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Biomedical subjects

Song Li

Publications and source records attributed to Song Li.

At least 55 records · Page 3Linked to original sources
PubMed2005

Downregulation of endothelin-1 by farnesoid X receptor in vascular endothelial cells.

The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that is highly expressed in liver, kidney, adrenals, and intestine. FXR may play an important role in the pathogenesis of cardiovascular diseases via regulating the metabolism and transport of cholesterol. In this study, we report that FXR is also expressed in rat pulmonary artery endothelial cells (EC), a "nonclassical" bile acid target tissue. FXR is functional in EC, as demonstrated by induction of its target genes such as small heterodimer partner (SHP) after treatment with chenodeoxycholic acid, a FXR agonist. Interestingly, activation of FXR in EC led to downregulation of endothelin (ET)-1 expression. Reporter assays showed that activation of FXR inhibited transcriptional activation of the human ET-1 gene promoter and also repressed the activity of a heterologous promoter driven by activator protein (AP)-1 response elements. Electrophoretic mobility-shift and chromatin immunoprecipitation assays indicated that FXR reduced the binding activity of AP-1 transcriptional factors, suggesting that FXR may suppress ET-1 expression via negatively interfering with AP-1 signaling. These studies suggest that FXR may play a role in endothelial homeostasis and may serve as a novel molecular target for manipulating ET-1 expression in vascular EC.

Animals↗
PubMed2005

Effects of shear stress on endothelial cell haptotaxis on micropatterned surfaces.

Endothelial cell (EC) migration plays a critical role in vascular remodeling. Here we investigated the interactions between haptotaxis (induced by extracellular matrix gradient) and mechanotaxis (induced by mechanical forces) during EC migration. A micropatterning technique was used to generate step changes of collagen surface density. Due to haptotaxis, ECs developed focal adhesions and migrated into the area with higher surface density of collagen. Different levels of fluid shear stress were applied on ECs in the direction perpendicular to collagen strips. Shear stress at 2 dyn/cm2 did not affect haptotaxis, while shear stress at 3 dyn/cm2 or higher was sufficient to drive the migration of most ECs in the flow direction and against haptotaxis. Immunostaining revealed the increase of focal adhesions and lamellipodial protrusion in the direction of flow. These results suggest that shear stress beyond a certain threshold can be a predominant factor to determine the direction of EC migration.

Animals↗
PubMed2005

Sphingosine-1-phosphate induces a PDGFR-dependent cell detachment via inhibiting beta1 integrin in HEK293 cells.

Several different types of interactions between sphingosine-1-phosphate (S1P) receptors and platelet-derived growth factor receptor (PDGFR) have been revealed recently. In this work, we used HEK293 cells to further investigate the potential crosstalk. Interestingly, we observed that S1P specifically induced a PDGFR-dependent cell detachment in HEK293 cells, which could be inhibited by AG1296, a specific inhibitor for PDGFR. EGFR on the other hand, did not have any effect on cell detachment. The detachment was extracellular matrix (ECM) protein specific, suggesting the involvement of specific integrin molecules. When beta(1) integrin was engaged into an active state, S1P-induced cell detachment was blocked, suggesting that S1P induced an inside-out inhibitory effect on beta(1) integrin. G(i) protein and ERK activation were required for the cell detachment induced by S1P, suggesting an endogenous receptor for S1P is likely to be involved.

Blotting, Western↗
PubMed2005

Inhibition of Pkhd1 impairs tubulomorphogenesis of cultured IMCD cells.

Fibrocystin/polyductin (FPC), the gene product of PKHD1, is responsible for autosomal recessive polycystic kidney disease (ARPKD). This disease is characterized by symmetrically large kidneys with ectasia of collecting ducts. In the kidney, FPC predominantly localizes to the apical domain of tubule cells, where it associates with the basal bodies/primary cilia; however, the functional role of this protein is still unknown. In this study, we established stable IMCD (mouse inner medullary collecting duct) cell lines, in which FPC was silenced by short hairpin RNA inhibition (shRNA). We showed that inhibition of FPC disrupted tubulomorphogenesis of IMCD cells grown in three-dimensional cultures. Pkhd1-silenced cells developed abnormalities in cell-cell contact, actin cytoskeleton organization, cell-ECM interactions, cell proliferation, and apoptosis, which may be mediated by dysregulation of extracellular-regulated kinase (ERK) and focal adhesion kinase (FAK) signaling. These alterations in cell function in vitro may explain the characteristics of ARPKD phenotypes in vivo.

