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Biomedical subjects

Y C Yang

Publications and source records attributed to Y C Yang.

At least 163 records · Page 9Linked to original sources
PubMed1993

Heparin-steroid conjugates: new angiogenesis inhibitors with antitumor activity in mice.

Inhibitors of angiogenesis hold potential in the treatment of cancer and other diseases where the disease is caused or maintained by the inappropriate growth of blood vessels. In the present study, a novel inhibitor of angiogenesis was synthesized by covalently linking a nonanticoagulating derivative of heparin, heparin adipic hydrazide (HAH), by an acid-labile bond to the antiangiogenic steroid, cortisol. The rationale was that the heparin derivative, which binds to sulfated polyanion receptors on endothelial cells, should concentrate the steroid on the surface of vascular endothelial cells. Endocytosis of the conjugate and decomposition of the acid-labile linkage inside lysosomes and other acidic intracellular compartments should then lead to release of the cortisol and expression of its antiproliferative activity. Analysis of the stability of HAH-cortisol showed that it was stable at pH 7.4 and broke down rapidly (t1/2 15 min) at pH 4.8 at 37 degrees C. Treatment of murine pulmonary capillary endothelial cells with HAH-cortisol at 10(-5) M (with respect to cortisol) suppressed their DNA synthesis by 50% and inhibited their migration into wounded areas of confluent monolayers. HAH-cortisol at 10(-4) M (with respect to cortisol) did not suppress the DNA synthesis of Lewis lung carcinoma cells. Daily i.p. injections of HAH-cortisol into mice bearing s.c. sponge implants retarded vascularization of the sponge, and injections directly into the sponge abolished vascularization for as long as the injections were continued. Daily i.v. injections of HAH-cortisol at doses causing no apparent toxicity retarded the growth of solid s.c. Lewis lung carcinomas in mice by up to 65%. In all of these assays, equivalent treatments with a mixture of the HAH plus cortisol was significantly less effective. The antiproliferative effect of HAH-cortisol on endothelial cells appeared independent of the glucocorticoid activity of the steroid since HAH conjugated to 5 beta-pregnane-3 alpha,17 alpha,21-triol-20-one, a steroid lacking glucocorticoid or mineralocorticoid activity, was even more effective at inhibiting DNA synthesis by murine pulmonary capillary endothelial cells than was HAH-cortisol. In conclusion, HAH-cortisol represents the prototype of a new class of angiogenesis inhibitors for the treatment of cancer and other angiogenic diseases.

Animals↗
PubMed1993

Activation of ADP-ribosylation factor by Golgi membranes. Evidence for a brefeldin A- and protease-sensitive activating factor on Golgi membranes.

Recent evidence has implicated ADP-ribosylation factor (ARF) proteins as critical regulators of the protein secretory pathway, particularly in the endoplasmic reticulum-Golgi pathway. We have examined whether Golgi membranes contain activators of ARF and the consequences of ARF activation and acylation on its membrane association. Two means were used to assess ARF activation. First, guanosine 5'-3-O-(thio)triphosphate (GTP gamma S) binding to protein was found to be greater when ARF and Golgi were incubated together than when either was incubated alone. These data suggested that ARF GTP gamma S was formed. This was confirmed by showing that the GTP gamma S-bound protein functioned as a cofactor for cholera toxin-stimulated ADP-ribosylation of Gs alpha, a reaction for which activated ARF is a necessary cofactor. Trypsin treatment of Golgi, an inhibitory ARF peptide, and brefeldin A each inhibited Golgi-mediated activation by approximately 70%, demonstrating that a specific protein interaction is required for the majority of the ARF activation. This ARF-activating protein is a strong candidate for the molecular target for brefeldin A. The ubiquitous nature of ARF proteins and their importance in both the exocytic and endocytic pathways may explain the effects of brefeldin A on both exocytic and endocytic membrane traffic in animal cells. A protease-insensitive activation of ARF by Golgi could also be demonstrated and was the dominant activity observed in submicromolar concentrations of magnesium. We believe this to be the lipid-mediated process described previously for purified ARF proteins. ARF activation resulted in tight association of ARF with phospholipid vesicles. Vesicle association required amino-terminal myristoylation of ARF whereas activation did not. These studies indicate that the brefeldin A-sensitive ARF-activating protein and other factors that determine the level of activation of ARF in animal cells are fundamental regulators of membrane traffic in animal cells.

