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Li Zhang

Publications and source records attributed to Li Zhang.

At least 415 records · Page 23Linked to original sources
PubMed2004

A DFT-based QSARs study of protoporphyrinogen oxidase inhibitors: phenyl triazolinones.

The equilibrium geometries, electronic structures, and electrostatic potentials of a series of substituted phenyl triazolinones, a kind of important protoporphyrinogen oxidase (Protox) inhibitors, had been investigated using density functional theory (DFT) method at the B3LYP/6-31G(d,p) basis set. The quantum chemical descriptors, such as energy difference (DeltaE) between the lowest unoccupied molecular orbital and the highest occupied molecular orbital, electrophilic and nucleophilic frontier electron density (f(i)(E) and f(i)(N)), and net atomic charge (Q(i)), were computed at the same DFT level. Based on these useful quantum chemical descriptors, the quantitative structure-activity relationships was carried out and the results showed that descriptors, Q(C11), f(N5)(E), f(C10)(N), f(O6)(E), f(C11)(N), and DeltaE, were most likely to be responsible for the in vitro biological activity and the greenhouse pre-emergence activity of phenyl triazolinones. The descriptors accounted for 77-86% of the variation in the in vitro biological activity among the herbicidal phenyl triazolinone analogs 1-26 (except compounds 19 and 20). The results of the regression analysis showed that the activity was parabolically related not only with the descriptor f(O6)(E), but also with the descriptor f(C11)(N) . The optimum values of the terms f(O6)(E) and f(C11)(N) were about 11.15 and 0, respectively. Studies also showed that compound 19 exhibiting the highest in vitro activity mimicked the three-ring portion of protoporphyrinogen IX (Protogen). The present work had proved that the DFT-based quantum chemical descriptors could lead to the better correlation relationship than that the PM3-based electronic descriptors, therefore, DFT-based QSARs could be expected to help facilitate the design of additional substituted phenyl triazolinone derivatives of Protox inhibitors with good biological activity.

Enzyme Inhibitors↗
PubMed2004

Quantitative structure-activity relationships for phenyl triazolinones of protoporphyrinogen oxidase inhibitors: a density functional theory study.

The equilibrium geometries, electronic structures, and electrostatic potentials of a series of substituted phenyl triazolinones of protoporphyrinogen oxidase (PPO) inhibitors have been investigated by using the density functional theory (DFT) method. The quantum chemical descriptors, highest occupied molecular orbital and lowest unoccupied molecular orbital energy gap (DeltaE), weighted electrophilic, and nucleophilic atomic frontier electron density (FAE and FAN), and net atomic charge (QA), were computed at the same DFT level. Based on these precise quantum chemical descriptors, a quantitative structure-activity relationships study has been carried out and shown that QC11, FN5E, FC10N, and DeltaE of individual molecules are most likely to be responsible for the in vitro biological activity and greenhouse preemergence activity of phenyl triazolinones. The ability to quite accurately predict the biological activity of phenyl triazolinones by using DFT-based QSAR can be expected to help facilitate the design of additional substituted phenyl triazolinones as PPO inhibitors with good biological activity.

Benzene Derivatives↗
PubMed2004

In vivo mechanisms of tissue-selective drug toxicity: effects of liver-specific knockout of the NADPH-cytochrome P450 reductase gene on acetaminophen toxicity in kidney, lung, and nasal mucosa.

Acetaminophen overdose causes toxicity in liver and extrahepatic tissues. Although it is well established that cytochrome P450 enzymes play a critical role in the metabolic activation of acetaminophen, it is not yet clear whether acetaminophen toxicity in extrahepatic tissues is a consequence of hepatic biotransformation. The aim of this study was to determine whether extrahepatic acetaminophen toxicity is altered in a mouse model that has liver-specific deletion of the NADPH-cytochrome P450 reductase (Cpr) gene. Liver-specific Cpr-null (Null) mice were resistant to acetaminophen hepatotoxicity, and they showed faster acetaminophen clearance than did wild-type mice at a toxic acetaminophen dose (400 mg/kg i.p.). However, when circulating acetaminophen levels were made equivalent in the two strains, the severity of extrahepatic acetaminophen toxicity was decreased in the Null relative to that in the wild-type mice in the lung, kidney, and lateral nasal glands, although not in the nasal olfactory and respiratory mucosa. In the lung and liver, the decreased acetaminophen toxicity was accompanied by substantial decreases in the formation of acetaminophen-protein adducts in the Null mice; adducts were not detected in other tissues examined. These results indicate that acetaminophen toxicity in the nasal mucosa is not dependent on hepatic microsomal P450-catalyzed metabolic activation and that acetaminophen toxicity in the lung, kidney, and lateral nasal glands is at least partly caused by liver-derived acetaminophen metabolites.

