Biomedical subjects
Publications and source records attributed to Jing Li.
A new photocatalytic system involving iron(II) bipyridine supported on NaY zeolite (FeBY) shows excellent reactivity and selectivity in the oxidation of organic compounds. This approach allows highly controlled oxidation reaction to occur but avoids undesirable mineralization into CO2 and H2O.
A detailed biochemical and mechanistic study of in vitro selected variants of 8-17 DNAzymes is presented. Even though the 8-17 DNAzyme motif has been obtained through in vitro selection under three different conditions involving 10 mM Mg(2+) (called 8-17), 0.5 mM Mg(2+)/50 mM histidine (called Mg5), or 100 microM Zn(2+) (called 17E), all variants are shown to be the most active with Pb(2+) (8-17: k(obs) approximately 0.5 min(-1); Mg5: k(obs) approximately 2 min(-1); 17E: k(obs) approximately 1 min(-1) with 200 microM Pb(2+) at pH 5.0). For the 17E variant of the 8-17 DNAzyme, the single-turnover rate constants followed the order of Pb(2+) >> Zn(2+) >> Mn(2+) approximately Co(2+) > Ni(2+) > Mg(2+) approximately Ca(2+) > Sr(2+) approximately Ba(2+). The catalytic rate is half-maximal at 13.5 microM Pb(2+), 0.97 mM Zn(2+), or 10.5 mM Mg(2+), suggesting that the metal-binding affinity of the DNAzymes is in the order of Pb(2+) > Zn(2+) > Mg(2+). The Pb(2+)-dependent activity increases linearly with pH and the slope of the plot of log k(obs) versus pH is approximately 1, suggesting a single deprotonation in the rate-limiting step of the reaction. Sequence variations of the DNAzyme confirm the importance of the G*T wobble pair, the two loops and the intervening stem in maintaining the active conformation of the system. While Mg(2+) and Zn(2+) catalyze only a transesterification reaction with formation of a product containing a 2',3'-cyclic phosphate, Pb(2+) catalyzes a transesterification reaction followed by hydrolysis of the 2',3'-cyclic phosphate. Although this two-step mechanism has shown to be operative in protein ribonucleases and in the leadzyme RNAzyme, it is now demonstrated for the first time that this DNAzyme may also use the same mechanism. Therefore, the two-step mechanism is observed in metalloenzymes of all classes, and this 8-17 DNAzyme provides a simple, stable, and cost-effective model system for understanding the structure of Pb(2+)-binding sites and their roles in the two-step mechanism.
Two novel metal polyselenides, KPdCu(Se(2))(Se(3)) (I) and RbPdCu(Se(2))(Se(3)) (II), have been synthesized from solvothermal reactions in superheated ethylenediamine at 160 degrees C. The isostructural compounds crystallize in the monoclinic space group P2(1)/m, Z = 2, with a = 6.145(1) A, b = 7.268(1) A, c = 8.865(2) A, beta = 102.41(3) degrees for I, and a = 6.253(1) A, b = 7.267(1) A, c = 8.993(2) A, beta = 102.28(3) degrees for II. Their crystal structures are two-dimensional networks with [PdCu(Se(2))(Se(3))](-) anionic layers built from one-dimensional [Pd(Se(2))(Se(3))](2)(-) "chains" that are "stitched" together by tetrahedrally coordinated Cu atoms. The DSC data show that I and II are stable up to 400 degrees C and decompose at ca. 436 and 424 degrees C, respectively. Both compounds are narrow band-gap semiconductors with estimated band gaps of about 0.7 eV (I) and 0.8 eV (II), respectively. They are the first structurally characterized quaternary copper palladium polychalcogenides with a (Se(2))(2)(-) and a (Se(3))(2)(-) fragment, both exhibiting interesting and unusual metal-selenium coordination.
