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Biomedical subjects

T Chu

Publications and source records attributed to T Chu.

At least 19 recordsLinked to original sources
PubMed2002

Selective inhibition of Abeta42 production by NSAID R-enantiomers.

Non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with reduced risk for Alzheimer's disease (AD) and selected NSAIDs racemates suppress beta-amyloid (Abeta) accumulation in vivo and Abeta42 production in vitro. Clinical use of NSAIDs for preventing or treating AD has been hampered by dose-limiting toxicity believed to be due to cyclooxygenase (COX)-inhibition that is reportedly not essential for selective Abeta42 reduction. Profens have racemates and R-enantiomers were supposed to be inactive forms. Here we demonstrate that R-ibuprofen and R-flurbiprofen, with poor COX-inhibiting activity, reduce Abeta42 production by human cells. Although these R-enantiomers inhibit nuclear factor-kappaB (NF-kappaB) activation and NF-kappaB can selectively regulate Abeta42, Abeta42 reduction is not mediated by inhibition of NF-kappaB activation. Because of its efficacy at lowering Abeta42 production and low toxicity profile, R-flurbiprofen is a strong candidate for clinical development.

Amyloid beta-Peptides↗
PubMed2001

The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse.

Inflammation in Alzheimer's disease (AD) patients is characterized by increased cytokines and activated microglia. Epidemiological studies suggest reduced AD risk associates with long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs). Whereas chronic ibuprofen suppressed inflammation and plaque-related pathology in an Alzheimer transgenic APPSw mouse model (Tg2576), excessive use of NSAIDs targeting cyclooxygenase I can cause gastrointestinal, liver, and renal toxicity. One alternative NSAID is curcumin, derived from the curry spice turmeric. Curcumin has an extensive history as a food additive and herbal medicine in India and is also a potent polyphenolic antioxidant. To evaluate whether it could affect Alzheimer-like pathology in the APPSw mice, we tested a low (160 ppm) and a high dose of dietary curcumin (5000 ppm) on inflammation, oxidative damage, and plaque pathology. Low and high doses of curcumin significantly lowered oxidized proteins and interleukin-1beta, a proinflammatory cytokine elevated in the brains of these mice. With low-dose but not high-dose curcumin treatment, the astrocytic marker GFAP was reduced, and insoluble beta-amyloid (Abeta), soluble Abeta, and plaque burden were significantly decreased by 43-50%. However, levels of amyloid precursor (APP) in the membrane fraction were not reduced. Microgliosis was also suppressed in neuronal layers but not adjacent to plaques. In view of its efficacy and apparent low toxicity, this Indian spice component shows promise for the prevention of Alzheimer's disease.

Alzheimer Disease↗
PubMed2001

Convergence in discrete-time neural networks with specific performance.

We analyze convergence in discrete-time neural networks with specific performance such as decay rate and trajectory bounds in terms of componentwise absolute (exponential) stability. Simple necessary and sufficient stability and positive invariance conditions are presented, which allow us to design a convergent network with prescribed performance. Our approach is based on a decomposition of competitive-cooperative connectivity or inhibitory-excitatory interaction that abounds in neural networks, without assuming symmetry of the connection matrices. The key idea is that through the decomposition, we can always relate a competitive-cooperative network with a cooperative dynamical system. The latter possesses significant order-preserving properties that are basic to our analysis. The explicit division of connection weights into inhibitory and excitatory types offers a higher potential for relating formal neural network models to neurophysiology.

Algorithms↗
PubMed2001

Cortex, a Drosophila gene required to complete oocyte meiosis, is a member of the Cdc20/fizzy protein family.

