bluuebunny/crossref_metadata_2025 huggingface dataset:
Type 1 corticotropin-releasing factor receptors in the ventromedial hypothalamus promote hypoglycemia-induced hormonal counterregulation
Authors: Cheng Haiying , Zhou Ligang , Zhu Wanling , Wang Ajin , Tang Chuyan , Chan Owen , Sherwin Robert S. , McCrimmon Rory J.
Published: June 2007

Type 2 corticotropin-releasing factor (CRF) receptors (CRFR2) within the ventromedial hypothalamus (VMH), a key glucose-sensing region, play a major role in regulating the hormonal counterregulatory responses (CRRs) to acute hypoglycemia. The VMH expresses both subtypes of CRF receptors, CRFR1 and CRFR2. The objective of this study was to examine the role of the CRFR1 receptor in the VMH in the regulation of the CRR to acute hypoglycemia. To compare the hormonal CRR to hypoglycemia, awake and unrestrained Sprague-Dawley rats were bilaterally microinjected to the VMH with either 1) aECF, 2) CRF (1 pmol/side), 3) CRFR1 antagonist Antalarmin (500 pmol/side), or 4) CRF + Antalarmin prior to undergoing a hyperinsulinemic hypoglycemic (2.8 mM) clamp. A second series of studies also incorporated an infusion of [3H]glucose to allow the calculation of glucose dynamics. In addition the effect of CRFR1 antagonism in the paraventricular nucleus (PVN) was studied. Activation of VMH CRFR1 increased, whereas inhibition of CRFR1 suppressed hypoglycemia-induced CRRs. Inhibition of VMH CRFR1 also increased peripheral glucose utilization and reduced endogenous glucose production during hypoglycemia, whereas VMH CRF reduced peripheral glucose utilization. In contrast CRFR1 inhibition in the PVN blunted corticosterone but not epinephrine or glucagon CRR to hypoglycemia. In contrast to CRFR2 activation, CRFR1 activation within the VMH amplifies CRRs to acute hypoglycemia. The balance between these two opposing CRFRs in this key glucose-sensing region may play an important role in determining the magnitude of CRRs to acute hypoglycemia.
Age-induced hypercholesterolemia in the rat relates to reduced elimination but not increased intestinal absorption of cholesterol
Authors: Gälman Cecilia , Matasconi Manuela , Persson Lena , Parini Paolo , Angelin Bo , Rudling Mats
Published: June 2007

Plasma cholesterol increases in normal aging in both rodents and humans. This is associated with reduced elimination of cholesterol as bile acids (BAs) and decreased receptor-mediated clearance of plasma LDL, changes that can be reversed by treatment with growth hormone (GH). The level of intestinal absorption of cholesterol may also contribute to the development of hypercholesterolemia. In this study, we investigated whether cholesterol absorption increases with age and whether any such age-related change could be influenced by treatment with GH or ezetimibe (EZE). Male rats aged 6 and 18 mo were studied with and without GH or EZE treatment. BA synthesis was reduced and plasma cholesterol was increased in the old animals, whereas cholesterol absorption was unaltered. Cholesterol absorption was not altered by GH treatment but was reduced by EZE in both groups of animals. Hepatic LDL receptors (LDLRs), scavenger receptor class B type 1, and proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) transcripts were unchanged in old animals. GH treatment induced LDLRs, PCSK9 transcripts, and BA synthesis. We conclude that the age-induced hypercholesterolemia in the rat and its reversal by GH treatment relates to altered degradation of cholesterol in the liver and is not due to changes in cholesterol absorption.
Unacylated ghrelin acts as a potent insulin secretagogue in glucose-stimulated conditions
Authors: Gauna Carlotta , Kiewiet Rosalie M. , Janssen Joop A. M. J. L. , van de Zande Bedette , Delhanty Patric J. D. , Ghigo Ezio , Hofland Leo J. , Themmen Axel P. N. , van der Lely Aart Jan
Published: June 2007

Acylated and unacylated ghrelin (AG and UAG) are gut hormones that exert pleiotropic actions, including regulation of insulin secretion and glucose metabolism. In this study, we investigated whether AG and UAG differentially regulate portal and systemic insulin levels after a glucose load. We studied the effects of the administration of AG (30 nmol/kg), UAG (3 and 30 nmol/kg), the ghrelin receptor antagonist [d-Lys3]GHRP-6 (1 μmol/kg), or various combinations of these compounds on portal and systemic levels of glucose and insulin after an intravenous glucose tolerance test (IVGTT, d-glucose 1 g/kg) in anesthetized fasted Wistar rats. UAG administration potently and dose-dependently enhanced the rise of insulin concentration induced by IVGTT in the portal and, to a lesser extent, the systemic circulation. This UAG-induced effect was completely blocked by the coadministration of exogenous AG at equimolar concentrations. Similarly to UAG, [d-Lys3]GHRP-6, alone or in combination with AG and UAG, strongly enhanced the portal insulin response to IVGTT, whereas exogenous AG alone did not exert any further effect. Our data demonstrate that, in glucose-stimulated conditions, exogenous UAG acts as a potent insulin secretagogue, whereas endogenous AG exerts a maximal tonic inhibition on glucose-induced insulin release.
Ectopic expression of Wnt10b decreases adiposity and improves glucose homeostasis in obese rats
Authors: Aslanidi George , Kroutov Vadim , Philipsberg Glenn , Lamb Kenneth , Campbell-Thompson Martha , Walter Glenn A. , Kurenov Sergei , Ignacio Aguirre J. , Keller Pernille , Hankenson Kurt , MacDougald Ormond A. , Zolotukhin Sergei
Published: June 2007

