Biomedical subjects

Q Mei

Publications and source records attributed to Q Mei.

At least 19 recordsLinked to original sources

PubMed2006

Orientational correlations in the glacial state of triphenyl phosphite.

Spallation neutron and high-energy X-ray diffraction experiments have been performed to investigate the local structure of the glacial and supercooled liquid states in triphenyl phosphite. The observed diffraction patterns have been interpreted using a Reverse Monte Carlo modeling technique. The results show that the glacial state forms unusually weak intermolecular hydrogen bonds between an oxygen atom connected to a phenyl ring and an adjacent phenyl ring aligned in an approximately antiparallel configuration. The structure is very different from the hexagonal crystal which is characterized by two weaker hydrogen bonds between linear arrays of molecules which are offset from each other and packed in a hexamer arrangement.

Journal Article↗

PubMed2006

Isotope quantum effects in water around the freezing point.

We have measured the difference in electronic structure factors between liquid H(2)O and D(2)O at temperatures of 268 and 273 K with high energy x-ray diffraction. These are compared to our previously published data measured from 279 to 318 K. We find that the total structural isotope effect increases by a factor of 3.5 over the entire range, as the temperature is decreased. Structural isochoric temperature differential and isothermal density differential functions have been used to compare these data to a thermodynamic model based upon a simple offset in the state function. The model works well in describing the magnitude of the structural differences above approximately 310 K, but fails at lower temperatures. The experimental results are discussed in light of several quantum molecular dynamics simulations and are in good qualitative agreement with recent temperature dependent, rotationally quantized rigid molecule simulations.

Journal Article↗

PubMed2005

Change of nitric oxide in experimental colitis and its inhibition by melatonin in vivo and in vitro.

AIM: To investigate the change of nitric oxide (NO) in rat colitis and its inhibition by melatonin in vivo and in vitro. METHODS: In vivo, rat colitis was established intracolonically with trinitrobenzenesulphonic acid (TNBS) and ethanol. The animals were randomised into five groups: control group, model group, melatonin group (2.5, 5.0, 10.0 mg/kg), and treated intracolonically with saline, saline and melatonin respectively (once a day, from day 7 after colitis was established to day 28). After the end of the experiment, the mucosal damage index (CMDI) and histology score (HS) were evaluated and the level of myeloperoxidase (MPO) and malondiadehyde (MDA) and NO in the colon tissue were measured. In vitro, the co-culture model of the inflamed colon mucosa (from the colitis) with lipopolysaccharide (LPS), and the colonocytes oxidative injury model by hydroxyl radical, were designed respectively to elucidate the inhibition of NO by melatonin. RESULTS: After treated with TNBS/ethanol, the extent of CMDI and HS, the levels of MPO, MDA, and NO in the model group, were higher than that in the control group; melatonin ameliorated these parameters effectively. The stimulation of LPS increased the level of NO and MPO and MDA in the co-culture model of inflamed colon mucosa, and melatonin significantly reduced the level of MPO, MDA, and NO. In the coloncyte oxidative injury model by hydroxyl radical, the contents of LDH, MDA, and NO were increased; melatonin reversed this oxidative injury considerably. CONCLUSION: This study showed that TNBS/ethanol induced colitis was pharmacologically controlled by melatonin in vivo and in vitro.

Animals↗

PubMed2002

Autonomic mechanism and defects in the glucagon response to insulin-induced hypoglycaemia.

In summary, this article briefly reviews the evidence that three separate autonomic inputs to the islet are capable of stimulating glucagon secretion and that each is activated during IIH. We have reviewed our evidence that these autonomic inputs mediate the glucagon response to IIH, both in non-diabetic animals and humans. Finally, we outline our new preliminary data suggesting an eSIN in an autoimmune animal model of T1DM. We conclude that the glucagon response to IIH is autonomically mediated in non-diabetic animals and humans. We further suggest that at least one of these autonomic inputs, the sympathetic innervation of the islet, is diminished in autoimmune T1DM. These data raise the novel possibility that an autonomic defect contributes to the loss of the glucagon response to IIH in T1DM.

Animals↗

PubMed2001

Human papillomavirus type 16 is an important infectious factor in the high incidence of esophageal cancer in Anyang area of China.

