Biomedical subjects

Y Fan

Publications and source records attributed to Y Fan.

At least 19 recordsLinked to original sources

PubMed2006

An optimal range of transcription potency is necessary for efficient cell transformation by c-Rel to ensure optimal nuclear localization and gene-specific activation.

c-Rel is overexpressed in several B-cell lymphomas and c-rel gene overexpression can transform primary chicken lymphoid cells and induce tumors in animals. Although c-Rel is generally a stronger transcriptional activator than its viral derivative v-Rel, its oncogenic activity is significantly weaker. Among the mutations acquired during c-Rel's evolution into v-Rel are deletion of c-Rel's transactivation domain 2 (cTAD2) and mutations in cTAD1. Given the critical role of the Rel TADs in cell transformation, we investigated how mutations in c-Rel's cTAD1 and cTAD2 contribute to its oncogenicity and that of v-Rel. Mutations in cTAD2 noticeably increased c-Rel's transforming activity by promoting its nuclear localization and gene-specific transactivation, despite an overall decrease in kappaB site-dependent transactivation potency. Conversely, substitution of vTAD by cTAD1 increased v-Rel's transactivation and transforming efficiencies, whereas its substitution by the stronger cTAD2 compromised activation of mip-1beta but not irf-4 and was detrimental to cell transformation. These results suggest that the Rel TADs differentially contribute to gene-specific activation and that an optimal range of transcription potency is necessary for efficient transformation. These findings may have important implications for understanding how Rel TAD mutations can lead to a more oncogenic phenotype.

Amino Acid Sequence↗

PubMed2006

Current insights into the regulation of programmed cell death by NF-kappaB.

The nuclear factor-kappaB (NF-kappaB) transcription factors have emerged as major regulators of programmed cell death (PCD) whether via apoptosis or necrosis. In this context, NF-kappaB's activity has important ramifications for normal tissue development, homoeostasis and the physiological functions of various cell systems including the immune, hepatic, epidermal and nervous systems. However, improper regulation of PCD by NF-kappaB can have severe pathologic consequences, ranging from neurodegeneration to cancer, where its activity often precludes effective therapy. Although NF-kappaB generally protects cells by inducing the expression genes encoding antiapoptotic and antioxidizing proteins, its role in apoptosis and necrosis can vary markedly in different cell contexts, and NF-kappaB can sensitize cells to death-inducing stimuli in some instances. This article describes our current knowledge of the role of NF-kappaB in apoptosis and necrosis, and focuses on the many advances since we last reviewed this rapidly evolving topic in Oncogene 3 years ago. There has been substantial progress in understanding NF-kappaB's mode of action in apoptosis and necrosis and the mechanisms that regulate its anti- vs proapoptotic activities. These recent developments shed new light on the role of NF-kappaB in many disease conditions including tumor development, tumor progression and anticancer treatment.

Animals↗

PubMed2006

In vitro pharmacological characterization of AM1241: a protean agonist at the cannabinoid CB2 receptor?

BACKGROUND AND PURPOSE: The CB2 receptor has been proposed as a novel target for the treatment of pain, and CB2 receptor agonists defined in in vitro assays have demonstrated analgesic activity in animal models. Based on its in vivo analgesic efficacy, AM1241 has been classified as a CB2-selective agonist. However, in vitro characterization of AM1241 in functional assays has not been reported. EXPERIMENTAL APPROACH: In this study, AM1241 was characterized across multiple in vitro assays employing heterologous recombinant receptor expression systems to assess its binding potencies at the human CB2 and CB1 receptors and its functional efficacies at the human CB2 receptor. KEY RESULTS: AM1241 exhibited distinct functional properties depending on the assay conditions employed, a unique profile in contrast to those of the agonist CP 55,940 and the inverse agonist SR144528. AM1241 displayed neutral antagonist activities in FLIPR and cyclase assays. However, when cyclase assays were performed using lower forskolin concentrations for stimulation, AM1241 exhibited partial agonist efficacy. In addition, it behaved as a partial agonist in ERK (or MAP) kinase assays. CONCLUSIONS AND IMPLICATIONS: The unusual phenomenon of inconsistent functional efficacies suggests that AM1241 is a protean agonist at the CB2 receptor. We postulate that functional efficacies displayed by protean agonists in various assay systems may depend on the levels of receptor constitutive activities exhibited in the assay systems, and therefore, efficacies observed in in vitro assays may not predict in vivo activities.