The Wnt family of secreted glycoproteins had previously been shown to regulate diverse processes during early development. Wnt signaling also plays a key role in the homeostasis of adult tissues maintaining stem cell pluripotency and determining differentiating cell fate. The age-related decrease in Wnt signaling may contribute to increased muscle adiposity and diminished bone strength. In the current study, we investigated the long-term metabolic consequences of the upregulated Wnt/β-catenin signaling in skeletal muscles of adult diet-induced obese (DIO) rats. To this end, we generated a recombinant adeno-associated virus (rAAV) vector encoding murine Wnt10b cDNA. The long-term expression of rAAV1-Wnt10b was tested after intramuscular injection in the female DIO rat. Animals fed high-fat diet and treated with rAAV1-Wnt10b showed a sustained reduction in body weight compared with controls, and expression of Wnt10b was accompanied by a reduction in hyperinsulinemia and triglyceride plasma levels as well as improved glucose homeostasis. Nuclear magnetic resonance methods revealed that ectopic expression of Wnt10b resulted in a decrease in both global and muscular fat deposits in DIO rats. The long-range effect of locally expressed Wnt10b was also manifested through the increased bone mineral density. The detailed analysis of molecular markers revealed fibroblast growth factor-4 and vascular endothelial growth factor as possible mediators of the systemic effect of Wnt10b transgene expression. Our data demonstrate that altering Wnt/β-catenin signaling in the skeletal muscle of an adult animal invokes moderate responses with favorable metabolic profile, bringing the notion of alternative therapeutic modality in the treatment of obesity, diabetes, and osteoporosis.
Effect of statin and angiotensin-converting enzyme inhibition on structural and hemodynamic alterations in autosomal dominant polycystic kidney disease model
Authors: Zafar Iram , Tao Yunxia , Falk Sandor , McFann Kimberly , Schrier Robert W. , Edelstein Charles L.
Published: June 2007

Autosomal dominant polycystic kidney disease (ADPKD) is the most common life-threatening hereditary disease and is the fourth most common cause of end-stage kidney disease. Preclinical studies to identify effective interventions to prevent or slow progression of PKD nephropathy are therefore direly needed. Heterozygous Han:SPRD rats are an autosomal dominant PKD model with many of the characteristics of ADPKD in humans. In the present study, parameters known to antedate the decrease in renal function, namely, renal structure, renal blood flow (RBF), and mean arterial pressure (MAP), were evaluated with three different interventions, namely, HMG-CoA reductase inhibition with lovastatin, angiotensin-converting enzyme (ACE) inhibition with enalapril, and a combination of these two treatments. The statin therapy demonstrated structural and functional benefits, including increased RBF and decreased BUN, independently of a change in MAP, while the ACE inhibition therapy demonstrated structural benefit in association with a decrease in MAP. An enhancement of these protective interventions in this autosomal dominant PKD model was not demonstrated with the combined treatment.
Distinct profiles of expressed sequence tags during intestinal regeneration in the sea cucumberHolothuria glaberrima
Authors: Rojas-Cartagena Carmencita , Ortíz-Pineda Pablo , Ramírez-Gómez Francisco , Suárez-Castillo Edna C. , Matos-Cruz Vanessa , Rodríguez Carlos , Ortíz-Zuazaga Humberto , García-Arrarás José E.
Published: June 2007

Repair and regeneration are key processes for tissue maintenance, and their disruption may lead to disease states. Little is known about the molecular mechanisms that underline the repair and regeneration of the digestive tract. The sea cucumber Holothuria glaberrima represents an excellent model to dissect and characterize the molecular events during intestinal regeneration. To study the gene expression profile, cDNA libraries were constructed from normal, 3-day, and 7-day regenerating intestines of H. glaberrima. Clones were randomly sequenced and queried against the nonredundant protein database at the National Center for Biotechnology Information. RT-PCR analyses were made of several genes to determine their expression profile during intestinal regeneration. A total of 5,173 sequences from three cDNA libraries were obtained. About 46.2, 35.6, and 26.2% of the sequences for the normal, 3-days, and 7-days cDNA libraries, respectively, shared significant similarity with known sequences in the protein database of GenBank but only present 10% of similarity among them. Analysis of the libraries in terms of functional processes, protein domains, and most common sequences suggests that a differential expression profile is taking place during the regeneration process. Further examination of the expressed sequence tag dataset revealed that 12 putative genes are differentially expressed at significant level ( R > 6). Experimental validation by RT-PCR analysis reveals that at least three genes (unknown C-4677-1, melanotransferrin, and centaurin) present a differential expression during regeneration. These findings strongly suggest that the gene expression profile varies among regeneration stages and provide evidence for the existence of differential gene expression.
Association of CA repeat polymorphism at intron 1 of insulin-like growth factor (IGF-I) gene with circulating IGF-I concentration, growth, and fatness in swine
Authors: Estany Joan , Tor Marc , Villalba Daniel , Bosch Lluís , Gallardo David , Jiménez Neus , Altet Laura , Noguera Jose L. , Reixach Josep , Amills Marcel , Sánchez Armand
Published: June 2007