To investigate the potential role of human papillomavirus (HPV) infection in the pathogenesis of esophageal carcinomas in the Anyang area of China, we have evaluated specimens collected by balloon cytology examination from volunteers in two regions with significantly different incidences of esophageal carcinoma. 138 donors were from a village in a county with an esophageal carcinoma (EC) age-adjusted mortality rate of 132x10(5), the remaining 68 were resident in a second village from another county with an EC mortality rate of 52x10(5). Specimens were evaluated using both polymerase chain reaction (PCR) amplification and in situ hybridization (ISH) protocols. PCR results showed that the prevalence of the human papillomavirus type 16 (HPV-16) E6 gene in the high incidence area was 1.9-fold higher than that of the low incidence area (72 and 37%, respectively, P < 0.01). Moreover, the positive rate corresponded with pathology grade. Similar results were obtained with the HPV-16 E7 gene. As the cells undergoing cytopathological progress, the HPV-16 E6 positive rate was increased, in both villages. In contrast to HPV-16 E6 and E7, detection of the HPV L1 gene was consistently lower, and its prevalence decreased with increasing dysplasia grades (P < 0.05). By ISH analyses, the expression rate of HPV-16 E6 in the specimens collected from the high incidence area was 2.2-fold higher than those from the low incidence area (49 versus 22%, respectively; P < 0.05), and transcription of the E6 gene paralleled cytopathology. HPV-18 was also detected in 17 and 15% of the specimens from the high and low incidence areas, respectively, but most of these samples were also simultaneously HVP-16 positive. These results suggest that HVP-16 plays a causative role in the high incidence of esophageal cancer in the Anyang region of CHINA:

China↗

PubMed2001

In-vitro metabolism of celecoxib, a cyclooxygenase-2 inhibitor, by allelic variant forms of human liver microsomal cytochrome P450 2C9: correlation with CYP2C9 genotype and in-vivo pharmacokinetics.

In-vitro studies were conducted to assess the impact of CYP2C9 genotype on the metabolism (methyl hydroxylation) and pharmacokinetics of celecoxib, a novel cyclooxygenase-2 inhibitor and CYP2C9 substrate. When compared to cDNA-expressed wild-type CYP2C9 (CYP2C9*1), the Vmax/Km ratio for celecoxib methyl hydroxylation was reduced by 34% and 90% in the presence of recombinant CYP2C9*2 and CYP2C9*3, respectively. These data indicated that the amino acid substitution at position 359 (Ile to Leu) elicited a more pronounced effect on the metabolism of celecoxib than did a substitution at position 144 (Arg to Cys). The Vmax/Km ratio was also decreased in microsomes of livers genotyped CYP2C9*1/*2 (47% decrease, mean of two livers), or CYP2C9*1/*3 (59% decrease, one liver). In all cases, these changes were largely reflective of a decrease in Vmax, with a minimal change in Km. Based on simulations of the in-vitro data obtained with the recombinant CYP2C9 proteins, it was anticipated that the pharmacokinetics of celecoxib (as a much as a five-fold increase in plasma AUC) would be altered (versus CYP2C9*1/*1 subjects) in subjects genotyped heterozygous or homozygous for the CYP2C9*2 (Cys144) or CYP2C9*3 (Leu359) allele. In a subsequent clinical study, the AUC of celecoxib was increased (versus CYP2C9*1/*1 subjects) approximately 2.2-fold (range, 1.6-3-fold) in two CYP2C9*1/*3 subjects and one CYP2C9*3/*3 subject receiving a single oral dose (200 mg) of the drug. In contrast, there was no significant change in celecoxib AUC in two subjects genotyped CYP2C9*1/*2.

Administration, Oral↗

PubMed2001

Fos expression in rat celiac ganglion: an index of the activation of postganglionic sympathetic nerves.

