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Biomedical subjects

J J Liu

Publications and source records attributed to J J Liu.

At least 91 records · Page 5Linked to original sources
PubMed1994

Total synthesis of taxol.

Taxol, a substance originally isolated from the Pacific yew tree (Taxus brevifolia) more than two decades ago, has recently been approved for the clinical treatment of cancer patients. Hailed as having provided one of the most significant advances in cancer therapy, this molecule exerts its anticancer activity by inhibiting mitosis through enhancement of the polymerization of tubulin and consequent stabilization of microtubules. The scarcity of taxol and the ecological impact of harvesting it have prompted extension searches for alternative sources including semisynthesis, cellular culture production and chemical synthesis. The latter has been attempted for almost two decades, but these attempts have been thwarted by the magnitude of the synthetic challenge. Here we report the total synthesis of taxol by a convergent strategy, which opens a chemical pathway for the production of both the natural product itself and a variety of designed taxoids.

Models, Molecular↗
PubMed1994

Vascular responses to vasopressin antagonists in man and rat.

1. The effects of the non-peptide arginine vasopressin V1 receptor antagonist (OPC-21268) and the non-peptide V2 receptor antagonist (OPC-31260) on vasopressin-induced contraction of human internal mammary arteries and rat mesenteric resistance arteries were investigated. 2. In human internal mammary arteries, the non-peptide V1 receptor antagonist, OPC-21268, failed to antagonize vasopressin-induced contraction at low concentrations and potentiated the contraction at higher concentrations (300 nmol/l, P < 0.05). A peptide selective V1 receptor antagonist ([d(CH2)5, sarcosine7]arginine vasopressin) potently inhibited the vasopressin-induced contraction, indicating the presence of functionally constrictor V1 receptors in human internal mammary arteries. Both peptide (desGly-NH29[d(CH2)5, D-Ile2, Ile4]arginine vasopressin) and non-peptide 'selective' V2 receptor antagonists (OPC-31260, 3 mumol/l) significantly antagonized vasopressin-induced contraction (P < 0.01), indicating partial V1 receptor antagonist activity. 3. The vasopressin-induced contraction in human internal mammary arteries was reversed by high concentrations of the non-peptide V2 receptor antagonist, OPC-31260, but not by the non-peptide V1 receptor antagonist, OPC-21268. 4. The effects of OPC-21268 and OPC-31260 were specific to vascular vasopressin receptors as neither compound influenced endothelin- or noradrenaline-induced contraction in human internal mammary arteries. 5. In rat mesenteric resistance arteries, both OPC-21268 (10 nmol/l) and OPC-31260 (1 mumol/l) antagonized vasopressin-induced contraction (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Autologous neutrophil derived supernatants inhibit endothelium dependent relaxation in human coronary bypass graft.

OBJECTIVE: Spasm of internal mammary artery is a problem during coronary artery bypass grafting. The mechanism is unknown. The aim of this study was to determine whether supernatants derived from neutrophils affected endothelium dependent relaxation of human internal mammary artery. METHODS: The studies involved use of an organ chamber, measurement of cytosolic Ca2+, electron microscopy, and chemical characterisation. RESULTS: Autologous neutrophils and internal mammary artery were obtained from patients undergoing the bypass grafting. Supernatants derived from the neutrophils were used to treat the patients' internal mammary artery rings. The results showed that the supernatants derived from 1 x 10(3)-5 x 10(6) cells.ml-1 neutrophils produced a potent concentration dependent inhibition of the endothelium dependent relaxation to ATP, acetylcholine, and the calcium ionophore A23187, but not the endothelium independent relaxation to sodium nitroprusside. In cultured human endothelial cells, the neutrophil derived supernatants induced an increase in cytosolic calcium ([Ca2+]i), caused calcium oscillations, and desensitised the ATP induced increase in [Ca2+]i. The increased [Ca2+]i resulted from a calcium influx. The supernatants also induced an increase in vesicle formation and possibly exocytosis in the internal mammary artery endothelium. Chemical characterisation showed that the effect of the supernatants was caused by a factor that is stable to heat, extreme pH and protease, is negatively charged and weakly hydrophobic, and has a molecular weight under 500 Dalton. CONCLUSIONS: Autologous neutrophils release a stable non-protein small molecule that disturbs internal mammary artery endothelial function. Since it raises [Ca2+]i and causes possible exocytosis, it may have functions beyond its inhibition of vascular relaxation. This factor could be one of the contributors to internal mammary artery spasm and late atherosclerosis.