Mutations in cortex and grauzone cause abnormal arrest in Drosophila female meiosis. cortex was mapped to a 14 kb interval in 26F-27A by the male recombination mapping method. While these experiments mapped the gene accurately, they also illustrated some complexities of this method. Rescue results showed that a 2.8 kb genomic fragment from this interval was able to fully rescue the cortex phenotype. The 2.8 kb rescuing fragment contains a single open reading frame. The predicted amino acid sequence indicates that cortex encodes a WD-repeat protein and is a distant member of the Cdc20 protein family. Results from a developmental Northern analysis showed that the cortex transcript is expressed at high levels during oogenesis and early embryogenesis. Interestingly, the meiotic metaphase-anaphase II arrest defect in embryos laid by cortex homozygous females resembles the mitotic metaphase-anaphase defects observed in yeast cdc20 mutants. The predicted nature of the Cortex protein, together with the observed meiotic phenotype in cortex mutants, suggest that a similar pathway to the cdc20 dependent APC-mediated proteolysis pathway, which governs the metaphase-anaphase transition in mitosis, is also important in regulating oocyte meiosis.

Alleles↗
PubMed2001

Langerhans cell histiocytosis.

Langerhans cell histiocytosis is a rare condition that can affect any organ of the body. Patients of all ages may present to the dermatologist and it is important to make the diagnosis as quickly as possible, because time from presentation to diagnosis is of prognostic importance in adults with the disease. Langerhans cell histiocytosis is now classified as a class I histiocytosis and research into this disease has been very active over the past 10 years. We now know that the disease represents a clonal expansion of a Langerhans cell, which shows phenotypic evidence of activation. The tissue damage induced by the disease appears to be related to local cytokine release. In single system disease, Langerhans cell histiocytosis is responsive to local therapy but, in resistant single system disease or in multisystem disease, etoposide is the most effective monochemotherapy. Some patients will need maintenance treatment with azathioprine or 6-mercaptopurine with or without methotrexate. In such cases, physicians who are used to treating chronic and relapsing diseases and who have experience with these drugs, such as dermatologists, are the most appropriate to manage patients with Langerhans cell histiocytosis.

Adult↗
PubMed2001

Identification of genes involved in the host response to neurovirulent alphavirus infection.

Single-amino-acid mutations in Sindbis virus proteins can convert clinically silent encephalitis into uniformly lethal disease. However, little is known about the host gene response during avirulent and virulent central nervous system (CNS) infections. To identify candidate host genes that modulate alphavirus neurovirulence, we utilized GeneChip Expression analysis to compare CNS gene expression in mice infected with two strains of Sindbis virus that differ by one amino acid in the E2 envelope glycoprotein. Infection with Sindbis virus, dsTE12H (E2-55 HIS), resulted in 100% mortality in 10-day-old mice, whereas no disease was observed in mice infected with dsTE12Q (E2-55 GLN). dsTE12H, compared with dsTE12Q, replicated to higher titers in mouse brain and induced more CNS apoptosis. Infection with the neurovirulent dsTE12H strain was associated with both a greater number of host genes with increased expression and greater changes in levels of host gene expression than was infection with the nonvirulent dsTE12Q strain. In particular, dsTE12H infection resulted in greater increases in the levels of mRNAs encoding chemokines, proteins involved in antigen presentation and protein degradation, complement proteins, interferon-regulated proteins, and mitochondrial proteins. At least some of these increases may be beneficial for the host, as evidenced by the demonstration that enforced expression of the antiapoptotic mitochondrial protein peripheral benzodiazepine receptor (PBR) protects neonatal mice against lethal Sindbis virus infection. Thus, our findings identify specific host genes that may play a role in the host protective or pathologic response to neurovirulent Sindbis virus infection.

Alphavirus Infections↗
PubMed2000

Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer's disease.

