Biomedical subjects

Jin Chen

Publications and source records attributed to Jin Chen.

85 records · Page 5Linked to original sources

PubMed2002

Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo.

The Eph family of receptor tyrosine kinases and their ligands, known as ephrins, play a crucial role in vascular development during embryogenesis. The function of these molecules in adult angiogenesis has not been well characterized. Here, we report that blocking Eph A class receptor activation inhibits angiogenesis in two independent tumor types, the RIP-Tag transgenic model of angiogenesis-dependent pancreatic islet cell carcinoma and the 4T1 model of metastatic mammary adenocarcinoma. Ephrin-A1 ligand was expressed in both tumor and endothelial cells, and EphA2 receptor was localized primarily in tumor-associated vascular endothelial cells. Soluble EphA2-Fc or EphA3-Fc receptors inhibited tumor angiogenesis in cutaneous window assays, and tumor growth in vivo. EphA2-Fc or EphA3-Fc treatment resulted in decreased tumor vascular density, tumor volume, and cell proliferation, but increased cell apoptosis. However, EphA2-Fc had no direct effect on tumor cell growth or apoptosis in culture, yet inhibited migration of endothelial cells in response to tumor cells, suggesting that the soluble receptor inhibited blood vessel recruitment by the tumor. These data provide the first functional evidence for Eph A class receptor regulation of pathogenic angiogenesis induced by tumors and support the function of A class Eph receptors in tumor progression.

Adenoma, Islet Cell↗

PubMed2002

Ephrin-B1 transduces signals to activate integrin-mediated migration, attachment and angiogenesis.

Ephrin-B/EphB family proteins are implicated in bidirectional signaling and were initially defined through the function of their ectodomain sequences in activating EphB receptor tyrosine kinases. Ephrin-B1-3 are transmembrane proteins sharing highly conserved C-terminal cytoplasmic sequences. Here we use a soluble EphB1 ectodomain fusion protein (EphB1/Fc) to demonstrate that ephrin-B1 transduces signals that regulate cell attachment and migration. EphB1/Fc induced endothelial ephrin-B1 tyrosine phosphorylation, migration and integrin-mediated (alpha(v)beta(3) and alpha(5)beta(1)) attachment and promoted neovascularization, in vivo, in a mouse corneal micropocket assay. Activation of ephrin-B1 by EphB1/Fc induced phosphorylation of p46 JNK but not ERK-1/2 or p38 MAPkinases. By contrast, mutant ephrin-B1s bearing either a cytoplasmic deletion (ephrin-B1DeltaCy) or a deletion of four C-terminal amino acids (ephrin-B1DeltaPDZbd) fail to activate p46 JNK. Transient expression of intact ephin-B1 conferred EphB1/Fc migration responses on CHO cells, whereas the ephrin-B1DeltaCy and ephrin-B1DeltaPDZbd mutants were inactive. Thus ephrin-B1 transduces 'outside-in' signals through C-terminal protein interactions that affect integrin-mediated attachment and migration.

Amino Acid Sequence↗

PubMed2002

Constitutive expression of BCL-X(L) in the T lineage attenuates collagen-induced arthritis in Bcl-X(L) transgenic mice.

OBJECTIVE: To determine if inhibition of T cell apoptosis through constitutive expression of Bcl-X(L) in the T lineage influences inflammatory arthritis in the mouse collagen-induced arthritis (CIA) model. METHODS: The incidence and severity of arthritis were quantified in Bcl-X(L) transgenic mice and nontransgenic littermates after immunization with type II collagen (CII). To correlate T cell responses with disease phenotype, antigen-specific T cell proliferation was measured by (3)H-thymidine incorporation. Apoptosis and cell cycle progression were analyzed by flow cytometry using propidium iodide. Production of CII-specific interferon-gamma (IFNgamma), interleukin-5 (IL-5), and IL-10 was determined by enzyme-linked immunosorbent assay. RESULTS: Disease severity in CIA was significantly attenuated in Bcl-X(L) transgenic mice compared with their nontransgenic littermates. Inhibition of CIA was associated with decreased T cell apoptosis, delayed cell cycle progression, and reduced IFNgamma production. CONCLUSION: Rather than promoting inflammation, inhibition of apoptosis by expression of the Bcl-X(L) protein in the T lineage attenuates disease progression in CIA, probably through inhibition of IFNgamma production.