Animals↗
PubMed2005

Cationic lipids enhance siRNA-mediated interferon response in mice.

RNA interference mediated by small interfering RNAs (siRNAs) shows promise as a powerful research tool for gene function studies. However, controversy exists over the potential of siRNA-induced interferon response in vitro and in vivo. In this study, we showed that although intravenous administration of siRNA alone is essentially inert, injection of siRNA complexed with cationic liposomes resulted in a potent induction of both type I and type II interferon responses. Furthermore, i.v. administration of cationic lipid/siRNA complexes led to activation of STAT1. This study suggests caution in data interpretation and the potential toxicity with in vivo use of siRNA, particularly when delivered via a cationic lipid vector. This study also suggests the potential of siRNA as an immunostimulatory agent for immunotherapy.

Animals↗
PubMed2005

Molecular basis of mechanical modulation of endothelial cell migration.

Vascular endothelial cells (ECs) play important roles in the regulation of vascular functions. Loss of endothelial integrity can lead to vascular diseases such as stenosis resulting from atherosclerosis. The migration of ECs into wounded area in the vessel wall is required for the restoration of its integrity and functions. EC migration results from a balance of externally applied forces (e.g. shear stress), intracellular forces (e.g., those generated by contractile and cytoskeletal proteins), adhesion force between ECs and extracellular matrix (ECM) proteins, and the force of EC-EC coupling through junction proteins. Shear stress modulates EC migration through the regulation of multiple signaling pathways, gene expression, and the reorganization of cytoskeleton, focal adhesion sites, and cell junctions. Investigations of EC migration under shearing can provide valuable knowledge on vascular remodeling process under physiological and pathological conditions.

Animals↗
PubMed2005

Dual role of orphan nuclear receptor pregnane X receptor in bilirubin detoxification in mice.

The pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) are implicated in xenobiotic and endobiotic detoxification, including the clearance of toxic bilirubin. Previous studies have suggested both overlapping and preferential regulation of target genes by these receptors, but the mechanism of cross-talk remains elusive. Here we reveal a dual role of PXR in bilirubin detoxification in that both the loss and activation of PXR led to protection from hyperbilirubinemia induced by bilirubin infusion or hemolysis. The increased bilirubin clearance in PXR-null mice was associated with selective upregulation of detoxifying enzymes and transporters, and the pattern of regulation is remarkably similar to that of transgenic mice expressing the activated CAR. Interestingly, the increased bilirubin clearance and associated gene regulation were absent in the CAR-null or double-knockout mice. In cell cultures, ligand-free PXR specifically suppressed the ability of CAR to induce the multidrug resistance associated protein 2 (MRP2), a bilirubin-detoxifying transporter. This suppression was, at least in part, the result of the disruption of ligand-independent recruitment of coactivator by CAR. In conclusion, PXR plays both positive and negative roles in regulating bilirubin homeostasis, and this provides a novel mechanism that may govern receptor cross-talk and the hierarchy of xenobiotic and endobiotic regulation. PXR is a potential therapeutic target for clinical treatment of jaundice. (HEPATOLOGY 2005;41:497-505.).

Animals↗
PubMed2005

Role of cell surface heparan sulfate proteoglycans in endothelial cell migration and mechanotransduction.