Acetylcholine↗
PubMed1994

Effects of calcium- and ETA-receptor antagonists on endothelin-induced vasoconstriction and levels of endothelin in the human internal mammary artery.

1. The effects of the ETA receptor antagonist BQ123 and dihydropyridine calcium antagonists on the vasoconstrictor effect of endothelin-1 (ET-1) were studied in human isolated internal mammary artery (IMA). The effect of the calcium antagonist, nisoldipine, on ET-1 levels has also been examined in cultured IMA endothelial cells (IMAEC). 2. The results showed that BQ123 and the calcium antagonists nisoldipine, isradipine, nitrendipine and nifedipine fully relaxed IMA precontracted with 3 nmol/L ET-1 with the EC50 values of 7.18 +/- 0.09 (-log mol/L) for BQ123, and 7.68 +/- 0.07, 7.02 +/- 0.12, 6.96 +/- 0.08 and 6.89 +/- 0.09 for the calcium antagonists, respectively. 3. Pretreatment of IMA with 10, 30, 100 and 300 nmol/L nisoldipine significantly depressed the maximal response (Max; 88.3 +/- 5.1, 75.2 +/- 4.9, 59.3 +/- 5.6 and 56.2 +/- 4.8% of maximal noradrenaline response versus 99.1 +/- 13.2% in control, P < 0.01) of IMA to ET-1 without a significant change in the EC50 values. 4. Pretreatment of IMA with 300 nmol/L BQ123 significantly increased both the EC50 (7.97 +/- 0.09 vs 8.36 +/- 0.08 in the control, P < 0.05) and the Max (138.1 +/- 10.2% vs the control, P < 0.01) of IMA to ET-1. 5. Incubation of IMAEC with nisoldipine for 7 h resulted in a dose-dependent (10(-8)-10(-5) mol/L) reduction up to 93.1% in ET levels in the conditioned media.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium Channel Blockers↗
PubMed1994

Human internal mammary artery responses to non-peptide vasopressin antagonists.

1. OPC-21268 and OPC-31260 are newly developed orally active non-peptide vasopressin (AVP) V1 and V2 receptor antagonists, respectively. The effects of the two compounds on human vessels have not been studied. 2. The effects of the two compounds on AVP-induced contraction of human internal mammary arteries (IMA) were investigated. Their effects were compared with the peptide V1 and V2 antagonists d(CH2)5Sar7AVP (SAVP) and d(CH2)5D-Ileu2Ileu4AVP (Ileu2Ileu4AVP), respectively. 3. The V1 antagonist OPC-21268 failed to antagonize AVP-induced contraction at low concentrations and potentiated the contraction at higher concentration (3 x 10(-7) mol/L, P < 0.05). It also caused a mild direct contractile effect on IMA. In contrast, the peptide V1 antagonist SAVP potently inhibited the AVP-induced contraction, indicating that functionally constrictor V1 receptors exist in IMA. Both the nonpeptide and peptide V2 antagonists OPC-31260 (3 x 10(-6) mol/L) and Ileu2Ileu4AVP significantly antagonized the AVP-induced contraction (P < 0.01). 4. The AVP-induced contraction was reversed by high concentrations of OPC-31260 (10(-6) mol/L-3 x 10(-5) mol/L) but not by OPC-21268 (up to 3 x 10(-5) mol/L). 5. These studies indicate that, in human IMA, OPC-21268 is a partial V1 receptor agonist with no V1 receptor antagonist activity, while OPC-31260 is a V1 receptor antagonist. The results also indicate that Ileu2Ileu4AVP may be a V1 receptor antagonist in humans.

