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T Lu

Publications and source records attributed to T Lu.

At least 55 records · Page 3Linked to original sources
PubMed2000

Use of inhibitory monoclonal antibodies to assess the contribution of cytochromes P450 to human drug metabolism.

Three inhibitory monoclonal antibodies specific to cytochrome P450 3A4/5 (CYP3A4/5), CYP2C8/9/19 and CYP2E1, respectively, were used to assess the contribution of the P450s to the metabolism of seven substrates in liver microsomes from 18 human donors, as measured by monoclonal antibody inhibition phenotyping of the substrate conversion to product(s). Metabolism of seven substrates by recombinant cytochromes P450 and human liver microsomes was performed in the presence of monoclonal antibodies and their metabolites were analyzed by high-performance liquid chromatography (HPLC) or gas chromatography-mass spectrophotometry (GC-MS) to measure the magnitude of inhibition. Our results showed that CYP3A4/5 contributes to testosterone 6beta-hydroxylation, taxol phenol formation, diazepam 3-hydroxylation, diazepam N-demethylation, and aflatoxin B1 3-hydroxylation in human liver by 79.2%, 81.5%, 73. 2%, 34.5% and 80%, respectively. CYP2E1 contributes to chlorzoxazone 6-hydroxylation, p-nitroanisole O-demethylation, and toluene hydroxylation by 45.8%, 27.7% and 44.2% respectively, and CYP2C8/9/19 contribute to diazepam N-demethylation by 30.6%. The additive contribution (75.3%) of human CYP3A and CYP2C to diazepam N-demethylation was also observed in the presence of both anti-CYP3A4/5 and anti-CYP2C8/9/19 monoclonal antibodies. The contribution of individual P450s to the specific metabolic reaction in human liver varies greatly in the individual donors and the substrates examined. Thus, inhibitory monoclonal antibodies could play a unique role in defining the single or subfamily of cytochrome P450 that is responsible for the metabolism of specific drugs.

Antibodies, Blocking↗
PubMed2000

Non-peptidic phenyl-based thrombin inhibitors: exploring structural requirements of the S1 specificity pocket with amidines.

We expand the structural requirements and structure-activity relationship of a novel class of non-peptidic aryl-based thrombin inhibitors through exploration of the S1 specificity pocket of thrombin using flexible and constrained amidines. The most active compound of this class is 11 with Ki = 69 nM, which is ca. 15-fold less potent than constrained guanidine 5.

Amidines↗
PubMed2000

Amidinohydrazones as guanidine bioisosteres: application to a new class of potent, selective and orally bioavailable, non-amide-based small-molecule thrombin inhibitors.

We describe a new class of potent, non-amide-based small molecule thrombin inhibitors in which an amidinohydrazone is used as a guanidine bioisostere on a non-peptide scaffold. Compound 4 exhibits nM inhibition of thrombin, is selective for thrombin, and shows 60 and 23% bioavailability in rabbits and dogs, respectively. Crystallographic analysis of 4 bound to thrombin confirmed the amindinohydrazone binding mode.

Administration, Oral↗
PubMed2000

Circular dichroism and resonance raman comparative studies of wild type cytochrome c and F82H mutant.

The UV-visible, circular dichroism (CD), and resonance Raman (RR) spectra of the wild type yeast iso-1-cytochrome c (WT) and its mutant F82H in which phenylalanine-82 (Phe-82) is substituted with His are measured and compared for oxidized and reduced forms. The CD spectra in the intrinsic and Soret spectral region, as well as RR spectra in high, middle, and low frequency regions, are discussed. From the analysis of the spectra, it is determined that in the oxidized F82H the two axial ligands to the heme iron are His-18 and His-82 whereas in the reduced form the sixth ligand switches from His-82 to Met-80 providing the coordination geometry similar to that of WT. Based on the spectroscopic data, the conclusion is that the porphyrin macrocycle is less distorted in the oxidized F82H compared to the oxidized WT. Similar distortions are present in the reduced form of the proteins. Frequency shifts of Raman bands, as well as the decrease of the alpha-helix content in the CD spectra, indicate more open conformation of the protein around the heme.

Amino Acid Substitution↗
PubMed2000

Genitourinary complications of systemic lupus erythematosus.