Endothelial cell (EC) migration is critical in wound healing and angiogenesis. Fluid shear stress due to blood flow plays an important role in EC migration. However, the role of EC surface heparan sulfate proteoglycans (HSPGs) in EC adhesion, migration, and mechanotransduction is not well understood. Here, we investigated the effects of HSPG disruption on the adhesion, migration, and mechanotransduction of ECs cultured on fibronectin. We showed that disruption of HSPGs with heparinase decreased EC adhesion rate by 40% and adhesion strength by 33%. At the molecular level, HSPG disruption decreased stress fibers and the size of focal adhesions (FAs), increased filopodia formation, and enhanced EC migration. Under flow condition, heparinase treatment increased EC migration speed, but inhibited shear stress-induced directionality of EC migration and the recruitment of phosphorylated focal adhesion kinase in the flow direction, suggesting that HSPGs are important for sensing the direction of shear stress. In addition, decreasing cell adhesion by lowering fibronectin density enhanced EC migration under static and flow condition, but did not affect the directional migration of ECs under flow. Based on our results, we propose that HSPGs play dual roles as mechanotransducer on the EC surface: (1) HSPGs-matrix interaction on the abluminal surface regulates EC migration speed through an adhesion-dependent manner, and (2) HSPGs without binding to matrix (e.g., on the luminal surface) are involved in sensing the direction of flow through an adhesion-independent manner.

Animals↗
PubMed2005

Toward automatic computer aided dental X-ray analysis using level set method.

A Computer Aided Dental X-rays Analysis (CADXA) framework is proposed to semi-automatically detect areas of bone loss and root decay in digital dental X-rays. In this framework, first, a new proposed competitive coupled level set method is proposed to segment the image into three pathologically meaningful regions using two coupled level set functions. Tailored for the dental clinical environment, the segmentation stage uses a trained support vector machine (SVM) classifier to provide initial contours. Then, based on the segmentation results, an analysis scheme is applied. First, the scheme builds an uncertainty map from which those areas with bone loss will be automatically detected. Secondly, the scheme employs a method based on the SVM and the average intensity profile to isolate the teeth and detect root decay. Experimental results show that our proposed framework is able to automatically detect the areas of bone loss and, when given the orientation of the teeth, it is able to automatically detect the root decay with a seriousness level marked for diagnosis.

Algorithms↗
PubMed2005

Targeted delivery of oligodeoxynucleotides to mouse lung endothelial cells in vitro and in vivo.

Pulmonary endothelium plays an important role in the maintenance of normal pulmonary physiology and its dysfunction is involved in a number of pulmonary diseases. Correction of endothelial dysfunction via antisense oligodeoxynucleotides (ODN) is dependent on the development of a delivery vehicle that can efficiently deliver the ODN to pulmonary endothelium with minimal toxicity. To this end, we have developed a novel lipidic vector that is highly efficient in targeted delivery of ODN to pulmonary endothelium. This is based on a method that utilizes an ionizable aminolipid (1,2-dioleoyl-3-dimethylammonium propane) and an ethanol-containing buffer system for encapsulating large quantities of polyanionic ODN in lipid vesicles. An endothelium-specific antibody (273-34A) is incorporated into the lipid vesicles via a distearoylphosphatidylethanolamine-poly(ethylene glycol) spacer. The 273-34A antibody efficiently mediated delivery of ODN to mouse lung endothelial cells in vitro and in vivo. Furthermore, systemic administration of this formulation is associated with minimal hematological toxicities and induces little acute change in systemic and pulmonary hemodynamics. These results provide a basis for lipid-mediated delivery of ODN for the treatment of pulmonary diseases. They also suggest the utility of this approach as a research tool to characterize the function of genes in the pulmonary endothelium.

Animals↗
PubMed2005

Targeted delivery of therapeutic oligonucleotides to pulmonary circulation.

Functional oligodeoxynucleotides (ODN) such as antisense ODN (AS-ODN) show promise as new therapeutics for the treatment of a number of pulmonary diseases. They also hold potential to serve as a research tool for the study of gene function related to lung physiology. The success of their application is largely dependent on the development of an efficient delivery vehicle. This chapter summarizes work toward the development of lipidic vectors for targeted ODN delivery to pulmonary circulation. Recent advancements in the development of novel ODN are also discussed briefly.

Animals↗
PubMed2005

C16, a novel advanced glycation endproduct breaker, restores cardiovascular dysfunction in experimental diabetic rats.

