Biomedical subjects

Wei Lu

Publications and source records attributed to Wei Lu.

At least 91 records · Page 5Linked to original sources

PubMed2005

One-dimensional hole gas in germanium/silicon nanowire heterostructures.

Two-dimensional electron and hole gas systems, enabled through band structure design and epitaxial growth on planar substrates, have served as key platforms for fundamental condensed matter research and high-performance devices. The analogous development of one-dimensional (1D) electron or hole gas systems through controlled growth on 1D nanostructure substrates, which could open up opportunities beyond existing carbon nanotube and nanowire systems, has not been realized. Here, we report the synthesis and transport studies of a 1D hole gas system based on a free-standing germanium/silicon (Ge/Si) core/shell nanowire heterostructure. Room temperature electrical transport measurements clearly show hole accumulation in undoped Ge/Si nanowire heterostructures, in contrast to control experiments on single-component nanowires. Low-temperature studies show well-controlled Coulomb blockade oscillations when the Si shell serves as a tunnel barrier to the hole gas in the Ge channel. Transparent contacts to the hole gas also have been reproducibly achieved by thermal annealing. In such devices, we observe conductance quantization at low temperatures, corresponding to ballistic transport through 1D subbands, where the measured subband energy spacings agree with calculations for a cylindrical confinement potential. In addition, we observe a "0.7 structure," which has been attributed to spontaneous spin polarization, suggesting the universality of this phenomenon in interacting 1D systems. Lastly, the conductance exhibits little temperature dependence, consistent with our calculation of reduced backscattering in this 1D system, and suggests that transport is ballistic even at room temperature.

Journal Article↗

PubMed2005

Synthesis and antitumor activity of the hexacyclic camptothecin derivatives.

A series of hexacyclic camptothecin derivatives were synthesized to test for antitumor activity as topoisomerase I inhibitor. The strategy of synthesis was used for the formation of additional furan and dihydrofuran rings fused with 9- and 10-positions of camptothecin. All of the hexacyclic camptothecins were assayed for cytotoxicity against four human tumor cell lines, HL60, BEL-7402, HCT-116, and HeLa, and showed very impressive cytotoxicity activity in vitro. Enzyme activity of the hexacyclic camptothecins was evaluated, being equal or superior to that of SN-38. The stability of four compounds was assessed in human plasma. Two of these compounds were chosen to test for antitumor activity in vivo against Sarcoma-180. The results suggested that additional furan and dihydrofuran rings could improve the antitumor activity in vitro and vivo, though the stability of the lactone ring did not increase.

Animals↗

PubMed2005

Anti-proliferative effects, cell cycle G2/M phase arrest and blocking of chromosome segregation by probimane and MST-16 in human tumor cell lines.

BACKGROUND: Anticancer bisdioxopiperazines, including ICRF-154, razoxane (Raz, ICRF-159) and ICRF-193, are a family of anticancer agents developed in the UK, especially targeting metastases of neoplasms. Two other bisdioxopiperazine derivatives, probimane (Pro) and MST-16, were synthesized at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. Cytotoxic activities and mechanisms of Raz (+)-steroisomer (ICRF-187, dexrazoxane), Pro and MST-16 against tumor cells were evaluated by MTT colorimetry, flow cytometry and karyotyping. RESULTS: Pro was cytotoxic to human tumor cell lines in vitro (IC50<50 microM for 48 h). Four human tumor cell lines (SCG-7901, K562, A549 and HL60) were susceptible to Pro at low inhibitory concentrations (IC50 values < 10 microM for 48 h). Although the IC50 against HeLa cell line of vincristine (VCR, 4.56 microM), doxorubicin (Dox, 1.12 microM) and 5-fluoruouracil (5-Fu, 0.232 microM) are lower than Pro (5.12 microM), ICRF-187 (129 microM) and MST-16 (26.4 microM), VCR, Dox and 5-Fu shows a low dose-related - high cytotoxic activity. Time-response studies showed that the cytotoxic effects of Pro are increased for 3 days in human tumor cells, whereas VCR, Dox and 5-Fu showed decreased cytotoxic action after 24 h. Cell cycle G2/M phase arrest and chromosome segregation blocking by Pro and MST-16 were noted. Although there was similar effects of Pro and MST-16 on chromosome segregation blocking action and cell cycle G2/M phase arrest at 1- 4 microM, cytotoxicity of Pro against tumor cells was higher than that of MST-16 in vitro by a factor of 3- 10 folds. Our data show that Pro may be more effective against lung cancer and leukemia while ICRF-187 and MST-16 shows similar IC50 values only against leukemia. CONCLUSION: It suggests that Pro has a wider spectrum of cytotoxic effects against human tumor cells than other bisdioxopiperazines, especially against solid tumors, and with a single cytotoxic pathway of Pro and MST-16 affecting chromosome segregation and leading also to cell G2/ M phase arrests, which finally reduces cell division rates. Pro may be more potent than MST-16 in cytotoxicity. High dose- and time- responses of Pro, when compared with VCR, 5-Fu and Dox, were seen that suggest a selectivity of Pro against tumor growth. Compounds of bisdioxopiperazines family may keep up their cytotoxic effects longer than many other anticancer drugs.

