Biomedical subjects

Y Huang

Publications and source records attributed to Y Huang.

At least 577 records · Page 32Linked to original sources

PubMed1998

Overexpression and accumulation of apolipoprotein E as a cause of hypertriglyceridemia.

The molecular mechanisms of hypertriglyceridemia (HTG), a common lipid metabolic disorder in humans, often of genetic origin, are not well understood. In studying the effect of apolipoprotein (apo) E on the metabolism of triglyceride-rich lipoproteins, we found that expressing high plasma levels of human apoE3 in transgenic mice lacking endogenous mouse apoE caused HTG. These transgenic animals had 3-fold higher plasma triglyceride levels, higher very low density lipoproteins (VLDL), and lower high density lipoproteins than did nontransgenics. Removing one or both low density lipoprotein receptor alleles in the apoE3-overexpressing mice caused severe HTG (8-11-fold over nontransgenics) and increased VLDL and decreased low and high density lipoproteins, and apoE3-enriched VLDL were markedly depleted in apoC-II. At least two mechanisms could explain HTG associated with apoE3 overexpression: stimulated VLDL triglyceride production and impaired VLDL lipolysis. The apoE3 mice with HTG had a 50% increase in hepatic VLDL triglyceride production. Furthermore, overexpression of apoE (E2, E3, or E4) in cultured hepatocytes (McA-RH7777 cells) correlated positively with secretion of VLDL into the medium. However, apoE3 overexpression-associated HTG was only partially explained by VLDL overproduction, as lipoprotein lipase-mediated VLDL lipolysis was also decreased 20-86% depending on apoE3 levels, most likely by displacing or masking apoC-II on the particles. In human subjects, HTG correlated positively with increased VLDL triglyceride and plasma and VLDL apoE levels. However, plasma and VLDL apoE correlated negatively with VLDL apoC-II levels and lipoprotein lipase-mediated VLDL lipolysis. Thus, optimal expression of apoE is crucial for normal metabolism of triglyceride-rich lipoproteins, and overexpression and/or accumulation of apoE may contribute to HTG by stimulating VLDL triglyceride production and by impairing VLDL lipolysis. The apoE3-overexpressing mice will be useful for studying the pathophysiology of this disorder.

Animals↗

PubMed1998

Biological and molecular basis of human breast cancer.

Human breast cancer remains the most common malignancy in the American women. The ultimate cure of this disease relies on a better understanding of the mechanisms underlying the initiation and progression of this disease. The neoplastic transformation of HBEC in vitro represents a successful model for obtaining knowledge on the molecular and biological alterations that may contribute to the tumorigenic mechanisms. We have presented here a current understanding of chemically transformed HBEC in the following aspects: 1. Factors affecting the transformation of HBEC such as genetic predisposition and differentiation status and prior immortalization; 2. New targets for studying the mechanism of cell immortalization such as alterations in telomerase activity and differential expression of cell cycle dependent genes as well as others recently isolated through differential cloning such as H-ferritin, and a calcium binding protein; 3. Epigenetic and genetic mechanisms underlying cell transformation; 4. The association of microsatellite instability in specific loci on chromosomes 11, 13, and 16 with the progression of cell transformation; and 5. The application of microcell mediated chromosome transfer technique as an approach to testing the functional role of specific genes whose dysregulation or loss of function may contribute to the ultimate cell transformation. Further efforts in this cell system will be directed to determine the roles of identified molecular changes as well as the mapping/cloning of tumor suppressor or senescence genes such as those that may reside on chromosomes 11 or 17.

Breast Neoplasms↗

PubMed1998

Transcriptional regulation of the GluR2 gene: neural-specific expression, multiple promoters, and regulatory elements.