Acetaminophen↗
PubMed2004

A model for estimating joint maternal-offspring effects on seed development in autogamous plants.

We present a statistical model for testing and estimating the effects of maternal-offspring genome interaction on the embryo and endosperm traits during seed development in autogamous plants. Our model is constructed within the context of maximum likelihood implemented with the EM algorithm. Extensive simulations were performed to investigate the statistical properties of our approach. We have successfully identified a quantitative trait locus that exerts a significant maternal-offspring interaction effect on amino acid contents of the endosperm in maize, demonstrating the power of our approach. This approach will be broadly useful in mapping endosperm traits for many agriculturally important crop plants and also make it possible to study the genetic significance of double fertilization in the evolution of higher plants.

Algorithms↗
PubMed2004

High-performance liquid chromatographic method for simultaneous determination of baicalein and baicalein 7-glucuronide in rat plasma.

A simple HPLC method with ultraviolet detection was developed for the simultaneous determination of baicalein and its major metabolite, baicalein 7-glucuronide (baicalin) in rat plasma. Following solid phase extraction with HLB cartridge, the analytes were separated using a gradient mobile phase consisting of methanol-acetonitrile-phosphate buffer. The flow-rate was set at 1ml/min and the eluent was detected at 320nm. The method is linear over the studied range of 1-10 and 0.05-1microg/ml for baicalein and baicalin, respectively. The intra-day and inter-day variations of the analysis were less than 6.38%, with relative error ranging from -3.6 to 6%. The limit of quantification in plasma was 0.05microg/ml for both baicalein and baicalin. The developed method proves to be an improved and more reliable method because of its capability for determining baicalein and baicalin simultaneously in a single chromatographic run.

Animals↗
PubMed2004

Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress.

The identification of rare monogenic forms of Parkinson's disease (PD) has provided tremendous insight into the molecular pathogenesis of this disorder. Heritable mutations in alpha-synuclein, parkin, DJ-1 and PINK1 cause familial forms of PD. In the more common sporadic form of PD, oxidative stress and derangements in mitochondrial complex-I function are considered to play a prominent role in disease pathogenesis. However, the relationship of DJ-1 with other PD-linked genes and oxidative stress has not been explored. Here, we show that pathogenic mutant forms of DJ-1 specifically but differentially associate with parkin, an E3 ubiquitin ligase. Chemical cross-linking shows that pathogenic DJ-1 mutants exhibit impairments in homo-dimer formation, suggesting that parkin may bind to monomeric DJ-1. Parkin fails to specifically ubiquitinate and enhance the degradation of L166P and M26I mutant DJ-1, but instead promotes their stability in cultured cells. The interaction of parkin with L166P DJ-1 may involve a larger protein complex that contains CHIP and Hsp70, perhaps accounting for the lack of parkin-mediated ubiquitination. Oxidative stress also promotes an interaction between DJ-1 and parkin, but this does not result in the ubiquitination or degradation of DJ-1. Parkin-mediated alterations in DJ-1 protein stability may be pathogenically relevant as DJ-1 levels are dramatically increased in the detergent-insoluble fraction from sporadic PD/DLB brains, but are reduced in the insoluble fraction from parkin-linked autosomal recessive juvenile-onset PD brains. These data potentially link DJ-1 and parkin in a common molecular pathway at multiple levels that may have important implications for understanding the pathogenesis of inherited and sporadic PD.

Cell Line, Tumor↗
PubMed2004

Intravenous administration of a GPIIb/IIIa receptor antagonist extends the therapeutic window of intra-arterial tenecteplase-tissue plasminogen activator in a rat stroke model.