Antineoplastic Agents↗

PubMed2005

Population pharmacokinetics of cyclosporine in clinical renal transplant patients.

Population pharmacokinetics of cyclosporine (CsA) in clinical renal transplant patients has been reported in the present study. A total of 2,548 retrospective drug monitoring data points were collected from 120 renal transplant patients receiving CsA. Population modeling was performed using the NONMEM (nonlinear mixed-effect modeling) program, using a one-compartment model with first-order absorption and elimination. The final regression model for CsA clearance (CL/F) with the influence of six significant covariates, comprising postoperative days (POD), total bilirubin level (TBIL, micromolar concentration), current body weight (CBW, kilograms), age (years), concurrent metabolic inhibitors of cyclosporine (INHI), and hematocrit (HCT, percentage), has been established and expressed as CL/F=28.5 -- 1.24 . POD -- 0.252 . (TBIL -- 11)+0.188 . (CBW -- 58) --0.191 . (Age -- 42) -- 2.45 . INHI -- 0.212 . (HCT-- 28) (liters per hour). The values in parentheses represent the median level for each of the corresponding covariates. The population estimates for CL/F (28.5 l/h), V/F (volume of distribution, 133 l), and interpatient variability (CV%=19.7%) for CL/F were achieved, respectively. The population model was further validated by internal and external approaches, and was demonstrated to be effective and stable. Moreover, simulation was conducted to facilitate the individualized treatment based on patient information and the final model.

Adolescent↗

PubMed2005

Cationic albumin conjugated pegylated nanoparticle with its transcytosis ability and little toxicity against blood-brain barrier.

Our newly developed drug delivery carrier, cationic bovine serum albumin (CBSA) conjugated with poly(ethyleneglycol)-poly(lactide) (PEG-PLA) nanoparticle (CBSA-NP), was designed for brain drug delivery. CBSA, as a brain specific targetor, was covalently conjugated with the maleimide function group at the distal of poly(ethyleneglycol) (PEG) surrounding the nanoparticles. To evaluate its blood-brain barrier (BBB) transcytosis and toxicity against the BBB endothelial tight junction, we have explored a method of coculture with brain capillary endothelial cells (BCECs) on the top of micro-porous membrane of cell culture insert and astrocytes on the bottom side. The permeability of 14C-labeled sucrose was determined. For the CBSA-NP transcytosis study, a lipophilic fluorescent probe, 6-coumarin, was incorporated into nanoparticles. The BBB permeability of CBSA-NP in vitro was calculated and compared with native bovine serum albumin (BSA) conjugated pegylated nanoparticles (BSA-NP). As the coculture model, the transendothelial electrical resistance reached up to 313+/-23 ohms cm2. The tight junction between BCECs in the coculture could be visualized by scanning electron microscopy and transmission electron microscopy. The unchanged permeability of 14C-labeled sucrose comparing to that in the appearance of 200 microg/ml of CBSA-NP proved that CBSA-NP did not impact the integrity of BBB endothelial tight junctions. CBSA-NP also showed little toxicity against BCECs. The permeability of CBSA-NP was about 7.76 times higher than that of BSA-NP, while the transcytosis was inhibited in the excess of free CBSA. It was concluded that CBSA-NP preferentially transported across BBB with little toxicity, which offered the possibility to deliver therapeutic agents to CNS.