To develop an index of the activation of abdominal sympathetic nerves, we used Fos immunostaining of the celiac ganglion (CG) taken from rats receiving nicotine, preganglionic nerve stimulation, or glucopenic agents. Subcutaneous nicotine injection moderately increased Fos expression in the principal ganglionic cells of the CG (17 +/- 4 Fos+ per mm(2), approximately 12% of all principal CG cells), whereas subcutaneous saline had no effect (0 +/- 0 Fos+ per mm(2); n = 7; P < 0.01). Greater Fos expression was obtained by applying nicotine topically to the CG (71 +/- 8 Fos+ per mm(2); 52% of all principal CG cells, n = 5; P < 0.01 vs. topical saline, n = 4) and by preganglionic nerve stimulation (126 +/- 9 Fos+ per mm(2); 94% of all principal CG cells, n = 11; P < 0.01 vs. nerve isolation, n = 7). Moderate Fos expression was also observed in the CG after intraperitoneal 2-deoxy-D-glucose (2DG) injection (21 +/- 2 Fos+ per mm(2); 16% of all principal CG cells, n = 5; P < 0.01 vs. saline ip) or insulin injection (16 +/- 2 Fos+ per mm(2); 12% of all principal CG cells, n = 6; P < 0.01 vs. saline ip). Furthermore, Fos expression induced by 2DG was dose and time dependent. These data demonstrate significant Fos expression in the CG in response to chemical, electrical, and reflexive stimulation. Thus Fos expression in the CG may be a useful index to describe various levels of activation of its postganglionic sympathetic neurons.

Animals↗

PubMed2001

P2 purinergic receptor activation enhances cardiac contractility in isolated rat and mouse hearts.

Activation of P2 purinergic receptors exerts a potent positive inotropic effect in the cardiac myocyte. However, it is unknown whether its activation can also cause an increased contractility in intact heart. With the use of isolated rat and mouse hearts, the objective of the present study was to investigate the effect of P2 receptor agonist on the function of the intact heart. In both Langendorff rat hearts and working rat and mouse heart models, the P2X receptor agonist 2-methylthio-ATP (2-meSATP) caused dose-dependent increases in left ventricular developed pressure, rate of contraction, and rate of relaxation. The extent of P2X receptor agonist-stimulated increase in contractility was significantly less than that stimulated by the beta-adrenergic agonist isoproterenol. However, the increase in contractility occurred without a significant effect on the basal heart rate, in contrast to that caused by isoproterenol. In isolated rat ventricular myocytes, both ATP and the P2X receptor agonist 2-meSATP stimulated large increases in the myocyte contractile amplitude (107 +/- 13% and 99 +/- 9%, n = 17 cells from 5 rats and n = 19 cells from 6 rats, respectively). 2-meSATP caused only a slight increase in phospholipase C activity and could stimulate myocyte contractility in the presence of phospholipase C inhibitor U-73122, consistent with the role of a phospholipase C-independent P2X receptor in mediating the positive inotropic effect of 2-meSATP. The data provide evidence for a potentially important physiological role of the cardiac P2X receptor and for the concept that agonist at this receptor may be beneficial for the treatment of cardiac dysfunction.

Adenosine Triphosphate↗

PubMed2001

Type 1 protein tyrosine kinases in Chinese breast carcinomas: a clinicopathologic study.

Immunostaining for epidermal growth factor receptor (EGFR), c-erbB-2, c-erbB-3, c-erbB-4, ER, and PR was performed in 107 cases of primary breast carcinomas from Anyang, China. The expression rates of EGFR, c-erbB-2, c-erbB-3 and c-erbB-4 in this series were 43.9%, 36%, 27%, and 45.8%, respectively, and a stronger c-erbB-4 staining of "normal" glandular structures inside tumors and in the vicinity of tumor clusters was confirmed. Larger tumor size, lymph node metastases, and higher histologic grade in invasive ductal carcinomas were shown to be statistically valuable negative prognostic factors, and c-erbB-2 expression was also weakly associated with a poor prognosis no matter what the nodal status. The expressions of c-erbB-4 and ER in invasive ductal carcinomas were inversely associated with histologic grade of the tumors. Associations between the expression of c-erbB-4 and ER (p = 0.001) and the expression of ER and PR study (p = 0.004) were found in the present study. No significant associations between the expressions of EGFR, c-erbB-3, c-erbB-4, ER, and PR and overall survival were detected. The expression of c-erbB-4 in the node negative group was, however, associated with a better prognosis, indicating a different role of c-erbB-4 protein in breast tumor development than other EGFR family members have. Int J Surg Pathol 9(3):177-187, 2001

Adult↗

PubMed2001

Enzyme kinetics of cytochrome P450-mediated reactions.