Antidiuretic Hormone Receptor Antagonists↗
PubMed1994

[Evaluation of plasma neuropeptide Y levels in patients with congestive heart failure].

Plasma neuropeptide Y (NPY) was measured by radioimmunoassay in 43 patients with congestive heart failure (CHF) and 20 healthy control subjects. The results showed that plasma NPY levels were elevated in patients with CHF compared with control subjects (366 +/- 28 ng/L VS. 89 +/- 22 ng/L, P < 0.001). There was a close relationship between the severity of CHF and plasma NPY levels. The severer the CHF, the higher the NPY level. In addition, 20 of the 43 patients with symptoms improved after treatment for heart failure were followed. The results indicated a significant decrease of plasma NPY levels (333 +/- 42 ng/L VS. 157 +/- 25 ng/L, P < 0.01) in these patients. Furthermore, multiple logistic regression analysis demonstrated that the presence and severity of CHF were related to plasma NPY levels significantly and independently. Because of its potent vasoconstrictive and negative cardiac inotropic effects, NPY might be involved in the pathophysiology of CHF. Plasma NPY levels might be taken as a prognostic indicator in patients with CHF, but further investigation is needed.

Adult↗
PubMed1994

Synergistic effect of nisoldipine and nitroglycerin on human internal mammary artery.

Perioperative spasm of the internal mammary artery (IMA) can be a problem in coronary artery bypass surgery, which may be prevented by vasodilator drugs. The relaxing effect of a new calcium antagonist nisoldipine used alone or in combination with nitroglycerin (NTG) was studied in human isolated IMA in organ chambers. The results showed that nisoldipine exhibited a potent relaxing effect on IMA precontracted by membrane depolarization (K+ induced) with an EC50 of 7.58 +/- 0.08 (-log M). Nisoldipine was about 10 times more potent than was nifedipine (EC50, 6.72 +/- 0.10). However, both calcium antagonists showed much less relaxing effect on IMA precontracted with the thromboxane mimetic U46619. When IMA was pretreated with nisoldipine, this drug (range, 10-300 nM) inhibited contraction induced by either K+ or U46619 in a concentration-dependent manner. The relaxing effect of nisoldipine was long lasting and extremely hard to wash out (more than 3 hr). NTG showed a rapid and short-lasting relaxing effect on IMA precontracted with either K+ or U46619. Pretreatment of IMA with NTG had little effect for prevention of contraction to K+ or U46619. Combining nisoldipine with NTG at low concentrations (1-30 nM) produced a synergistic effect in the prevention of IMA contraction to K+ or U46619 and in relaxation of IMA precontracted with these agents. These studies reveal that combining nisoldipine with NTG combines the advantages of both and provide a scientific basis for a future clinical trial using combined nisoldipine and NTG at low concentrations for the preparation of IMA (pretreatment) to prevent IMA spasm during coronary artery bypass grafting.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1993

Reduction of endothelin levels by the dihydropyridine calcium antagonist nisoldipine and a 'natural factor' in cultured human endothelial cells.