Evidence is accumulating that intronic polymorphic cytosine-adenosine (CA) repeats may play a role in gene expression. In this work, we investigated whether a polymorphic CA short tandem repeat (STR) located at the first intron of the pig insulin-like growth factor I (IGF-I) gene influences plasma IGF-I concentration in pigs as well as phenotypic variation in growth and fatness traits. We measured plasma IGF-I levels at one to four time points from 35 to 215 days of age in 340 performance-tested Landrace and Duroc pigs previously genotyped for the IGF-I STR. Data were analyzed within breed with a linear mixed model with the number of CA repeats as a covariate. At least five alleles were segregating in each breed, differing in one to seven repeats. The results showed that in each breed, circulating IGF-I at 160 days of age increased with the length of the shortest allele, accounting for an average trend of 4.38 ± 1.28 ng/ml of IGF-I per additional repeat ( P = 0.001). Longer repeats were associated with early growth in Landrace boars (1.92 ± 0.92 kg per CA at 160 days; P = 0.038) and with back fat thickness (−0.57 ± 0.20 mm per CA; P = 0.005) and lean content (7.52 ± 3.00 g/kg per CA at 105 kg; P = 0.013) adjusted for carcass weight in Duroc barrows, as expected from the effect of circulating IGF-I on these traits. The consistency of the results across populations supports the hypothesis that the length of the CA repeats at intron 1 of the IGF-I gene is associated with circulating IGF-I levels, and that this effect is not neutral with respect to growth and fatness.
Mesenchymal to Epithelial Transition in Development and Disease
Authors: Chaffer Christine L. , Thompson Erik W. , Williams Elizabeth D.
Published: June 2007

Cellular plasticity is fundamental to embryonic development. The importance of cellular transitions in development is first apparent during gastrulation when the process of epithelial to mesenchymal transition transforms polarized epithelial cells into migratory mesenchymal cells that constitute the embryonic and extraembryonic mesoderm. It is now widely accepted that this developmental pathway is exploited in various disease states, including cancer progression. The loss of epithelial characteristics and the acquisition of a mesenchymal-like migratory phenotype are crucial to the development of invasive carcinoma and metastasis. However, given the morphological similarities between primary tumour and metastatic lesions, it is likely that tumour cells re-activate certain epithelial properties through a mesenchymal to epithelial transition (MET) at the secondary site, although this is yet to be proven. MET is also an essential developmental process and has been extensively studied in kidney organogenesis and somitogenesis. In this review we describe the process of MET, highlight important mediators, and discuss their implication in the context of cancer progression.
A Human Three-Dimensional Cell Line Model Allows the Study of Dynamic and Reversible Epithelial-Mesenchymal and Mesenchymal-Epithelial Transition That Underpins Colorectal Carcinogenesis
Authors: Vincan Elizabeth , Brabletz Thomas , Faux Maree C. , Ramsay Robert G.
Published: June 2007

Developmental morphogenesis relies on cell transitions between epithelial and mesenchymal states. Colorectal cancer (CRC) progression can also be described as ‘morphogenesis’ as it involves epithelial-mesenchymal transition (EMT), whereby tumour cells become more invasive and metastatic. Subsequently, the disseminated tumour cells must undergo a reverse transition (MET), as the pathology of most primary tumours is re-capitulated by their established metastases. Disseminated tumour cells can remain ‘dormant’ for many years. Consequently, tumour initiation at the secondary site is the rate-limiting step in metastasis. Metastasis is governed by cell intrinsic and extrinsic (microenvironment) factors, thus much of what we know about metastasis is drawn from in vivo model systems. However, the molecular mechanisms controlling release from ‘dormancy’ are still largely unknown due to the complexity this presents for the in vivo situation. An in vitro morphogenesis culture system would present a great advantage. To this end, we have established a unique model of CRC morphogenesis, using a variant of the human cell line LIM1863 (LIM1863-Mph). In this model system LIM1863-Mph cells show plasticity between epithelial and mesenchymal states. The transitions are reversible and bear the phenotypic hallmarks of CRC morphogenesis. Importantly, we have demonstrated a pivotal role for FZD7 in these phenotype transitions, implicating Wnt signalling in orchestrating CRC morphogenesis.
Epithelial-Mesenchymal Transition in Rhesus Monkey Embryonic Stem Cell Colonies: A Model for Processes Involved in Gastrulation?
Authors: Denker Hans-Werner , Behr Rüdiger , Heneweer Carola , Viebahn Christoph , Thie Michael
Published: June 2007

A characteristic feature of embryonic stem (ES) cells is their ability to give rise to differentiated cell types that are derived from all three primary germ layers. In the embryo of higher vertebrates, formation of mesoderm and definitive endoderm (gastrulation) occurs at the primitive streak through a spatially highly ordered process of cell ingression, combined with epithelial-mesenchymal transition (EMT). With respect to ES cell differentiation in vitro, however, germ layer derivative formation has not been studied in much detail, and data on any degree of spatial order that may be attained here are lacking. In the investigations to be reviewed here, rhesus monkey ES cells (line R366.4) were grown on mouse embryonic fibroblast feeder layers for up to 10 days during which time they formed multilayered disc-like colonies with an upper epithelial and a lower mesenchymal cell layer. Processes of epithelialization as well as EMT were studied by transmission electron microscopy, immunohistochemistry combined with confocal laser scanning microscopy, and marker mRNA expression (in situ hybridization, RT-PCR). It was found that under the culture conditions used most of the ES cell colonies developed transitorily a central pit where the epithelial upper layer cells underwent an EMT-like process and appeared to ingress to form the lower, mesenchymal layer, accompanied by appropriate changes of morphology and molecular markers. Similarities and differences in comparison with gastrulation/primitive streak formation in vivo are briefly discussed, as are ethical implications with respect to human ES cells. It is concluded that this rhesus ES cell colony system may be an interesting in vitro model for studies on some basic processes involved in early embryogenesis such as EMT/gastrulation and may open new ways to study the regulation of these processes experimentally in vitro in nonhuman primates.
Nuclear Localization Signals of the E-Cadherin Transcriptional Repressor Snail
Authors: Ko Hyeonseok , Kim Hyun Sil , Kim Nam Hee , Lee Sang Hwy , Kim Kun Hong , Hong Su Hyung , Yook Jong In
Published: June 2007

