Biomedical subjects

Jun Zhou

Publications and source records attributed to Jun Zhou.

At least 91 records · Page 5Linked to original sources

PubMed2005

EM012, a microtubule-interfering agent, inhibits the progression of multidrug-resistant human ovarian cancer both in cultured cells and in athymic nude mice.

Drug resistance, in particular multidrug resistance, is a serious problem that impedes the effectiveness of chemotherapy. Multidrug resistance results mainly from an enhanced efflux of drugs by drug pumps located on the cell membrane such as P-glycoprotein. In the study reported here we showed that EM012, a microtubule-interfering agent, is a weak substrate for P-glycoprotein and inhibited the proliferation of A2780/ADR human ovarian cancer cells, which possess multidrug resistance due to P-glycoprotein overexpression. A2780/ADR cells treated with EM012 exhibited pronounced mitotic arrest, developed large multilobed nuclei, and eventually died through the initiation of apoptosis. Intraperitoneal treatment of A2780/ADR xenograft tumors in athymic nude mice with EM012 significantly inhibited tumor progression through triggering apoptosis and conferred an apparent survival advantage. Furthermore, EM012 treatment did not cause detectable toxicity to normal tissues. These findings suggest that EM012 may serve as a novel chemotherapeutic agent for the treatment of multidrug-resistant human ovarian cancer.

Animals↗

PubMed2005

The Genomes of Oryza sativa: a history of duplications.

We report improved whole-genome shotgun sequences for the genomes of indica and japonica rice, both with multimegabase contiguity, or almost 1,000-fold improvement over the drafts of 2002. Tested against a nonredundant collection of 19,079 full-length cDNAs, 97.7% of the genes are aligned, without fragmentation, to the mapped super-scaffolds of one or the other genome. We introduce a gene identification procedure for plants that does not rely on similarity to known genes to remove erroneous predictions resulting from transposable elements. Using the available EST data to adjust for residual errors in the predictions, the estimated gene count is at least 38,000-40,000. Only 2%-3% of the genes are unique to any one subspecies, comparable to the amount of sequence that might still be missing. Despite this lack of variation in gene content, there is enormous variation in the intergenic regions. At least a quarter of the two sequences could not be aligned, and where they could be aligned, single nucleotide polymorphism (SNP) rates varied from as little as 3.0 SNP/kb in the coding regions to 27.6 SNP/kb in the transposable elements. A more inclusive new approach for analyzing duplication history is introduced here. It reveals an ancient whole-genome duplication, a recent segmental duplication on Chromosomes 11 and 12, and massive ongoing individual gene duplications. We find 18 distinct pairs of duplicated segments that cover 65.7% of the genome; 17 of these pairs date back to a common time before the divergence of the grasses. More important, ongoing individual gene duplications provide a never-ending source of raw material for gene genesis and are major contributors to the differences between members of the grass family.

Base Sequence↗

PubMed2005

Physiological relevance of antigen presentasome (APS), an acquired MHC/costimulatory complex, in the sustained activation of CD4+ T cells in the absence of APCs.

T-cell interaction with antigen-presenting cells (APCs) results in activation and clonal expansion of naive T cells. CD80 expression/acquisition in T cells has been implicated in disease processes in patients with rheumatoid arthritis and multiple myeloma and patients infected with HIV. Our previous data indicate that antigen-specific activation of naive T cells results in T-cell acquisition of CD80 molecules from APCs. However, the functional relevance of the acquired CD80 by T cells in signal pathways has remained unresolved. This study aims to define for the first time the role of acquired CD80 in T-cell clonal expansion. We demonstrate the following: (1) T cells, upon CD80 acquisition, sustain their proliferative response in the absence of APCs; (2) T cells that acquire CD80 sustain the activity of transcriptional factors such as nuclear factor-kappaB (NFkappaB) and activator protein-1 (AP1) for 24 hours after separation from APCs and up-regulate signal transducer and activator of transcription-5 (Stat5) in the absence of APCs or exogenous signal 1; and (3) maintenance of these signals results in unique cytokine production. Collectively, our data support the unique concept that naive T cells sustain their activation by removing "antigen presentasome" (APS; eg, antigen-presenting complex) from APCs, thereby releasing the constraint of APC requirement for further activation.

Animals↗

PubMed2005

A sumoylation site in PML/RARA is essential for leukemic transformation.

