Biomedical subjects
Publications and source records attributed to Z C Liu.
Chronic lead exposure is recognized as a potential cause of hyperuricaemia, kidney damage and hypertension. The fascinating story of lead poisoning and nephrotoxicity illustrates the utility of descriptive studies in the early elucidation of a new disease entity. The pursuit towards understanding lead nephropathy is presented as a successful illustration of human occupational and public health.
BACKGROUNDS/AIMS: This study investigates the ammonia removal capacity of coencapsulated hepatocytes and bone marrow stem cells in culture, and the treatment effect on hyperbilirubinemia Gunn rats when transplanted. METHODS: The hepatocytes and bone marrow stem cells isolated from Wistar rats were encapsulated alone or coencapsulated. In vitro, the encapsulated cells were cultured in media supplemented with 2.4 mMol/L concentration of ammonium chloride and the ammonia removal and urea synthesis were evaluated. In vivo, the encapsulated cells were transplanted intraperitoneally into hyperbilirubinemia Gunn rats and plasma bilirubin levels were measured before and after transplantation at intervals of 85 days. RESULTS: The ammonia removal capacity was maintained longer in the different ammonia concentration media in the coencapsulated hepatocytes and bone marrow cells culture. In the coencapsulation transplantation group, the plasma bilirubin levels were significantly lower than those in the group of hepatocytes encapsulation transplantation during the period of 3 to 10 weeks posttransplantion. CONCLUSIONS: The coencapsulated heaptocytes and bone marrow cells when compared to encapsulated hepatocytes could improve the maintenance of hepatocyte function both in vitro of ammonia removal in culture, and in vivo of the lowering the Gunn rats blood total bilirubin when transplanted.
Nasopharyngeal carcinoma (NPC), which occurs with a high incidence in southern China and southeast Asia, is of epithelial origin with overexpression of EGF receptor. To study the effect of inhibition of EGFR signaling on nasopharyngeal carcinoma cell proliferation and cell cycle distribution, EGFR tyrosine kinase inhibitor AG1478 was employed to treat Nasopharyngeal Carcinoma CNE2 cells. The results showed that AG1478 inhibited proliferation of CNE2 cells. Immunoblot showed that AG1478 inhibited EGFR phosphorylation in CNE2 cells without reduced expression of EGFR protein. The activation of Akt and MAPK which are downstream molecules of EGFR signaling pathway, were also inhibited by AG1478. AG1478 induced cell cycle arrest in G1 phase, and the levels of protein p27 were significantly up-regulated. We concluded that inhibition of the EGFR signaling induced cell cycle arrest in G1 phase in CNE2 cells and p27 up-regulation was involved in this process. The EGFR kinase specific inhibitor is of potential to be developed into drugs for NPC treatment.
AIM: To investigate the effect of vascular endothelial growth factor 165 (VEGF165) on sensitivity of endothelial cells to anticancer drugs. METHODS: Human dermal microvessel endothelial cells (HDMEC) were incubated with anticancer drugs in the presence of VEGF165. Survival of endothelial cells was assayed by MTT method. DNA fragments of apoptosis were detected by agarose electrophoresis. Potential mechanisms underlying the effect of VEGF165 on endothelial cells were investigated with RT-PCR and Western blot analysis. RESULTS: VEGF165 induced the multidrug resistance phenotype of HDMEC to a wide variety of anticancer drugs such as epirubicin, cisplatin, etoposide, mytomycin C, vincristine, CPT-11, and taxol in vitro. This protective effect was partly due to the up-regulation of lung drug resistance protein (LRP) and multidrug resistance-associated protein (MRP), as well as the down-regulation of Bax protein induced by VEGF165. CONCLUSION: VEGF165 induced multidrug resistance phenotype of endothelial cells, which implicated the anti-angiogenic effect of anticancer drugs might depend on microenvironment of tumors in vivo.