A 14-year-old African-American girl was diagnosed with antiphospholipid-positive systemic lupus erythematosus (SLE) in July 1994. The course was complicated by nephrotic syndrome, sepsis, hemolytic anemia, acute renal failure, saphenous vein thrombosis, cutaneous vasculitis, mesenteric vasculitis, appendicitis, hemorrhagic cystitis, and avascular necrosis of the hips. In August 1997, she developed ovarian and fallopian tube complications secondary to SLE. Genitourinary complications of SLE, however, are uncommon, and ovarian vasculitis has not previously been reported as a complication of SLE. This report describes the course of an adolescent patient with SLE and focuses specifically on her genitourinary complications.

Acute Kidney Injury↗
PubMed2000

Inhibitory transmission mediated by asynchronous transmitter release.

At fast CNS synapses, the role of asynchronous release following initial synchronous release is poorly understood. We examined the contribution of asynchronous release to GABAergic transmission in the cochlear nucleus across a 40-fold range of electrical stimulus frequencies. Whereas quantal release was highly synchronized at low frequencies, it was largely continuous and desynchronized at high frequencies. Despite the change in release mode, intense and steady inhibitory transmission was virtually maintained. Experimental analyses and modeling studies indicated that this "desynchronization" process was dependent on presynaptic Ca2+ accumulation, facilitation of vesicle release, and short-term depletion of available vesicles. Asynchronous release at high frequencies may help generate a smooth inhibitory "tone" by minimizing the consequences of random timing of presynaptic action potentials.

Animals↗
PubMed2000

Antisense inhibition of membrane-bound human interleukin-5 receptor-alpha chain does not affect soluble receptor expression and induces apoptosis in TF-1 cells.

Binding of human interleukin-5 (HuIL-5) to its membrane-anchored receptor (IL-5R) triggers multiple signaling pathways, cellular proliferation, and maturational responses, as well as protection from apoptosis. In contrast, soluble forms of the HuIL-5R have been shown to inhibit IL-5 signaling and, therefore, may represent naturally occurring negative regulators of IL-5 function. Because of the central role of IL-5 in promoting eosinophilia and airway hyperresponsiveness in animal models of asthma, antisense oligonucleotides specific either for the membrane form alone or for sequences shared between both the membrane and soluble forms of the HuIL-5Ralpha ligand binding chain were designed. The activities of these oligonucleotides were characterized in IL-5R-expressing erythroleukemic TF-1 cells. Herein we report that an antisense oligonucleotide targeted to a sequence unique to the alternatively spliced membrane-bound form of the HuIL-5Ralpha chain has been developed that selectively inhibits membrane, but not soluble, mRNA isoform expression. Both this membrane-specific oligonucleotide and an antisense oligonucleotide targeted to sequence common to both membrane and soluble isoforms were found to potently suppress cell surface IL-5Ralpha levels and IL-5-mediated cell survival by inducing apoptosis similar to IL-5 withdrawal. Thus, these oligonucleotides represent unique genetic agents with therapeutic potential for diseases with an eosinophilic component.

Alternative Splicing↗
PubMed2000

Mutant prevention concentration as a measure of fluoroquinolone potency against mycobacteria.

Mutant prevention concentration (MPC) has been proposed as a new measure of antibiotic potency by which the ability to restrict selection of resistant mutants is evaluated. To determine whether MPC provides potency information unavailable from the more customary measurement of the MIC, 18 fluoroquinolones were examined for their ability to block the growth of Mycobacterium smegmatis and to select resistant mutants from wild-type populations. Both MPC and MIC were affected by changes in the moiety at the fluoroquinolone C-8 position and in alkyl groups attached to the C-7 piperazinyl ring. When eight resistant mutants, altered in the gyrase A protein, were tested with fluoroquinolones having either a methoxy or a hydrogen at the C-8 position, the MIC for the most resistant mutant correlated better with the MPC than did the MIC for wild-type cells. For C-8-fluorine derivatives, which were generally less active than the C-8-methoxy compounds but which were more active than C-8-hydrogen derivatives, the MICs for both the mutant and the wild type correlated well with the MPCs. Thus, measurement of the MICs for wild-type cells can reflect the ability of a quinolone to restrict the selection of resistance, but often it does not. With the present series of compounds, the most potent contained a C-8-methoxy and a small group attached to the C-7 ring.

Anti-Infective Agents↗
PubMed2000

Selective targeting of topoisomerase IV and DNA gyrase in Staphylococcus aureus: different patterns of quinolone-induced inhibition of DNA synthesis.