Animals↗

PubMed2002

The ephrins and Eph receptors in angiogenesis.

Eph receptors are a unique family of receptor tyrosine kinases that play critical roles in embryonic patterning, neuronal targeting, vascular development and adult neovascularization. Engagement of Eph receptors by ephrin ligands mediates critical steps of angiogenesis, including juxtacrine cell-cell contacts, cell adhesion to extracellular matrix, and cell migration. Recent evidence from in vitro angiogenesis assays and analysis of mice deficient for one or more members of the Eph family establishes the role of Eph signaling in sprouting angiogenesis and blood vessel remodeling during vascular development. Furthermore, elevated expression of Eph receptors and ephrin ligands is associated with tumors and associated tumor vasculature, suggesting that Eph receptors and their ephrin ligands also play critical roles in tumor angiogenesis and tumor growth. This review will focus on the relevance of Eph receptor signaling in embryonic and adult neovascularization, and possible contributions to tumor growth and metastasis.

Animals↗

PubMed2002

Beta-adrenergic receptor activation inhibits keratinocyte migration via a cyclic adenosine monophosphate-independent mechanism.

There is increasing evidence that G-protein-coupled receptors cross-talk with growth factor receptor-mediated signal transduction in a variety of cell types. We have investigated mechanisms by which the activation of beta-adrenergic receptors, classically GTP-binding proteins coupled receptors, influence the migration of cultured human keratinocytes. We found that iso-proterenol, a beta-adrenergic receptor-selective agonist, inhibited cell migration stimulated by either epidermal growth factor, or extracellular Ca2+ in a concentration-dependent manner. This was prevented by pretreatment of the cells with the beta-adrenergic receptor-selective antagonist timolol. Interestingly, isoproterenol, at a concentration of 1 nm, did not measurably increase intracellular cyclic adenosine monophosphate concentrations yet inhibited cell migration by 50%. To test further if isoproterenol's actions were mediated via activation of adenylyl cyclase, two inhibitors of its activity, 2'5'-dideoxyadenosine and SQ22536, were used. Both compounds significantly diminished iso-proterenol-induced increases in intracellular cyclic adenosine monophosphate concentrations but did not attenuate isoproterenol-induced inhibition of cell migration. Also, forskolin (1 microm) markedly increased intracellular cyclic adenosine monophosphate concentrations but did not significantly inhibit cell migration. As mitogen-activated protein kinases are known to signal growth factor-stimulated cell migration, we examined whether beta-adrenergic receptor-mediated inhibition of keratinocyte migration might occur via inactivation of mitogen-activated protein kinases. We found that isoproterenol inhibited phosphorylation of extracellular signal-regulated kinase mitogen-activated protein kinase in a concentration-dependent manner but had no effect on the phosphorylation of the stress mitogen-activated protein kinases c-jun N-terminal kinase and stress-activated protein kinase-2. Neither forskolin nor a membrane permeable cyclic adenosine monophosphate analog inhibited phosphorylation of any of these mitogen-activated protein kinases. These findings suggest that beta-adrenergic receptor-induced inhibition of keratinocyte migration is mediated through inhibition of the extracellular signal-regulated kinase mitogen-activated protein kinase signaling in a cyclic adenosine monophosphate-independent manner.

Adrenergic beta-Agonists↗

PubMed2002

Blockade of TGF-beta inhibits mammary tumor cell viability, migration, and metastases.