AIM: Advanced glycation endproducts (AGE) have been implicated in the pathogenesis of diabetic complications, including diabetic cardiovascular dysfunction. 3-[2-(4-Bromo-phenyl)-1-methyl-2-oxo-ethyl]-4,5,6,7-tetrahydro-benzothiazol-3-ium bromide (C16), a novel AGE breaker, was investigated for its effects on the development of cardiovascular disease in diabetic rats. METHODS: Rats that had streptozotocin-induced diabetes for 12 weeks were divided into groups receiving C16 or vehicle by gavage. RESULTS: In hemodynamic studies of the left ventricle, C16 treatment (25 or 50 mg/kg) for 4 weeks resulted in a significant increase in left ventricular systolic pressure, +dp/dt(max), and -dp/dt(max) as compared with vehicle-treated diabetic rats. Furthermore, in hemodynamic studies of the cardiovascular system, C16 (12.5, 25, or 50 mg/kg) treatment for 4 weeks resulted in a dose-dependent and significant increase in cardiac output, a reduction of total peripheral resistance, and an increase in systemic arterial compliance when compared with vehicle-treated diabetic rats. Biochemical studies showed that C16 treatment also resulted in a significant decrease in immunoglobulin G-red blood cell surface crosslink content and an increase in collagen solubility. Morphological and immunohistochemical examinations indicated that C16 was able to prevent increases of the collagen type III/I ratio in the aorta and decrease the accumulation of AGE in the aorta. CONCLUSION: C16 has the ability to reduce AGE accumulation in tissues in vivo, and can restore diabetes-associated cardiovascular disorders in rats. This provides a potential therapeutic approach for cardiovascular disease associated with diabetes and aging in humans.

Animals↗
PubMed2005

Biochemistry and biomechanics of cell motility.

Cell motility is an essential cellular process for a variety of biological events. The process of cell migration requires the integration and coordination of complex biochemical and biomechanical signals. The protrusion force at the leading edge of a cell is generated by the cytoskeleton, and this force generation is controlled by multiple signaling cascades. The formation of new adhesions at the front and the release of adhesions at the rear involve the outside-in and inside-out signaling mediated by integrins and other adhesion receptors. The traction force generated by the cell on the extracellular matrix (ECM) regulates cell-ECM adhesions, and the counter force exerted by ECM on the cell drives the migration. The polarity of cell migration can be amplified and maintained by the feedback loop between the cytoskeleton and cell-ECM adhesions. Cell migration in three-dimensional ECM has characteristics distinct from that on two-dimensional ECM. The migration of cells is initiated and modulated by external chemical and mechanical factors, such as chemoattractants and the mechanical forces acting on the cells and ECM, as well as the surface density, distribution, topography, and rigidity of the ECM.

Actins↗
PubMed2005

In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells.

OBJECTIVE: To study irinotecan (CPT-11)-induced changes in expression profiles of genes associated with cell cycle control and apoptosis in myeloid leukemia cells in vitro and in vivo. METHODS: HL60 cells were exposed to clinically achievable concentrations of 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of CPT-11, and blood sampled from patients with acute myeloid leukemia and chronic myeloid leukemia in myeloid blast transformation treated with CPT-11. Gene expression changes were studied by cDNA microarray and correlated with biological responses by studying DNA distributions by flow cytometry. RESULTS: cDNA microarray analysis showed down-regulation and up-regulation of specific cell cycle-associated genes, consistent with loss of S-phase cells and temporary delay of G(1)-S-phase transition seen by flow cytometry. Flow cytometry showed that cells in S phase during SN-38 exposure underwent apoptosis, whereas cells in G(2)-M and G(1) were delayed in G(1) and entered S phase only 6 to 8 hours after drug removal, consistent with the observed changes in gene expression. Proapoptotic changes in gene transcription included down-regulation of antiapoptotic genes and up-regulation of proapoptotic genes. Many gene expression changes observed following in vitro SN-38 exposure were also seen following in vivo administration of 10 or 15 mg/m(2) CPT-11; notably, proapoptotic changes included reduced transcription of survivin pathway-associated genes and increased transcription of death receptor 5. CONCLUSION: CPT-11-induced changes in gene expression profiles in vitro and in vivo are consistent with temporary delay in G(1)-S transition and enhanced responsiveness to apoptosis, both of which may contribute to the synergistic interactions of this drug with antimetabolites.