The effect of quinolones on the inhibition of DNA synthesis in Staphylococcus aureus was examined by using single resistance mutations in parC or gyrA to distinguish action against gyrase or topoisomerase IV, respectively. Norfloxacin preferentially attacked topoisomerase IV and blocked DNA synthesis slowly, while nalidixic acid targeted gyrase and inhibited replication rapidly. Ciprofloxacin exhibited an intermediate response, consistent with both enzymes being targeted. The absence of RecA had little influence on target choice by this assay, indicating that differences in rebound (repair) DNA synthesis were not responsible for the results. At saturating drug concentrations, norfloxacin and a gyrA mutant were used to show that topoisomerase IV-norfloxacin-cleaved DNA complexes are distributed on the S. aureus chromosome at intervals of about 30 kbp. If cleaved complexes block DNA replication, as indicated by previous work, such close spacing of topoisomerase-quinolone-DNA complexes should block replication rapidly (replication forks are likely to encounter a cleaved complex within a minute). Thus, the slow inhibition of DNA synthesis at growth-inhibitory concentrations suggests that a subset of more distantly distributed complexes is physiologically relevant for drug action and is unlikely to be located immediately in front of the DNA replication fork.

Anti-Infective Agents↗
PubMed2000

Temporal discharge patterns evoked by rapid sequences of wide- and narrowband clicks in the primary auditory cortex of cat.

The present study investigated neural responses to rapid, repetitive stimuli in the primary auditory cortex (A1) of cats. We focused on two important issues regarding cortical coding of sequences of stimuli: temporal discharge patterns of A1 neurons as a function of inter-stimulus interval and cortical mechanisms for representing successive stimulus events separated by very short intervals. These issues were studied using wide- and narrowband click trains with inter-click intervals (ICIs) ranging from 3 to 100 ms as a class of representative sequential stimuli. The main findings of this study are 1) A1 units displayed, in response to click train stimuli, three distinct temporal discharge patterns that we classify as regions I, II, and III. At long ICIs nearly all A1 units exhibited typical stimulus-synchronized response patterns (region I) consistent with previously reported observations. At intermediate ICIs, no clear temporal structures were visible in the responses of most A1 units (region II). At short ICIs, temporal discharge patterns are characterized by the presence of either intrinsic oscillations (at approximately 10 Hz) or a change in discharge rate that was a monotonically decreasing function of ICI (region III). In some A1 units, temporal discharge patterns corresponding to region III were absent. 2) The boundary between regions I and II (synchronization boundary) had a median value of 39.8 ms ICI ([25%, 75%] = [20.4, 58. 8] ms ICI; n = 131). The median boundary between regions II and III was estimated at 6.3 ms ([25%, 75%] = [5.2, 9.7] ms ICI; n = 47) for units showing rate changes (rate-change boundary). 3) The boundary values between different regions appeared to be relatively independent of stimulus intensity (at modest sound levels) or the bandwidth of the clicks used. 4) There is a weak correlation between a unit's synchronization boundary and its response latency. Units with shorter latencies appeared to also have smaller boundary values. And 5) based on these findings, we proposed a two-stage model for A1 neurons to represent a wide range of ICIs. In this model, A1 uses a temporal code for explicitly representing long ICIs and a rate code for implicitly representing short ICIs.

Acoustic Stimulation↗
PubMed2000

[Changes of collagenase activity in immune hepatic fibrosis following pig's serum injection and therapeutic effect of HanDanGanLe].

OBJECTIVE: To investigate the changes of collagenase activity in immune hepatic fibrosis following pig's serum injection and the therapeutic effect of HanDanGanLe. METHODS: Pig's serum was injected intraperitoneally to Wistar rats to duplicate the hepatic fibrosis model due to immunologic injury. HanDanGanLe was used as therapeutic medicine and colchicine as control. The animals were killed at 12th week to detect hepatic collagenase activity, the staining semiquantity of hepatic collagenous fibre, and the content of hepatic collagen. RESULTS: HanDanGanLe can increase collagenase activity, decrease the content of collagenous fibre and collagen in the liver. The beneficial effect achieved in HanDanGanLe-treatment group especially in high-dose group in comparison to colchicine-treatment group. CONCLUSION: HanDanGanLe can effectively increase collagenase activity, improve collagen degradation, and abate hepatic fibrosis.

Animals↗
PubMed2000

[Evaluation on soil anti-erodibility of soil and water conservation forest].

Indexes including organic matter content, water stable aggregate content, mean weight diameter of water stable aggregate, aggregate degree and disperse coefficient were selected to evaluate soil anti-erodibility of soil and water conservation forests component of different tree species at different ages. The results showed that soil and water conservation forest played an important role in improving soil anti-erodibility, especially to the topsoil. Compared with that of Chinese pine pure forests, Chinese pine-broadleaved mixed forests had higher soil organic matter content, and water stable aggregate content increased by 1.71%-38.53%, and soil anti-erodibility was also increased with increasing stand age.