To understand how neurons control the expression of the AMPA receptor subunit GluR2, we cloned the 5' proximal region of the rat gene and investigated GluR2 promoter activity by transient transfection. RNase protection and primer extension of rat brain mRNA revealed multiple transcription initiation sites from -340 to -481 bases upstream of the GluR2 AUG codon. The relative use of 5' start sites was different in cortex and cerebellum, indicating complexity of GluR2 transcript expression among different sets of neurons. When GluR2 promoter activity was investigated by plasmid transfection into cultured cortical neurons, cortical glia, and C6 glioma cells, the promoter construct with the strongest activity, per transfected cell, was 29.4-fold (+/- 3.7) more active in neurons than in non-neural cells. Immunostaining of cortical cultures showed that >97% of the luciferase-positive cells also expressed the neuronal marker MAP-2. Evaluation of internal deletion and substitution mutations identified a functional repressor element I RE1-like silencer and functional Sp1 and nuclear respiratory factor-1 (NRF-1) elements within a GC-rich proximal GluR2 promoter region. The GluR2 silencer reduced promoter activity in glia and non-neuronal cell lines by two- to threefold, was without effect in cortical neurons, and could bind the RE1-silencing transcription factor (REST) because cotransfection of REST into neurons reduced GluR2 promoter activity in a silencer-dependent manner. Substitution of the GluR2 silencer by the homologous NaII RE1 silencer further reduced GluR2 promoter activity in non-neuronal cells by 30-47%. Maximal positive GluR2 promoter activity required both Sp1 and NRF-1 cis elements and an interelement nucleotide bridge sequence. These results indicate that GluR2 transcription initiates from multiple sites, is highly neuronal selective, and is regulated by three regulatory elements in the 5' proximal promoter region.

Animals↗

PubMed1998

Characterization of a regulatory region in the N-terminus of rabbit kv1.3.

The N-terminus of rabbit Kv1.3 contains a signal sequence which regulates expression of Kv1.3 proteins in the plasma membrane. Removal of an N-terminal region (aa3-39) produced an increase in expressed K+ current. Progressive deletion at the N-terminus demonstrated that the shortest deletion required for the elevation of K current is D6-34. Since the functional signal sequence must include both ends of the peptide segment aa6-34 where charged residues are densely distributed, it is conceivable that this N-terminal signal sequence is related to charge or its associated hydrophilicity. Removal of two charged residues (31R, 33E) through amino acid substitution which converts deletion construct D3-27 to D3-27* effectively raises the amplitude of expressed current, further indicating the importance of charged residues. With the use of a mutated dynamin and a soluble N-terminal peptide, we also revealed that the N-terminal signal sequence may not act through the endocytotic pathway.

Amino Acid Sequence↗

PubMed1998

Redox modulation of AP-2 DNA binding activity in vitro.

Transcription factor AP-2 plays a critical role in regulating gene expression during vertebrate development and cellular differentiation. We report here that AP-2 DNA binding in vitro can be reversibly modulated by redox conditions and that thioredoxin is a potent stimulator of AP-2 DNA binding. Our studies indicate that oxidation of recombinant human AP-2 with diamide or hydrogen peroxide inhibits its DNA binding activity to synthetic AP-2 oligodeoxynucleotides. The inhibitory effect of diamide on AP-2 DNA binding was dose-dependent and was reversible by addition of reducing agents beta-mercaptoethanol, dithiothreitol, and thioredoxin. Immunoblot assays indicated that treatment with oxidants caused a change in migration of the AP-2 protein in nonreducing gels and that this effect was also reversible by treatment of the oxidized AP-2 with reducing agents. These data suggest a mechanism by which the oxidation state of conserved cysteine residues in the AP-2 DNA binding domain may contribute to its DNA binding activity. AP-2 joins a group of other transcription factors whose functions are regulated in part by their redox states.

Animals↗

PubMed1998

Langmuir-Blodgett Film Formation of a Fullerene Dicarboxylic Acid Derivative C60(HOOCCHNHCHCOOH) and its Photocurrent Generation.