The brain in Alzheimer's disease (AD) shows a chronic inflammatory response characterized by activated glial cells and increased expression of cytokines and complement factors surrounding amyloid deposits. Several epidemiological studies have demonstrated a reduced risk for AD in patients using nonsteroidal anti-inflammatory drugs (NSAIDs), prompting further inquiries about how NSAIDs might influence the development of AD pathology and inflammation in the CNS. We tested the impact of chronic orally administered ibuprofen, the most commonly used NSAID, in a transgenic model of AD displaying widespread microglial activation, age-related amyloid deposits, and dystrophic neurites. These mice were created by overexpressing a variant of the amyloid precursor protein found in familial AD. Transgene-positive (Tg+) and negative (Tg-) mice began receiving chow containing 375 ppm ibuprofen at 10 months of age, when amyloid plaques first appear, and were fed continuously for 6 months. This treatment produced significant reductions in final interleukin-1beta and glial fibrillary acidic protein levels, as well as a significant diminution in the ultimate number and total area of beta-amyloid deposits. Reductions in amyloid deposition were supported by ELISA measurements showing significantly decreased SDS-insoluble Abeta. Ibuprofen also decreased the numbers of ubiquitin-labeled dystrophic neurites and the percentage area per plaque of anti-phosphotyrosine-labeled microglia. Thus, the anti-inflammatory drug ibuprofen, which has been associated with reduced AD risk in human epidemiological studies, can significantly delay some forms of AD pathology, including amyloid deposition, when administered early in the disease course of a transgenic mouse model of AD.

Alzheimer Disease↗
PubMed2000

Spatial and temporal changes in natural and target deprivation-induced cell death in the mouse inferior olive.

The survival of inferior olive neurons is dependent on contact with cerebellar Purkinje cells. There is evidence that this dependence changes with time. Because inferior olivary axons, called climbing fibers, already show significant topographical ordering in cerebellar target zones during late embryogenesis in mice, the question arises as to whether olive neurons are dependent on target Purkinje cells for their survival at this early age. To better characterize this issue, inferior olive development was studied in two transgenic mouse mutants, wnt-1 and L7ADT, with embryonic and early postnatal loss of cerebellar target cells, respectively, and compared to that in the well-studied mutant, Lurcher. Morphological criteria as well as quantitative measures of apoptosis were considered in this developmental analysis. Survival of inferior olive neurons is observed to be independent of Purkinje cells throughout embryogenesis, but dependence begins immediately at birth in both wild types and mutants. Thereafter, wild types and mutants show a rapid increase in olive cell apoptosis, with a peak at postnatal day 4, followed by a period of low-level, but significant, apoptosis that continues to at least postnatal day 11; the main difference is that apoptosis is quantitatively enhanced in the mutants compared to wild types. The multiphasic course of these effects roughly parallels the known phases of climbing fiber synaptogenesis. In addition, despite significant temporal differences among the mutants with respect to absolute numbers of dying cells, there are common spatial features suggestive of distinct intrinsic programs linking different olivary subnuclei to their targets.

Animals↗
PubMed2000

The only function of Grauzone required for Drosophila oocyte meiosis is transcriptional activation of the cortex gene.

The grauzone and cortex genes are required for the completion of meiosis in Drosophila oocytes. The grauzone gene encodes a C2H2-type zinc-finger transcription factor that binds to the cortex promoter and is necessary for high-level activation of cortex transcription. Here we define the region of the cortex promoter to which Grauzone binds and show that the binding occurs through the C-terminal, zinc-finger-rich region of the protein. Mutations in two out of the five grauzone alleles result in single amino acid changes within different zinc-finger motifs. Both of these mutations result in the inability of Grauzone to bind DNA effectively. To determine the mechanism by which Grauzone regulates meiosis, transgenic flies were produced with an extra copy of the cortex gene in homozygous grauzone females. This transgene rescued the meiosis arrest of embryos from these mutants and allowed their complete development, indicating that activation of cortex transcription is the primary role of Grauzone during Drosophila oogenesis. These experiments further define a new transcriptional pathway that controls the meiotic cell cycle in Drosophila oocytes.

Alleles↗
PubMed2000

Completion of meiosis in Drosophila oocytes requires transcriptional control by grauzone, a new zinc finger protein.

Mutations in grauzone or cortex cause abnormal arrest in Drosophila female meiosis. We cloned grauzone and identified it as a C2H2-type zinc finger transcription factor. The grauzone transcript is present in ovaries and at later developmental stages. A Grauzone-GFP fusion protein is functional and localizes to nuclei of both nurse cells and follicle cells during oogenesis. Three lines of evidence indicate that grauzone and cortex interact: reducing cortex function enhanced the grauzone mutant phenotype; cortex transcript abundance is reduced in the absence of grauzone function and Grauzone protein binds to the cortex promoter. These results demonstrate that activation of cortex transcription by grauzone is necessary for the completion of meiosis in Drosophila oocytes, and establish a new pathway that specifically regulates the female meiotic cell cycle.

