Biomedical subjects
Publications and source records attributed to L Liu.
The contents of phenacetin, aminopyrine and caffeine in Keganmin tablet were determined simultaneonsly with multiwavelength K -factor spectrophotometry. The result is accurate and the method is rapid. The average recoveries and relative standard deviations of the analysis for phenacetin, aminopyrine and caffeine were 99.91%, 0.41%; 100.1%, 0.29%; 100.1%, 0.56%, respectively.
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The human DNA repair enzyme apurinic/apyrimidinic endonuclease (APE/ref-1) is a multifunctional protein in the DNA base excision repair (BER) pathway that is responsible for repair of apurinic/apyrimidinic (AP) sites in DNA. DNA repair and programmed cell death both function using different mechanisms to protect the organism from the consequences of extensive cellular damage; however, little is known about the relationship of the DNA BER repair pathway to apoptosis. We have determined the relationship of a BER DNA repair enzyme, APE, to apoptosis using the myeloid leukemia cell line HL-60, which can be induced to differentiate down the granulocytic or monocytic/ macrophage pathway. Treatment of HL-60 cells with retinoic acid/DMSO (granulocytic) or phorbol 12-myristate 13-acetate (monocytic) results in apoptosis and in down-regulation of APE expression at both the RNA and protein levels. Moreover, double-labeling experiments using APE immunohistochemistry and the terminal deoxyribonucleotidyl transferase-mediated dUTP-fluorescein nick end labeling assay for apoptosis demonstrate that individual cells undergoing apoptosis lose expression of APE regardless of their state of differentiation. Blocking apoptosis by overexpression of the bcl-2 proto-oncogene in HL-60 cells or by a bcr-abl-related mechanism in K562 cells and subsequent differentiation results in morphological differentiation but no loss of APE expression. These studies establish that down-regulation of APE expression is associated with programmed cell death in cells of the myeloid lineage.
Mutations in the gene encoding the cell cycle inhibitor CDKN2A have been identified in some melanoma kindreds linked to 9p21. However, many such families show no evidence of mutations in the coding regions of CDKN2A. In this study, we examined whether two other potential tumor suppressors, CDKN2B and p19ARF, which also map within the 9p21 region, play a role in the development of familial melanoma. We found no mutations in the coding regions of either gene in melanoma-prone families with evidence of linkage to 9p21. We conclude either that another melanoma susceptibility gene exists within this chromosomal area or that mutations in noncoding regions of CDKN2A, CDKN2B, or p19ARF predispose to melanoma.
Although studies with truncated erythropoietin receptors (EpoRs) have suggested the tyrosine phosphorylation (Yphos) of the EpoR may not play a significant role in Epo-induced proliferation, we found, using a full length EpoR mutant designed Null, in which all 8 of the intracellular tyrosines (Ys) were substituted with phenylalanines (Fs), that Null cells required 5-10 fold more Epo than wild type (WT) EpoR containing cells in order to proliferate as well. Moreover, a comparison of Epo-induced proliferation with Epo-induced Yphos patterns, using DA-3 cells expressing WT, Null and various Y to F EpoR point mutants revealed that Stat5 Yphos and activation correlated directly with proliferation and was mediated primarily throuhg the most membrane proximal Y, i.e., Y343, although other tyrosines (most likely Y401 and Y431) within the EpoR could activate Stat5 in its absence. We also found that EpoR Yphos was essential for the Yphos of Shc and for the Yphos and association of a 145 kDa protein with Shc. We purified and cloned this Shc-associated 145 kDa protein and found that it was a unique SH2 containing inositol polyphosphate-5-phosphatase. This novel enzyme, which we have called SHIP for SH2-containing inositol-phosphatase, may modulate both Ras and inositol signaling pathways.
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Simvastatin (SV) is a lactone prodrug used for the treatment of hypercholesterolemia. Upon incubation of SV with liver microsomal preparations from human donors, four major metabolic products were formed (3'-hydroxy SV, 6'-exomethylene SV, 3',5'-dihydrodiol SV, and the active hydroxy acid, SVA), together with several minor unidentified metabolites. The 3',5'-dihydrodiol SV, a new metabolite, was inactive as an inhibitor of HMG-CoA reductase. Kinetic studies of SV metabolism in human liver microsomes suggested that the major NADPH-dependent metabolites (3'-hydroxy SV, 6'-exomethylene SV, and 3',5'-dihydrodiol SV) were formed with relatively high intrinsic clearances, consistent with the extensive metabolism of SV observed in vivo. Based on four different in vitro approaches, namely 1) correlation analysis, 2) chemical inhibition, 3) immunoinhibition, and 4) metabolism by recombinant human P450, it is concluded that CYP3A is the major enzyme subfamily responsible for the metabolism of SV by human liver microsomes. Both CYP3A4 and CYP3A5 were capable of catalyzing the formation of 3',5'-dihydrodiol, 3'-hydroxy, and 6'-exomethylene metabolites. However, CYP3A4 exhibited higher affinity (> 3 fold) for SV than CYP3A5. Also, the studies indicated that CYP2D6, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP1A2, and CYP2E1 did not play significant roles in the metabolism of SV in vitro. Over the concentration range of 0-40 microM, SV inhibited the activity of CYP3A, but not the activities of CYP2C8/9, CYP2C19, or CYP2D6 in human liver microsomes. The inhibition of hepatic midazolam 1'-hydroxylase, a CYP3A marker activity, by SV was competitive with a Ki value of approximately 10 microM. SV was > 30-fold less potent than ketoconazole and itraconazole as an inhibitor of CYP3A. Under the same conditions, SVA, the hydrophilic hydroxy acid form of SV, did not inhibit CYP3A, CYP2C8/9, CYP2C19, or CYP2D6 activities. The results suggested that the in vivo inhibitory effects of SV on the metabolism of CYP3A substrates likely would be less than those of ketoconazole and itraconazole at their respective therapeutic concentrations. In addition, metabolic activities mediated by the other P450 enzymes tested are unlikely to be affected by SV.