The Langmuir films of a fullerene dicarboxylic acid derivative I, C60(HOOCCHNH2CHCOOH)CF3SO3H (FDA), at the air/water interface have been investigated. FDA formed a stable monolayer on pure water when dilute solution (1.04 x 10(-5) mol/L) was used as the spreading solution. The monolayer formation on various subphases was investigated, including solutions containing different monovalent (Na+, Ag+) and divalent (Ca2+, Cd2+, Cu2+) cations. The introduction of these cations makes the monolayer more stable. The limiting molecular area is also dependent on the pH of the subphase. The surface pressure versus area isotherms at different temperature clearly indicate that FDA molecules easily aggregate at high temperature. The monolayer and multilayer LB films of FDA were deposited on quartz and glass substrates from Ca2+, Cd2+, Cu2+, or Cu2+/Phen solution subphase, and their UV-vis and XPS spectra were obtained. The data showed that for Cd2+ and Cu2+/Phen subphase the cation can be transferred onto the substrates together with FDA but not the other two. The photoelectrochemical behavior of FDA on an ITO electrode was investigated, which showed that the photocurrent is cathodic. Oxygen and negative bias are beneficial factors for the photocurrent generation. The external quantum yield is ca. 4%. Copyright 1998 Academic Press.

Journal Article↗

PubMed1998

Development and pathway formation of peripheral neurons during leech embryogenesis.

By labeling the germinal plates of staged leech embryos with monoclonal antibodies to the immunoglobulin superfamily member Tractin, we have documented the distribution and initial development of peripheral neurons in a hirudinid leech. We find, in addition to sensillar and extrasensillar sensory neurons, that there are 21 identifiable peripheral neurons in each hemisegment. These neurons are found in highly stereotyped positions, and all but two of them are associated with the segmental nerves. We show that eight of the peripheral neurons have the characteristic morphology of stretch receptor neurons and that they form a circumferentially distributed grid aligned in such a way that each of five specialized longitudinal muscle fascicles are monitored by at least two stretch receptor cells covering ventral, lateral, and dorsal regions of the body wall. Furthermore, we show that, in contrast to the dorsal posterior nerve, which is pioneered by central projections, the pathways of the three remaining segmental nerves are likely to be pioneered or guided by peripheral neurons.

Animals↗

PubMed1998

Relationship between intracellular calcium store depletion and calcium release-activated calcium current in a mast cell line (RBL-1).

The kinetic relationship between depletion of endoplasmic reticulum calcium stores and the activation of a calcium release-activated calcium current (Icrac) was investigated in the RBL-1 mast cell line. The inositol trisphosphate receptor activator, inositol 2,4, 5-trisphosphate ((2,4,5)IP3), the sarcoplasmic-endoplasmic reticulum calcium ATPase inhibitor, thapsigargin, and the calcium ionophore, ionomycin, were used to deplete stored calcium. For (2,4,5)IP3 and thapsigargin, a significant delay was observed between the initiation of calcium store depletion and the activation of Icrac. However, for ionomycin, little or no delay was observed. This may indicate that a specialized subcompartment of the endoplasmic reticulum functions as a regulator of calcium entry and that this compartment is relatively resistant to depletion by (2,4,5)IP3 and thapsigargin but not to depletion by ionomycin. For all three calcium-depleting agents, the rate of development of Icrac, once initiated, was relatively constant, suggesting an all-or-none mechanism. However, there were also clear experimental situations in which submaximal, graded depletion of stored calcium resulted in submaximal activation of Icrac. This complex behavior could also result from the existence of a specific subcompartment of endoplasmic reticulum regulating Icrac. The kinetic behavior of this compartment may not be accurately reflected by the kinetics of calcium changes in the bulk of endoplasmic reticulum. These findings add to the growing body of evidence suggesting specialization of the endoplasmic reticulum calcium stores with regard to the control of capacitative calcium entry.

Animals↗

PubMed1998

Inhibition of phosphatidylinositol 3-kinase activity by adenovirus-mediated gene transfer and its effect on insulin action.