In an effort to make semiconductor nanomaterials with tunable properties, we have deliberately designed and synthesized a family of novel organic-inorganic hybrid nanocomposites based on II-VI semiconductors with structures ranging from one-dimensional (1-D) chain to two-dimensional layer (2-D) to three-dimensional (3-D) framework. All nanostructures exhibit strong quantum confinement effect (QCE), while possessing a perfectly periodic arrangement. The optical absorption experiments show that all compounds generate a very large blue shift in the absorption edge (1.0-2.0 eV) due to the strong QCE. More significantly, their band edge shift and optical properties can be tuned by changing the dimensionality of inorganic motifs as well as overall crystal structures. Raman studies reveal that not only do these structures have distinctly different vibrational signatures from those of the II-VI host semiconductors, but they also differ significantly from each other as a result of changes in dimensionality. The crystal structures of these nanocomposite materials have been characterized by single crystal and/or powder X-ray diffraction methods. [ZnTe(pda)] (1; pda = propanediamine) is composed of 1-D chains of [ZnTe] with pda chelating to Zn atoms. [ZnTe(N(2)H(4))] (2; N(2)H(4) = hydrazine) and [ZnTe(ma)] (3; ma = MeNH(2) = methylamine) are two-dimensional (2-D) layered structures containing [ZnTe] slabs and terminal hydrazine (2) or methylamine (3) molecules. The crystal structures of [CdSe(en)(0.5)] (4; en = ethylenediamine) and [CdSe(pda)(0.5)] (5) are 3-D networks containing [CdSe] slabs bridged by bidentate organic diamine molecules. Crystal data for 1: Orthorhombic, space group Pbcm, a = 9.997(2), b = 6.997(1), c = 10.332(2) A, Z = 4. For 2: Monoclinic, space group P2(1), a = 4.2222(6), b = 6.9057(9), c = 7.3031(10) A, beta = 98.92(8) degrees, Z = 2. For 3: Orthorhombic, Pbca, a = 7.179(1), b = 6.946(1), c = 18.913(4) A, Z = 8. For 4: Orthorhombic, Pbca, a = 7.0949(3), b = 6.795(3), c = 16.7212(8) A, Z = 8. For 5: Orthorhombic, Cmc2(1), a = 20.6660(12), b = 6.8900(4), c = 6.7513(4) A, Z = 8.
Airway epithelial cells synthesize proinflammatory molecules such as IL-8, GM-CSF, RANTES, and ICAM-1, the expression of which is increased in the airways of patients with asthma. We investigated the regulation of these NF-kappa B-dependent genes by the novel protein kinase C (PKC) isoform PKC delta in 16HBE14o- human airway epithelial cells, focusing on IL-8 expression. Transient transfection with the constitutively active catalytic subunit of PKC delta (PKC delta-CAT), and treatment with bryostatin 1, an activator of PKC delta, each increased transcription from the IL-8 promoter, whereas overexpression of PKC epsilon had minor effects. Expression of a dominant negative PKC delta mutant (PKC delta-KR) or pretreatment of cells with rottlerin, a chemical PKC delta inhibitor, attenuated TNF-alpha- and phorbol ester-induced transcription from the IL-8 promoter. Bryostatin 1 treatment increased IL-8 protein abundance in primary airway epithelial cells. Selective activation of PKC delta by bryostatin also activated NF-kappa B, as evidenced by p65 RelA and p50 NF-kappa B1 binding to DNA, NF-kappa B trans-activation, and I kappa B degradation. The sufficiency of PKC delta to induce NF-kappa B nuclear translocation and binding to DNA was confirmed in a 16HBE14o- cell line inducibly expressing PKC delta-CAT under the tet-off system. Deletion of the NF-kappa B response element severely attenuated PKC delta-induced IL-8 promoter activity. Finally, PKC delta-CAT induced transcription from the GM-CSF, RANTES, and ICAM-1 promoters. Together these data suggest that PKC delta plays a key role in the regulation of airway epithelial cell NF-kappa B-dependent gene expression.
To define the molecular basis of ethanol dependence, changes in the phosphorylation of cAMP response element binding protein (CREB) in the nucleus accumbens of rats after acute and chronic ethanol administration were detected using immunohistochemistry. The results demonstrate that the expression of phospho-CREB (p-CREB) protein in the rat nucleus accumbens significantly increased after 15 min of acute ethanol exposure, reaching a peak at 30 min after ethanol administration. The increment remained after 1 or 6 h of ethanol exposure compared to the control rats. In contrast, chronic intake of ethanol solution obviously decreased the expression of p-CREB protein compared to the control rats. The decrement remained 24 h or 72 h after ethanol withdrawal, and returned to the control levels after 7 d of ethanol withdrawal. The results suggest that an acute ethanol administration led to an increase in the phosphorylation of CREB in the nucleus accumbens, but chronic ethanol administration produced a decrement, which is possibly one of the molecular mechanisms of alcohol dependence.