Biological methods for cancer therapies are very important. A small and efficient target carrier is the key component for anti-cancer drugs. In our laboratory, the antibody IgY was extracted from egg yolk of a SPF hen. The SPF hen was immunized with an antigene of P110 protein which was purified from human stomach cancer MGC-803 cells. Results indicated that the antibody IgY can specifically recognize gastrointestinal system cancers. It may become an important carrier for antitumorigenic drugs.
The aims of this study were to examine how the imidazoline (I)1/alpha-2 receptor agonist moxonidine and the putative endogenous imidazoline receptor agonist agmatine might affect intestinal motility and fluid transport. The effects of moxonidine were compared with those of UK 14,304, a highly selective alpha-2 adrenoceptor agonist with very low affinity for I1 receptors. Moxonidine and UK 14,304 inhibited the peristaltic reflex in the isolated rat ileum. The inhibitory effects were antagonized by the selective alpha-2 adrenoceptor antagonist yohimbine and the I1/alpha-2 antagonist efaroxan and almost completely blocked by the irreversible alpha-2 adrenoceptor antagonist EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), which has a low affinity for imidazoline receptors. Yohimbine (3 microM) and efaroxan (0.01 and 1 microM) caused parallel rightward shifts to the concentration-response curves of moxonidine and UK 14,304, yielding pKB values corresponding to those at alpha-2 binding sites. Moxonidine induced dose-dependent proabsorptive effects in the jejunum and ileum and also reversed the secretory phase of the vasoactive intestinal peptide-induced responses. The degree of antagonism by yohimbine and efaroxan was similar against moxonidine and UK 14,304 on the proabsorptive and antisecretory effects. We conclude that the effects of moxonidine in mediating inhibition of intestinal motility and enhancing fluid transport are attributed predominantly to interaction with alpha-2 adrenoceptors. Agmatine had no effect on peristalsis but significantly decreased the rate of fluid absorption from the jejunum and ileum, an effect in contrast to moxonidine. A physiological role for agmatine in the regulation of intestinal transport remains to be clarified.
Fibroblast growth factor-2 (FGF-2) promotes cardiac myocyte proliferation and has been detected in extracellular as well as cytoplasmic and nuclear compartments. As a first step in examining the participation of intracellular FGF-2 in cardiac myocyte cell cycle we have investigated its localization in proliferative chicken cells during interphase and the various stages of mitosis in culture. We have used a previously characterized and affinity-purified anti-FGF-2 antibody preparation which recognizes the 19-22 kDa variants of chick FGF-2. By immunofluorescence, bright, punctate anti-FGF-2 labelling was observed in 26% of interphase nuclei from myocytes derived from 5 day embryonic heart ventricles; these nuclei were positive for anti-bromodeoxyuridine staining indicating that they are at the S- or G2 phase of the cell cycle. In prophase and metaphase, bright anti-FGF-2 staining was detected in apparent association with chromosomes. During anaphase, however, anti-FGF-2 staining dissociated from chromosomal locations distinctly remaining in strand-like structures in the area of ensuing cleavage furrow formation. In late telophase and cytokinesis, strong staining persisted in the area of the midbody and reappeared in a small fraction of newly formed daughter nuclei. Absorption of the antibody preparation with immobilized FGF-2 eliminated all staining. This dynamic pattern of anti-FGF-2 staining suggests that chick FGF-2 or immunologically related protein(s) not only increase in DNA-synthesizing nuclei but they may play a role in subsequent stages of mitosis and cytokinesis.
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OBJECTIVE: To investigate the relationship between the clinical outcome of childhood acute lymphoblastic leukemia and the status of minimal residual disease after termination of therapy. METHODS: A total of 18 children with acute lymphoblastic leukemia were studied. Eleven cases were treated with chemotherapy, the other 7 with autologous peripheral blood stem cell transplantation (ABSCT) or autologous bone marrow transplantation (ABMT). The outcome of the 18 patients was obtained by clinical follow-up. Minimal residual disease was detected by means of the polymerase chain reaction (PCR) and restriction analysis. RESULTS: Minimal residual disease was detected in 9 patients after completion of therapy. Three out of the 9 patients relapsed within 3 to 6 months. Among the other 9 patients with no detectable minimal residual disease, no one relapsed. CONCLUSIONS: PCR detection of minimal residual disease after termination of therapy can identify patients at risk for relapse in future. Minimal residual disease that cannot be detected after termination of therapy may be one of the important factors for long-term disease-free survival.