Phosphatidylinositol 3-kinase (PI 3-K) is implicated in cellular events including glucose transport, glycogen synthesis, and protein synthesis. It is activated in insulin-stimulated cells by binding of the Src homology 2 (SH2) domains in its 85-kDa regulatory subunit to insulin receptor substrate-1 (IRS-1), and, others. We have previously shown that IRS-1-associated PI 3-kinase activity is not essential for insulin-stimulated glucose transport in 3T3-L1 adipocytes, and that alternate pathways exist in these cells. We now show that adenovirus-mediated overexpression of the p85N-SH2 domain in these cells behaves in a dominant-negative manner, interfering with complex formation between endogenous PI 3-K and its SH2 binding targets. This not only inhibited insulin-stimulated IRS-1-associated PI 3-kinase activity, but also completely blocked anti-phosphotyrosine-associated PI 3-kinase activity, which would include the non-IRS-1-associated activity. This resulted in inhibition of insulin-stimulated glucose transport, glycogen synthase activity and DNA synthesis. Further, Ser/Thr phosphorylation of downstream molecules Akt and p70 S6 kinase was inhibited. However, co-expression of a membrane-targeted p110(C) with the p85N-SH2 protein rescued glucose transport, supporting our argument that the p85N-SH2 protein specifically blocks insulin-mediated PI 3-kinase activity, and, that the signaling pathways downstream of PI 3-kinase are intact. Unexpectedly, GTP-bound Ras was elevated in the basal state. Since p85 is known to interact with GTPase-activating protein in 3T3-L1 adipocytes, the overexpressed p85N-SH2 peptide could titrate out cellular GTPase-activating protein by direct association, such that it is unavailable to hydrolyze GTP-bound Ras. However, insulin-induced mitogen-activated protein kinase phosphorylation was inhibited. Thus, PI 3-kinase may be required for this action at a step independent of and downstream of Ras. We conclude that, in 3T3-L1 adipocytes, non-IRS-1-associated PI 3-kinase activity is crucial for insulin's metabolic signaling, and that overexpressed p85N-SH2 protein inhibits a variety of insulin's ultimate biological effects.

3T3 Cells↗

PubMed1998

Separate domains for desensitization of GABA rho 1 and beta 2 subunits expressed in Xenopus oocytes.

Desensitization of ligand-gated receptor channels is an intrinsic feedback mechanism and prevents the receptor/channels from becoming overly activated thereby maintaining biological function of the nervous system. Desensitization also plays an important role in neuronal plasticity. By taking advantage of biophysical and pharmacological diversities of GABA beta2 subunits from the brain and rho1 subunits from the retina, structural determinants that confer agonist-induced desensitization were identified. A synthetic chimeric receptor/channel was created from the beta2 and rho1 subunits for this investigation. The chimera was constructed from the extracellular N-domain of the beta2 subunit, extending from the amino terminus to the beginning region of the M1 transmembrane segment, and from the C-domain of the rho1 subunit extending from the M1 transmembrane segment to the carboxyl terminus. The C-domain region included the M1 to M4 transmembrane regions and the large intracellular loop between the M3 and M4 transmembrane segments. Homo-oligomeric GABA beta2, rho1, and beta2/rho1 chimeric receptor/channels were individually expressed in Xenopus oocytes, and the desensitization characteristics attributable to each type of subunit were compared. Results from the present study reveal that motifs in the amino-terminal and carboxyl-terminal domains of the beta2 subunit conferred the agonist-induced desensitization; chloroform modulation was linked to specific phases of the GABA-activated current decay.

Amino Acid Sequence↗

PubMed1998

Apolipoprotein E2 reduces the low density lipoprotein level in transgenic mice by impairing lipoprotein lipase-mediated lipolysis of triglyceride-rich lipoproteins.