ADP-Ribosylation Factors↗
PubMed1993

In vivo effects of recombinant interleukin-11 on myelopoiesis in mice.

Purified recombinant human interleukin-11 (rhuIL-11) was assessed for its in vivo effects on the proliferation and differentiation of hematopoietic progenitors as well as its capacity to accelerate the recovery of a drug-suppressed hematopoietic system. Dosage and time sequence studies demonstrated that administration of IL-11 to normal mice resulted in increases in absolute numbers of femoral marrow and splenic myeloid (granulocyte-macrophage colony-forming unit [CFU-GM], burst-forming unit-erythroid [BFU-E], CFU-granulocyte, erythroid, macrophage, megakaryocyte) progenitor cells and in stimulation of these progenitors to a higher cell cycling rate. This was associated with increased numbers of circulating neutrophils. Administration of IL-11 to mice pretreated with cyclophosphamide decreased the time required to regain normal levels of neutrophil and platelet counts in peripheral blood. In addition, IL-11 accelerated reconstitution to normal range of myeloid progenitors from bone marrow and spleen of myelosuppressed mice. These data suggest that IL-11 may play an important role in the regulation of hematopoiesis, and the application of this novel cytokine may have clinical therapeutic benefits.

Animals↗
PubMed1993

Interleukin 11: an overview.

Interleukin (IL)-11 is a bone marrow fibroblast derived cytokine with a wide spectrum of in vitro biological activities in the hematopoietic, lymphopoietic, hepatic, adipose, neuronal and osteoclast systems, either alone or in synergy with other hematopoietic growth factors. In vivo administration of IL-11 in mice, rats and nonhuman primates has demonstrated the thrombopoietic effects of this cytokine. The expression of the human IL-11 gene, which is localized at 19q13.3-13.4, can be controlled at both the transcriptional and post-transcriptional levels. Initial biochemical characterization has identified a 151 kD protein as the potential IL-11 binding subunit of the receptor complex. Like other cytokines such as IL-6, leukemia inhibitory factor (LIF), oncostatin M (ONC) and ciliary neurotrophic factor (CNTF), IL-11 has been shown to utilize IL-6 signal transducer, gp130. Because of the overlapping biological activities, the similarities in the predicted tertiary structures, and the sharing of common signal transducer protein, we have compared the signal transduction pathways mediated by these cytokines in various cell types. Studies of protein tyrosine phosphorylation, primary response gene expression and signaling molecules known to be important in transducing mitogenic signals have suggested that there are convergent and divergent points along the signal transduction pathways utilized by IL-11, IL-6, LIF and ONC. These observations may explain the biological pleiotropy and redundancy of this group of cytokines.

Animals↗
PubMed1993

[Inhibitory effects of psoralen plus ultraviolet irradiation on human leukemic cell lines].

A semi-solid cell culture technique was used to study the sensitivity of K562, HL-60, and Raji leukemic cell lines to the inhibitory effect of psoralen plus ultraviolet irradiation. Results indicated that: 1) the inhibition rate of K562, HL-60, and Raji cell lines were 86%, 35%, and 36%, respectively; and 2) K562, HL-60, and Raji cell lines were treated with psoralen (20 micrograms.ml-1) for 1 h, then irradiated with ultraviolet (1 J/cm2) for 10 min, none of the leukemic cell lines showed colony or cluster formation. These suggested that the cytocidal effect of psoralen plus ultraviolet might be useful to eradicate the residual leukemic cells in the bone marrow transplantation.