Pathogenesis of acute promyelocytic leukemia (APL) has been proposed to involve transcriptional repression through enhanced corepressors binding onto RARA moieties of PML/RARA homodimers. Unexpectedly, we show that the K160 sumoylation site in the PML moiety of PML/RARA is required for efficient immortalization/differentiation arrest ex vivo, implying that RARA homodimerization is insufficient to fully immortalize primary hematopoietic progenitor cells. Similarly, PML/RARAK160R transgenic mice develop myeloproliferative syndromes, but never APL. The Daxx repressor no longer binds PML/RARAK160R, but fusion of these two proteins restores the differentiation block ex vivo. Thus, transcriptional repression dependent on a specific sumoylation site in PML is critical for the APL phenotype, while forced RARA dimerization could control expansion of the myeloid compartment.

Animals↗

PubMed2005

A mitochondrial genome sequence of the Tibetan antelope (Pantholops hodgsonii).

To investigate genetic mechanisms of high altitude adaptations of native mammals on the Tibetan Plateau, we compared mitochondrial sequences of the endangered Pantholops hodgsonii with its lowland distant relatives Ovis aries and Capra hircus, as well as other mammals. The complete mitochondrial genome of P. hodgsonii (16,498 bp) revealed a similar gene order as of other mammals. Because of tandem duplications, the control region of P. hodgsonii mitochondrial genome is shorter than those of O. aries and C. hircus, but longer than those of Bos species. Phylogenetic analysis based on alignments of the entire cytochrome b genes suggested that P. hodgsonii is more closely related to O. aries and C. hircus, rather than to species of the Antilopinae subfamily. The estimated divergence time between P. hodgsonii and O. aries is about 2.25 million years ago. Further analysis on natural selection indicated that the COXI (cytochrome c oxidase subunit I) gene was under positive selection in P. hodgsonii and Bos grunniens. Considering the same climates and environments shared by these two mammalian species, we proposed that the mitochondrial COXI gene is probably relevant for these native mammals to adapt the high altitude environment unique to the Tibetan Plateau.

Amino Acid Sequence↗

PubMed2005

Preliminary DNA identification for the tsunami victims in Thailand.

The 2004 Southeast Asia Tsunami killed nearly 5,400 people in Southern Thailand, including foreign tourists and local residents. To recover DNA evidence as much as possible from the seriously decomposed bodies, we explored procedures of sample preparation from both bone and tooth samples as well as both mitochondrial and nuclear markers. Despite having failed to recover enough DNA for nuclear marker typing, we succeeded in obtaining fully informative results for mitochondrial markers (HV1 and HV2) from 258 tooth samples with a success rate of 51% (258/507). Using an organic DNA extraction method coupled with an ultrafiltration step, we obtained 16 STR (including 13 CODIS loci, one sex discrimination locus, and two Identifiler loci) profiles for 834 samples with a success rate of 79% (834/1,062). In addition, by comparing the allelic frequencies between the typed samples as a group and other index populations, we conclude that the Thai tsunami victims are a combined group of several populations. Our results provide valuable evidence and protocols for the future forensic practice.

Bone and Bones↗

PubMed2005

Quinones from Chirita eburnea.

Five new quinone derivatives, (R)-7-hydroxy-alpha-dunnione (1), (R)-8-hydroxy-alpha-dunnione (2), (R)-7,8-dihydroxy-alpha-dunnione (3), (R)-7-methoxy-6,8-dihydroxy-alpha-dunnione (4), and 1,7-dihydroxy-2-hydroxymethylanthraquinone (5), along with seven known compounds, were isolated from Chirita eburnea. All structures were elucidated by spectroscopic techniques (NMR, MS, UV, and IR). The EtOAc fraction of the EtOH extract and compounds 3 and 4 showed free radical (DPPH) scavenging activity, with IC50 values of 101.7 +/- 5.2 microg/mL, 124.82 +/- 8.4 microM, and 45.72 +/- 3.6 microM, respectively, compared with 86.91 +/-6.8 microM for ascorbate.

Algorithms↗

PubMed2005

Pentamidine reduces hERG expression to prolong the QT interval.