Apolipoprotein (apo) E2 is often associated with low levels of low density lipoprotein (LDL) cholesterol and high levels of plasma triglycerides in humans. Mice expressing apoE2 also have low LDL levels. To evaluate the possible role of the LDL receptor in the cholesterol-lowering effect of apoE2, we bred transgenic mice expressing low levels of apoE2 with LDL receptor-null mice (hE2(+/0), LDLR-/-). Even in the absence of the LDL receptor, plasma total and LDL cholesterol levels decreased progressively with increasing levels of plasma apoE2. At plasma apoE2 levels >20 mg/dl, LDL cholesterol was approximately 45% lower than in LDLR-/- mice. Thus, the LDL cholesterol-lowering effect of apoE2 is independent of the LDL receptor. In contrast, plasma triglyceride levels increased (mostly in very low density lipoproteins (VLDL) and intermediate density lipoproteins (IDL)) progressively as apoE2 levels increased. At plasma apoE2 levels >20 mg/dl, triglycerides were approximately 150% higher than in LDLR-/- mice. Furthermore, in apoE-null mice (hE2(+/0), mE-/-), apoE2 levels also correlated positively with plasma triglyceride levels, suggesting impaired lipolysis in both hE2(+/0),LDLR-/- and hE2(+/0),mE-/- mice. Incubating VLDL or IDL from the hE2(+/0),LDLR-/- or the hE2(+/0),mE-/- mice with mouse postheparin plasma inhibited lipoprotein lipase-mediated lipolysis of apoE2-containing VLDL and IDL by approximately 80 and approximately 70%, respectively, versus normal VLDL and IDL. This observation was confirmed by studies with triglyceride-rich emulsion particles, apoE2, and purified lipoprotein lipase. Furthermore, apoE2-containing VLDL had much less apoC-II than normal VLDL. Adding apoC-II to the incubation partially corrected the apoE2-impaired lipolysis in apoE2-containing VLDL or IDL and corrected it completely in apoE2-containing emulsion particles. Thus, apoE2 lowers LDL cholesterol by impairing lipoprotein lipase-mediated lipolysis of triglyceride-rich lipoproteins (mostly by displacing or masking apoC-II). Furthermore, the effects of apoE2 on both plasma cholesterol and triglyceride levels are dose dependent and act via different mechanisms. The increase in plasma cholesterol caused by apoE2 is due mostly to impaired clearance, whereas the increase in plasma triglycerides is caused mainly by apoE2-impaired lipolysis of triglyceride-rich lipoproteins.

Animals↗

PubMed1998

Complement-inhibiting cucurbitacin glycosides from Picria fel-terrae.

Four cucurbitacin glycosides were isolated from Picriafel-terrae and identified by MS and NMR spectroscopy as picfeltarraenin IA (1), picfeltarraenin IB (2), picfeltarraenin IV (4), and a new compound picfeltarraenin VI (3) (picfeltarraegenin I 3-O-beta-D-xylopyranoside). All four compounds acted as inhibitors on both the classical and alternative pathways of the complement system, with compound 3 exhibiting the highest inhibitory activity (IC50 29 +/- 2 microM and 21 +/- 1 microM, respectively). Compounds 1-4 showed no antiviral, antibacterial, or antifungal activities. Picfeltarraenin IA and IB were tested in an in vitro human tumor cell line panel, but displayed no cytotoxic activity.

Anti-Infective Agents↗

PubMed1998

Synthesis and quantitative structure-activity relationships of N-(1-benzylpiperidin-4-yl)phenylacetamides and related analogues as potent and selective sigma1 receptor ligands.

A series of N-(1-benzylpiperidin-4-yl)phenylacetamide derivatives was synthesized and evaluated for affinity at sigma1 and sigma2 receptors. Most of these compounds showed a high affinity for sigma1 receptors and a low to moderate affinity for sigma2 receptors. The unsubstituted compound N-(1-benzylpiperidin-4-yl)phenylacetamide, 1, displayed a high affinity and selectivity for sigma1 receptors (Ki values of 3.90 nM for sigma1 receptors and 240 nM for sigma2 receptors). The influence of substitutions on the phenylacetamide aromatic ring on binding at both the sigma1 and sigma2 receptor has been examined through Hansch-type quantitative structure-activity relationship (QSAR) studies. In general, all 3-substituted compounds, except for the OH group, had a higher affinity for both sigma1 and sigma2 receptors when compared with the corresponding 2- and 4-substituted analogues. The selectivity for sigma1 receptors displayed a trend of 3 > 2 approximately 4 for Cl, Br, F, NO2, and OMe substituted analogues. Halogen substitution on the aromatic ring generally increased the affinity for sigma2 receptors while maintaining a similar affinity for sigma1 receptors. Substitution with electron-donating groups, such as OH, OMe, or NH2, resulted in weak or negligible affinity for sigma2 receptors and a moderate affinity for sigma1 receptors. The 2-fluoro-substituted analogue, 11, exhibited the highest selectivity for sigma1 receptors among all compounds tested, with a Ki value of 3.56 nM for sigma1 receptors and 667 nM for sigma2 receptors. Compounds 1, 5, 9, 11, and 20 had no affinity for dopamine D2 (IC50 > 10 000 nM) and D3 (IC50 > 10 000 nM) receptors. The nanomolar binding affinity and high selectivity for sigma1 receptors suggest that these compounds may be developed as potential radiotracers for positron emission tomography or single photon emission computerized tomography imaging studies.