Ficusin↗
PubMed1993

Clinical case-controlled study of small-for-gestational-age babies.

In this series, we compared the prenatal risk factors and perinatal complications of small-for-gestational-age (SGA) and appropriate-for-gestational-age (AGA) babies systemically through a case-controlled study. A total of 115 SGA babies were retrospectively compared with 115 AGA matched pairs at the National Cheng Kung University Hospital. We analyzed the prenatal risk factors, signs of fetal distress and perinatal outcome between these two groups. Univariate analysis showed significant differences for the following items: 1) maternal risk factors, 2) fetal risk factors, 3) presence of prenatal risk factors, 4) abnormal fetal heart rate tracings, 5) low one-minute Apgar scores, 6) low five-minute Apgar scores, 7) thick meconium staining, 8) presence of fetal distress, 9) pediatric ICU care, and 10) presence of perinatal complications. Multivariate logistic regression showed that maternal hypertension and fetal anomaly were statistically significant risk factors associated with SGA in this series. In conclusion, SGA babies demonstrate higher frequencies of maternal and fetal risk factors, signs of fetal distress and perinatal complications than AGA babies.

Case-Control Studies↗
PubMed1993

Doppler velocimetry study of maternal hemodynamics and fetal vascular pattern in a case of chronic hypertension with superimposed severe preeclampsia and impending fetal death.

A case is presented of chronic hypertension with superimposed severe preeclampsia; absence of end-diastolic velocity in the umbilical artery had been noted at gestational age of 20 weeks. Because the fetus was previable, the mother was treated with pharmacotherapy according to the maternal hemodynamics; uteroplacental circulation and fetal vascular blood flow were monitored by Doppler velocimetry. Deterioration of the fetal condition occurred during crossover of maternal hemodynamics from a low-resistance to a high-resistance state. Serial Doppler velocimetry studies done within 40 minutes of fetal death are described. There were two types of absent end-diastolic velocity in the umbilical artery, and the pathophysiology and clinical management may be quite a different in these two situations.

Adult↗
PubMed1993

Protein tyrosine phosphorylation and activation of primary response genes by interleukin 11 in B9-TY1 cells.

Interleukin (IL) 11 is a multifunctional cytokine derived from bone marrow stromal cells. To understand the mechanisms by which IL-11 exerts its pleiotropic actions, we have analyzed IL-11-mediated signal transduction pathways in IL-11-dependent B9-TY1, which is a subclone of an IL-6-dependent B-cell hybridoma, B9. IL-11 stimulation of B9-TY1 cells resulted in tyrosine phosphorylation of a 97/95 kilodalton cellular protein in a dose-dependent manner, and this effect was inhibited by tyrosine kinase inhibitors genistein and herbimycin A, but not by a serine/threonine kinase inhibitor, H7. We next examined the early nuclear events in the IL-11-triggered intracellular signaling cascade. The data showed that tis11, tis21, and junB early response genes were rapidly activated following IL-11 treatment. The kinetic studies indicated that activation of tis11 and junB genes peaked at 30-60 min and then declined slowly afterward. The tis21 gene was constitutively expressed, and the level of tis21 mRNA was significantly increased and maintained at the elevated level following IL-11 stimulation. Inhibitor studies with genistein, herbimycin A, and H7 revealed that tyrosine kinases and H7-sensitive serine/threonine kinases are required for the IL-11-mediated activation of tis11, tis21, and junB genes. Using a variety of known protein kinase inhibitors or activators, we have demonstrated that H7-sensitive protein kinases activated by IL-11 are distinct from those of well-characterized protein kinase-second messenger systems.(ABSTRACT TRUNCATED AT 250 WORDS)

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1992

Recombinant human interleukin-9 induces protein tyrosine phosphorylation and synergizes with steel factor to stimulate proliferation of the human factor-dependent cell line, M07e.