Cannabinoids↗

PubMed2006

White-spot syndrome virus (WSSV) introduction into the Gulf of Mexico and Texas freshwater systems through imported, frozen bait-shrimp.

We analysed 20 boxes of, frozen imported bait-shrimp (China: Parapenaeopsis sp. and Metapenaeopsis sp.) and 8 boxes of native, frozen bait-shrimp (Gulf of Mexico: Litopenaeus setiferus and Farfantepenaeus duorarum) by RT-PCR or PCR for Taura syndrome virus (TSV), yellowhead virus/gill-associated virus (YHV/GAV), white-spot syndrome virus (WSSV) and infectious hypodermal and hematopoietic necrosis virus (IHHNV). All 28 boxes of shrimp were negative for TSV, YHV/GAV and IHHNV; 2 boxes of imported bait-shrimp were WSSV-positive by 3 different PCR assays. Intramuscular injection of replicate groups of SPF (specific pathogen-free) L. vannamei juveniles with 2 different tissue homogenates prepared from the 2 WSSV-positive bait boxes resulted in 100% mortality of the test shrimp within 48 to 72 h post-injection. No mortality occurred among injected negative control groups. Histological and in situ hybridization analyses of 20 moribund treatment-shrimp demonstrated severe WSSV infections in each sample. Oral exposure of SPF L. vannamei postlarvae, PL (PL 25 to 30 stage; approximately 0.02 g) to minced tissue prepared from the 2 WSSV-positive bait-lots did not induce infection, possibly because of an insufficient infectious dose and/or viral inactivation resulting from multiple freeze-thaw cycles of the bait-shrimp during PCR testing. Use of an electric drill and collection of drill-tailings (tissue from approximately 20 to 30 shrimp) from frozen blocks of shrimp was successfully employed as an alternate tissue-sampling method without thawing. Our findings indicate that imported WSSV-infected bait shrimp, originating from China, are being sold in Texas for the purpose of sport fishing and represent a potential threat to freshwater and marine crustacean fisheries, as well as to coastal US shrimp farms.

Animals↗

PubMed2006

Compensation of strong thermal lensing in high-optical-power cavities.

In an experiment to simulate the conditions in high optical power advanced gravitational wave detectors, we show for the first time that the time evolution of strong thermal lenses follows the predicted infinite sum of exponentials (approximated by a double exponential), and that such lenses can be compensated using an intracavity compensation plate heated on its cylindrical surface. We show that high finesse approximately 1400 can be achieved in cavities with internal compensation plates, and that mode matching can be maintained. The experiment achieves a wave front distortion similar to that expected for the input test mass substrate in the Advanced Laser Interferometer Gravitational Wave Observatory, and shows that thermal compensation schemes are viable. It is also shown that the measurements allow a direct measurement of substrate optical absorption in the test mass and the compensation plate.

Journal Article↗

PubMed2006

Nucleostemin mRNA is expressed in both normal and malignant renal tissues.

Nucleostemin (NS), a p53-binding protein, has been shown essential for stem and cancer cell proliferation and implicated in oncogenesis. To explore potential contributions of NS to the development of clear cell renal cell carcinomas (ccRCCs), we determined NS expression in ccRCC cell lines, and in paired normal and malignant renal tissues from 31 patients with ccRCC. Nucleostemin mRNA and/or protein expression was observed in all four cell lines and 27 of 31 (87%) tumour specimens. Surprisingly, 16 of 31 (52%) adjacent normal renal samples also expressed NS mRNA and its levels in four of them were comparable with those in paired tumour tissues. Three of the patients had detectable NS mRNA in their normal renal tissues whereas lacked its expression in the matched tumours. Compared to the oncogene c-MYC expression in these same samples, NS expression showed a much less specificity for ccRCC. We further demonstrated that NS mRNA expression was closely associated with cellular proliferation in normal fibroblasts or T lymphocytes and renal cell carcinoma cell lines. Collectively, NS expression widely occurs in normal and malignant renal tissues, and is likely a proliferation marker rather than a unique regulator of cell proliferation and survival in stem and cancer cells.