The most common drug-drug interactions may be understood in terms of alterations of metabolism, associated primarily with changes in the activity of cytochrome P450 (CYP) enzymes. Kinetic parameters such as Km, Vmax, Ki and Ka, which describe metabolism-based drug interactions, are usually determined by appropriate kinetic models and may be used to predict the pharmacokinetic consequences of exposure to one or multiple drugs. According to classic Michaelis-Menten (M-M) kinetics, one binding site models can be employed to simply interpret inhibition (pure competitive, non-competitive and uncompetitive) or activation of the enzyme. However, some cytochromes P450, in particular CYP3A4, exhibit unusual kinetic characteristics. In this instance, the changes in apparent kinetic constants in the presence of inhibitor or activator or second substrate do not obey the rules of M-M kinetics, and the resulting kinetics are not straightforward and hamper mechanistic interpretation of the interaction in question. These unusual kinetics include substrate activation (autoactivation), substrate inhibition, partial inhibition, activation, differential kinetics and others. To address this problem, several kinetic models can be proposed, based upon the assumption that multiple substrate binding sites exist at the active site of a particular P450, and the resulting kinetic constants are, therefore, solved to adequately describe the observed interaction between multiple drugs. The following is an overview of some cytochrome P450-mediated classic and atypical enzyme kinetics, and the associated kinetic models. Applications of these kinetic models can provide some new insights into the mechanism of P450-mediated drug-drug interactions.

Algorithms↗

PubMed2001

Substrate inhibition kinetics for cytochrome P450-catalyzed reactions.

Most cytochrome P450 (P450 or CYP)-catalyzed reactions are adequately described by classical Michaelis-Menten kinetic parameters (e.g., Km and Vmax), which are usually determined by a saturation profile of velocity of product formation versus substrate concentration. In turn, these parameters may be used to predict pharmacokinetics. However, some P450 enzymes exhibit atypical or non-Michaelis-Menten kinetics, due largely to substrate inhibition at higher concentrations of substrate. Although the mechanism of substrate inhibition is unknown, ignoring it and truncating the data can lead to erroneous estimates of kinetic parameters. In the present study, 13 P450 marker substrates were examined with 10 recombinant P450 proteins, and 6 were found, to varying degrees, to exhibit substrate inhibition. To understand the nature of the inhibition, a kinetic model was proposed (assuming that two binding sites exist on the enzyme) and used to fit the experimental data. The derived data indicated that 1) the K(I) values (substrate inhibition) were approximately 1.2- to 10-fold greater than the respective K(S) values; 2) both K(S) and K(I) values may be affected by the interaction of the two bound substrates within the enzyme, exhibited by a factor alpha (alpha = 5.1-23.3); and 3) enzyme activity was inhibited markedly (39-97%) at excess concentrations of the substrates (beta = 0.03-0.61). These findings suggest that substrates have access to both the inhibitory site and catalytic site simultaneously (K(I) > K(S)). Furthermore, the two sites, in the presence of substrate, can interact with each other. Therefore, the degree of inhibition of the enzyme is dependent on the concentration of the substrate (usually >K(I)) that sufficiently occupies the inhibitory site.

Antineoplastic Agents↗

PubMed2001

[Study on anti-inflammatory, analgesic and antipyretic effects of bagmaking tea of sanyaku].

OBJECTIVE: To observe anti-inflammatory, analgesic and antipyretic effects of the Bagmaking Tea of Sanyaku in rats. METHODS: mouse torsion modle induced by glacial acetic acid, mouse auricle swelling model induced by xylene and rat fever model induced by baker yeast were used. RESULTS: Bagmaking Tea of Sanyaku could inhibit mouse torsion action, mouse auricle swelling and rat fever. CONCLUSION: Bagmaking Tea of Sanyaku possessed anti-inflammatory, analgesic and antipyretic effects.