Pentamidine, an antiprotozoal agent, has been traditionally known to cause QT prolongation and arrhythmias; however, its ionic mechanism has not been illustrated. In a stable HEK-293 cell line, we observed a concentration-dependent inhibition of the hERG current with an IC50 of 252 microM. In freshly isolated guinea-pig ventricular myocytes, pentamidine showed no effect on the L-type calcium current at concentrations up to 300 microM, with a slight prolongation of the action potential duration at this concentration. Since the effective concentrations of pentamidine on the hERG channel and APD were much higher than clinically relevant exposures (approximately 1 microM free or lower), we speculated that this drug might not prolong the QT interval through direct inhibition of I(Kr) channel. We therefore incubated hERG-HEK cells in 1 and 10 microM pentamidine-containing media (supplemented with 10% serum) for 48 h, and examined the hERG current densities in the vehicle control and pentamidine-treated cells. In all, 36 and 85% reductions of the current densities were caused by 1- and 10-microM pentamidine treatment (P<0.001 vs control), respectively. A similar level of reduction of the hERG polypeptides and a reduced intensity of the hERG protein on the surface membrane in treated cells were observed by Western blot analysis and laser-scanning confocal microscopy, respectively. Taken together, our data imply that chronic administration of pentamidine at clinically relevant exposure reduces the membrane expression of the hERG channel, which may most likely be the major mechanism of QT prolongation and torsade de pointes reported in man.

Animals↗

PubMed2005

QT prolongation and proarrhythmia by moxifloxacin: concordance of preclinical models in relation to clinical outcome.

Moxifloxacin, a fluoroquinolone antibiotic associated with QT prolongation, has been recommended as a positive control by regulatory authorities to evaluate the sensitivity of both clinical and preclinical studies to detect small but significant increases in QT interval measurements. In this study, we investigated effects of moxifloxacin on the hERG current in HEK-293 cells, electrocardiograms in conscious telemetered dogs, and repolarization parameters and arrhythmogenic potentials in the arterially perfused rabbit ventricular wedge model. Moxifloxacin inhibited the hERG current with an IC50 of 35.7 microM. In conscious telemetered dogs, moxifloxacin significantly prolonged QTc at 30 and 90 mg kg(-1), with mean serum Cmax of 8.52 and 22.3 microg ml(-1), respectively. In the wedge preparation, moxifloxacin produced a concentration-dependent prolongation of the action potential duration, QT interval, and the time between peak and end of the T wave, an indicator for transmural dispersion of repolarization. Phase 2 early after-depolarizations were observed in one of five experiments at 30 microM and five of five experiments at 100 microM. The arrhythmogenic potential was also concentration-dependent, and 100 microM ( approximately 18-fold above the typical unbound Cmax exposure in clinical usage) appeared to have a high risk of inducing torsade de pointes (TdP). Our data indicated a good correlation among the concentration-response relationships in the three preclinical models and with the available clinical data. The lack of TdP report by moxifloxacin in patients without other risk factors might be attributable to its well-behaved pharmacokinetic profile and other dose-limiting effects.

Action Potentials↗

PubMed2005

Three new norlignans from Curculigo capitulata.

From the ethanolic extract of the rhizomes of Curculigo capitulata have been isolated, and structurally elucidated by spectral evidences and chemical methods, three new norlignans, capituloside (1), a mixture of curculigenin (2) and isocurculigenin (3), along with four known compounds (4-7), a mixture of 1-O-methylcurculigine (4) and 1-O-methylisocurculigine (5) and a mixture of curculigine (6) and isocurculigine (7).

Curculigo↗

PubMed2005

A new diterpenoid and active stilbenes from Pinus armandii heartwood.

8(17),13-Labdadien-16,14-olid-18-oic acid (1), a new diterpenoid, has been isolated from the heartwood of Pinus armandii Francher, along with seven known diterpenoids (2-8) and four known stilbenes (9-12). Their structures have been elucidated by spectral evidence. (E)-3-Hydroxy-5-methoxystilbene (9) showed significant inhibition against white-rot fungi.

Diterpenes↗

PubMed2005

Capitulatin B, a new eudesmane derivative from Curculigo capitulata, and revised assignment of 13C NMR data of 6alpha,15alpha-epoxy-1beta,4beta-dihydroxyeudesmane.

A new eudesmane derivative named capitulatin B (1) along with 6alpha,15alpha-epoxy-1beta,4beta-dihydroxyeudesmane (2) has been isolated from the rhizomes of Curculigo capitulata. The structure of compound 1 was established as 4alpha,6alpha-epoxy-1beta-hydroxy-4beta-methyleudesmane, and the 13C NMR data of compound 2 was reassigned on the basis of the spectral data, including 1D and 2D NMR (HMQC, HMBC, COSY, ROESY).