AIM: To investigate the mechanism of apoptosis of HL60 cells induced by the annonaceous acetogenin, squamocin. METHODS: Induction of apoptosis was determined through Hoechst33258 dye staining and DNA agarose gel electrophoresis. Expression of the proteins was detected using Western blot analysis. Caspase-3 activity was detected using caspase-3 kit. RESULTS: Treatment of HL-60 cells with squamocin resulted in extensive nuclear condensation, DNA fragmentation, cleavage of the death substrate poly(ADP-ribose) polymerase (PARP) and induction of caspase-3 activity. Pretreatment of HL-60 cells with caspase-3 specific inhibitor DEVD-CHO prevented squamocin-induced DNA fragmentation, PARP cleavage and cell death. Stress-activated protein kinase (SAPK/JNK) was activated after treatment with squamocin in HL-60 cells. CONCLUSION: These results suggest that apoptosis of HL-60 cells induced by squamocin require caspase-3 activation, and could be related to SAPK activation.
Ticlopidine is associated with a relatively high incidence of agranulocytosis and aplastic anemia. We have shown that other drugs associated with agranulocytosis are metabolized to reactive metabolites by activated human neutrophils or by HOCl, which is the major oxidant produced by activated neutrophils. We set out to test the hypothesis that ticlopidine also fits this pattern and is oxidized to a reactive intermediate by activated neutrophils and HOCl. As much as 8% ticlopidine was metabolized by activated human neutrophils to a dehydro-ticlopidine; however, this product did not account for all of the decrease in ticlopidine concentration. The oxidation products of ticlopidine by the combination of myeloperoxidase and hydrogen peroxide were the same as those by HOCl: dehydrogenated ticlopidine and 2-chloroticlopidine. A neutrophil-derived reactive metabolite of ticlopidine was trapped with GSH and the same ticlopidine-GSH conjugate was found in both the myeloperoxidase and HOCl systems. Evidence for the identity of the reactive metabolite was obtained by reaction of ticlopidine with HOCl in a flow reaction system coupled to a mass spectrometer. The mass spectra suggested that the reactive metabolite was a thiophene-S-chloride. We conclude that ticlopidine follows the same pattern of reactive metabolite formation by activated neutrophils as other drugs associated with a high incidence of agranulocytosis, and the putative thiophene-S-chloride formed by activated neutrophils may be responsible for ticlopidine-induced agranulocytosis.
AIM: To study the biological function of ceramide signaling in Bel7402 cells. METHODS: Inhibition of cell growth was assayed using MTT method. Morphologic assessment of apoptosis was performed with fluorescence microscope. DNA fragmentation was detected by electrophoresis and flow cytometry. The levels of protein p53, Bcl-2, and Bax were measured with Western blot. RESULTS: Bel7402 cells treated with C2-ceramide underwent cell proliferation inhibition. IC50 value was 14.28 mumol.L-1. After treatment of Bel7402 with ceramide, the morphologic changes including reduction in volume, nuclear chromatin condensation, fluorescence strength were observed. SubG1 peaks were detected on flow cytometry (FCM). Agarose gel electrophoresis of DNA from cells treated with ceramide revealed "ladder" pattern. The Western blot assay from cell extracts showed that the levels of protein p53 were decreased after ceramide treatment. The levels of protein Bcl-2 were decreased also. But the levels of Bax protein showed no difference between untreated cells and treated cells. CONCLUSION: Ceramide induces apoptosis in Bel7402 cells, related to Bcl-2 down-regulation.
OBJECTIVE: To observe the effects of simulated weightlessness on the nutritional state and contents of serum lipids in human. METHOD: Eighteen healthy men were exposed to 21 d bed rest with -6 degrees head down tilt (HDT -6 degrees). Nutrients intake was calculated and the lipids levels were determined on the first, eleventh and twenty-first day. RESULT: Intake of the three main nutrients, carbohydrates, protein and fat met the physiological requirement essentially, but carbohydrates intake was significantly reduced in the second week. There were no significant differences among the lipid levels during different periods. CONCLUSION: Simulated weightlessness may exert a short-term and reversible influence on human nutritional intake except for lipids.