Adult↗

PubMed2006

Human glutathione S-transferase P1-1 interacts with TRAF2 and regulates TRAF2-ASK1 signals.

Human glutathione S-transferase P1-1 (GSTP1-1) is an ubiquitously expressed protein that plays an important role in the detoxification and xenobiotics metabolism. It has been shown that GSTP1-1 interacts with c-Jun NH(2)-terminal kinase (JNK) and suppresses its activity. Here, we report a novel function of GSTP1-1 in regulating tumor necrosis factor-alpha (TNF-alpha)-triggered signaling. The present experiments showed that GSTP1-1 physically associated with tumor necrosis factor receptor-associated factor 2 (TRAF2) in vivo and in vitro. Overexpression of GSTP1-1 inhibited TRAF2-induced activation of both JNK and p38 but not of nuclear factor-kappaB (NF-kappaB). Glutathione S-transferase P1-1 also attenuated TRAF2-enhanced apoptosis signal-regulating kinase 1 (ASK1) autophosphorylation and inhibited TRAF2-ASK1-induced cell apoptosis by suppressing the interaction of TRAF2 and ASK1. Conversely, silencing of GSTP1-1 expression through RNA interference (RNAi) resulted in increase of TNF-alpha-dependent TRAF2-ASK1 association followed by hyper-activation of ASK1 and JNK. A mutant GSTP1-1 lacking TRAF domain-binding motif exhibited a significant decline of capacity to bind TRAF2 and block TRAF2-ASK1 signaling compared with the wild type of GSTP1-1. Moreover, the glutathione-conjugating activity of GSTP1-1 was not involved in the regulation of TRAF2 signaling. These findings indicate that GSTP1-1 plays an important regulatory role in TNF-alpha-induced signaling by forming ligand-binding interactions with TRAF2, which provides a new insight for analysing the protective effects of GSTP1-1 in tumor cells.

Cell Line↗

PubMed2006

Dendritic plasticity of CA1 pyramidal neurons after transient global ischemia.

Dendrites and spines undergo dynamic changes in physiological conditions, such as learning and memory, and in pathological conditions, such as Alzheimer's disease and epilepsy. Long-term dendritic plasticity has also been reported after ischemia/hypoxia, which might be compensatory effects of surviving neurons for the functional recovery after the insults. However, the dendritic changes shortly after ischemia, which might be associated with the pathogenesis of ischemic cell death, remain largely unknown. To reveal the morphological changes of ischemia-vulnerable neurons after ischemia, the present study investigated the alteration of dendritic arborization of CA1 pyramidal neurons in rats after transient cerebral ischemia using intracellular staining technique in vivo. The general appearance of dendritic arborization of CA1 neurons within 48 h after ischemia was similar to that of control neurons. However, a dramatic increase of dendritic disorientation was observed after ischemia with many basal dendrites coursed into the territory of apical dendrites and apical dendrites branched into the region of basal dendrites. In addition, a significant increase of apical dendritic length was found 24 h after ischemia. The increase of dendritic length after ischemia was mainly due to the dendritic sprouting rather than the extension of individual dendrites, which mainly occurred in the middle segment of the apical dendrites. These results reveal a plasticity change in dendritic arborization of CA1 neurons shortly after cerebral ischemia.

Animals↗

PubMed2006

Plant polyphenols and multidrug resistance: effects of dietary flavonoids on drug transporters in Caco-2 and MDCKII-MDR1 cell transport models.