Alleles↗
PubMed1999

Mapping biochemistry to metabolism: FDG-PET and amyloid burden in Alzheimer's disease.

We evaluated the relationship between amyloid-beta protein (A beta) concentration and the metabolic abnormality in an Alzheimer's disease (AD) patient as measured by [18F]fluorodeoxyglucose positron emission tomography (FDG-PET). Across most regions there were significant inverse correlations among FDG-PET intensity values and both insoluble. The temporal lobe samples showed no significant correlation between FDG-PET values and A beta deposition. Findings support A beta as contributing to the hypometabolism in regions of the AD brain that are still relatively viable metabolically; those regions with chronic pathologic damage, such as temporal cortex, may have other factors that contribute to metabolic deficits.

Aged↗
PubMed1999

Cloning of a novel MHC-encoded serine peptidase highly expressed by cortical epithelial cells of the thymus.

Antigen presentation by cortical thymic epithelial cells (cTEC) during the positive selection of T cells has been shown to differ from that of other antigen-presenting cells. In the case of MHC class II presentation, cathepsin L as opposed to cathepsin S is responsible at least in part for the degradation of invariant chain. Other proteases, however, must be involved. We have identified a putative serine protease that is specifically expressed in the thymus. Encoded within the class I major histocompatibility complex (MHC) region, this gene has sequence homology with lysosomal prolylcarboxypeptidase, suggesting that it is a serine protease. We have, therefore, designated this gene thymus-specific serine protease (TSSP). In situ hybridization and immunofluorescence staining reveal that TSSP is expressed exclusively by cortical thymic epithelial cells, with the strongest staining noted around vessels and the thymic capsule. The identification of TSSP further supports the theory that MHC class II antigen processing and presentation in the thymic cortex involves a proteolytic milieu that differs from that of other antigen-presenting cells.

Amino Acid Sequence↗
PubMed1999

Anti-inflammatory properties of triblock siloxane copolymer-blended materials.

Implantable biomaterials often trigger a variety of adverse responses. Because polydimethyl siloxane surfaces have good hemo- and bio-compatibility, it is generally believed that surface biocompatibility may be improved by modifying biomaterial surfaces with silicone-like properties. For this, we developed a series of polycaprolactone-polydimethylsiloxane-polycaprolactone (PDMS-PCL) copolymers. By mixing the substrate material--polyvinyl chloride--with low concentrations (1.2 and 2.4%) of the PDMS-PCL copolymer, we generated materials with silicone-like surface properties as reflected by increased surface silicon content and surface contact angles. We assessed the biocompatibility of these surfaces in vitro and found that the addition of PDMS-PCL significantly reduced the percentages of surface-'denatured' fibrinogen, a critical element of genesis of many adverse responses to implanted biomaterials. Indeed, using an animal implantation model, we find that PDMS-PCL-blended materials triggered significantly weaker inflammatory responses than did polyvinyl chloride, the substrate control. The results from these experiments suggest that the use of PDMS-PCL additives (2.4%) in polymer blends is a useful means of camouflaging the substrate surface properties and improving the biocompatibility of biomaterials.

Adsorption↗
PubMed1999

ETB receptor activation leads to activation and phosphorylation of NHE3.