The equipment of using Azolla for O2-supplementation and food-production in future space station was developed and tested. Dog was used as the O2-consuming animal. The design of this device considered both the requirement of Azolla growth, such as illumination, temperature, humidity, nutrition and biomass harvesting, and also the food supplement, excretion draining and temperature controlling for the dog under the condition of an airtight chamber for a relatively long duration. This device was preliminarily tested for O2-release by Azolla, and data about O2-supplement by Azolla were obtained.
AIM: To study the effect of mitoxantrone (Mit) on DNA polymerases of tumor cells. METHODS: DNA polymerases of Ehrlich ascites carcinoma cells were isolated by phosphocellulose column chromatography. The effects of Mit on DNA polymerase alpha, beta, and gamma were detected by method of K Ono. RESULTS: Mit inhibited DNA polymerase alpha, beta, and gamma, IC50 values were 11.9, 6.5, and 11.9 mumol.L-1, and Ki 1.86, 2.22, and 2.05 mumol.L-1, respectively. The inhibitory mode of Mit on DNA polymerase alpha, beta, and gamma was competitive. CONCLUSION: Mit is a strong inhibitor on DNA polymerase alpha, beta, and gamma. The inhibitory mode was competition with respect to template DNA.
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Cytochrome P450 (P450) can utilize organic hydroperoxides and peracids to support hydroxylation and dealkylation of various P450 substrates. However, the biological significance of this P450 peroxygenase/peroxidase activity in the bioactivation of xenobiotics in intact cells has not been demonstrated. We have shown that tert-butyl hydroperoxide (tBHP) markedly enhances 3-20-fold the cytotoxicity of various aromatic hydrocarbons and their phenolic metabolites. The tBHP-enhanced hepatocyte cytotoxicity of 4-nitroanisole (4-NA) and 4-hydroxyanisole (4-HA) was also accompanied by an increase in the hepatocyte O-demethylation of 4-NA and 4-HA up to 7.5- and 21-fold, respectively. Hepatocyte GSH conjugation by 4-HA was also markedly increased by tBHP. An LC/MS analysis of the GSH conjugates identified hydroquinone-GSH and 4-methoxy-catechol:GSH conjugates as the predominant adducts. Pretreatment of hepatocytes with P450 inhibitors, e.g., phenylimidazole, prevented tBHP-enhanced 4-HA metabolism, GSH depletion, and cytotoxicity. In conclusion, hydroperoxides can therefore be used by intact cells to support the bioactivation of xenobiotics through the P450 peroxidase/peroxygenase system.
In order to investigate the regulatory effect of acupuncture on obesity patients with the Stomach-Intestine Excessive Heat Type, the pre-acupunctural and post-acupunctural obesity index and biochemical indices of 718 patients with simple obesity was observed. It was showed that the marked weight loss effects was achieved in the cases by acupuncture, while the biochemical indices improved. It suggests that acupuncture had a good regulatory effect on the function of nerve, endocrine, digestion and energy metabolism.
5-Aminosalicylic acid (5-ASA) is an agent widely used in the treatment of inflammatory bowel disease. 5-ASA has been shown to be a potential scavenger of the oxidants, such as hypochlorous acid (HOCl), that are released by neutrophils present in inflammatory bowel disease. We studied the oxidation of 5-ASA by HOCl and characterized the reaction pathway involving reactive intermediates. The reactive intermediates in the reaction of 5-ASA with HOCl were identified by use of a flow system interfaced with a Sciex API III mass spectrometer. The mass spectral analysis revealed the formation of iminoquinone and quinone reactive intermediates. The major stable product formed was identified as gentisic acid. The iminoquinone and quinone intermediates were trapped by glutathione (GSH) and the products analyzed by LC/MS. The major conjugate was formed from the quinone with one dominant isomer. In contrast, three isomers of the iminoquinone-GSH conjugates were observed in almost equal proportion. Covalent binding of the reactive intermediates to the alpha-chain of human hemoglobin was also observed. We propose that the iminoquinone is the major intermediate formed in the scavenging of neutrophil-generated HOCl by 5-ASA. Although this reaction may inactivate HOCl and be responsible for the antiinflammatory effects of the drug, it also forms reactive intermediates that covalently bind to protein and may be responsible for adverse reactions that are associated with the use of the drug.