OBJECTIVES: To study the association of narcolepsy with HLA class II alleles in Chinese narcoleptic patients. METHODS: 31 patients with narcolepsy underwent brain computed tomography (CT) scan and magnetic resonance imaging (MRI) testing. All patients received a MSLT test following a routine night's sleep, and serological HLA typing for HLA DR(2). 21 patients received PCR-SSP HLA DR and DQ typing. RESULTS: All patients had sleepiness and cataplexy. There was no evidence for other functional or structural diseases. Sleep paralysis was elicited in 45%; hypnagogic hallucinations, in 61%. Mean sleep latency on MSLT was 2.1 min +/- 1.3 min; sleep-onset rapid eye movement (SOREM) occurred during 2/5 naps in 30 of 31 patients. The average number and latency of SOREM episodes were 4.2 +/- 1.0 episodes and 4.0 min +/- 1.8 min, respectively. All patients but one were HLA DR(2) positive and 86% were HLADRB(1) * 1501-HLADQB(1)*0602 positive. CONCLUSIONS: HLA DR(2) and HLADQw6 are markers for narcolepsy-cataplexy in Chinese.
OBJECTIVE: To investigate the long-term effects of iodophor on thyroid function and autoimmunity in females. METHODS: 119 medical personnel who have been using iodophor as preoperative skin disinfectant more for than 2 years and 123 medical personnel who have not exposed to iodophor were studied. The urinary iodine, thyroid-stimulating hormone (TSH), free triiodothyronine (FT(3)), free thyroxine (FT(4)), thyroid peroxydase antibody (TPO-Ab) and TG-Ab in serum were measured and the thyroid were examined by B mode ultrasound apparatus. RESULTS: The median urinary iodine (MUI) was 300.4 micro g/L in the exposed group, not significantly higher than that in the non-exposed group (269.1 micro g/L, P > 0.05). The TSH levels of the exposed group and non-exposed group were 1.66 mU/L and 1.62 mU/L (P = 0.84). B mode ultrasound examination showed that the prevalence rate of thyroid disorders was 3.36% in the exposed group, not significantly different from that in the non-exposed group (2.44%). The thyroid autoantibody positive rate was not significantly different between these two groups too. The titer of autoantibody in the exposed group was 29.5 IU/L, significantly higher than that in the non-exposed group (22.4 IU/L, P = 0.048). The titer of TG-Ab in the exposed group was 21.85 IU/L, not significantly different from that in the non-exposed group (18.7 IU/L, P = 0.542). The mean titer of TPO-Ab in exposed group was 29.5 IU/L, significantly higher than that in non-exposed group (22.4 IU/L, P = 0.048). The total prevalence rate of all sorts of thyroid disorders in the exposed group was 11.76%, significantly higher than that in non-exposed group (4.07%, P = 0.026). The thyroid disorders discovered included clinical hyperthyroidism and subclinical hypothyroidism. CONCLUSION: Using iodophor as preoperative skin disinfectant may result in an increased incidence of thyroid disorders in female medical personnel. Medical personnel with iodophor exposure history should have their thyroid function and thyroid autoimmune status examined regularly.
The control of lipid and glucose metabolism is closely linked. The nuclear receptors liver X receptor (LXR)alpha and LXR beta have been implicated in gene expression linked to lipid homeostasis; however, their role in glucose metabolism is not clear. We demonstrate here that the synthetic LXR agonist GW3965 improves glucose tolerance in a murine model of diet-induced obesity and insulin resistance. Analysis of gene expression in LXR agonist-treated mice reveals coordinate regulation of genes involved in glucose metabolism in liver and adipose tissue. In the liver, activation of LXR led to the suppression of the gluconeogenic program including down-regulation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1), phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase expression. Inhibition of gluconeogenic genes was accompanied by an induction in expression of glucokinase, which promotes hepatic glucose utilization. In adipose tissue, activation of LXR led to the transcriptional induction of the insulin-sensitive glucose transporter, GLUT4. We show that the GLUT4 promoter is a direct transcriptional target for the LXR/retinoid X receptor heterodimer and that the ability of LXR ligands to induce GLUT4 expression is abolished in LXR null cells and animals. Consistent with their effects on GLUT4 expression, LXR agonists promote glucose uptake in 3T3-L1 adipocytes in vitro. Thus, activation of LXR alters the expression of genes in liver and adipose tissue that collectively would be expected to limit hepatic glucose output and improve peripheral glucose uptake. These results outline a role for LXRs in the coordination of lipid and glucose metabolism.