Apoptosis↗
PubMed2005

Angiogenesis inhibitor Z24 induces endothelial cell apoptosis and suppresses tumor growth and metastasis.

Z24, a small molecular compound with similar chemical structure to SU5416 designed and synthesized by our lab, has been proved to be an angiogenesis inhibitor. In this study, Z24 was shown to induce human umbilical venous endothelial cell (HUVEC) apoptosis confirmed by morphologic changes including the presence of apoptotic bodies, significant apoptotic sub-G1 peak upon flow-cytometric analysis, formation of DNA ladders upon agarose gel electrophoresis, and TUNEL (TdT mediated X-dUTP nick-end labeling) results. Systemic administration of Z24 at non-toxic dose in nude mice resulted in inhibition of subcutaneous tumor growth of human colon cancer HCT-8, while it did not inhibit this cell line in vitro, with 100-fold more potent growth-inhibition against endothelial cells. The immunohistochemical results showed that the microvessel density of tumor tissue of the Z24 group was significantly lower than that of the control groups (P<0.05), which supported its anti-angiogenic property. We further found that Z24 inhibited the pulmonary metastasis of mouse lung adenocarcinoma LA795, with fewer surface lung metastases (89.6%, P<0.0001) and decreased lung weights (38.5%, P<0.01) compared to the vehicle group. All these findings support that Z24 is a promising angiogenesis inhibitor for limiting tumor growth and metastasis.

Angiogenesis Inhibitors↗
PubMed2005

Analysis of endothelial cell migration under flow.

The migration of endothelial cells (ECs) play an important role in embryonic vasculogenesis, angiogenesis, and post-angioplasty reendothelialization. ECs are constantly subjected to fluid shear stress (the tangential component of hemodynamic forces) from blood flow, but the effects of shear stress on EC migration have not been well characterized until recently. We have used an in vitro flow system to apply shear stress to EC cultures and used imaging and biochemical techniques to analyze EC migration under well-defined flow conditions. Time-lapse microscopy and cell tracing analysis generated quantitative information on EC migration under flow, and this assay was used to dissect the signaling events involved in shear stress-induced EC migration. By expressing green fluorescent protein-tagged molecules in EC, cell focal adhesions and cytoskeleton were visualized and quantified in living cells under flow, which provides temporal and spatial resolution for mechanotransduction at the molecular level. The studies on EC migration under flow will advance our understandings on vascular repair and remodeling in vivo, and provide a rational basis for the development of strategy to promote endothelialization and vascularization in tissue-engineered constructs.

Animals↗
PubMed2005

[Relationship of the genetic diversity within the V-region, P-region and C-terminus of surface protein of Streptococcus mutans to dental caries].

OBJECTIVE: To gain an understanding of the relationship between the genetic diversity within the V-region, P-region, C-terminus of surface protein of Streptococcus mutans (serotype c) and their adherent abilities. METHODS: The clinical isolates of S. mutans (serotype c) in two groups with different adherent abilities (cpm>2000, cpm<1000) had been prepared in our experimental laboratory. The genome DNA was extracted, and the spaP-pv (2060-3157 bp) and spaP-c (4003-4851 bp) were amplified by PCR, respectively. Genetic diversity was assessed by restriction fragment-length polymorphism (RFLP) with restriction endonucleases Alu I. RESULTS: (1) Two different patterns of spaP-pv RFLP among strains were revealed after the amplified product being digested with Alu I. The distributions of two genotypes (a and b) in the clinical strains with different adherent abilities differed significantly (P<0.05). The proportion of genotype b in the strains with higher adherent abilities was higher than that in the strains with lower adherent abilities. (2) Two different patterns (c and d) of spaP-c RFLP among strains were also revealed after the spaP-c being digested with Alu I. No statistically significant difference was observed in the distribution of the two genotypes in the clinical strains. CONCLUSION: The genetic diversity within spaP-pv of clinical isolates of S. mutans might be related to the differences of their adherent abilities.

Antigens, Surface↗