Acetamides↗

PubMed1998

Disease sequence from mutant rhodopsin allele to rod and cone photoreceptor degeneration in man.

Mutations in the gene encoding rhodopsin, the visual pigment in rod photoreceptors, lead to retinal degeneration in species from Drosophila to man. The pathogenic sequence from rod cell-specific mutation to degeneration of rods and cones remains unclear. To understand the disease process in man, we studied heterozygotes with 18 different rhodopsin gene mutations by using noninvasive tests of rod and cone function and retinal histopathology. Two classes of disease expression were found, and there was allele-specificity. Class A mutants lead to severely abnormal rod function across the retina early in life; topography of residual cone function parallels cone cell density. Class B mutants are compatible with normal rods in adult life in some retinal regions or throughout the retina, and there is a slow stereotypical disease sequence. Disease manifests as a loss of rod photoreceptor outer segments, not singly but in microscopic patches that coalesce into larger irregular areas of degeneration. Cone outer segment function remains normal until >75% of rod outer segments are lost. The topography of cone loss coincides with that of rod loss. Most class B mutants show an inferior-nasal to superior-temporal retinal gradient of disease vulnerability associated with visual cycle abnormalities. Class A mutant alleles behave as if cytotoxic; class B mutants can be relatively innocuous and epigenetic factors may play a major role in the retinal degeneration.

Adult↗

PubMed1998

Hydroxylamine-induced relaxation inhibited by K+ channel blockers in rat aortic rings.

Hydroxylamine, a putative endogenous nitric oxide donor, relaxed rat aorta in a concentration-dependent manner (0.01-30 microM). Removal of endothelium or pretreatment of aortic tissue with N(G)-nitro-L-arginine (L-NOARG, 100 microM) did not affect the relaxant effect of hydroxylamine but L-NOARG at 100 microM abolished the acetylcholine-induced relaxation. Methylene blue (10 microM) significantly reduced the relaxant effect of hydroxylamine in endothelium-denuded arteries. Tetrapentylammonium ions (0.3-3 microM), tetraethylammonium ions (1-3 mM) and charybdotoxin (100 nM) reduced the relaxant effect of hydroxylamine in the endothelium-denuded arteries while glibenclamide (3 microM) had no effect. Neither tetrapentylammonium nor tetraethylammonium ions affected relaxations induced by forskolin and verapamil. The effects of tetrapentylammonium ions (3 microM) and charybdotoxin (100 nM) were additive. Tetrapentylammonium ions (3 microM), tetraethylammonium ions (3 mM) and charybdotoxin (100 nM) decreased the relaxation induced by sodium nitroprusside in the endothelium-denuded arteries while glibenclamide (3 microM) had no effect. The concentration-relaxation curve for the relaxant effect of hydroxylamine was shifted to the right in the presence of high extracellular K+ (15-60 mM). Neither tetrapentylammonium ions (3 microM) nor charybdotoxin (100 nM) affected hydroxylamine-induced relaxation of the endothelium-denuded aorta precontracted with 60 mM K+. These results indicate that hydroxylamine relaxes the rat aorta partially through activation of tetrapentylammonium-, tetraethylammonium- and charybdotoxin-sensitive K+ channels and its action is comparable with that of sodium nitroprusside, an exogenous nitric oxide donor. The endothelium is not involved in the aortic response to hydroxylamine.

Adenosine Triphosphate↗

PubMed1998

Increased expression of apolipoprotein E in transgenic rabbits results in reduced levels of very low density lipoproteins and an accumulation of low density lipoproteins in plasma.