Human interleukin-9 (IL-9) was originally identified and cloned based on its stimulatory effect on proliferation of human myeloid cell line, M07e. IL-9 synergized with Steel factor, the ligand for the c-kit product, to stimulate M07e cell proliferation. To investigate potential mechanisms for this, IL-9 was assessed for effects on protein tyrosine kinase activities in M07e cells by immunoblotting with anti-phosphotyrosine monoclonal antibody; results were compared with those of Steel factor alone and in combination with IL-9, and those of 12-0-tetradecanoyl phorbol-13-acetate (TPA). Recombinant human IL-9 (10 ng/mL) rapidly and transiently induced or enhanced at least four tyrosine phosphorylated protein bands with molecular weights of 105, 97, 85, and 81 Kd. This tyrosine phosphorylation pattern was different from that generated by recombinant murine Steel factor or TPA stimulation and the combination of IL-9 and Steel factor did not change the IL-9-induced pattern. IL-9-induced tyrosine phosphorylated bands were completely blocked by treatment of IL-9 with anti-IL-9 antibody under conditions that also neutralized the synergistic effect of IL-9 with Steel factor on M07e cell proliferation. Genistein, a tyrosine kinase inhibitor, blocked phosphorylation of IL-9 and Steel factor-induced bands. Unlike Steel factor or TPA, IL-9 did not appear to stimulate phosphorylation of 42-Kd mitogen-activated protein (MAP) kinase or Raf-1, or enhance MAP kinase activity. MAP kinase and Raf-1 are serine/threonine kinases that are phosphorylated and activated by many growth factors and by agonists for protein kinase C. While the combination of IL-9 plus SLF did not appear to induce phosphorylation of new bands not already seen with either IL-9 or SLF alone, or enhance the phosphorylation of those bands seen with either cytokine alone, the results suggest that IL-9 activates specific and unique signal transduction pathways.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1992

Effect of interleukin-11 on cycling status and clonogenic maturation of fetal and adult hematopoietic progenitors.

A recently cloned human cytokine, interleukin-11 (IL-11), has functional similarities to IL-6. We tested the hypothesis that the hematopoietic actions of IL-11 in vitro also resemble those of IL-6. The effect of IL-11 on the cell cycle status of fetal and adult hematopoietic progenitors was assessed using serum-free incubations followed by tritiated thymidine suicide studies. Its effect on clonogenic maturation was assessed by including IL-11, either as a single agent or with subplateau or plateau concentrations of other recombinant cytokines, in cultures that contained neutralizing monoclonal antibodies directed against relevant growth factors. Similar to IL-6, IL-11 resulted in accelerated cycling of fetal colony-forming units-mixed (CFU-MIX), CFU-granulocyte macrophage (CFU-GM), and erythroid burst-forming units (BFU-E). This effect was additive to that of submaximal, but not to plateau, concentrations of IL-6. However, no effect of IL-11 was observed on cycling status of adult progenitors. As a single agent, IL-11 failed to support clonal maturation of either fetal or adult progenitors. IL-11 was additive to GM-CSF in supporting clonal maturation of CFU-GM from adult marrow but not from fetal blood. We conclude that the in vitro hematopoietic actions of IL-11 on cell cycle status of hematopoietic progenitors resemble those of IL-6. However, unlike IL-6, IL-11 as a single agent failed to support clonal maturation of fetal CFU-GM, BFU-E, and CFU-MIX.

Adult↗
PubMed1992

Characterization of interleukin-11 receptor and protein tyrosine phosphorylation induced by interleukin-11 in mouse 3T3-L1 cells.