The E-cadherin transcriptional repressor, Snail, plays a critical role in driving the epithelial-mesenchymal transition programs that mark gastrulation as well as invasion of cancer cells. Recent data suggest that Snail is phosphorylated by GSK3-β, resulting in β-TRCP-mediated ubiquitination and proteasomal degradation. Accordingly, Wnt signaling inhibits Snail phosphorylation, and consequently increases Snail protein levels. In the present study, we examine the function of nuclear localization motifs embedded within the Snail sequence. A typical bipartite nuclear localization signal (NLS) motif is located at the N-terminal of Snail, where it overlaps with the SNAG domain (residues 8–16), while a basic cluster NLS motif is found proximal to zinc finger domains (residues 151–152). Mutational inactivation of these NLS signals resulted in decreased levels of nuclear and total Snail protein as well as attenuated Snail repressor activity on an E-cadherin promoter construct, suggesting that NLS motifs are essential for proper function. In the presence of GSK3 inhibitor LiCl, the cytoplasmic levels of the NLS mutants increased, suggesting that cytosolic Snail undergoes rapid phosphorylation and degradation. Given the highly conserved nature of the Snail NLS motifs (from Xenopus to human), these results indicate that nuclear localization signals regulate Snail expression and subcellular localization via GSK3-β-dependent phosphorylation.
Rho Proteins and Cell-Matrix Interactions in Cancer
Authors: Wu Mei , Wu Zhi-fen , Merajver Sofia D.
Published: June 2007

Dynamic interactions and dissolution of cell-extracellular matrix contacts are required steps to support cell growth and survival during cancer cell metastasis. Malignant cells acquire the ability to remodel extracellular matrix (ECM) and to modulate the expression of ECM receptors. Integrins are cellular receptors for molecules in the extracellular matrix. Integrin signaling is known to regulate metastatic cancer phenotypes by interacting synergistically with several signaling pathways, including the growth factor receptor pathway, the Ras-MAP kinase (Ras-MAPK) pathway and the Rho-effector pathway. In this mini-review, we discuss the functions of the Rho proteins and their relationship with other signaling pathways in matrix remodeling and integrin signaling of highly motile and invasive cancer cells.
Matrix Metalloproteinase-Induced Malignancy in Mammary Epithelial Cells
Authors: Stallings-Mann Melody , Radisky Derek
Published: June 2007

In development, epithelial-mesenchymal transition (EMT) allows interconnected sheets of epithelial cells to reorganize and to pass into and through the surrounding extracellular matrix (ECM). In cancer, EMT-associated processes facilitate invasive growth and development of metastases. Matrix metalloproteinases (MMPs) are enzymes capable of degrading the ECM and altering cell-cell and cell-ECM interactions. MMPs are upregulated in nearly all tumor types, have been shown to induce EMT in cultured cells, and are involved in the development of tumor formation, invasion, and metastasis. We have identified the induction of Rac1b, an alternatively spliced variant of Rac1, as a key event in MMP-induced EMT. Induction of the Rac1b isoform leads to increased cellular reactive oxygen species (ROS), which causes in turn upregulation of Snail, a transcription factor previously implicated in physiological and pathological EMT. MMP/Rac1b-induced ROS also causes DNA damage and induces genomic instability. These findings reveal a new pathway in which a key element of the tumor microenvironment directly stimulates the phenotypic and genotypic alterations involved in malignant transformation, and provides many opportunities for investigation of therapeutic interventions.
Epithelial-Mesenchymal Transition in Prostate Cancer and the Potential Role of Kallikrein Serine Proteases
Authors: Lawrence Mitchell G. , Veveris-Lowe Tara L. , Whitbread Astrid K. , Nicol David L. , Clements Judith A.
Published: June 2007

Prostate cancer is associated with significant mortality once the tumour has spread outside the gland. Epithelial-mesenchymal transition (EMT) has been proposed to facilitate this dissemination of tumour cells. In this article we summarize the evidence for EMT in prostate cancer, drawing on the expression of EMT-related markers and the functions of factors known to induce EMT in other systems. We also discuss our recent findings that two members of the tissue kallikrein family of serine proteases, prostate-specific antigen (PSA/KLK3) and kallikrein-related peptidase 4 (KLK4), lead to EMT-like changes in PC3 prostate cancer cells.
Smad4-Independent TGF-β Signaling in Tumor Cell Migration
Authors: Giehl Klaudia , Imamichi Yukiko , Menke Andre
Published: June 2007

Transforming growth factor-β (TGF-β) belongs to a family of multifunctional growth factors that participates in the regulation of a variety of cellular activities. Beside induction of growth inhibition and differentiation of epithelial cells, TGF-β has been shown to promote epithelial-mesenchymal transition in most epithelial tumors. While inhibition of epithelial cell proliferation in response to TGF-β is mainly mediated by the well-characterized Smad pathway and subsequent inhibition of gene transcription, the molecular mechanism leading to TGF-β-induced invasiveness and metastasis of epithelial tumors is less clear. Recent results from several groups suggest that the induction of tumorigenic activity by TGF-β includes not only signaling by Smads, but also by Rho-GTPases and mitogen-activated protein kinases (MAP kinases). Activation of the MAP kinases extracellular signal-regulated kinases (ERK) 1 and 2 as well as c-jun N-terminal kinase (JNK) has been identified as important steps in TGF-β-induced, Smad4-independent signal transduction in epithelial cells. Recent results identify a role of activated ERK and JNK and their association with focal complexes in TGF-β-induced, Smad4-independent cell migration of breast carcinoma cells, and are reviewed here.
Transforming Growth Factor-β and microRNA:mRNA Regulatory Networks in Epithelial Plasticity
Authors: Zavadil Jiri , Narasimhan Manisha , Blumenberg Miroslav , Schneider Robert J.
Published: June 2007