TGF-betas are potent inhibitors of epithelial cell proliferation. However, in established carcinomas, autocrine/paracrine TGF-beta interactions can enhance tumor cell viability and progression. Thus, we studied the effect of a soluble Fc:TGF-beta type II receptor fusion protein (Fc:TbetaRII) on transgenic and transplantable models of breast cancer metastases. Systemic administration of Fc:TbetaRII did not alter primary mammary tumor latency in MMTV-Polyomavirus middle T antigen transgenic mice. However, Fc:TbetaRII increased apoptosis in primary tumors, while reducing tumor cell motility, intravasation, and lung metastases. These effects correlated with inhibition of Akt activity and FKHRL1 phosphorylation. Fc:TbetaRII also inhibited metastases from transplanted 4T1 and EMT-6 mammary tumors in syngeneic BALB/c mice. Tumor microvessel density in a mouse dorsal skin window chamber was unaffected by Fc:TbetaRII. Therefore, blockade of TGF-beta signaling may reduce tumor cell viability and migratory potential and represents a testable therapeutic approach against metastatic carcinomas.

Animals↗

PubMed2002

[The effects of non-pharmacotherapy in decreasing the levels of serum lipid in patients with hyperlipidemia].

OBJECTIVE: To develop a non-pharmacotherapy program for patients with hyperlipidemia and assess its effectiveness. METHODS: A cluster control trial was used. The experimental group was given non-pharmacotherapy for hyperlipidemia once a week for 6 weeks; the content of non-pharmacotherapy included the basic knowledge about hyperlipidemia, a guide of changing unhealthy diet and life-style. Patients were followed for once every two weeks in the department of out-patient. The control group received general care conducted by university clinicians, without the non-pharmacotherapy program. A self-completion questionnaire on hyperlipidemia-related knowledge level, questionnaires on diet and exercise, body weight, body height and the serum TG, TC were measured at entry point and at the end of 6 month. RESULTS: One hundred and fifty-four patients in experimental group and 150 patients in control group completed the study. The non-pharmacotherapy group showed a significant increase of knowledge on hyperlipidemia in the experimental group comparing with the control group: the mean (sd) score of hyperlipidemia-related knowledge were 22.5 (4.8), 17.4 (4.2) (95% CI: 4.1, 6.1). The diet score and the proportion of regular physical activity had increased 27.20%, 21.78% respectively in experimental group. The mean (sd) of serum TG, TC and body mass index (BMI) for experimental group [2.0 (0.9) mmol/L, 5.4 (0.9) mmol/L, 23.4 (1.9)] lowered significantly comparing to those for control group [2.4 (0.9) mmol/L, 5.9 (1.0) mmol/L, 24.2 (3.0)]. CONCLUSION: Non-pharmacotherapy seemed to be an important intervention for the patients with hyperlipidemia. If same patients with hyperlipidemia failed to respond to non-pharmacotherapy, it is necessary to use pharmacotherapy. However, non-pharmacotherapy should be viewed as basic therapy.

Adult↗

PubMed2002

[Effects of telomerase sense and antisense oligodeoxynucleotides on growth and differentiation of nasopharyngeal carcinoma cells].