Animals↗

PubMed2005

Synthesis and antitumor activity of 7-ethyl-9-alkyl derivatives of camptothecin.

A series of new camptothecin derivatives, as topoisomerase I inhibitor, were synthesized to identify potent antitumor agents. The synthesis method was based on the Claisen rearrangement of 10-allyloxy-7-ethylcamptothecin. All of the compounds were assayed for cytotoxicity against two human tumor cell lines, Bel7402, HCT116, and showed good potency in vitro. Compounds 2, 4, 9, were assessed for the stability of lactone in human plasma. And then compound 2 was tested for antitumor activity in vitro against mouse tumor sarcoma-180. The results suggested that the small alkyl groups in the both 7- and 9-positions of camptothecin could promote liposolubility, antitumor activity in vitro and vivo, though did not bring much increase of the stability of lactone.

Antineoplastic Agents, Phytogenic↗

PubMed2005

Evidence for the presence of disease-perturbed networks in prostate cancer cells by genomic and proteomic analyses: a systems approach to disease.

Prostate cancer is initially responsive to androgen ablation therapy and progresses to androgen-unresponsive states that are refractory to treatment. The mechanism of this transition is unknown. A systems approach to disease begins with the quantitative delineation of the informational elements (mRNAs and proteins) in various disease states. We employed two recently developed high-throughput technologies, massively parallel signature sequencing (MPSS) and isotope-coded affinity tag, to gain a comprehensive picture of the changes in mRNA levels and more restricted analysis of protein levels, respectively, during the transition from androgen-dependent LNCaP (model for early-stage prostate cancer) to androgen-independent CL1 cells (model for late-stage prostate cancer). We sequenced >5 million MPSS signatures, obtained >142,000 tandem mass spectra, and built comprehensive MPSS and proteomic databases. The integrated mRNA and protein expression data revealed underlying functional differences between androgen-dependent and androgen-independent prostate cancer cells. The high sensitivity of MPSS enabled us to identify virtually all of the expressed transcripts and to quantify the changes in gene expression between these two cell states, including functionally important low-abundance mRNAs, such as those encoding transcription factors and signal transduction molecules. These data enable us to map the differences onto extant physiologic networks, creating perturbation networks that reflect prostate cancer progression. We found 37 BioCarta and 14 Kyoto Encyclopedia of Genes and Genomes pathways that are up-regulated and 23 BioCarta and 22 Kyoto Encyclopedia of Genes and Genomes pathways that are down-regulated in LNCaP cells versus CL1 cells. Our efforts represent a significant step toward a systems approach to understanding prostate cancer progression.

Cell Line, Tumor↗

PubMed2005

Patterning multilayers of molecules via self-organization.

The electric dipole interaction among adsorbate molecules may cause them to form regular nanopatterns. In a multilayer system, the self-organization of each layer is also influenced by the underlying layers. This Letter develops a phase field model to simulate the molecular patterning process. The study reveals self-alignment, scaling down of size, and the effect of guided self-assembly with embedded electrodes.

Journal Article↗

PubMed2005

Synthesis of core/shell nanoparticles of Au/CdSe via Au-Cd bialloy precursor.