Transgenic rabbits expressing human apo E3 were generated to investigate mechanisms by which apo E modulates plasma lipoprotein metabolism. Compared with nontransgenic littermates expressing approximately 3 mg/dl of endogenous rabbit apo E, male transgenic rabbits expressing approximately 13 mg/dl of human apo E had a 35% decrease in total plasma triglycerides that was due to a reduction in VLDL levels and an absence of large VLDL. With its greater content of apo E, transgenic VLDL had an increased binding affinity for the LDL receptor in vitro, and injected chylomicrons were cleared more rapidly by the liver in transgenic rabbits. In contrast to triglyceride changes, transgenic rabbits had a 70% increase in plasma cholesterol levels due to an accumulation of LDL and apo E-rich HDL. Transgenic and control LDL had the same binding affinity for the LDL receptor. Both transgenic and control rabbits had similar LDL receptor levels, but intravenously injected human LDL were cleared more slowly in transgenic rabbits than in controls. Changes in lipoprotein lipolysis did not contribute to the accumulation of LDL or the reduction in VLDL levels. These observations suggest that the increased content of apo E3 on triglyceride-rich remnant lipoproteins in transgenic rabbits confers a greater affinity for cell surface receptors, thereby increasing remnant clearance from plasma. The apo E-rich large remnants appear to compete more effectively than LDL for receptor-mediated binding and clearance, resulting in delayed clearance and the accumulation of LDL in plasma.

Animals↗

PubMed1998

New wiggler beamlines at BSRF.

A new multipole wiggler has been installed in the ring of the Beijing Electron Positron Collider (BEPC), and two new beamlines were extracted from it for experiments, including LIGA, microprobe fluorescence analysis, high-pressure diffraction and soft X-ray research. The beam profile and photon intensity were measured and compared with the calculated values. The main parameters and characteristics of the two beamlines are illustrated. Some experimental results are presented.

Journal Article↗

PubMed1998

p53-dependent and -independent regulation of the death receptor KILLER/DR5 gene expression in response to genotoxic stress and tumor necrosis factor alpha.

The death receptor (DR) KILLER/DR5 gene has recently been identified as a doxorubicin-regulated transcript that was also induced by exogenous wild-type p53 in p53-negative cells. KILLER/DR5 gene encodes a DR containing cell surface protein that is highly homologous to DR4, another DR of the tumor necrosis factor (TNF) receptor family. Both DR4 and KILLER/DR5 independently bind to their specific ligand TRAIL and engage the caspase cascade to induce apoptosis. TRID (also known as TRAIL-R3) is an antiapoptotic decoy receptor that lacks the cytoplasmic death domain and competes with KILLER/DR5 and DR4 for binding to TRAIL. In this study, we demonstrate that the DR KILLER/DR5 gene is regulated in a p53-dependent and -independent manner during genotoxic and nongenotoxic stress-induced apoptosis. Just like other p53-regulated genes, ionizing radiation induction of KILLER/DR5 occurs in p53 wild-type cells, whereas methyl methanesulfonate regulation of KILLER/DR5 occurs in a p53-dependent and -independent manner. However, unlike other p53-regulated genes, KILLER/DR5 is not regulated following UV irradiation. TNF-alpha, a nongenotoxic cytokine, also induced the expression of KILLER/DR5 in a number of cancer cell lines, irrespective of p53 status. TNF-alpha did not alter the KILLER/DR5 mRNA stability, suggesting that the TNF-alpha regulation of KILLER/DRS expression appears transcriptional. We also provide evidence that KILLER/DR5 is regulated in a trigger and cell type-specific manner and that its induction by TNF-alpha, p53, or DNA damage is not the consequence of apoptosis induced by these agents. Unlike KILLER/DR5, none of the other KILLER/DR5 family members, including DR4, TRID, or the ligand TRAIL, displayed genotoxic stress or TNF-alpha regulation in a p53 transcription-dependent manner. Thus, KILLER/DR5 appears a bona fide downstream target of p53 that is also regulated in a cell type-specific, trigger-dependent, and p53-independent manner.

Apoptosis↗