Noncoding microRNAs act as posttranscriptional repressors of gene function and are often deregulated in cancers and other diseases. Here we review recent findings on microRNA roles in tumorigenesis and report a microRNA profiling screen in transforming growth factor-β1 (TGF-β)-induced epithelial-mesenchymal transition (EMT) in human keratinocytes, a model of epithelial cell plasticity underlying epidermal injury and skin carcinogenesis. We describe a novel EMT-specific microRNA signature that includes induction of miR-21, a candidate oncogenic microRNA associated with carcinogenesis. By integrating the microRNA screen results with target prediction algorithms and gene expression profiling data, we outline a framework for TGF-β-directed microRNA:messenger RNA (mRNA) regulatory circuitry and discuss its biological relevance for tumor progression.
Chromatin Structure Regulation in Transforming Growth Factor-β-Directed Epithelial-Mesenchymal Transition
Authors: Blumenberg Miroslav , Gao Shujuan , Dickman Kathleen , Grollman Arthur P. , Bottinger Erwin P. , Zavadil Jiri
Published: June 2007

Epithelial-mesenchymal transitions (EMTs) occur in organogenesis throughout embryonic development and are recapitulated during epithelial tissue injury and in carcinoma progression. EMTs are regulated by complex, precisely orchestrated cell signaling and gene expression networks, with the participation of key developmental pathways. Here we review context-dependent modules of gene regulation by hairy/enhancer-of-split-related (H/E(spl)) repressors downstream of transforming growth factor-β (TGF-β)/Smad and Notch signals in EMT and in other phenotype transitions such as differentiation and cancer. Based on multiple models of disease-related EMT, we propose that Polycomb group epigenetic silencers and histone-lysine methyl-transferases EZH1 and EZH2 are candidate targets of H/E(spl)-mediated transcriptional repression, in a process accompanied by replacement of modified core histone H3 with de novo synthesized histone variant H3.3B. Finally, we discuss the potential significance of this scenario for EMT in the light of recent findings on gene regulation by histone modifications and chromatin structure changes.
Posttranslational Truncation of E-Cadherin and Significance for Tumour Progression
Authors: Masterson Joanne , O’Dea Shirley
Published: June 2007

Stable intraepithelial adhesion complexes are essential for the maintenance of epithelial integrity. Alterations in these complexes are key events in the development and progression of many diseases. One of the major proteins involved in maintaining epithelial cell-cell adhesion is the cell-adhesion junction protein E-cadherin, a member of the cadherin family of transmembrane adhesion proteins. E-cadherin is involved in many cellular processes including morphogenesis, adhesion, recognition, communication and oncogenesis. Inactivation of its adhesive properties is often a key step in tumour progression and metastasis, leading to its recent description as a tumour suppressor gene. Mutations of the E-cadherin gene CDH1 in gastric and mammary cancers have been well documented and reports of transcriptional repression during tumour progression are increasing. This review examines the role of posttranslational truncation of E-cadherin in cancer cells focusing on implications for tumour progression. The various proteins involved in the directed cleavage of E-cadherin and consequences of these truncations are discussed.
Signaling Pathways Involved in Collagen-Induced Disruption of the E-Cadherin Complex during Epithelial-Mesenchymal Transition
Authors: Imamichi Yukiko , Menke Andre
Published: June 2007

There is substantial interest in the influence of the microenvironment on tumor cells. Cell-cell as well as cell-matrix interactions have been correlated with the control of different processes such as tumor cell proliferation, differentiation, survival and migration. In this review, we focus on the influence of collagen types I and III expressed in carcinomata on the E-cadherin-mediated adhesion between epithelial tumor cells. Recently published studies described the ability of fibrillar collagen to reduce E-cadherin gene expression and to induce disruption of the E-cadherin adhesion complex. The reduced cellular adhesion influences tissue integrity and has been correlated with elevated cell migration and invasion of different carcinoma cells. Altered tyrosine phosphorylation of the intracellular, cadherin-associated catenins was identified as an important regulator of collagen-induced disassembly of the E-cadherin adhesion complex. The molecular mechanisms involved in collagen-induced cell transformation include activation of integrins, activation and translocation of the focal adhesion kinase to the E-cadherin/catenin complex as well as inhibition of the phosphatase PTEN.
Analysis of the E-Cadherin Repressor Snail in Primary Human Cancers
Authors: Becker K.-F. , Rosivatz E. , Blechschmidt K. , Kremmer E. , Sarbia M. , Höfler H.
Published: June 2007

Epithelial-mesenchymal transition (EMT), a normal developmental process, is known to play a crucial role in tumor progression. Molecules involved in this process, such as the E-cadherin repressor Snail, facilitate migration and invasion of carcinoma cells. A growing number of studies addressing the expression of Snail in clinical samples have been reported and are discussed in this review. A total of 2,112 cases from 9 different tumor types were evaluated. So far, a clear picture has emerged only in some cancer types analyzed with regard to overexpression of Snail and clinical-pathological parameters. Currently, it seems that Snail may play a role in hormone-dependent carcinomas but may be of minor importance in gastrointestinal cancers for tumor dedifferentiation and the maintenance of the invasive phenotype. It should be kept in mind, however, that the threshold for Snail activity does not have to be the same in every tumor type analyzed. The recent introduction of well-characterized novel monoclonal antibodies reacting with the short-lived nuclear Snail protein may help to establish a potential clinical usefulness for this master molecule of EMT, at least for certain types of cancer.
PRL-3: A Metastasis-Associated Phosphatase in Search of a Function
Authors: Bessette Darrell C. , Wong Patrick C.W. , Pallen Catherine J.
Published: June 2007