Structural transformation via deliberate and partial topological changes in a grid network structure has led to a three-dimensional, fully recyclable porous material (RPM-2) with a very high sorption capability.
A new series of substituted 2-sulfonyphenyl-3-phenyl-indole derivatives were synthesized and evaluated for their ability to inhibit COX-2 and COX-1enzymes. Most of the compounds synthesized were found to be highly potent and selective inhibitors of COX-2. This work led to the discovery of 2-aminosulfonylphenyl-3-phenyl-indole 5a which possesses higher activity and selectivity for COX-2 than Celecoxib both in vitro and in vivo.
PURPOSE: Clinical studies indicate that anthracycline cardiotoxicity increases with patient age. This may be due to altered pharmacokinetics or pharmacodynamics. A parameter termed 'early clearance' has been shown to decrease with age in patients receiving intravenous doxorubicin. This parameter, as defined, has no immediate relationship to any physiologically based pharmacokinetic parameter. We therefore reevaluated the pharmacokinetic data to better define the relationship between doxorubicin disposition and patient age. METHODS: Four studies provided a total of 56 patients with evaluable pharmacokinetics. The volume of the central compartment, V(c), the distribution clearance, CL(d), and total body clearance, CL, were determined for each patient and regressed against age. A physiologically based pharmacokinetic (PBPK) model for doxorubicin was also used to evaluate the effects of age on doxorubicin disposition. Published blood flows associated with various patient ages were used to simulate plasma and tissue doxorubicin concentrations. The relationship between CL(d) and initial tumor regression was also evaluated. RESULTS: No correlation was found between V(c) and age ( P>0.05). A highly significant correlation was observed between CL(d) and age ( P<0.0005) and there was a mild but significant relationship between CL and age ( P<0.01). Use of the PBPK model with different age-related blood flows yielded virtually identical parameter values to the clinical data analyzed. Furthermore, relative tissue AUCs simulated in old and young patients compared well with those reported for daunorubicin disposition in young and old rats. In addition, a linear relationship was observed between initial tumor regression and CL(d). CONCLUSIONS: Initial concentrations of doxorubicin following intravenous administration are higher in the elderly due to a decrease in CL(d) rather than in V(c). On the basis of simulations with the PBPK model, the reduced CL(d) appears to be related to altered regional blood flows in the elderly, and such changes may be of clinical significance.
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OBJECTIVE: To study the function of MMP-2 (matrix metalloproteinase-2), MMP-9 (matrix metalloproteinase-9) and TIMP-1 (tissue inhibitor of metalloproteinase-1) in the pathogenesis of EAM (experimented autoimmune myositis) rats, and to evaluate the effect of methylprednisolone on the mRNA and protein expression of MMP-2, MMP-9 and TIMP-1. METHODS: The expression levels of MMP-2, MMP-9 and TIMP-1 in the peripheral blood, spleen lymphocytes and muscles were examined among the EAM group, EAMM group and control group by RT-PCR and immunohistochemical techniques. RESULTS: 1. The degree of episode in the EAMM group was lower than that in the EAM group. Also, the infiltration of the inflammatory cells and the necrosis of the muscles were milder in the EAMM group than those in the EAM group. 2. The mRNA expression of MMP-2 and MMP-9 in the lymphocytes of the peripheral blood and spleen and the protein expression of MMP-2 and MMP-9 in the muscle tissues all increased significantly in the EAM group compared with those of the control group. However, the mRNA and protein expression of MMP-2 and MM-9 was suppressed significantly in contrast with that in the EAM group. 3. The mRNA and protein expression of TIMP-1 in the EAMM group increased with statistical significance compared with that in the EAM group. CONCLUSION: The upregulation of the expression of MMP-2 and MMP-9 may be related with the onset of EAM. TIMP-1 may be involved in the suppression of immunoreaction. Methylprednisolone may reduce the pathological damages of EAM, and this protective mechanism may be due to the inhibited expression of MMP-2 and MMP-9 and promoted expression of TIMP-1.