In OKP cells expressing ETB endothelin receptors, activation of Na+/H+ antiporter activity by endothelin-1 (ET-1) was resistant to low concentrations of ethylisopropyl amiloride, indicating regulation of Na+/H+ exchanger isoform 3 (NHE3). ET-1 increased NHE3 phosphorylation in cells expressing ETB receptors but not in cells expressing ETA receptors. Receptor specificity was not due to demonstrable differences in receptor-specific activation of tyrosine phosphorylation pathways or inhibition of adenylyl cyclase. Phosphorylation was associated with a decrease in mobility on SDS-PAGE, which was reversed by treating immunoprecipitated NHE3 with alkaline phosphatase. Phosphorylation was first seen at 5 min and was maximal at 15-30 min. Phosphorylation was maximal with 10(-9) M ET-1. Phosphorylation occurred on threonine and serine residues at multiple sites. In summary, ET-1 induces NHE3 phosphorylation in OKP cells on multiple threonine and serine residues. ETB receptor specificity, time course, and concentration dependence are all similar between ET-1-induced increases in NHE3 activity and phosphorylation, suggesting that phosphorylation plays a key role in activation.

Animals↗
PubMed1998

Effects of transforming growth factor-beta (isoforms 1-3) on amyloid-beta deposition, inflammation, and cell targeting in organotypic hippocampal slice cultures.

The transforming growth factor-beta (TGF-beta) family consists of three isoforms and is part of a larger family of cytokines regulating differentiation, development, and tissue repair. Previous work from our laboratory has shown that TGF-beta1 can increase amyloid-beta protein (Abeta) immunoreactive (Abetair) plaque-like deposits in rat brain. The aim of the current study was to evaluate all three isoforms of TGF-beta for their ability to affect the deposition and neurotoxicity of Abeta in an organotypic, hippocampal slice culture model of Abeta deposition. Slice cultures were treated with Abeta either with or without one of the TGF-beta isoforms. All three isoforms can increase Abeta accumulation (over Abeta treatment alone) within the slice culture, as determined by ELISA. However, there are striking differences in the pattern of Abetair among the three isoforms of TGF-beta. Isoforms 1 and 3 produced a cellular pattern of Abeta staining that colocalizes with GS lectin staining (microglia). TGF-beta2 produces dramatic Abeta staining of pyramidal neurons in layers CA1-CA2. In addition to cellular Abeta staining, plaque-like deposits are increased by all of the TGF-betas. Although no gross toxicity was observed, morphological neurodegenerative changes were seen in the CA1 region when the slices were treated with Abeta plus TGF-beta2. Our results demonstrate important functional differences among the TGF-beta isoforms in their ability to alter the cellular distribution and degradation of Abeta. These changes may be relevant to the pathology of Alzheimer's disease (AD).

Amyloid beta-Peptides↗
PubMed1998

Effect of chloroquine and leupeptin on intracellular accumulation of amyloid-beta (A beta) 1-42 peptide in a murine N9 microglial cell line.

Murine N9 microglia accumulated A beta from media containing 0.67 microM A beta within 6 h. In N9 and in primary rat microglia, chloroquine, which disrupts lysosomal pH, increased A beta-induced accumulation of A beta, particularly A beta1-42. Leupeptin similarly enhanced A beta accumulation. The scavenger receptor antagonist fucoidan did not affect acute chloroquine-dependent A beta1-42 accumulation, demonstrating uptake of non-aggregated A beta. After prolonged incubations, chloroquine enhanced A beta multimer (8-12 kDa) accumulation, an effect inhibited by fucoidan. Disruptions of the lysosomal system enhance A beta and its multimer formation. Despite negligible effects of fucoidan on initial A beta uptake, chronic exposure inhibits multimer accumulation, demonstrating a role for scavenger receptor in multimer accumulation.

Amyloid beta-Peptides↗
PubMed1998

Mapping of Drosophila mutations using site-specific male recombination.

Although recombination does not usually occur in the male Drosophila germline, site-specific recombination can be induced at the ends of P elements. This finding suggested that male recombination could be used to map Drosophila mutations. In this article, we describe the general method and its application to the mapping of two EMS-induced female-sterile mutations, grauzone and cortex. Within two months, the grauzone gene was mapped relative to seven different P-element insertion sites, and cortex was mapped relative to 23 different P-elements. The results allowed us to map grauzone to a region of about 50 kb, and cortex distal to the chromosomal region 33E. These experiments demonstrate that P-element-induced site-specific male recombination is an efficient and general method to map Drosophila autosomal mutations.

Animals↗