We present a novel method for the preparation of ultrasmall Au/CdSe core/shell particles. Au-Cd bialloy particles of 4.7 nm diameter were prepared as the precursor. The Cd component in the precursor reacted with the Se source at a temperature of 205 degrees C and was heated to 250 degrees C, leading to formation of a Au/CdSe core/shell structure. The sizes of Au/CdSe nanoparticles have a narrow distribution with an average size of 6.0 nm and Au core of 2.2 nm diameter. The X-ray diffraction pattern and the images of the high-resolution electron transmission microscopy show that the Au cores and the CdSe shells of Au/CdSe core/shell nanoparticles are both well crystallized, and the CdSe shells are in a cubic phase. The absorption spectrum of the Au/CdSe nanoparticles combines the absorption behaviors of the Au cores and the CdSe shells.

Journal Article↗

PubMed2005

Synthetic peptides derived from SARS coronavirus S protein with diagnostic and therapeutic potential.

The spike (S) protein of severe acute respiratory syndrome coronavirus (SARS-CoV) is an important viral structural protein. Based on bioinformatics analysis, 10 antigenic peptides derived from the S protein sequence were selected and synthesized. The antigenicity and immunoreactivity of all the peptides were tested in vivo and in vitro. Four peptides (P6, P8, P9 and P10) which contain B cell epitopes of the S protein were identified, and P8 peptide was confirmed in vivo to have a potential in serological diagnosis. By using a syncytia formation model, we tested the neutralization ability of all 10 peptides and their corresponding antibodies. It is interesting to find that P8 and P9 peptides inhibited syncytia formation, suggesting that the P8 and P9 spanning regions may provide a good target for anti-SARS-CoV drug design. Our data suggest that we have identified peptides derived from the S protein of SARS-CoV, which are useful for SARS treatment and diagnosis.

Amino Acid Sequence↗

PubMed2005

Roles of tyrosine phosphorylation and cleavage of protein kinase Cdelta in its protective effect against tumor necrosis factor-related apoptosis inducing ligand-induced apoptosis.

Protein kinase Cdelta (PKCdelta) regulates cell apoptosis in a cell- and stimulus-specific manner. Here, we studied the role of PKCdelta in the apoptotic effect of TRAIL in glioma cells. We found that transfection of the cells with a PKCdelta kinase-dead mutant (K376R) or with a small interfering RNA targeting the PKCdelta mRNA increased the apoptotic effect of tumor necrosis factor-related apoptosis inducing ligand (TRAIL), whereas overexpression of PKCdelta decreased it. PKCdelta acted downstream of caspase 8 and upstream of cytochrome c release from the mitochondria. TRAIL induced cleavage of PKCdelta within 2-3 h of treatment, which was abolished by caspase 3, 8, and 9 inhibitors. The cleavage of PKCdelta was essential for its protective effect because overexpression of a caspase-resistant mutant (PKCdeltaD327A) did not protect glioma cells from TRAIL-induced apoptosis but rather increased it. TRAIL induced translocation of PKCdelta to the perinuclear region and the endoplasmic reticulum and phosphorylation of PKCdelta on tyrosine 155. Using a PKCdeltaY155F mutant, we found that the phosphorylation of PKCdelta on tyrosine 155 was essential for the cleavage of PKCdelta in response to TRAIL and for its translocation to the endoplasmic reticulum. In addition, phosphorylation of PKCdelta on tyrosine 155 was necessary for the activation of AKT in response to TRAIL. Our results indicate that PKCdelta protects glioma cells from the apoptosis induced by TRAIL and implicate the phosphorylation of PKCdelta on tyrosine 155 and its cleavage as essential factors in the anti-apoptotic effect of PKCdelta.

Animals↗

PubMed2005

Genes encoding catalytic subunits of protein kinase A and risk of spina bifida.