In this study, we have characterized the biochemical nature of interleukin (IL)-11 receptors (IL-11R) and determined the possible signal transduction pathways mediated by IL-11 in 3T3-L1 mouse preadipocytes. The results show that IL-11 strongly inhibited lipoprotein lipase activity and adipogenesis in 3T3-L1 cells, and the suppression of lipoprotein lipase activity by IL-11 was controlled at the post-transcriptional level. The ability of IL-11 to inhibit lipoprotein lipase activity and adipogenesis therefore reflected the expression of functional IL-11R on the cell surface. Scatchard plot analysis according to specific binding data revealed the existence of a single class of high affinity IL-11R with a Kd of 3.49 x 10(-10) M and a receptor density of 5140 sites/cell on 3T3-L1 cells. Affinity cross-linking studies with 125I-IL-11 indicated that IL-11R consists of a single polypeptide chain of 151 kDa in size. Furthermore, we have studied the role of protein tyrosine phosphorylation in the IL-11R-linked signal transduction pathways. The results show that IL-11R ligation rapidly and transiently stimulated tyrosine phosphorylation of 152-, 94-, 47-, and 44-kDa proteins. This effect is specific for IL-11 since neutralizing antibody to IL-11 abrogated IL-11-induced tyrosine phosphorylation, and other cytokines such as IL-6 and IL-1 alpha did not change the tyrosine phosphorylation pattern in 3T3-L1 cells. These results suggest that IL-11R is closely linked to a functional protein-tyrosine kinase pathway, and tyrosine phosphorylation may be a key step in the initiation of the IL-11R-mediated transmembrane signaling.

3T3 Cells↗
PubMed1992

Modification of chromaffin cells with pertussis toxin or N-ethylmaleimide lowers cytoskeletal F-actin and enhances Ca(2+)-dependent secretion.

In an attempt to identify proteins involved in the secretory response, bovine chromaffin cells were modified with N-ethylmaleimide (NEM). NEM concentrations less than 30 microM enhanced norepinephrine secretion evoked by nicotine or by K+ depolarization and increased Ca(2+)-dependent secretion from digitonin-permeabilized cells. Higher concentrations of NEM inhibited secretion. The protein modified by NEM which was responsible for the enhancement of secretory activity appeared to rapidly diffuse out of the digitonin-permeabilized cells. When proteins which diffuse from control digitonin-permeabilized cells were incubated with pertussis toxin and [32P]NAD, several proteins were ADP-ribosylated. However, when proteins from cells preincubated with 30 microM NEM were incubated with pertussis toxin and [32P]NAD, these GTP-binding proteins (G-proteins) were not ADP-ribosylated, which suggests that they were modified in the cell by NEM. Stimulation of norepinephrine secretion by NEM was not additive with that caused by pertussis toxin. Modification of chromaffin cells with pertussis toxin or with 30 microM NEM caused a 40-50% decrease in the amount of cytoskeletal F-actin. This decrease in cytoskeletal F-actin may account for the increase in secretory activity.

Actins↗
PubMed1992

Effects of ketanserin on blood pressure and heart rate in sinoaortic denervated rats.

The effects of ketanserin on blood pressure and heart rate were studied in sinoaortic denervated (SAD) rats. It was found that the dose-effect curves for blood pressure and heart rate were the same in anesthetized SAD and sham-operated rats. However, SAD sharpened the dose-effect curves in conscious freely moving rats. It is concluded that the lack of hypotensive effect of ketanserin in conscious normotensive animals is due in large part to the integrity of the arterial baroreflex.

Animals↗
PubMed1992

Guanine nucleotide stimulation of norepinephrine secretion from permeabilized PC12 cells: effects of Mg2+, other nucleotide triphosphates and N-ethylmaleimide.