BACKGROUND & OBJECTIVE: It was reported that telomere and telomerase were associated with the development of cancers. Telomerase antisense oligodeoxynucleotides(ASODN) directly act on telomerase, or induce tumor cells to differentiate, result in telomerase activity decreases, and cells growth inhibited. However, whether the inhibition of telomerase activity by ASODN could induce tumor cells to differentiate is still unknown. Telomerase RNA acts as a template for synthesis of telomere, so telomerase sense oligodeoxynucleotides(SODN) can be hybridized to the telomere DNA. Whether this reaction could affect the growth of tumor cells is worth being studied. This research was just to investigate the effects of telomerase SODN and ASODN on the growth and differentiation of nasopharyngeal carcinoma(NPC) cells. METHODS: After transfecting telomerase SODN and ASODN into NPC CNE1 and CNE2Z cells by lipofectin, the proliferation of the cells was identified by MTT method, and the expression of keratin was detected by immunohistochemistry. Meanwhile, the morphological changes of the cells were observed. RESULTS: SODN inhibited the growth of CNE1 and CNE2Z cells as well as ASODN in dose- and time-dependent manner. After being treated with 1.5 mumol/L, 3.0 mumol/L, 4.5 mumol/L, and 6.0 mumol/L SODN, the inhibition rates in CNE1 cells for 6 h were 16.28%, 19.38%, 22.48%, and 23.26%, respectively; for 48 h were 26.26%, 38.89%, 39.90%, and 38.89%, respectively; the inhibition rates in CNE2Z cells for 6 h were 7.69%, 8.24%, 18.13%, and 20.32%, respectively, and for 48 h were 28.84%, 28.88%, 32.89%, and 31.54%, respectively. The keratin expressions in cells of SODN and ASODN groups were significantly increased and the cells tended to be mature. CONCLUSION: The telomerase SODN and ASODN could both inhibit the growth of NPC cells and induce cells to differentiate.

Cell Differentiation↗

PubMed2002

Blockade of EphA receptor tyrosine kinase activation inhibits vascular endothelial cell growth factor-induced angiogenesis.

Angiogenesis is a multistep process involving a diverse array of molecular signals. Ligands for receptor tyrosine kinases (RTKs) have emerged as critical mediators of angiogenesis. Three families of ligands, vascular endothelial cell growth factors (VEGFs), angiopoietins, and ephrins, act via RTKs expressed in endothelial cells. Recent evidence indicates that VEGF cooperates with angiopoietins to regulate vascular remodeling and angiogenesis in both embryogenesis and tumor neovascularization. However, the relationship between VEGF and ephrins remains unclear. Here we show that interaction between EphA RTKs and ephrinA ligands is necessary for induction of maximal neovascularization by VEGF. EphA2 RTK is activated by VEGF through induction of ephrinA1 ligand. A soluble EphA2-Fc receptor inhibits VEGF-, but not basic fibroblast growth factor-induced endothelial cell survival, migration, sprouting, and corneal angiogenesis. As an independent, but complementary approach, EphA2 antisense oligonucleotides inhibited endothelial expression of EphA2 receptor and suppressed ephrinA1- and VEGF-induced cell migration. Taken together, these data indicate an essential role for EphA receptor activation in VEGF-dependent angiogenesis and suggest a potential new target for therapeutic intervention in pathogenic angiogenesis.

Angiogenesis Inhibitors↗

PubMedDate not supplied

Discovering reliable protein interactions from high-throughput experimental data using network topology.

OBJECTIVE: Current protein-protein interaction (PPI) detection via high-throughput experimental methods, such as yeast-two-hybrid has been reported to be highly erroneous, leading to potentially costly spurious discoveries. This work introduces a novel measure called IRAP, i.e. "interaction reliability by alternative path", for assessing the reliability of protein interactions based on the underlying topology of the PPI network. METHODS AND MATERIALS: A candidate PPI is considered to be reliable if it is involved in a closed loop in which the alternative path of interactions between the two interacting proteins is strong. We devise an algorithm called AlternativePathFinder to compute the IRAP value for each interaction in a complex PPI network. Validation of the IRAP as a measure for assessing the reliability of PPIs is performed with extensive experiments on yeast PPI data. All the data used in our experiments can be downloaded from our supplementary data web site at . RESULTS: Results show consistently that IRAP measure is an effective way for discovering reliable PPIs in large datasets of error-prone experimentally-derived PPIs. Results also indicate that IRAP is better than IG2, and markedly better than the more simplistic IG1 measure. CONCLUSION: Experimental results demonstrate that a global, system-wide approach-such as IRAP that considers the entire interaction network instead of merely local neighbors-is a much more promising approach for assessing the reliability of PPIs.