OBJECTIVE: To explore the interactive effect of low-dosage aspirin (ASA) combined with perindopril (PER), on prostacyclin (PGI2), thromboxone A2 (TXA2), and norepinephrine (NE) in the blood of arteriosclerosis rabbit models and the cardiac function. METHODS: Sixty adult New Zealand rabbits were randomly distributed into 5 groups with 12 rabbits in each group. One group was fed with standard fodder; the others were fed with high lipoid-diet (1% cholesterol content). Before and after 8 weeks' administration consecutively, LVEDP, LVSP, HR, +/- dp/dtmax, plasma PGI2 and TXA2, serum NE, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-ch), high-density lipoprotein cholesterol (HDL-ch) and triglycerides (TG) were evaluated. RESULTS: TG, TC, LDL-ch and pathological results confirmed arteriosclerosis rabbit models successfully. ASA combined with PER led to a significant increase in PGI2/TXA2 (P < 0.01) together with a significant decrease in the NE levels (P < 0.01) in the rabbits' blood, and then improved the cardiac output, i.e. increased LVSP (P < 0.01), and decreased the heart rate (P < 0.01) and LVEDP (P < 0.01) to a greater extent in the arteriosclerosis rabbit models. CONCLUSION: The ratio of PGI2 to TXA2 increased, and the NE levels decreased significantly; meanwhile, the heart rate decreased and the cardiac function improved during the administration of aspirin combined with perindopril in arteriosclerosis rabbit models. The results suggest that there is a synergism-action between low-dosage aspirin and ACE inhibitors due to increased PGI2/TXA2 and decreased NE levels.
An efficient stereoselective synthesis of the orally active NK(1) receptor antagonist Aprepitant is described. A direct condensation of N-benzyl ethanolamine with glyoxylic acid yielded a 2-hydroxy-1,4-oxazin-3-one which was activated as the corresponding trifluoroacetate. A Lewis acid mediated coupling with enantiopure (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol afforded a 1:1 mixture of acetal diastereomers which was converted into a single isomer via a novel crystallization-induced asymmetric transformation. The resulting 1,4-oxazin-3-one was converted via a unique and highly stereoselective one-pot process to the desired alpha-(fluorophenyl)morpholine derivative. Interesting and unexpected [1,2]-Wittig and [1,3]-sigmatropic rearrangements were identified during the optimization of these key steps. In the final step, a triazolinone side chain was appended to the morpholine core. The targeted clinical candidate was thus obtained in 55% overall yield over the longest linear sequence.
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In 16HBE14o- human bronchial epithelial cells, maximal tumor necrosis factor (TNF)-alpha-induced interleukin (IL)-8 expression depends on the activation of two distinct signaling pathways, one constituted in part by activator protein (AP)-1 and the other by nuclear factor (NF)-kappaB. We examined the upstream signaling intermediates responsible for IL-8 and granulocyte-macrophage colony-stimulating factor (GM-CSF) expression in this system, hypothesizing that p21 Ras and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase (MEKK)-1 function as common upstream activators of both the AP-1 and NF-kappaB pathways. TNF-alpha treatment induced both Ras and MEKK1 activation. Dominant-negative forms of Ras (N17Ras) and MEKK1 (MEKK1-KM) each inhibited TNF-alpha-induced transcription from IL-8 and GM-CSF promoters. Ras was required for maximal activation of extracellular signal-regulated kinase (ERK) and Jun amino terminal kinase (JNK) as well as AP-1 and NF-kappaB transcriptional activities, but not for activation of IkappaB kinase (IKK)-beta, an upstream activator of NF-kappaB. MEKK1 was required for maximal activation of ERK, JNK, and IKK, as well as for maximal AP-1 and NF-kappaB transcriptional activities. We conclude that Ras regulates TNF-alpha-induced chemokine expression by activating the AP-1 pathway and enhancing transcriptional function of NF-kappaB, whereas MEKK1 activates both the AP-1 and NF-kappaB pathways.