BACKGROUND AND PURPOSE: Occlusion of the middle cerebral artery triggers platelet accumulation at the site of occlusion and in downstream microvessels. The platelet-induced secondary thrombosis promotes the progressive development of ischemic brain damage and contributes to the resistance to thrombolysis and to the tight 3-hour therapeutic window. We tested the hypothesis that combination of intravenous (IV) administration of a GPIIb/IIIa receptor antagonist, 7E3 F(ab')2, with intra-arterial (IA) administration of tenecteplase-tissue plasminogen activator (TNK-tPA) increases the efficacy of thrombolysis and extends the therapeutic window of stroke. METHODS: Rats subjected to embolic stroke were treated with IV 7E3 F(ab')2 (6 mg/kg) in combination with IA or IV TNK-tPA (5 mg/kg) at 4 and 6 hours after onset of stroke, respectively; IA TNK-tPA (5 mg/kg) alone at 6 hours after onset of stroke; or saline at 6 hours after onset of stroke. RESULTS: The combination of IV 7E3 F(ab')2 (4 hours) and IA TNK-tPA (6 hours) significantly (P<0.05) reduced infarct volume and improved neurological functional deficits, which was associated with significant (P<0.05) reductions in the size of embolus at the origin of the occluded middle cerebral artery and in down-stream microvascular platelet and fibrin deposition, and enhanced microvascular patency compared with saline-treated rats. However, combination of IV 7E3 F(ab')2 (4 hours) and IV TNK-tPA (6 hours) or IA TNK-tPA (6 hours) alone failed to reduce infarct volume and improve neurological function compared with the saline-treated rats. No significant differences of the incidence of hemorrhage were detected among groups. CONCLUSIONS: These data suggest that the combination of IV 7E3 F(ab')2 (4 hours) and IA TNK-tPA (6 hours) extends the therapeutic window of thrombolysis to 6 hours after stroke.

Animals↗
PubMed2004

Progressive loss of Syk and abnormal proliferation in breast cancer cells.

The tumor suppressor gene Syk tyrosine kinase is absent or reduced in invasive breast cancer tissues and cell lines; its loss in breast tissues is linked to poor prognosis and metastasis. Also, evidence shows that in vitro Syk is involved in regulating proliferation. Here, we show by in situ hybridization on breast tissue sections that the loss of Syk expression is progressive during tumor development. Strikingly, Syk is already partially lost in normal epithelial tissue adjacent to the cancer lesion. In vivo, cell proliferation (as measured by the proliferative index Ki67) increased from normal to ductal carcinoma in situ to invasive, whereas Syk in situ staining in the same tissues decreased. In vitro, the presence of Syk was associated with reduced cell proliferation in an epidermal growth factor receptor-overexpressing breast cancer cell line, BT549, whereas changes in apoptosis were undetected. Concomitantly, the kinase activity of the proto-oncogene Src was reduced by approximately 30%. A 5-fold increase in abnormal mitoses was observed in the Syk-transfected cells compared with vector control. We propose that Syk is involved in the regulation of cell proliferation, possibly by controlling mechanisms of mitosis and cytokinesis via Src signal transduction pathway(s). Because of its progressive and early loss during tumor onset and development, monitoring of Syk loss in breast epithelial cells by noninvasive techniques such as ductal lavage may be a powerful tool for screening purposes.

Apoptosis↗
PubMed2004

An intronic mutation causes long QT syndrome.

OBJECTIVES: The purpose of this research was to determine whether an intronic variant (T1945+6C) in KCNH2 is a disease-causing mutation, and if expanded phenotyping criteria produce improved identification of long QT syndrome (LQTS) patients. BACKGROUND: Long QT syndrome is usually caused by mutations in conserved coding regions or invariant splice sites, yet no mutation is found in 30% to 50% of families. In one such family, we identified an intronic variant in KCNH2. Long QT syndrome diagnosis is hindered by reduced penetrance, as the long QT phenotype is absent on baseline electrocardiogram (ECG) in about 30%. METHODS: Fifty-two family members were phenotyped by baseline QTc, QTc maximum on serial ECGs (Ser QTc-max), and on exercise ECGs (Ex QTc-max) and by T-wave patterns. Linkage analysis tested association of the intronic change with phenotype. The consequences of T1945+6C on splicing was studied using a minigene system and on function by heterologous expression. RESULTS: Expanded phenotype/pedigree criteria identified 23 affected and 29 unaffected. Affected versus unaffected had baseline QTc 484 +/- 48 ms versus 422 +/- 20 ms, Ser QTc-max 508 +/- 48 ms versus 448 +/- 10 ms, Ex QTc-max 513 +/- 54 ms versus 444 +/- 11 ms, and LQT2 T waves in 87% versus 0%. Linkage analysis demonstrated a logarithm of odds score of 10.22. Splicing assay showed T1945+6C caused downstream intron retention. Complementary deoxyribonucleic acid with retained intron 7 failed to produce functional channels. CONCLUSIONS: T1945+6C is a disease-causing mutation. It alters KCNH2 splicing and cosegregates with the LQT2 phenotype. Expanded ECG criteria plus pedigree analysis provided accurate clinical diagnosis of all carriers including those with reduced penetrance. Intronic mutations may be responsible for LQTS in some families with otherwise negative mutation screening.

Adult↗
PubMed2004

MRI evaluation of treatment of embolic stroke in rat with intra-arterial and intravenous rt-PA.