China↗
PubMed2000

Interventional treatment of huge hepatic cavernous hemangioma.

OBJECTIVE: To study the methods of interventional treatment of huge hepatic cavernous hemangioma (HCH). METHOD: A total of 14 patients with HCH were treated with lipiodol-ultrafluid (10-15 ml), bleomycin A (PYM 16-32 mg), and gelatin-sponge particles. RESULTS: DSA hepatic arteriography showed multiple vascular lakes in the early arterial phase, so-called "to hang the fruits on the branches", which persisted for a long time. CT scan showed a significant reduction in tumor size in 8 of the 14 patients after the treatment. CONCLUSION: Embolization with lipiodol-ultrafluid, PYM and gelatin sponge particles is one of the best methods for the treatment of HCH.

Adult↗
PubMed2000

[The rearrangements of immunoglobulin heavy chain and T cell receptor delta genes in patients with acute nonlymphocytic leukemia].

OBJECTIVE: To explore the clinical significance of rearrangements of immunoglobulin heavy chain (IgH) and T cell receptor (TCR) genes in patients with acute nonlymphocytic leukemias. METHODS: Polymerase chain reaction (PCR) was used to study IgH and TCRdelta genes rearrangements in 30 untreated acute nonlymphocytic leukemia patients. RESULTS: IgH gene rearrangements were found in 9 patients, and TCRdelta gene rearrangements in 5 patients. CONCLUSION: The lineage infidelity does occur in acute nonlymphocytic leukemia, showing not only a high frequency of IgH gene rearrangement, but also of TCRdelta gene rearrangement.

Gene Rearrangement↗
PubMed2000

[Studies on antiplatelet aggregation and anticoagulant action of Curcuma phaeocaulis].

OBJECTIVE: To study the effects of Curcuma phaeocaulis Valeton on platelet aggregation and anticoagulant action. METHODS: Antiplatelet aggregation and anticoagulant action of Curcuma phaeocaulis Valeton of mice is observed in platelet aggregation and coagulant time. RESULTS: The experimental results show that Curcuma phaeocaulis Valeton can inhibit platelet aggregation, prolong time of mice coagulation. CONCLUSION: Antiplatelet aggregation and anticoagulant action of processed products with vinegar is the most powerful.

Animals↗
PubMed2000

[The clinical significance of poststyloid space extension in nasopharyngeal carcinoma].

OBJECTIVE: To explore the clinical significance of poststyloid space extension in nasopharyngeal carcinoma. METHODS: One hundred and ninety-eight patients with newly treated nasopharyngeal carcinoma (stage I-IV a) were analyzed. These patients were divided into two groups depending on whether the poststyloid space was extended or normal. The 5-year survival rate, relapse and distant metastasis after the treatment were estimated using the Kaplan-Meier, Log-Rank methods. RESULTS: The rates of patients with oropharyngeal extension for these two groups were 72.1% and 16.8% respectively (P < 0.001). The rates of the cases with involvement of the 9, 10, 11, 12th cranial nerves were 20.9% and 6.2% respectively (P < 0.01). The rates of metastasis to cervical lymph node were 69.8% and 35.4% respectively (P < 0.01). The 5-year survival rates were 46.76% and 68.88% respectively (P = 0.0027). The local control rates were 63.7%, 78.7% respectively (P = 0.0862). The distant metastasis free survival rates were 71.7% and 84.2% respectively (P = 0.0468). These results showed that the survival rate, the local control rate were reduced and the distant metastasis was increased for patients with poststyloid space extension. CONCLUSIONS: The poststyloid space extension was an important prognostic factor with poorer treatment outcome. It is reasonable to classify such condition as stage T3 of nasopharyngeal carcinoma.

Adult↗
PubMed2000

[Resonance Raman and surface-enhanced Raman spectroscopic study of microperoxidase-11].

The electron transfer and structure of microperoxidase-11 (MP-11) in solution and at electrode/solution interface were studied by electrochemical, resonance Raman and surface-enhanced Raman spectroscopic techniques. Results show that the central iron in heme group was six-coordinated in solution, whereas it was converted to five-coordinated state as MP-11 was adsorbed on the surface of a roughened silver electrode, due to the reorientation of MP-11 molecules. The electrochemical properties of MP-11 were directly affected by the coordination state of heme iron.

Electrochemistry↗