The molecular and cellular events involved in cancer progression and metastasis remain much less well-defined than those involved in oncogenesis, despite the fact that cell metastasis is the major factor in cancer mortality. Thus, the discovery that the expression of a protein tyrosine phosphatase, protein of regenerating liver-3 (PRL-3), is upregulated in colon cancer metastases provided an exciting indication that the altered regulation of specific protein tyrosine phosphorylation events and signaling pathways might characterize these metastatic cells and/or be key in promoting the tumor-to-metastasis transition in this, and perhaps other, cancers of epithelial origin. However, the cellular substrate(s) of PRL-3 has not been identified, and little is known of PRL-3-mediated cellular signaling pathways. This review illustrates the significance of PRL-3 in promoting metastasis and the importance of determining the endogenous role of PRL-3.
Radiotherapy for Localized Orbital Mucosa-Associated Lymphoid Tissue Lymphoma
Authors: Monzen Yoshio , Hasebe Haruyuki
Published: June 2007

Fourteen patients with localized orbital mucosa-associated lymphoid tissue lymphoma diagnosed between 1998 and 2005 were reviewed. Five patients were males and 9 were females, with a mean age of 58 years. In 8 patients, the disease arose from the conjunctiva, and in 6 patients, it originated from the retrobulbar space. Patients were treated with radiotherapy alone at a dose range from 30 to 54 Gy. All patients with conjunctival lymphoma achieved complete remission (CR). Four patients with retrobulbar lymphoma obtained CR, and unconfirmed CR (CRu) was observed in 2 cases. Orbital extraconal lymphoma disappeared. However, intraconal cord-like tumor and mass involving the medial extraocular muscle remained with the absence of regrowth over the long term. There have been very few reports discussing the histology of residual mass after radiotherapy. Residual mass was suggested to be reactive lymphoid hyperplasia. As a dose of more than 40 Gy induced dry eye syndrome or cataract, the dose must not exceed 40 Gy in order to achieve safe treatment of orbital mucosa-associated lymphoid tissue lymphoma.
Epidermal Growth Factor Receptor in Cultured Human Retinal Pigment Epithelial Cells
Authors: Yan Feng , Hui Yan-nian , Li Yang-jun , Guo Chang-mei , Meng Hao
Published: June 2007

Background: Migration and proliferation of retinal pigment epithelial (RPE) cells play an important role in proliferative vitreoretinopathy. Epidermal growth factor receptor (EGFR) is a cell surface receptor with intrinsic tyrosine kinase activity. The engagement of the receptor by its ligand can induce intracellular mitogenic signal transduction pathways and stimulate proliferation, migration and differentiation of cells. This experiment aimed to investigate the activation and role of EGFR signal transduction pathway in proliferation of human RPE cells. Methods: Cultured human RPE cells of the 3rd to 6th passages were studied by colorimetric assay for cellular growth and survival (MTT assay) to test the effects of EGF (0.1, 1, 10, 50, and 100 ng/ml) and fetal bovine serum (FBS) on proliferation of human RPE cells. An in vitro wound healing model was also set up, and the number of cells that had entered the denuded area was counted. The human RPE cells were cultured for 3 days with 0.1% FBS, 10% FBS, 10 ng/ml EGF + 0.1% FBS and a combination of EGF and 10% FBS, respectively. Immunohistochemical staining and in situ hybridization were used to observe the expressions of EGFR protein and mRNA, respectively. Activation of mitogen-activated protein kinase (MAPK) was detected by immunohistochemical method with specific antiphosphorylated extracellular signal-regulated kinase (ERK)1/2 antibody. Results: EGF stimulated proliferation and migration of cultured human RPE cells in a concentration-dependent manner. The maximum of the proliferation rate of RPE cells was 81.8% with EGF at a concentration of 10–100 ng/ml of EGF in serum-free Dulbecco’s modified essential medium (DMEM) and 122.7% at a concentration of 1–10 ng/ml of EGF in 5% FBS DMEM (p < 0.001); there was a significant difference between serum-free DMEM groups and 5% FBS DMEM groups. The maximum of the migration rate of the cells was 438.9% at a concentration of 10–100 ng/ml of EGF in 10% FBS DMEM, 147% with 10% FBS, and only 36% with EGF in 0.1% FBS at the concentration of 10 ng/ml (p < 0.001). EGF promoted the expression of EGFR protein and mRNA in RPE cells. FBS cooperated with EGF in the stimulation of EGFR expression, and it had a stronger effect in the process than EGF alone. After 3 days of incubation with EGF, phosphorylated ERK1/2 was detectable in the nucleus of RPE cells, whereas cells presented immunostaining positive for phosphorylated ERK1/2 in the cytoplasm before stimulation, indicating that EGF could induce MAPK nuclear translocation. Conclusion: EGF could induce EGF-EGFR-MAPK signal transduction pathway in human RPE cells in a concentration-dependent manner in vitro, which may play a key role in the activation of human RPE cell proliferation and migration.
Traumatic Pediatric Retinal Detachment following Open Globe Injury
Authors: Wang Nan-Kai , Chen Yen-Po , Yeung Ling , Chen Kuan-Jen , Chao An-Ning , Kuo Ya-Hui , Lee Jiahn-Shing , Lai Chi-Chun
Published: June 2007