Using magnetic resonance imaging (MRI), we investigated treatment of a rat model of embolic stroke with rt-PA via intra-arterial (IA) and intravenous (IV) routes of administration. Rats were treated with rt-PA by either IA (n = 13) or IV (n = 13) routes at 3 h after stroke induction. Diffusion, perfusion, T2, and magnetization transfer MRI were performed prior to and at 1-3 and at 24 h after embolization. The IA treated group exhibited smaller lesion volumes than the IV treated group (p = 0.02). The relative areas with low ADCW and cerebral blood flow (CBF) after IA rt-PA intervention were significantly (p < or = 0.03) smaller than those in the IV treated group at 24 h after embolization. Significant differences (p < 0.02) between IA and IV treated groups in the relative area with high T2 and inverse of the apparent forward transfer rate of magnetization (kINV) in the ipsilateral hemisphere were also detected at 24 h after embolization. The IA treated group exhibited less intracerebral hemorrhage (27%) than the IV treated (64%) groups. Our data suggest that the beneficial effects of IA rt-PA treatment can be detected by changes in CBF, ADCW, T2, and kINV.

Animals↗
PubMed2004

Structural evidence for direct hydride transfer from NADH to cytochrome P450nor.

Nitric oxide reductase cytochrome P450nor catalyzes an unusual reaction, direct electron transfer from NAD(P)H to bound heme. Here, we succeeded in determining the crystal structure of P450nor in a complex with an NADH analogue, nicotinic acid adenine dinucleotide, which provides conclusive evidence for the mechanism of the unprecedented electron transfer. Comparison of the structure with those of dinucleotide-free forms revealed a global conformational change accompanied by intriguing local movements caused by the binding of the pyridine nucleotide. Arg64 and Arg174 fix the pyrophosphate moiety upon the dinucleotide binding. Stereo-selective hydride transfer from NADH to NO-bound heme was suggested from the structure, the nicotinic acid ring being fixed near the heme by the conserved Thr residue in the I-helix and the upward-shifted propionate side-chain of the heme. A proton channel near the NADH channel is formed upon the dinucleotide binding, which should direct continuous transfer of the hydride and proton. A salt-bridge network (Glu71-Arg64-Asp88) was shown to be crucial for a high catalytic turnover.

Crystallography, X-Ray↗
PubMed2004

Multiparametric ISODATA analysis of embolic stroke and rt-PA intervention in rat.

To increase the sensitivity of MRI parameters to detect tissue damage of ischemic stroke, an unsupervised analysis method, Iterative Self-Organizing Data Analysis Technique Algorithm (ISODATA), was applied to analyze the temporal evolution of ischemic damage in a focal embolic cerebral ischemia model in rat with and without recombinant tissue plasminogen activator (rt-PA) treatment. Male Wistar rats subjected to embolic stroke were investigated using a 7-T MRI system. Rats were randomized into control (n=9) and treated (n=9) groups. The treated rats received rt-PA via a femoral vein at 4 h after onset of embolic ischemia. ISODATA analysis employed parametric maps or weighted images (T1, T2, and diffusion). ISODATA results with parametric maps are superior to ISODATA with weighted images, and both of them were highly correlated with the infarction size measured from the corresponding histological section. At 24 h after embolic stroke, the average map ISODATA lesion sizes were 37.7+/-7.0 and 39.2+/-5.6 mm2 for the treated and the control group, respectively. Average histological infarction areas were 37.9+/-7.4 mm2 for treated rats and 39.4+/-6.1 mm2 for controls. The R2 values of the linear correlation between map ISODATA and histological data were 0.98 and 0.96 for treated and control rats, respectively. Both histological and map ISODATA data suggest that there is no significant difference in infarction area between non-treated and rt-PA-treated rats when treatment was administered 4 h after the onset of embolic stroke. The ISODATA lesion size analysis was also sensitive to changes of lesion size during acute and subacute stages of stroke. Our data demonstrate that the multiparameter map ISODATA approach provides a more sensitive quantitation of the ischemic lesion at all time points than image ISODATA and single MRI parametric analysis using T1, T2 or ADCw.

Algorithms↗
PubMed2004

[Cardiopulmonary bypass of orthotopic heart transplantation].