Algorithms↗

PubMedDate not supplied

Inhibition of VEGF-dependent multistage carcinogenesis by soluble EphA receptors.

Elevated expression of Eph receptors has long been correlated with the growth of solid tumors. However, the functional role of this family of receptor tyrosine kinases in carcinogenesis and tumor angiogenesis has not been well characterized. Here we report that soluble EphA receptors inhibit tumor angiogenesis and tumor progression in vivo in the RIP-Tag transgenic model of vascular endothelial growth factor (VEGF)-dependent multistage pancreatic islet cell carcinoma. Soluble EphA receptors delivered either by a transgene or an osmotic minipump inhibited the formation of angiogenic islet, a premalignant lesion, and reduced tumor volume of solid islet cell carcinoma. EphA2-Fc or EphA3-Fc treatment resulted in decreased tumor volume but increased tumor and endothelial cell apoptosis in vivo. In addition, soluble EphA receptors inhibited VEGF and betaTC tumor cell-conditioned medium-induced endothelial cell migration in vitro and VEGF-induced cornea angiogenesis in vivo. A dominant negative EphA2 mutant inhibited--whereas a gain-of-function EphA2 mutant enhanced--tumor cell-induced endothelial cell migration, suggesting that EphA2 receptor activation is required for tumor cell-endothelial cell interaction. These data provide functional evidence for EphA class receptor regulation of VEGF-dependent tumor angiogenesis, suggesting that the EphA signaling pathway may represent an attractive novel target for antiangiogenic therapy in cancer.

Angiogenesis Inhibitors↗

PubMedDate not supplied

Large-scale quantitative proteomic study of PUMA-induced apoptosis using two-dimensional liquid chromatography-mass spectrometry coupled with amino acid-coded mass tagging.

By coupling two-dimensional liquid chromatography-tandem mass spectrometry (2D-LC-MS/MS) with amino acid-coded mass tagging (AACT), we have greatly increased the analytical throughput and sequence coverage of MS-based methods for proteome-wide quantitation. The dynamic range and reproducibility of this 2D-LC-AACT quantitative approach were evaluated by profiling the mixtures with different ratios of E. coli cells grown in either regular or AACT medium. A SQL-based high thoughput MASCOT data analysis tool was developed for proteomic data sorting and mining. We investigated the early stage of apoptosis by inducing the p53 upregulated modulator of apoptosis (PUMA) through the analyses of the relative ratios of the pairwise isotope signals that were originated from the control and labeled PUMA-induced cells. In 20-hour 2D-LC-MS/MS run, 480 proteins were conclusively identified, and more than half of them were quantified. A noteworthy change in the quantitative profile was that histones and a ubiquitin conjugate protein UBC9, which are involved in DNA double-strand break (DSB) repair were significantly down-regulated in the PUMA-overexpressing apoptotic cells, suggesting the detection of DSB in the apoptotic process. The quantitative profiling efficiency of this approach was compared with the gel-based quantitative analysis scheme.

Amino Acids↗

PubMedDate not supplied

A visualization system for space-time and multivariate patterns (VIS-STAMP).

The research reported here integrates computational, visual, and cartographic methods to develop a geovisual analytic approach for exploring and understanding spatio-temporal and multivariate patterns. The developed methodology and tools can help analysts investigate complex patterns across multivariate, spatial, and temporal dimensions via clustering, sorting, and visualization. Specifically, the approach involves a self-organizing map, a parallel coordinate plot, several forms of reorderable matrices (including several ordering methods), a geographic small multiple display, and a 2-dimensional cartographic color design method. The coupling among these methods leverages their independent strengths and facilitates a visual exploration of patterns that are difficult to discover otherwise. The visualization system we developed supports overview of complex patterns and, through a variety of interactions, enables users to focus on specific patterns and examine detailed views. We demonstrate the system with an application to the IEEE InfoVis 2005 Contest data set, which contains time-varying, geographically referenced, and multivariate data for technology companies in the US.

Algorithms↗