Purpose: It was the aim of this study to describe the clinical features and surgical outcomes of retinal detachment following open globe injuries in a pediatric population. Methods: The study was a retrospective chart review of 33 children who had undergone surgery for retinal detachment after open globe injury. Results: The mean age was 11 years (range 4–18) and the mean follow-up period was 57.1 months (range 6–204). Twenty-five patients (76%) were males. Of the open globe injuries, 21 (64%) were penetrations, 6 (18%) intraocular foreign bodies, and 6 (18%) ruptures. Eighteen retinal detachments (55%) were identified by B-scan. Eighteen eyes (55%) had total retinal detachment and 23 eyes (70%) showed macular involvement. Twenty-one eyes (64%) presented with proliferative vitreoretinopathy (PVR) grade C or worse. Retinal reattachment was successful in 12 eyes (36%). Best-corrected visual acuity of 20/100 or better was noted in 4 eyes (12%) preoperatively and in 12 eyes (35%) postoperatively. Features seen in patients with a poor surgical outcome included undetermined or light perception only preoperative vision (p = 0.012), diagnosis by B-scan (p = 0.003), the presence of PVR grade C or worse (p = 0.001), total retinal detachment (p = 0.001), and macula-off status (p = 0.016). Conclusions: Our findings suggest that retinal detachment caused by open globe injuries in the pediatric population is associated with worse surgical results and unsatisfied visual outcomes. Early vitrectomy, before a diagnosis of retinal detachment is made by serial echographic examinations, may be considered to reduce the incidence of PVR. Further clinical research is required to identify ways to improve the outcomes for these patients.
Tear Function and Ocular Surface Changes in Multinodular Goiter Patients
Authors: Cavusoglu Turgut , Nurozler Ayse Burcu , Titiz Cengiz , Ustun Huseyin , Aral Yalcın , Ozer Elif , Kasim Remzi , Tezel Savas
Published: June 2007

Aims: To evaluate preoperative and postoperative conjunctival surface changes in multinodular goiter (MNG) patients and to compare their results with healthy control subjects. Methods: Twenty MNG patients who had undergone near total thyroidectomy were evaluated pre- and postoperatively at the end of the 3rd month and the 1st year by performing tear function tests and conjunctival impression cytologic analysis. These results were compared with the results of 15 healthy volunteers. Results: When preoperative and postoperative tear function parameters were compared, the mean Schirmer test value and BUT value were decreased, the mean Rose Bengal staining score was increased during the postoperative period. These differences were statistically significant at the end of the 1st year (p < 0.001). The average goblet cell density of the MNG patients decreased significantly during the postoperative period when compared with the preoperative values (p < 0.001). All these findings of the MNG cases were significantly different from the results of the control group both before and after the operation. Conclusion: Tear function tests and the impression cytology findings of the MNG cases were statistically different from the results of the control group during the pre- and postoperative period. We recommend postoperative follow-up of these patients for ocular surface changes.
Incipient Diabetic Retinopathy – Insights from an Experimental Model
Authors: Feng Yuxi , vom Hagen Franziska , Lin Jihong , Hammes Hans-Peter
Published: June 2007

Vascular complications of chronic hyperglycemia including diabetic retinopathy are an increasing therapeutic and socioeconomic challenge. The epidemiology of diabetic eye disease has been well described, and there is as yet no clear indication for a reduction of incidence of blindness. Due to the complex multifactorial nature of the damage to diabetic vessels, it had been difficult to identify key targets for treatment and prevention. Novel techniques to study molecules and mechanisms involved in retinal vessel development and vascular cell interactions improved the understanding of retinal cell biology and pathobiology. A unifying concept has been proposed which links hyperglycemia-induced mitochondrial overproduction of reactive oxygen species with long-known biochemical alterations such as the formation of advanced glycation end products or the activation of the protein kinase C pathway. Specific inhibitors were identified that inhibited multiple biochemical abnormalities downstream of oxidative stress induced by high glucose.
Clinical Relevance of Nerve Growth Factor Serum Levels in Patients with Atopic Dermatitis and Psoriasis
Authors: Schulte-Herbrüggen O. , Fölster-Holst R. , von Elstermann M. , Augustin M. , Hellweg R.
Published: June 2007

Background: Nerve growth factor (NGF) is known to act as a potent mediator in neuroinflammatory processes. Recent studies point to a role of NGF in the skin pathophysiology of atopic dermatitis (AD) and psoriasis. Hereby, NGF was found to interact with the major cellular components (mast cells and eosinophils) of both skin diseases. Objectives: In order to investigate NGF serum levels as a possible clinical marker of disease activity and immunological status, we determined serum NGF, eosinophil cationic protein (ECP), total IgE and score of AD (SCORAD) in 57 patients with AD as well as NGF and the psoriasis area and severity index (PASI) in 17 patients with psoriasis. Fifty healthy subjects served as controls. Methods: We used a highly sensitive improved fluorometric two-site ELISA system for serum NGF detection. IgE and ECP were measured by CAP-FEIA and radioimmunoassay. Results: We did not find a significant correlation between NGF and either ECP, total IgE, or severity of disease assessed by SCORAD. Also in patients with psoriasis, there was no significant correlation with disease activity determined by PASI. Conclusion: Even though there is increasing evidence showing NGF to be involved in the local inflammatory pathophysiology of AD within skin lesions, our findings suggest that NGF systemic serum concentration is not a suitable parameter to estimate the clinical or immunological status of AD or psoriasis patients. This result is inconsistent with some previous studies showing a positive correlation of serum NGF with AD severity, which might be, for example, due to the fact that the present results are corrected for unspecific binding.
Plasminogen Activator Inhibitor-1 Plasma Concentration in Allergic Asthma Patients during Allergen Challenge
Authors: Kowal Krzysztof , Bodzenta-Lukaszyk Anna , Pampuch Agnieszka , Szmitkowski Maciej , Donati Maria Benedetta , Iacoviello Licia
Published: June 2007