OBJECTIVE: Endothelin is thought to be related to cardiovascular disease. The purpose of this study was to determine whether endothelin levels could be reduced by a calcium antagonist and a 'natural factor'. DESIGN: Since calcium ionophores can induce endothelin-1 messenger RNA synthesis in cultured endothelial cells, the calcium antagonist nisoldipine was used in this study to determine whether it could reduce endothelin levels. It has been reported that coculture of endothelial cells and smooth muscle cells from different species and different parts of the body can reduce endothelin levels. This study was also designed to determine whether coculture of the two cell types from the same species and the same section of an artery could reduce endothelin levels. METHODS: Cultured endothelial cells from human umbilical artery (HUAEC) and umbilical vein (HUVEC) were treated with increasing concentrations of nisoldipine. HUAEC were cocultured with human umbilical artery smooth muscle cells (HUASMC). Endothelin levels were measured by a radioimmunoassay. RESULTS: Incubation of the HUAEC with nisoldipine for either 7 or 24 h resulted in a dose-dependent (10(-8)-10(-5) mol/l) reduction in endothelin levels in the conditioned media. Endothelin levels in cell lysates were not detectable in either the absence or the presence of nisoldipine. This suggests that the reduction of endothelin levels in the media could be due to inhibition of endothelin synthesis. Under the same conditions, incubation of HUVEC with the same concentrations of nisoldipine produced a similar concentration-dependent reduction in endothelin levels. Endothelin levels were undetectable in the conditioned media from HUASMC. Coculture of HUAEC with HUASMC significantly reduced endothelin levels (P < 0.01) compared with HUAEC cultured alone. CONCLUSIONS: Endothelin levels can be reduced by the calcium antagonist nisoldipine and a 'natural factor' associated with smooth muscle cells.

Cells, Cultured↗
PubMed1993

Inhibition by a stable factor derived from neutrophils of endothelium-dependent relaxation in rat aorta.

Polymorphonuclear leukocytes (PMNs) may play an important role in many pathophysiological states. The effect of a factor derived from PMNs on endothelium-dependent relaxation was studied using rat aortic rings in organ chambers. PMNs were obtained from cardiac surgical patients and healthy volunteers. After incubation in Krebs solution for 3 h, supernatants of PMN suspensions were isolated and used to pretreat the aortic rings for 30 min. The results showed that the supernatants derived from 1 x 10(4) to 5 x 10(6) cells/ml PMNs produced a concentration-dependent inhibition of endothelium-dependent relaxation to acetylcholine but not endothelium-independent relaxation to sodium nitroprusside. The effect could not be prevented by oxygen free radical scavenger superoxide dismutase (150 U/ml), catalase (1,200 U/ml), or mannitol (20 mM) used alone or in combination. Heating the supernatants at 95 degrees C for 30 min did not reduce the inhibitory effect. L-Arginine at 3 x 10(-5) to 3 x 10(-3) M did not significantly reverse the inhibitory effect of the PMN-derived factor. In conclusion, this study reveals that a heat-stable factor derived from human PMNs potently inhibits acetylcholine-induced endothelium-dependent relaxation but not sodium nitroprusside-induced endothelium-independent relaxation in rat aorta. This inhibitory effect is not caused by oxygen free radicals, a limitation of nitric oxide precursor or other unstable factors.

Animals↗
PubMed1993

Alternatively spliced fibronectin molecules in the wounded cornea: analysis by PCR.

PURPOSE: To determine whether certain fibronectin isoforms participate in corneal epithelial wound healing, the authors used the polymerase chain reaction to detect different splicing patterns of the EIIIA segment of fibronectin mRNA in epithelial scrape-wounded cornea of rats. METHODS: Specific fibronectin cDNA sequences synthesized from rat cornea with total RNA were amplified with various sets of synthetic oligonucleotide primers. RESULTS: The authors detected both the EIIIA+ and EIIIA- fibronectin mRNA isoforms during corneal wound healing. The kinetics of corneal expression of both total fibronectin mRNA and the EIIIA- fibronectin mRNA isoform was polyphasic; an initial decrease was followed by an increase at 45 minutes, a second increase at 2 hours, and a third increase at 4 days after wounding. EIIIA+ fibronectin mRNA, not found in normal cornea, also was detected during healing. CONCLUSIONS: The expression of total fibronectin mRNA and both the EIIIA+ and EIIIA- fibronectin mRNA is upregulated during corneal epithelial wound healing. The expression of EIIIA+ fibronectin mRNA during wound healing, a fibronectin isoform that was highly expressed in embryonic tissue, suggests that this fibronectin isoform is involved functionally in corneal wound healing.