Curculigo↗

PubMed2005

Heat shock up-regulates expression of Toll-like receptor-2 and Toll-like receptor-4 in human monocytes via p38 kinase signal pathway.

Summary Heat stress can alert innate immunity by inducing stress proteins such as heat-shock proteins (HSPs). However, it remains unclear whether heat stress affects the activation of antigen-presenting cell (APC) in response to pathogen-associated molecule patterns (PAMPs) by directly regulating pathogen recognition receptors (PRRs). As an important kind of PRRs, Toll-like receptors (TLRs) play critical roles in the activation of immune system. In this study, we demonstrated that heat shock up-regulated the expression of HSP70 as well as TLR2 and TLR4 in monocytes. The induction of TLRs was prior to that of HSP70, which suggesting the up-regulation of TLR2 and TLR4 might be independent of the induction of HSP70. Heat shock activated p38 kinase, extracellular signal-related kinase (ERK) and nuclear factor-kappa B (NF-kappaB) signal pathways in monocytes. Pretreatment with specific inhibitor of p38 kinase, but not those of ERK and NF-kappaB, inhibited heat shock-induced up-regulation of TLR2 and TLR4. This indicates that p38 pathway takes part in heat shock-induced up-regulation of TLR2 and TLR4. Heat shock also increased lipoteichoic acid- or lipopolysaccharide-induced interleukin-6 production by monocytes. These results suggest that the p38 kinase-mediated up-regulation of TLR2 and TLR4 might be involved in the enhanced response to PAMP in human monocytes induced by heat shock.

Blotting, Western↗

PubMed2005

Design and development of a DNA array for rapid detection and genotyping of seven kinds of pathogenic microbes.

A DNA array for rapid detection and genotyping of the pathogenic microbes of epidemic hemorrhagic fever, tsutsugamushi disease, leptospirosis, malaria, schistosomiasis, cholera, and hemorrhagic colitis was developed. The specific and relatively conserved PCR primers and DNA probes were screened from the characteristic genes of the pathogenic microbes. The PCR or RT-PCR methods were established for amplifying and labeling the DNA fragments of the pathogenic microbes. All the probes with the same Tm value were synthesized chemically and modified with an NH2 at their 5' terminus, they were printed on glass slides for fabrication of a oligonucleotide DNA array. The developed DNA array could be used for detecting and genotyping the pathogenic microbes simultaneously, and they had a high sensitivity and specificity.

Animals↗

PubMed2005

Inhibitory effects of jujuboside A on EEG and hippocampal glutamate in hyperactive rat.

In this study, the inhibitory effect of jujuboside A (JuA) on a penicillin sodium (Na-PCN) induced hyperactivity model was investigated. Cortical EEG (electroencephalogram) and the concentration of hippocampal Glutamate (Glu) were monitored simultaneously in vivo as indicators of rat's excitatory state. Power spectral density (PSD) and gravity frequency of PSD were calculated. JuA (0.05 g/L and 0.1 g/L) inhibited the EEG excitation effect caused by Na-PCN by increasing the power of delta1 and delta2 bands (P<0.01 vs model) and lowering the gravity frequency of PSD (P<0.01 vs model). JuA also remarkably reduced the Glu elevation induced by Na-PCN (P<0.05 vs model). Diazepam also depressed Glu concentration and lowered the gravity frequency, but it showed a different EEG pattern in increased beta2-activity (P<0.01 vs model). EEG excitation caused by Na-PCN correlated with Glu elevation during the first hour. Neurophysiological inhibitory effects of JuA and diazepam were more persistent than their Glu inhibitory effects.

Animals↗

PubMed2005

Targeting microtubules for cancer chemotherapy.