Clozapine was oxidized to a reactive intermediate by HOCI, which is the major oxidant produced by activated neutrophils. A mass spectrum was obtained of this reactive intermediate by using a flow system in which the reactants were fed into a mixing chamber and the products flowed directly into a Sciex API III mass spectrometer. The intermediate was observed at m/z 325, which is 2 mass units less than the protonated molecular ion of the parent drug. This intermediate reacted with water to form several products with a m/z at 343. The same products were produced by the oxidation of clozapine by the combination of myeloperoxidase, hydrogen peroxide and chloride ion. The reactive intermediate was trapped by glutathione (GSH) and several conjugates were formed. Nuclear magnetic resonance spectra of the two major conjugates indicated GSH bound to the 6 and 9 positions of the aromatic ring. These data provide further evidence for the formation of a formal nitrenium ion in which the positive charge is highly delocalized. Clozapine was also oxidized by activated neutrophils, and in the presence of GSH, the same GSH conjugates were formed. When therapeutic concentrations of radiolabeled clozapine were used, up to 7% of the drug became irreversibly bound to the neutrophils. Covalent binding was inhibited by about 30% in the presence of 1 mM GSH but was almost abolished at 5 mM GSH. The putative nitrenium ion formed by activated leukocytes could be responsible for clozapine-induced agranulocytosis.
Experiments showed that in the rat model of alcohol-induced liver injury, a dosage of the pills (1-2g/kg, ig) could increase the cholesterol level, lower the triglyceride level, and improve the fatty degeneration and necrosis of liver (P < 0.05-0.01). The results suggest that the important mechanism of the pills in protecting and treating alcoholic fatty liver, lies in the regulation of metabolism of the lipid, especially of the triglyceride.
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The sulfation of dermatan sulfate by SO3-trimethylamine in N,N-dimethylformamide led to substitution initially at HO-6 of residues of 2-acetamido-2-deoxy-beta-D-galactopyranosyl 4-sulfate (1), to produce the 4,6-disulfate (6). When this step reached a level of greater than 50%, sulfation occurred with equal facility at HO-2 and HO-3 of residues of alpha-L-idopyranosyluronic acid (2), giving rise to a mixture of 2-,3-, and 2,3-disulfates. An analogous substitution pattern was observed for HO-2 and -3 of a simpler idopyranose unit, in the sulfation of methyl 4,6-O-benzylidene-alpha-D-idopyranoside (12). This lack of regioselectivity in the reaction of 2 (and 12) contrasts markedly with the high affinity of the reagent for HO-3 of residues of alpha-L-idopyranosyluronic acid present in a modified form of heparin. It is attributed to a difference between the two polymers in the relative orientation of their neighboring amino sugar residues, whereby there is an unobstructed access of the reagent in one instance, and hindrance of HO-2 selectively in the other. Enzymolysis by chondroitinase ABC was found to yield unsaturated disaccharide containing residues of 4,6-disulfate, as well as larger fragments containing unsaturated glycosyl groups derived from L-idopyranosyluronic acid 2-sulfate, evidence of a relatively broad enzyme specificity. The presence of extra sulfate groups in dermatan sulfate did not enhance its weak antithrombotic activity, as measured by anti Xa assay, in disagreement with earlier reports.