The addition of either Ca2+ or guanosine 5'-O-3-(thiotriphosphate), GTP gamma S, to digitonin-permeabilized rat pheochromocytoma PC12 cells stimulates norepinephrine release. Unlike Ca(2+)-stimulated release, there is a delay between the time of addition of GTP gamma S to digitonin-permeabilized PC12 cells and stimulation of norepinephrine release. Preincubation of the permeabilized cells in the absence of Mg2+ eliminates this lag and increases the initial rate of GTP-gamma S-stimulated norepinephrine secretion. This suggests that the rate of GDP dissociation from the GTP-binding protein responsible for this stimulation is faster in the absence of Mg2+ than in its presence. While an equimolar concentration of GTP gives 50% inhibition of GTP gamma S-stimulated release, 100-fold excesses of ITP, ATP, UTP and CTP gave no inhibition of GTP gamma S-stimulated release. Both the inability of ITP to inhibit GTP gamma S-stimulated secretion and the increase in GTP gamma S-stimulated secretion caused by preincubation in the absence of Mg2+ indicate that some of the properties of the GTP-binding protein responsible for this stimulation are more like those of the low molecular weight GTP-binding proteins rap1 and ras than those of a heterotrimeric G-protein. Low concentrations of N-ethylmaleimide gave more inhibition of GTP gamma S-stimulated release than Ca(2+)-stimulated release which suggests that the mechanisms by which Ca2+ and GTP gamma S stimulate norepinephrine release are at least in part distinct.

Animals↗
PubMed1992

Enhancement of in vitro and in vivo antigen-specific antibody responses by interleukin 11.

The availability of large quantities of highly purified recombinant interleukin 11 (rhuIL-11) has allowed us to investigate the effects of rhuIL-11 on sheep red blood cell (SRBC)-specific antibody responses in the murine system. The results showed that rhuIL-11 was effective in enhancing the generation of mouse spleen SRBC-specific plaque-forming cells (PFC) in the in vitro cell culture system in a dose-dependent manner. These effects of rhuIL-11 were abrogated completely by the addition of anti-rhuIL-11 antibody, but not by the addition of preimmunized rabbit serum. Cell-depletion studies revealed that L3T4 (CD4)+ T cells, but not Lyt-2 (CD8)+ T cells, are required in the rhuIL-11-stimulated augmentation of SRBC-specific antibody responses. The effects of rhuIL-11 on the SRBC-specific antibody responses in vivo were also examined. RhuIL-11 administration to normal C3H/HeJ mice resulted in a dose-dependent increase in the number of spleen SRBC-specific PFC as well as serum SRBC-specific antibody titer in both the primary and secondary immune responses. In mice immunosuppressed by cyclophosphamide treatment, rhuIL-11 administration significantly augmented the number of spleen SRBC-specific PFC as well as serum SRBC-specific antibody titer when compared with the cyclophosphamide-treated mice without IL-11 treatment. These results demonstrated that IL-11 is a novel cytokine involved in modulating antigen-specific antibody responses in vitro as well as in vivo.

Animals↗
PubMed1992

Genomic sequence and chromosomal location of human interleukin-11 gene (IL11).

The genomic sequence of human interleukin-11 (IL11) has been isolated based on its sequence homology with a cDNA clone encoding primate IL11. The human IL11 genomic sequence is 7 kb in length and consists of five exons and four introns. The IL11 gene has been localized to the long arm of human chromosome 19 at band 19q13.3-q13.4 by in situ hybridization. Several potential transcriptional control sequences that may play an important role in the control of IL11 gene expression have been identified within the 5'-flanking region of the human IL11 gene. The 5'-flanking region of the human IL11 gene contains sequences similar to those present in the 5'-regulatory regions of other cytokine genes. Four repeats of a 30-bp DNA segment were found in the fourth intron, and several copies of ATTTA and Alu repetitive sequences were identified in the 3'-noncoding region of the human IL11 gene. A DNA sequence (ACATGGCAAAACCC) that has 71% similarity with the IL1-responsive element of the IL6 gene was found in the 3'-flanking region of the human IL11 gene. The two polyadenylation sites located at nucleotide positions 6762 and 5591 correspond to the 2.5- and 1.5-kb IL11 transcripts expressed in IL1-induced PU-34 cells. The availability of the human IL11 genomic sequence should aid in studies of the regulatory mechanisms of IL11 gene expression in different cell types and the role of IL11 expression in the hematopoietic microenvironment.

Amino Acid Sequence↗