BACKGROUND: PRKACA and PRKACB are genes encoding the cAMP-dependent protein kinase A (PKA) catalytic subunits alpha and beta, respectively. PKA is known to be involved in embryonic development, as it down-regulates the Hedgehog (Hh) signaling pathway, which is critical to normal pattern formation and morphogenesis. The PKA-deficient mouse model, which has only a single catalytic subunit, provided intriguing evidence demonstrating a relationship between decreased PKA activity and risk for posterior neural tube defects (NTDs) in the thoracic to sacral regions of gene-knockout mice. Unlike most other mutant mouse models of NTDs, the PKA-deficient mice develop spina bifida with 100% penetrance. We hypothesized that sequence variations in human genes encoding the catalytic subunits may alter the PKA activity and similarly increase the risk of spina bifida. METHODS: We sequenced the coding regions and the exon/intron boundaries of PRKACA and PRKACB. We also examined 3 common single-nucleotide polymorphisms (SNPs) of these 2 genes by allele discrimination. RESULTS: Five sequence variants in coding region and 2 intronic sequence variants proximal to exons were detected. None of the 3 SNPs examined in the association study appeared to be associated with substantially increased risk for spina bifida. CONCLUSIONS: Our results did not reveal a strong association between these PKA SNPs and spina bifida risk. Nonetheless, it is important to examine the possible gene-gene interactions between PRKACA and PRKACB when evaluating the risk for NTDs, as well as genes encoding regulatory subunits of PKA. In addition, interactions with other genes such as Sonic Hedgehog (SHH) should also be considered for future investigations.

Alleles↗

PubMed2005

Synthesis and biological evaluation of novel compounds related to 1-arylnaphthalene lignans and isoquinolines.

Novel compounds designed as hybrids of 1-arylnaphthalene lignans with isoquinoline alkaloids were prepared and evaluated for their cytotoxicities on human tumor cell lines, such as A549, Hela, PC-3, CNE, BEL-7404, and KB. Some of the synthetic compounds exhibited their IC50 values on selected cell lines at 10(-6) M scale. The preliminary CoMFA molecular-modelling studies of these synthetic analogues were also performed.

Antineoplastic Agents↗

PubMed2005

Down-regulation of specific gene expression by double-strand RNA induces neural stem cell differentiation in vitro.

In the postgenomic era the elucidation of the physiological function of genes has become the rate-limiting step in the quest to understand the development and function of living organisms. Double-stranded RNA (dsRNA) interferes with gene expression in various species, a phenomenon known as RNA interference (RNAi). We show here that RNAi is also effective in modifying gene expression in neural stem cell differentiation. The progenitor cells were obtained from E14 mouse embryonic forebrain and maintained using N-2 medium containing basic fibroblast growth factor (bFGF), epidermal growth factor (EGF) and B27.A gene (NM017084.1) was previously discovered and validated to express obviously differently between differentiated and undifferentiated neural stem cells in our laboratory. Here we report a long double-stranded RNA to knock out or knock down this gene. The results demonstrated that following RNAi inhibition of expression of the NM017084.1 gene, the differentiation of neural stem cells is accelerated. Thus the NM017084.1 gene may play a pivotal role in the process of differentiation of neural stem cells.

Animals↗

PubMed2005

Tailoring of glycopeptide scaffolds by the acyltransferases from the teicoplanin and A-40,926 biosynthetic operons.

The teicoplanin acyltransferase (Atf) responsible for N-acylation of the glucosamine moiety to create the teicoplanin lipoglycopeptide scaffold has recently been identified. Here we use that enzyme (tAtf) and the cognate acyltransferase from the related A-40,926 biosynthetic cluster (aAtf) to evaluate specificity for glycopeptide scaffolds and for the acyl-CoA donor. In addition to acylation of 2-aminoglucosyl glycopeptide scaffolds with k(cat) values of 400-2000 min(-1), both Atfs transfer acyl groups to regioisomeric 6-aminoglucosyl scaffolds and to glucosyl scaffolds at rates of 0.2-0.5 min(-1) to create variant lipoglycopeptides. Using the teicoplanin glycosyltransferase tGtfA, tAtf, and GtfD, a glycosyltransferase from the vancomycin producer, it is possible to assemble a novel lipoglycopeptide with GlcNAc at beta-OH-Tyr(6) and an N(6)-acyl-glucosaminyl-vancosamine at Phegly(4). This study illustrates the utility of chemo- and regioselective acyltransferases and glycosyltransferases to create novel lipoglycopeptides.