The hypothesis tested was that specific flavonoids such as epicatechin gallate, epigallocatechin gallate, genistein, genistin, naringenin, naringin, quercetin and xanthohumol will modulate cellular uptake and permeability (P(e)) of multidrug-resistant substrates, cyclosporin A (CSA) and digoxin, across Caco-2 and MDCKII-MDR1 cell transport models. (3)H-CSA/(3)H-digoxin transport and uptake experiments were performed with and without co-exposure of the flavonoids. Aglycone flavonoids reduced the P(e) of CSA to a greater extent than glycosylated flavonoids with 30 microM xanthohumol producing the greatest effect (7.2 x 10(-6) to 6.6 x 10(-7) and 17.9 x 10(-6) to 4.02 x 10(-6) cm s(-1) in Caco-2 and MDCKII-MDR1 cells, respectively); while no measurable effects were seen with digoxin. Xanthohumol significantly demonstrated (1) saturable efflux, (2) increased uptake of (3)H-digoxin and (3) decreased uptake of (3)H-CSA in the Caco-2 cells. The transport data suggests that xanthohumol effects transport of CSA in a manner that is distinct from the digoxin efflux pathway and suggests that intestinal transport of these MDR1 substrates is more complex than previously reported.

Animals↗

PubMed2006

Bone allograft non-union is related to excessive osteoclastic bone resorption: a sheep model study.

Using a sheep femoral allograft model we have investigated the cellular and molecular mechanisms associated with non-union of bone allografts. Histomorphometric analysis revealed that allograft non-unions featured both marked increases in osteoclast (OC) numbers and total eroded bone surface as compared to allografts which had undergone direct union. Three distinct cellular layers lying adjacent to the allograft bone surface were identified in all non-union cases. The outer or fibroblastic layer contained an abundance of fibroblasts and connective tissue. Circumscribing this layer was a band of synovial-like cells consisting mainly of large spindle-shaped mononuclear cells mixed with scattered round-shaped mononuclear cells. The third layer, which was directly juxtaposed to the allograft bone surface, consisted predominantly of multinuclear OCs which were positively identified by calcitonin receptor immunohistochemistry. Interestingly, in-situ hybridisation revealed that surrounding synovial-like cells in non-union allografts, expressed abundant gene transcripts for receptor activator NF-kappaB ligand (RANKL), a membrane bound factor critical for both the induction of OC activity and osteoclastogenesis. We propose that excessive bone resorption by host OCs contributes, at least partially, to the failure of bone allografts. The production of RANKL by synovial-like fibroblasts may be the driving force responsible for the elevated generation and activation of OCs. Based on such evidence novel therapeutic strategies for the treatment of non-union bone allografts using anti-bone resorbing agents may be devised.

Animals↗

PubMed2005

Classifying spatial patterns of brain activity with machine learning methods: application to lie detection.

Patterns of brain activity during deception have recently been characterized with fMRI on the multi-subject average group level. The clinical value of fMRI in lie detection will be determined by the ability to detect deception in individual subjects, rather than group averages. High-dimensional non-linear pattern classification methods applied to functional magnetic resonance (fMRI) images were used to discriminate between the spatial patterns of brain activity associated with lie and truth. In 22 participants performing a forced-choice deception task, 99% of the true and false responses were discriminated correctly. Predictive accuracy, assessed by cross-validation in participants not included in training, was 88%. The results demonstrate the potential of non-linear machine learning techniques in lie detection and other possible clinical applications of fMRI in individual subjects, and indicate that accurate clinical tests could be based on measurements of brain function with fMRI.

Adult↗

PubMed2005

Effects of music on target-controlled infusion of propofol requirements during combined spinal-epidural anaesthesia.

The sedative effects of music were evaluated using the bispectral index (BIS) during target-controlled infusion (TCI) propofol. A total of 110 women undergoing hysterectomy were randomly allocated to receive either music or no music. Propofol was administered using target-controlled infusion and the concentration adjusted gradually to achieve an observer's assessment of alertness/sedation (OAA/S) score of 3 intra-operatively. The haemodynamic and bispectral index values during the sedation phase were recorded. Interleukin-6 was evaluated before, immediately after and 1 h following intervention. The music group had a significant reduction in mean (SD) induction time of sedation: 12 (12) min vs. 18 (12) min, p < 0.01; propofol target concentration: 1.6 (0.3) microg.ml(-1) vs. 2.4 (0.4) microg.ml(-1), p < 0.0001; intra-operative amount of propofol: 171 (98) mg vs. 251 (92) mg, p < 0.0001; and significantly higher levels of satisfaction with their peri-operative care: 9.6 (0.6) compared to the control group: 8.1 (1.0), p < 0.0001. No other differences were found. The results show the influence of music on the induction time of sedation, concentration and level of propofol during surgery, and suggest sedative benefits of music.