OBJECTIVE: To study the effect and toxicities of China-made paclitaxel in the treatment of advanced epithelial ovarian carcinoma. METHODS: Thirty-two patients were divided into two groups. single paclitaxel group (SPG): paclitaxel was only given to twelve untreated patients or those who had been given only one course of chemotherapy at a dose of 175 mg/m2 in 5% glucose 500 ml, i.v. for 3 hours; and combined paclitaxel group (CPG): paclitaxel 135 mg/m2 in 5% glucose 55 ml, i.v. for 3 hours on day 1 plus cisplatin 70-80 mg/m2 or carboplatin 300 mg/m2, i.v. on day 2, was administered to 20 patients with persistent or recurrent tumor after platinum based chemotherapy. Four weeks were defined as one course in both groups. At least two courses were given except those with tumor progression after one course. RESULTS: The overall response rate was 39%. It was 27% and 45% in the SPG and CPG. The chief side effects were moderate myelosuppression, peripheral neuropathy (myalgia, arthralgia, peripheral neuritis), severe alopecia, etc., but no hypersensitivity. One patient died from intestinal perforation. CONCLUSIONS: China-made paclitaxel is effective as in treating ovarian carcinoma especially for platinum-resistant patients. The toxic effects are tolerable to the patients.
The paper presents the treatment of vascular tumors in nasopharynx and nasal sinuses with digital subtraction angiography (DSA) and selective arterial embolization. By using preoperative embolization of blood supply arteries, the intraoperative bleeding was reduced significantly, the tumors were shrank and the tumor limits were clear. We recommend that DSA and selective arterial embolization should be used as a routine preoperative method adjunct to surgery for the treatment of vascular tumors of nasopharynx and nasal sinuses.
OBJECTIVE: To explore whether myocardial mitogen-activated protein kinase (MAPK) play an important role in hypertensive cardiac remodeling. METHODS: We compared myocardial MAPK activity by phosphocellular method and its localization and distribution by immunohistology in hypertrophic myocardium in SHRsp at age of 34 weeks (34 w group) and 54 weeks (54 w group) with age matched WKY served as control. RESULTS: SHRsp was compared with WKY. The heart weight to body weight ratio was significantly increased in both groups. Myocardial MAPK activity increased 1.81 fold in the 34 w group and 1.46 fold in the 54 w group. MAPK expressed abundantly in hypertrophic myocardium, mainly localized in interstitial cells. CONCLUSION: MAPK might be a major pathway of transducing hypertrophic signals.
Zinc deficiency (ZD) model was established in young rats starting from their lactation period. Effects of ZD in fodder on brain development and learning and memory were observed with electron microscopy and neurobiochemical and electroneurophysiological methods, and its mechanism was studied. Results showed that 1. brain weight, hippocampal weight, and serum and hippocampal zinc concentrations were significantly lower in ZD group than those in controls; 2. proportion of induced long-term potentiation (LTP) was zero in ZD group and proportion of active avoidance response decreased profoundly in ZD group, significantly lower than that in normal controls whose LTP proportion was 100%; 3. concentrations of excitatory and inhibitory amino acids, glutamic acid, gamma-aminobutyric acid in cerebral cortex and hippocampus and nitrous oxide in hippocampus were significantly higher in ZD group than those in normal one, and content of somatostatin in hippocampus and DNA in pyramidocytes were significantly lower in ZD group than those in normal one; and 4. number of synaptic vesicles in pyramidocytes of hippocampus decreased obviously in ZD group. It suggests that brain development and function are obviously affected by fodder zinc deficiency in rats.
Gliomas are tumors of the central nervous system that may be inherited in some patients. The gene(s) responsible for the clustering of gliomas in families have not yet been identified. Molecular studies of sporadic high-grade gliomas have revealed mutations or deletions of the genes encoding the protein kinase inhibitors p16(INK4A) and p15(INK4B) in a large proportion of tumors. Moreover, those tumors without deletions frequently display gene amplification and/or over-expression of mRNA encoding the protein kinase cdk4. We hypothesized that germ-line mutations in the p16(INK4A), p15(INK4B), or CDK4 genes might contribute to some cases of familial gliomas. To address this issue, we analyzed 36 kindreds with a predisposition to glial tumors. Genomic DNA from index members of these families was screened by PCR-single-strand conformational polymorphism analysis. We did not detect any functional mutations in the p16(INK4A), p15(INK4B), or CDK4 genes, although two individuals did have a previously described A140T polymorphism in p16(INK4A). Thus, despite the association between the sporadic forms of high-grade glioma and abnormalities of p16(INK4A), p15(INK4B), or CDK4, we found no evidence that germ-line mutations in the coding region of these three genes predispose to inherited glial tumors.
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