Background: The –675 4G/5G plasminogen activator inhibitor-1 (PAI-1) polymorphism is linked with asthma and bronchial hyperreactivity. The aim of this study was to evaluate the effect of allergen challenge on plasma PAI-1 concentration in relation to the –675 4G/5G PAI-1 gene polymorphism in house dust mite-allergic asthma patients (HDM-AAs). Materials and Methods: The study was performed in 54 HDM-AAs and 54 healthy nonatopic controls (HCs). Plasma samples were collected in HDM-AAs before, as well as 30 min, 6 h and 24 h after allergen challenge and at corresponding time points in sham-challenged HCs. Results: In subjects carrying the individual PAI-1 genotype, the mean baseline plasma PAI-1 concentration was greater in HDM-AAs than in HCs. At 30 min the mean increase in plasma PAI-1 concentration was significantly greater in HDM-AAs (14.4 ± 12.9 ng/ml) than in HCs (3.4 ± 3.2 ng/ml; p < 0.001). At 6 h, plasma PAI-1 concentration greater than before challenge was found in only 4 HCs (7.4%) but in 48 HDM-AAs (88.9%; p < 0.0001). An increase in plasma PAI-1 concentration at 6 h was found in all HDM-AAs carrying the 4G allele but only in 33.3% of the 5G homozygotes (p < 0.0001). The strongest correlation was found between log PC20 and PAI-1 plasma concentration over the period of 24 h (r = –0.507; p = 0.0001). Conclusion: Changes in plasma PAI-1 concentration associated with allergen-induced bronchoconstriction are modulated by the –675 4G/5G polymorphism of the PAI-1 gene. Allergen-induced upregulation of PAI-1 synthesis may participate in the development of bronchial hyperreactivity in HDM-AAs.
Renoprotective Effects of Rosiglitazone in Stroke-Prone Spontaneously Hypertensive Rats
Authors: Choi Bum Soon , Yang Hyun Ju , Ahn Kyung Ohk , Lim Sun Woo , Kim Su Hyun , Kim Jin Young , Li Can , Kim Yong Soo , Kim Jin , Bang Byung Kee , Yang Chul Woo
Published: June 2007

Background/Aims: Rosiglitazone (RGTZ) has a protective effect against various types of injury. We evaluated the effects of RGTZ on renal injury in a stroke-prone spontaneously hypertensive rat (SHRSP) model. Methods: Male SHRSP rats were observed with or without RGTZ treatment for 10 weeks. Age-matched male Wistar-Kyoto rats were used as controls. The effect of RGTZ on hypertensive nephropathy was evaluated by assessing renal function, pathology, pro-inflammatory cytokine (osteopontin), profibrotic cytokine (βig-h3), apoptotic cell death (TUNEL staining and caspase 3 expression), marker of oxidative stress (8-OHdG) and endothelial damage (eNOS). Results: RGTZ treatment improved renal function and histopathology compared with SHRSP rats without treatment (p < 0.05). Osteopontin and βig-h3 were significantly increased in SHRSP rat kidneys, but RGTZ treatment decreased both mediators. Apoptotic cell death was increased in renal tubular cells in the injured area in SHRSP rat kidneys, but RGTZ treatment decreased apoptotic cell death and caspase 3 expression. Increased urinary 8-OHdG excretion and decreased eNOS in SHRSP rats was reversed with RGTZ treatment. Conclusions: RGTZ protects hypertensive nephropathy in SHRSP rats.
Blood Pressure-Independent Effect of Long-Term Treatment with the Soluble Heme-Independent Guanylyl Cyclase Activator HMR1766 on Progression in a Model of Noninflammatory Chronic Renal Damage
Authors: Benz Kerstin , Orth Stephan R. , Simonaviciene Aurelia , Linz Wolfgang , Schindler Ursula , Rütten Hartmut , Amann Kerstin
Published: June 2007

Nitric oxide formation is impaired in chronic renal failure. The renoprotective effects of a nonhypotensive dose of HMR1766, a direct activator of the heme enzyme soluble guanylyl cyclase was studied in comparison to an ACE-i in the remnant kidney model. Male Sprague-Dawley rats were subtotally nephrectomized (SNX) or sham operated (sham) and left untreated or started on treatment with HMR1766 or ACE-i in non-hypotensive doses. BP, albumin excretion and parameters of renal damage were analyzed. After a 12-week study, urinary albumin excretion was significantly higher in untreated SNX than in sham; this increase was prevented by ACE-i and ameliorated by HMR1766. Relative kidney and left ventricular weight were significantly higher in untreated SNX compared to sham; these changes were completely prevented by HMR1766. In untreated SNX, glomerulosclerosis (1.02 ± 0.13) was significantly higher than in sham (0.12 ± 0.04), SNX+HMR1766 (0.27 ± 0.04) and SNX+ACE-i (0.46 ± 0.06). Tubulointerstitial changes went in parallel. Increased glomerular cell number after SNX (71.5 ± 14 vs. 60 ± 7.3 in sham) was prevented by HMR1766 (55.7 ± 7.3), but not by ACE-i (66.6 ± 9). The results document beneficial BP-independent HMR1766 effects on kidney structure and urinary albumin excretion in a noninflammatory model of renal failure and may argue for a novel therapeutic principle.