Alternative Splicing↗
PubMed1992

Use of helper-free retroviral vector to direct a high expression of porcine growth hormone in mouse fibroblast cells.

A retroviral vector has been employed to express the cDNA coding for porcine growth hormone (pGH) in the mouse fibroblast cell NIH 3T3 in large quantity. In this study, a single gene vector which contained no selectable marker was used. We have coinfected NIH 3T3 cells with pGH retrovirus and Neo(r) retrovirus to obtain a stable, high-expression clone. Using a superinfection strategy, we further increased the copy number of proviral DNA in the host chromosome, thus increasing the pGH secretion from 22 to 55 micrograms/10(6) cells/24 h. The recombinant pGH produced from mouse fibroblast cells was heterogeneous at the N-terminus, which mimicked the situation with bovine growth hormone either from natural sources or from recombinant products derived from mouse fibroblasts. This technology is useful for many biologically important genes to be stably transduced by retroviral vector into mammalian cells and highly expressed.

3T3 Cells↗
PubMed1991

Long term and large-scale cultivation of human hepatoma Hep G2 cells in hollow fiber bioreactor. Cultivation of human hepatoma Hep G2 in hollow fiber bioreactor.

Long-term and large scale cultivation of an anchorage-dependent cell line using an industrial scale hollow fiber perfusion bioreactor is described. Hep G2 cells (a human hepatoma cell line) were cultivated in an Acusyst-P (Endotronic) with a total fiber surface area of 7.2 m2 6 x 1.2m2) to produce Hep G2 crude conditioned medium (CCM). Pretreatment of the cellulose acetate hollow fibers with collagen enhances the attachment of the anchorage-dependent cells. We have succeeded in growing the Hep G2 cells in an antibiotics- and serum-free IMDM medium, supplemented with 50 micrograms/ml of Hep G2 CCM protein at inoculation. The Hep G2 cells replicate and secrete CCM protein in quantities comparable to those produced in DMEM containing 10% fetal calf serum (FCS). The highest CCM protein productivity during the 80-day cultivation was 1.1 g/day with a total of 30 g of protein accumulated. Hep G2 CCM (20-40 micrograms protein/ml) was comparable to or even better than 10% FCS in supporting the growth of Molt-4 (a human T leukemia cell line) and FO (a mouse myeloma cell line) cells in vitro. The availability of this large amount of Hep G2 CCM will aid the further purification and characterization of growth factor(s) which could be used as serum substituents.

Carcinoma, Hepatocellular↗
PubMed1991

Immunomodulation of human cytomegalovirus infection on interferon system in patients with systemic lupus erythematosus.

On the basis of the research on the relationship between human cytomegalovirus (HCMV) infection and systemic lupus erythematosus (SLE) a study of the effects of HCMV infection on the immunological pathogenesis of SLE was undertaken. Presented in this paper is a brief account of the study. It was found that SLE patients with active HCMV infection had significant higher level of serum interferon-alpha (IFN-alpha) than those without active HCMV infection, but the IFN-alpha induction capacity of peripheral blood mononuclear cells (PBMC) from SLE patients with active HCMV infection was evidently poorer than that from patients without it. There was not any statistically significant difference between the two SLE groups in the IFN-gamma induction capacity of PBMC.

Adult↗
PubMed1990

Solubilization and characterization of endothelin-1 receptors in rat cardiac tissue.

Adult rat cardiac endothelin-1 (ET-1) receptors were solubilized with 0.5% digitonin and then characterized. The receptors retained binding activity after solubilization. Binding was saturable (KD of 0.065 +/- 0.004 nM, Bmax of 94.6 +/- 4.5 fmol/mg protein; Hill coefficient of 0.987 +/- 0.017 n = 6) and pH dependent, with the binding increasing as the pH was decreased from 10 to 4, but decreasing dramatically as pH dropped to 2. Specifically bound [125I]-ET-1 was not dissociated by 2 x 10(-7) M unlabelled ET-1, but was dissociated by pH 10 and 2. Returning the pH to 7.4 restored the binding activity of the receptors. Unlabelled ET-1 (10(-12) - 10(-7) M) and sarafotoxin S6b(10(-12) - 10(-7) M) competed with [125I]-ET-1 for binding to the receptors.