Analgesics↗

PubMed2001

[Pharmacokinetical study of safflor yellow on rat acute model of blood stasis syndrome].

OBJECTIVE: To study the pharmacokinetical character of safflor yellow in rat acute model of blood stasis syndrome. METHODS: The rat acute model of blood stasis syndrome was made by i.p. adrenalin (0.07 ml/kg) and the stimulation of ice-water. At the time of 5, 10, 30, 60, 120, 180, 320, 480 min, the concentration of safflor yellow in the serum after i.v. safflor yellow (37.08 ml/kg) was determined. RESULTS: The concentration-time date of safflor yellow in rat acute model of blood stasis syndrome was shown to fit a double-compartment open model, t1/2 alpha = 1.43 min, t1/2 beta = 95.65 min, AUC = 49,632.90 micrograms.min/ml; while the concentration-time data of safflor yellow in normal rat was shown to fit a single-compartment open model, t1/2 alpha = 66.27 min, AUC = 42,267 micrograms.min/ml. CONCLUSION: The metabolism of safflor yellow was evidently later in rat acute model of blood stasis syndrome than in normal rat.

Acute Disease↗

PubMed2001

[The effects of safflor yellow on microcirculation and hemorheology of acute blood stasis rats].

OBJECTIVE: To observe the effects of safflor yellow on microcirculation and hemorheology of acute blood stasis rats. METHODS: The acute blood stasis medel was made by i.p. adrenalin (0.07 ml/(kg.time) for 2 times and the stimulation of ice-water. RESULTS: Safflor could markedly improve the number of net dot in microcirculation, and eta b, eta p, eta f in hemorheology (P < 0.05). CONCLUSION: Safflor yellow played an important role on blood stasis of rats.

Animals↗

PubMed2000

The tkNeo gene, but not the pgkPuro gene, can influence the ability of the beta-globin LCR to enhance and confer position-independent expression onto the beta-globin gene.

Whether drug-selectable genes can influence expression of the beta-globin gene linked to its LCR was assessed here. With the tkNeo gene placed in cis and used to select transfected cells, the beta-globin gene was expressed fourfold lower when it was positioned upstream of the LCR rather than downstream. This difference did not occur when the pgkPuro gene replaced tkNeo. Moreover, the beta-globin gene situated upstream of the LCR was transcribed without position effects when it was cotransfected with a pgkPuro-containing plasmid, whereas cotransfection with a tkNeo plasmid gave measurable position effects. Previous results from transfected cells selected via a linked tkNeo gene suggested that the 3' end of the beta-globin gene has no impact on LCR-enhanced expression. Here, removal of the 3' end of the beta-globin gene resulted in lower and much more variable expression in both transgenic mice and cells cotransfected with pgkPuro. Together, the results suggest that tkNeo, but not pgkPuro, can strongly influence expression of the beta-globin gene linked to its LCR. The findings could partly explain why data on beta-globin gene regulation obtained from transfected cells have often not agreed with those obtained using transgenic mice. Hence, one must be careful in choosing a drug-selectable gene for cell transfection studies.

Animals↗

PubMed2000

Innervation of the gastric mucosa.

A plethora of neuronal messengers ("classical" transmitters, gaseous messengers, amino acid transmitters, and neuropeptides) are capable of mediating or modulating gastric functions. Accordingly, the stomach is richly innervated. Gastric nerves are either intrinsic to the gastric wall, i.e., they have their cell bodies in the intramural ganglia and thus belong to the enteric nervous system, or they reach the stomach from outside, originating in the brainstem, in sympathetic ganglia, or in sensory ganglia. Topographically, the nerve fibers in the stomach reach all layers from the most superficial portions of the gastric glands to the outer smooth muscle layer. This wide distribution implies that virtually all different cell types may be reached by neuronal messengers. Within the gastric mucosa endocrine and paracrine cells (e.g., gastrin cells, ECL cells, somatostatin cells), exocrine cells (parietal cells, chief cells, mucous cells), smooth muscle cells, and stromal cells are regulated by neuronal messengers. The sensory innervation, responding to capsaicin, plays an important role in mucosal protection, and in ulcer healing. Presumably also other nerves are involved and a plasticity in the neuropeptide expression has been demonstrated at the margin of gastric ulcers. Taken together, available data indicate a complex interplay between hormones, paracrine messengers and neuronal messengers, growth factors and cytokines in the regulation of gastric mucosal activities such as secretion, local blood flow, growth, and restitution after damage.