Adult↗

PubMed2005

Tissue localization and regulation by juvenile hormone of human allergen Bla g 4 from the German cockroach, Blattella germanica (L.).

The German cockroach, Blattella germanica (L.), produces several potent protein aeroallergens, including Bla g 4, a approximately 20 kDa lipocalin. RT-PCR, Northern analyses and in situ hybridization showed that Bla g 4 is expressed only in the adult male reproductive system. Western blotting and ELISA with rBla g 4 antiserum detected immunoreactivity in the utricles and the conglobate gland, but not in other tissues of the male reproductive system. The Bla g 4 protein content of males increased from adult emergence to day 14, but during copulation Bla g 4 was depleted in the male and transferred to the female within the spermatophore. Topical application of juvenile hormone III stimulated Bla g 4 production by both conglobate gland and utricles.

Age Factors↗

PubMed2005

A novel blocking monoclonal antibody recognizing a distinct epitope of human CD40 molecule.

CD40, a member of the tumor necrosis factor receptor superfamily, is an important costimulatory molecule during the immune response. Here, we report a blocking mouse antihuman CD40 monoclonal antibody, mAb 3G3, of which the specificity was verified by flow cytometry and Western blot. It was shown by competition test that 3G3 bound to a different site (epitope) of CD40 from the reported CD40 mAbs, including clone mAb89, 3B2, and 5C11. It was also found that mAb 3G3 could inhibit homotypic aggregation of Daudi cells induced by the agonistic anti-CD40 mAb 5C11. Furthermore, mAb 3G3 effectively inhibited the proliferation of peripheral blood mononuclear cells in mixed lymphocyte reaction assay. Finally, a sensitive and specific soluble CD40 (sCD40) ELISA kit was established by matching mAb 3G3 with 5C11, and it was found that the levels of sCD40 in sera from patients with immune disorders such as hyperthyroidism, chronic nephritis, and rheumatoid arthritis were obviously higher than those from normal individuals. Thus, this blocking anti-CD40 mAb provides a novel tool for the study of CD40.

Antibodies, Monoclonal↗

PubMed2004

Beta-synuclein gene alterations in dementia with Lewy bodies.

OBJECTIVE: To determine whether mutations in the genes for alpha-synuclein or beta-synuclein are responsible for dementia with Lewy bodies (DLB), a disorder closely related to Parkinson disease (PD). METHODS: The authors ascertained 33 sporadic cases of DLB and 10 kindreds segregating DLB. DNA samples from the 43 index cases were screened for alterations in the genes for alpha-synuclein and beta-synuclein, as alpha-synuclein alterations cause PD and beta-synuclein may modulate alpha-synuclein aggregation and neurotoxicity. RESULTS: Two amino acid alterations were identified in unrelated DLB index cases: a valine to methionine substitution at codon 70 (V70M) and a proline to histidine substitution at codon 123 (P123H), both in the beta-synuclein gene. These amino acid substitutions occur at conserved residues in highly conserved regions of the beta-synuclein protein. Screening of at least 660 chromosomes from control subjects matched to the patients' population groups failed to identify another V70M or P123H allele. Cosegregation analysis of an extended pedigree segregating the P123H beta-synuclein alteration suggested that it is a dominant trait with reduced penetrance or a risk factor polymorphism. Histopathology and immunohistochemistry analysis of index case brain sections revealed widespread Lewy body pathology and alpha-synuclein aggregation without evidence of beta-synuclein aggregation. CONCLUSION: Mutations in the beta-synuclein gene may predispose to DLB.

Aged↗

PubMed2004

In vivo and in vitro evaluation of erianin, a novel anti-angiogenic agent.