Animals↗
PubMed1990

Nifedipine and experimental cardioprotection.

Experimental studies using animal models designed to mimic the effect of ischemia and postischemic reperfusion have provided data indicating that the calcium antagonists might be cardioprotective. The laboratory studies have indicated consistently, however, that the timing of such drug administration is of critical importance. In the case of nifedipine (a dihydropyridine-based calcium antagonist), the laboratory studies have shown that when used prophylactically it has a protective effect during short (as in the "stunned heart") and long episodes (greater than 30 minutes) of ischemia. This protection has been quantitated in a variety of ways, including preservation of left ventricular function. A complete understanding of whether and how calcium antagonists can be used to protect the myocardium requires further detailed knowledge of not only of the voltage-activated calcium channel and its binding sites, but also of the sequence of events triggered by ischemia and reperfusion. Recent data from our laboratories indicate that cardiac membranes contain specific binding sites for the novel, endothelial-derived vasoconstrictor peptide, ET, and that the density of these sites increases during ischemia. ET promotes Ca2+ influx through the voltage-sensitive channels by a mechanism that does not involve a direct interaction with the dihydropyridine (DHP)-sensitive binding sites. Nevertheless, the ET-induced Ca2+ influx is attenuated by the dihydropyridine-based calcium channel blockers.

Animals↗
PubMed1990

Reoxygenation, but neither hypoxia nor intermittent ischemia, increases [125I]endothelin-1 binding to rat cardiac membranes.

Standard binding techniques were used to establish whether either hypoxia, reoxygenation, perfusion under acidotic conditions, or "stunning" of the myocardium resembles ischemia and postischemic reperfusion in increasing cardiac membrane [125I]endothelin-1 (ET-1) binding site density (Bmax). Membranes from aerobically perfused rat hearts bound [125I]ET-1 to a single population of sites, with an affinity (KD) of 0.093 +/- 0.004 nM and a Bmax of 98.8 +/- 5.2 fmol/mg of protein. Bmax was increased (p less than 0.01) after 30 min of global ischemia, and further increased upon reperfusion, without changes in KD or selectivity. Neither three 10 min episodes of ischemia separated by 15 min of perfusion, nor perfusion at pH 6.8 instead of 7.4, nor 60 min of hypoxia altered Bmax, KD, or selectivity. Reoxygenation after 60 min of hypoxia increased Bmax (p less than 0.01) and KD (p less than 0.01) without changing selectivity. These results are interpreted to mean that the ischemia-induced increase in Bmax for [125I]ET-1 cannot be explained simply in terms of the ischemia-induced acidosis, or the accompanying reduction in tissue adenosine triphosphate and creatine phosphate.

Acidosis↗
PubMed1990

[Large-scale production of monoclonal antibodies using hollow fiber bioreactor].

Development of large-scale monoclonal antibody production using industrial scale hollow fiber bioreactor is described. Hybridoma cell lines H505AC and A306AA were cultivated in the hollow fiber perfusion bioreactor with a total fiber surface area of 7.2 m2 (6 x 1.2 m2) to produce anti-hepatitis B surface antigen (anti-HBsAg) monoclonal antibody IgM and anti-alpha-fetal protein (anti-AFP) monoclonal antibody IgG. The highest anti-HBsAg IgM productivity obtained during 49 days cultivation of H505AC was 0.135 g/day and the total accumulated IgM was 1.90 g. Results from the cultivation of A306AA in the hollow fiber module for 23 days showed the highest anti-AFP IgG productivity and the total accumulated IgG were 0.672 g/day and 7.21 g, respectively.

Animals↗