OBJECTIVE: To summarize the extracorporeal circulation(ECC) management experiences on 4 cases of orthotopic heart transplantation. METHODS: All patients received moderate hypothermia and high flow rate perfusion. Many strategies were taken to maximize the protection of myocardium, lung, kidney and blood conservation. The donor hearts were arrested with aorto perfusion using modified St. Thomas solution at 4 degrees C. After being flushed with 5,000 mL cold saline, the donor hearts were perfused with 1,000 mL UW solution in 4 degrees C and preserved in ice saline. Ice mud was covered on the donor heart and cold saline was dripped into left atrium in the period of anastomosis. RESULTS: The ECC time was 133.3+/-13.1 min, and the warm and cold ischemia time was respectively 1-3 min and 142.0+/-28.2 min. All the cases recovered heart beats automatically. Left ventricular ejection fractions were 60%-65% a month postoperatively. One patient died of acute rejection 150 days postoperatively. 3 cases survived. CONCLUSION: Proper ECC management, importment organs and donor heart protection are the key to success in heart transplant operations.

Adult↗
PubMed2004

Heme deficiency causes apoptosis but does not increase ROS generation in HeLa cells.

Mitochondria provide cellular energy supply via respiration and are the major sites for the generation of reactive oxygen species (ROS). Mitochondria also play a fundamental role in apoptosis. Heme is a key factor in mitochondrial function. Defective heme synthesis or altered heme metabolism is associated with numerous diseases. Here we investigated the molecular mechanism by which heme promotes HeLa cell growth and survival. We found that heme deficiency-induced apoptosis involves the release of cytochrome c and the activation of caspase 3. However, heme deficiency-induced apoptosis appears to occur by a unique mechanism distinct from those known to mediate mitochondrial-dependent apoptosis. Specifically, our data show that heme deficiency causes apoptosis in a pathway that is independent of ROS generation and the collapse of mitochondrial membrane potential. These results provide insights into how defective heme synthesis or altered heme metabolism causes diseases and how heme may control cell growth and cell death.

Apoptosis↗
PubMed2004

[Integrins mediate the increase of concentration of intracellular free calcium in mouse eggs].

For studying the effect of integrin on the [Ca(2+)](i) of mouse eggs and its transmembrane signaling mechanism, zona-free mouse eggs were loaded with calcium probe Fluo-3/AM and the intensity of fluorescence of the eggs treated with different factors was measured through laser confocal microscopy. The results showed that the [Ca(2+)](i) of zona-free mouse eggs was increased when the eggs were treated with RGD peptide, fibronectin (Fn) and anti-mouse integrin subunit alpha(6) and beta(1) monoclonal antibodies, respectively. The [Ca(2+)](i) of the mouse eggs was also increased when the eggs were placed in calcium-free medium and treated with RGD peptide or Fn. The changes in the mouse egg [Ca(2+)](i) caused by RGD and Fn were similar to those caused by sperm. However, the concentration of Ca(2+) of the zona-free mouse eggs pretreated with tyrosine kinase inhibitor was not increased when the eggs were treated in the same way, and, neither was the intracellular calcium increased in those eggs pretreated with PKC inhibitor when the eggs were treated with RGD peptide. It is therefore suggested that the occupancy of integrins on the membrane of mouse eggs by their ligands mediates the release of Ca(2+) and then the increase in the [Ca(2+)](i) of eggs, which is one of the early events of egg activation. The tyrosine kinase signaling pathway and PKC are involved in this process as well.

Animals↗
PubMed2004

Rate constants for hydrogen abstraction from alkoxides by a perfluoroalkyl radical. An oxyanion accelerated process.

A combination of laser flash photolysis and competitive kinetic methods has been used to measure the absolute bimolecular rate constants for hydrogen atom abstraction in water from a series of fluorinated alkoxides and aldehyde hydrates by the perfluoroalkyl radical, *CF2CF2OCF2CF2SO3- Na+. The bimolecular rate constants observed for the beta-fluorinated alkoxides were in the 10(5) M(-1) s(-1) range, such rates representing enhancements (relative to the respective alcohols) of between 100 and almost 1000-fold, depending on the reactivity of the alkoxide. Likewise, the monobasic sodium salts of chloral and fluoral hydrate exhibit similar rate enhancements, relative to their respective hydrates.

Journal Article↗
PubMed2004

Large primary kinetic isotope effects in the abstraction of hydrogen from organic compounds by a fluorinated radical in water.

Isotope effects have been measured for the abstraction of hydrogen from a series of organic substrates by the perfluoro radical, Na+ -O3SCF2CF2OCF2CF2*, in water. Both primary and secondary deuterium isotope effects were measured, with the primary isotope effects ranging in value from 4.5 for isopropanol to 19.6 for acetic acid. The values for the alpha- and beta-secondary deuterium isotope effects were 1.06 and 1.035, respectively. It was concluded that tunneling contributes significantly to the production of the observed, large primary kinetic isotope effects in these C-H abstraction reactions.

Journal Article↗