This study evaluated the anti-angiogenic activities of erianin in vivo and in vitro. Erianin, a natural product from Dendrobium chrysotoxum, caused moderate growth delay in xenografted human hepatoma Bel7402 and melanoma A375 and induced significant vascular shutdown within 4 h of administering 100 mg/kg of the drug. Erianin also displayed potent anti-angiogenic activities in vitro: it abrogated spontaneous or basic fibroblast growth factor-induced neovascularisation in chick embryo; it inhibited proliferation of human umbilical vein endothelial cells (EC(50) 34.1+/-12.7 nM), disrupted endothelial tube formation, and abolished migration across collagen and adhesion to fibronectin. Erianin also exerted selective inhibition toward endothelial cells, and quiescent endothelium showed more resistance than in proliferative and tumour conditions. In a cytoskeletal study, erianin depolymerised both F-actin and beta-tubulin, more significantly in proliferating endothelial cells than in confluent cells. In conclusion, erianin caused extensive tumour necrosis, growth delay and rapid vascular shutdown in hepatoma and melanoma models; it inhibited angiogenesis in vivo and in vitro and induced endothelial cytoskeletal disorganisation. These findings suggest that erianin has the therapeutic potential to inhibit angiogenesis in vivo and in vitro.

3T3 Cells↗

PubMed2004

Alleviating ischemia-reperfusion injury in aged rat liver by induction of heme oxygenase-1.

BACKGROUND: Heme oxygenase-1 (HO-1), a cytoprotective protein, may be important in ameliorating hepatic ischemia-reperfusion (I/R) injury, a critical factor in the dysfunction of the aged liver after transplantation. METHODS: We used hemin to overexpress HO-1 and analyze its effects in a model of I/R in aged livers used for orthotopic transplantation. RESULTS: The SGOT levels in the hemin group were significantly lower than those of the saline treatment group. Hemin liver grafts showed markedly fewer apoptotic (TUNEL+) liver cells after reperfusion compared with the controls. The plasma nitric oxide levels in the hemin group were significantly lower than those in the control group. Unlike untreated or hemin + Znpp-treated orthotopic liver transplant controls, iNOS expression in the hemin group was almost absent at 12 and 24 hours, after reperfusion. In contrast, eNOS was comparable in hemin and saline orthotopic liver transplants. The increased levels of Bcl-2 expression compared with saline controls were most pronounced at 12 hours after transplantation. In contrast, caspase 3 was lower at 24 hours among the hemin-pretreated group compared with saline-treated liver transplant controls. CONCLUSIONS: HO-1 alleviated the I/R injury in the aged liver by suppressing local expression of inducible nitric oxide synthase and by modulating pro- and antiapoptotic pathways.

Aging↗

PubMed2004

Bardet-Biedl syndrome 1 genotype and obesity in the Newfoundland population.

BACKGROUND AND OBJECTIVES: Obesity is one of the primary clinical features of Bardet-Biedl Syndrome (BBS), a genetically heterogeneous disorder that is usually inherited as an autosomal recessive trait. It has been suggested that heterozygous carriers of BBS are predisposed to obesity. We set out to identify the common mutation in BBS1 families from southwest Newfoundland and to examine the relationship between this mutation and obesity in the general population. METHODS AND SUBJECTS: We genotyped BBS1 families from Newfoundland to determine the nature of the mutation causing BBS in this population. We then screened 200 obese individuals (average body mass index (BMI)=37.9 kg/m2; average waist to hip ratio=0.935; average waist=113.8 cm) and 200 ethnically matched, unrelated, controls (average BMI=25.0 kg/m2; average waist to hip ratio=0.896; average waist=86.9 cm) from the same geographic region for the presence of this mutation. RESULTS: All affected members of the six Newfoundland BBS1 families were homozygous for the most common BBS1 mutation (M390R). This mutation was found in the heterozygous state in three of the 200 obese individuals and also in three of the 200 matched controls. CONCLUSIONS: The high frequency of BBS1 in Newfoundland appears to be the result of a founder event. Our data do not support the hypothesis that the M390R BBS1 mutation plays a significant role in the frequency of obesity in the general public in Newfoundland.

Adult↗