 has limbic and endocrine functions. In the present study, we investigated the expression of TIP39 and the PTH2 receptor in male and female rat brain during postnatal development by means of in situ hybridization histochemistry, quantitative RT-PCR, and immunocytochemistry. TIP39's distribution and expression levels are similar in young female and male brains. TIP39 mRNA levels peak at postnatal day 14 and subsequently decline both in the subparafascicular area and in the medial paralemniscal nucleus, the two major sites where TIP39 is synthesized. A greater developmental decrease in TIP39 expression in males leads to greater levels in older females than older males. The decrease is partially reversed by prepubertal but not postpubertal gonadectomy. TIP39 peptide levels in cell bodies change in parallel with mRNA levels, whereas TIP39 appears and disappears somewhat later in nerve fibers. In addition, TIP39 peptide levels are also sexually dimorphic in older rats. In contrast, PTH2 receptor expression in the brain does not decrease during puberty and is not sexually dimorphic even in old animals. The appearance of TIP39 during early, and decline during late, postnatal development together with the gender-dependent levels in mature animals suggests that TIP39 may play a role in sexual maturation or gender-specific functions.

Aging↗
PubMed2006

Examination of depth-weighted optical signals during cardiac optical mapping: a simulation study.

Optical mapping has become a powerful tool to explore complex cardiac propagation. Many experiments and studies claimed that the fluorescence obtained from tissue surface is the averaged response of the transmembrane potential upon probing depth rather than only on the surface. With the electrical propagation model and the photon transport model, the effects of depth-weighted optical signals are examined both during a normal excitation wave and a spiral wave. Our results indicate that depth-weighted optical signals may infer cardiac activation dynamics, such as the mode and the direction of the propagation, the spatial distribution of depolarization or repolarization.

Action Potentials↗
PubMed2006

Protecting axonal degeneration by increasing nicotinamide adenine dinucleotide levels in experimental autoimmune encephalomyelitis models.

Axonal damage is a major morphological alteration in the CNS of patients with multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). However, the underlying mechanism for the axonal damage associated with MS/EAE and its contribution to the clinical symptoms remain unclear. The expression of a fusion protein, named "Wallerian degeneration slow" (Wld(S)), can protect axons from degeneration, likely through a beta-nicotinamide adenine dinucleotide (NAD)-dependent mechanism. In this study, we find that, when induced with EAE, Wld(S) mice showed a modest attenuation of behavioral deficits and axon loss, suggesting that EAE-associated axon damage may occur by a mechanism similar to Wallerian degeneration. Furthermore, nicotinamide (NAm), an NAD biosynthesis precursor, profoundly prevents the degeneration of demyelinated axons and improves the behavioral deficits in EAE models. Finally, we demonstrate that delayed NAm treatment is also beneficial to EAE models, pointing to the therapeutic potential of NAm as a protective agent for EAE and perhaps MS patients.

Animals↗
PubMed2006

Signature combinatorial splicing profiles of rat cardiac- and smooth-muscle Cav1.2 channels with distinct biophysical properties.

l-type (Ca(v)1.2) voltage-gated calcium channels play an essential role in muscle contraction in the cardiovascular system. Alternative splicing of the pore-forming Ca(v)1.2 subunit provides potent means to enrich the functional diversity of the channels. There are 11 alternatively spliced exons identified in rat Ca(v)1.2 gene and random rearrangements may generate up to hundreds of combinatorial splicing profiles. Due to such complexity, the real combinatorial splicing profiles of Ca(v)1.2 have not been solved. This study investigated whether the 11 alternatively spliced exons are spliced randomly or linked and if linked, how many combinatorial splicing profiles can be arranged in cardiac- and smooth-muscle cells. By examining three full-length cDNA libraries of the Ca(v)1.2 transcripts isolated from rat heart and aorta, our results showed that the arrangements of some of the alternatively spliced exons are tissue-specific and tightly linked, giving rise to only 41 alternative combinatorial profiles, of which 29 have not been reported. Interestingly, the 41 combinatorial profiles were distinctively distributed in the three Ca(v)1.2 libraries and the one named "heart 1-50" contained unexpected splice variants. Significantly, the tissue-specific cardiac- and smooth-muscle combinatorial splicing profiles of Ca(v)1.2 channels demonstrated distinct electrophysiological properties that may help rationalize the differences observed in native currents. The unique sequences in these tissue-specific splice variants may provide the potential targets for drug design and screening.

Alternative Splicing↗