Chemical compounds that interfere with microtubules such as the vinca alkaloids and taxanes are important chemotherapeutic agents for the treatment of cancer. As our knowledge of microtubule-targeting drugs increases, we realize that the mechanism underlying the anti-cancer activity of these agents may mainly lie in their inhibitory effects on spindle microtubule dynamics, rather than in their effects on microtubule polymer mass. There is increasing evidence showing that even minor alteration of microtubule dynamics can engage the spindle checkpoint, arresting cell cycle progression at mitosis and eventually leading to apoptotic cell death. The effectiveness of microtubule-targeting drugs for cancer therapy has been impaired by various side effects, notably neurological and hematological toxicities. Drug resistance is another notorious factor that thwarts the effectiveness of these agents, as with many other cancer chemotherapeutics. Several new microtubule-targeting agents have shown potent activity against the proliferation of various cancer cells, including cells that display resistance to the existing microtubule-targeting drugs. Continued investigation of the mechanisms of action of microtubule-targeting drugs, development and discovery of new drugs, and exploring new treatment strategies that reduce side effects and circumvent drug resistance may provide more effective therapeutic options for cancer patients.

Angiogenesis Inhibitors↗

PubMed2005

CpG island hypermethylation profiling of lung cancer using restriction landmark genomic scanning (RLGS) analysis.

Lung cancer remains the leading cause of cancer related mortality, accounting for almost one-third of cancer deaths in men and one-fourth of cancer deaths in women; 160,440 lung cancer deaths are expected in 2004. Survival from lung cancer depends mainly upon the stage at presentation. As localized tumors generally do not cause symptoms, the disease is usually diagnosed in symptomatic patients at advanced stages when the prognosis is poor. As a result, the overall 5-year lung cancer survival rate is only 15%. It is well known that epigenetic alterations such as DNA methylation of CpG dinucleotides located in CpG islands within the regulatory (promoter) regions of genes are associated with transcriptional silencing in cancer. Promoter hypermethylation of critical pathway genes could identify potential biomarkers for lung cancer risk. Our goal for this study is to identify novel hypermethylated genes in lung cancer. We have investigated the methylation profiles of DNA samples from 14 paired lung tumor and adjacent normal tissues resected from the same individuals using restriction landmark genomic scanning (RLGS). We could assess the DNA methylation status of an average of 2,012 CpG islands for each tumor. We identified 162 differentially methylated loci where CpG islands were hypermethylated in lung tumors but not in adjacent non-cancer tissues. Among 162 sites of differential DNA methylation, detected from at least one tumor/normal pair, 21 hypermethylated genes were identified that were not reported previously as hypermethylated in lung tumor tissue.

Adenocarcinoma↗

PubMed2005

[Association study of apolipoprotein e gene polymorphism and cerebral infarction in type 2 diabetic patients].

In order to explore the association of apolipoprotein E (ApoE) gene polymorphism with cerebral infarction in type 2 diabetic patients of Han nationality in Northeast China , the genotypes of ApoE gene were analyzed by polymerase chain reaction -restriction fragment length polymorphism (PCR-RFLP) in the 208 cases, including 69 cases in control (CON) group and 67 in type 2 diabetes mellitus (T2DM) group as well as 72 in type 2 diabetes mellitus with cerebral infarction (T2DMCI) group. Plasma lipid content in T2DMCI was also detected for 70 cases. The distribution of genotypes in ApoE gene,epsilon(2)epsilon(3),epsilon(3)epsilon(3) as well as epsilon(3)epsilon(4) was no significant difference in three groups (epsilon(2)epsilon(3) : 13.2%,epsilon(3)epsilon(3) : 67.6%,epsilon(3)epsilon(4) : 16.2%in CON group;epsilon(2)epsilon(3) : 19.4%,epsilon(3)epsilon(3): : 70.1%epsilon(3)epsilon(4) : 9%in T2DM group;epsilon(2)epsilon(3) : 15.2%,epsilon(3)epsilon(3) : 75%,epsilon(3)epsilon(4) : 4.2%in T2DMCI group). The allele frequencies of epsilon(2),epsilon(3) and epsilon(4) were not significantly different in the three groups, either(epsilon(2) : 9.6%,epsilon(3) : 82.4%,epsilon(4) : 8.1%in CON group; epsilon(2) :10.5%,epsilon(3) :84.3%,epsilon(4) : 5.2%in T2DM group; epsilon(2) :11.8%,epsilon(3) :84.7%,epsilon(4) : 3.5%in T2DMCI group). The levels of total cholesterol (TC), tryglyceride (TG), high density lipoprotein-cholesterol (HDL-C) and low density lipoprotein-cholesterol (LDL-C) were not significantly different among the different genotypes in T2DMCI group. The study confirmed that the polymorphisms of ApoE gene are neither associated with the T2DMCI, nor with the levels of plasma lipid in T2DMCI.

Apolipoproteins E↗