Adrenergic Fibers↗

PubMed2000

Major role of human liver microsomal cytochrome P450 2C9 (CYP2C9) in the oxidative metabolism of celecoxib, a novel cyclooxygenase-II inhibitor.

In vitro studies were conducted to identify the cytochromes P450 (CYP) involved in the oxidative metabolism of celecoxib. The hydroxylation of celecoxib conformed to monophasic Michaelis-Menten kinetics (mean +/- S.D., n = 4 livers, K(m) = 3.8 +/- 0.95 microM, V(max) = 0.70 +/- 0.45 nmol/min/mg protein) in the presence of human liver microsomes, although substrate inhibition was significant at higher celecoxib concentrations. The treatment of a panel of human liver microsomal samples (n = 16 subjects) with antibodies against CYP2C9 and CYP3A4 inhibited the formation of hydroxy celecoxib by 72 to 92% and 0 to 27%, respectively. The presence of both antibodies in the incubation suppressed the activity by 90 to 94%. In addition, the formation of hydroxy celecoxib significantly correlated with CYP2C9-selective tolbutamide methyl hydroxylation (r = 0.92, P <. 001) and CYP3A-selective testosterone 6beta-hydroxylation (r = 0.55, P <.02). In contrast, correlation with activities selective for other forms of CYP was weak (r </= 0.46). Chemical inhibition studies showed that ketoconazole (selective for CYP3A4) and sulfaphenazole (selective for CYP2C9) inhibited the formation of hydroxy celecoxib in a concentration-dependent manner, whereas potent inhibitors selective for other forms of CYP did not show any significant effect over a range of 1 to 10 microM. In agreement, cDNA-expressed CYP2C9 catalyzed the formation of hydroxy celecoxib with an apparent K(m) value (microM) and a V(max) value (pmol/min/pmol recombinant CYP) of 5.9 and 21.7, whereas a higher K(m) value (18.2) and a lower V(max) value (1.42) were obtained with rCYP3A4. It is concluded that methyl hydroxylation of celecoxib is primarily catalyzed by human liver microsomal CYP2C9, although CYP3A4 also plays a role.

Animals↗

PubMed1999

Sigmoidal kinetic model for two co-operative substrate-binding sites in a cytochrome P450 3A4 active site: an example of the metabolism of diazepam and its derivatives.

Cytochrome P450 3A4 (CYP3A4) plays a prominent role in the metabolism of a vast array of drugs and xenobiotics and exhibits broad substrate specificities. Most cytochrome P450-mediated reactions follow simple Michaelis-Menten kinetics. These parameters are widely accepted to predict pharmacokinetic and pharmacodynamic consequences in vivo caused by exposure to one or multiple drugs. However, CYP3A4 in many cases exhibits allosteric (sigmoidal) characteristics that make the Michaelis constants difficult to estimate. In the present study, diazepam, temazepam and nordiazepam were employed as substrates of CYP3A4 to propose a kinetic model. The model hypothesized that CYP3A4 contains two substrate-binding sites in a single active site that are both distinct and co-operative, and the resulting velocity equation had a good fit with the sigmoidal kinetic observations. Therefore, four pairs of the kinetic estimates (KS1, kalpha, KS2, kbeta, KS3, kdelta, KS4 and kgamma) were resolved to interpret the features of binding affinity and catalytic ability of CYP3A4. Dissociation constants KS1 and KS2 for two single-substrate-bound enzyme molecules (SE and ES) were 3-50-fold greater than KS3 and KS4 for a two-substrate-bound enzyme (SES), while respective rate constants kdelta and kgamma were 3-218-fold greater than kalpha and kbeta, implying that access and binding of the first molecule to either site in an active pocket of CYP3A4 can enhance the binding affinity and reaction rate of the vacant site for the second substrate. Thus our results provide some new insights into the co-operative binding of two substrates in the inner portions of an allosteric CYP3A4 active site.

Adult↗