Acyl Coenzyme A↗

PubMed2005

AknT is an activating protein for the glycosyltransferase AknS in L-aminodeoxysugar transfer to the aglycone of aclacinomycin A.

During biosynthesis of the anthracycline antitumor agents daunomycin, adriamycin, and aclacinomycin, the polyketide-derived tetracyclic aglycone is enzymatically glycosylated at the C7-OH by dedicated glycosyltransferases (Gtfs) that transfer L-2,3,6-trideoxy-3-aminohexoses. In aclacinomycins, the first deoxyhexose is predicted to be transferred via AknS action, then subjected to further elongation to a trisaccharide by the subsequent Gtf, AknK. We report here that purified AknS has very low activity in the absence of the adjacently encoded AknT; however, at a 3:1 ratio, AknT stimulates AknS k(cat) by 40-fold up to 0.22 min(-1) for transfer of L-2-deoxyfucose (2-dF) to the aglycone aklavinone. It is likely that several other Gtfs that glycosylate polyketide aglycones also act as two-component catalytic systems. Incubations of purified AknS/AknT/AknK with two aglycones and two dTDP-2-deoxyhexoses produced previously uncharacterized anthracycline disaccharides.

Aclarubicin↗

PubMed2005

Population pharmacokinetic modeling for enterohepatic recirculation in Rhesus monkey.

Enterohepatic recirculation (EHR) occurs via biliary excretion and intestinal reabsorption of a drug. Drug recycling through EHR can lead to a change in pharmacokinetic (PK) properties, such as reduced clearance (CL), extended half-life (T(1/2)) and increased plasma exposure (AUC). As a result, EHR may prolong the pharmacological effect of drugs. In the present study, the compound (Cpd A) was found to exhibit EHR in Rhesus monkeys associated with a reduction in CL (from 3.8 to 0.33 Lh(-1), IV; from 2.3 to 0.4 Lh(-1), PO), and an increase in T(1/2) (from 0.9 to 18 h, IV) and in AUC (from 1.5 to 17.4 microg h/mL, IV; from 2.8 to 16.3 microg h/mL, PO), by comparing the PK in the monkeys via the interruption of EHR (bile-duct cannulation) with that in the intact monkeys. A population four-compartment model was constructed based on recirculation loops incorporating all possible inputs (bile secretion, a lag-time model for gall bladder emptying, routes and amounts of a single dose administration) to fully evaluate the EHR of Cpd A. The plasma concentrations versus time profiles predicted from the model had a good fit to the values observed in the subjects and were further simulated with 90% confidence interval to demonstrate its utility. Thus, the model could be applied as a useful tool to evaluate the drugs or compounds that undergo EHR in different species.

Animals↗

PubMed2005

Cochlear implantation in rats: a new surgical approach.

The laboratory rat has been used extensively in auditory research but has had limited use in cochlear implant related research due mainly to the surgically restricted access to the scala tympani. We have developed a new surgical method for cochlear implantation in rats. The key to this protocol was cauterizing the stapedial artery (SA) and making a small cochleostomy near the round window in order to enlarge the surgical access to the scala tympani. Five normal hearing Hooded Wistar rats were used to investigate the effect of cauterizing the SA on hearing and auditory nerve survival. Results showed that cauterizing the SA was surgically feasible, afforded excellent exposure of the round window niche for cochleostomy, and did not adversely affect acoustic thresholds measured electrophysiologically. Moreover, there was no difference in spiral ganglion cell densities for any cochlear turn when compared with the contralateral control ears. Three deafened rats were subsequently implanted with a scala tympani electrode array using this new surgical approach. Electrically evoked auditory brainstem responses using bipolar stimulation, and subsequent cochlear histopathology demonstrated that cochlear implantation using a custom-made rat electrode array was safe and effective. The surgical approach presented in this paper presents a safe and effective procedure for acute or chronic cochlear implantation in the rat model.

Animals↗