CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 11 2007
Sheng-Li Sun
SUMMARY 1Signal transducers and activators of transcription (STAT) factors are a family of transcription factors that mediate intracellular signalling initiated at cytokine cell surface receptors and transmitted to the nucleus. In the present study, we determined the global changes in STAT gene expression in the hippocampus of rats after focal cerebral ischaemia and reperfusion using microarray analysis. 2The present study used middle cerebral artery occlusion (MCAO) to induce ischaemia and reperfusion in Sprague-Dawley rats. Using superarray Q series Janus tyrosine kinases (Jak)/STAT signalling pathway gene array, a total of 96 genes was screened in adult male rat hippocampus after transient focal cerebral ischaemia. 3The results showed that 23 genes were upregulated at least twofold by ischaemia treatment and that 12 genes were downregulated at least threefold by ischaemia treatment compared with controls. 4After confirmation by quantitative real-time polymerase chain reaction, the data suggest that the gene expression of STAT2, 5a, 5b, 6 and suppressor of cytokine signalling (SOCS) 4 was increased by ischaemia, probably due to a compensatory response of the brain, which may play a protective role in damaged brain tissue. 5The results of the present study provide evidence on global changes in STAT gene expression in the hippocampus of rats after focal cerebral ischaemia and reperfusion, in which STAT2, 5a, 5b, 6 and SOCS4 were confirmed to be significantly modulated during focal cerebral ischaemia. [source]

Activator of G-protein signaling in asymmetric cell divisions of the sea urchin embryo

DEVELOPMENT GROWTH & DIFFERENTIATION, Issue 9 2006
Ekaterina Voronina
An asymmetric fourth cell division in the sea urchin embryo results in formation of daughter cells, macromeres and micromeres, with distinct sizes and fates. Several lines of functional evidence presented here, including pharmacological interference and dominant negative protein expression, indicate that heterotrimeric G protein Gi and its interaction partner, activator of G-protein signaling (AGS), are necessary for this asymmetric cell division. Inhibition of Gi signaling by pertussis toxin interferes with micromere formation and leads to defects in embryogenesis. AGS was isolated in a yeast two-hybrid screen with G,i as bait and was expressed in embryos localized to the cell cortex at the time of asymmetric divisions. Introduction of exogenous dominant-negative AGS protein, containing only G-protein regulatory (GPR) domains, selectively prevented the asymmetric division in normal micromere formation. These results support the growing evidence that AGS is a universal regulator of asymmetric cell divisions in embryos. [source]

Treatment of Acute Stroke with Recombinant Tissue Plasminogen Activator and Abciximab

ACADEMIC EMERGENCY MEDICINE, Issue 12 2003
Daniel C. Morris MD
Objectives: Preclinical data suggest that treatment of acute ischemic stroke (AIS) with the combination of recombinant tissue plasminogen activator (rt-PA) and abciximab may increase efficacy and decrease the rate of symptomatic intracranial hemorrhage (sICH). The authors report pilot data of five AIS patients with half-dose rt-PA and abciximab as part of an ongoing phase I safety trial with sICH as the primary outcome. Methods: Five patients with AIS were treated with the combination of half-dose rt-PA (0.45 mg/kg) and abciximab (0.25 mg/kg bolus followed by a 0.125 ,g/kg/min infusion over 12 hours). Head computed tomographic scan was obtained after 24 hours of treatment onset. Results: Four patients received the combination of half-dose abciximab and rt-PA without major complications. One patient experienced a parenchymal hematoma type-1 ICH without significant decline of his neurological status. The average National Institutes of Health Stroke Scale change at discharge in comparison with pretreatment was ,5.4 ± 7.0, and the median change was 6 points with a range of 4 points (worsening) to ,13 points (improvement) (p = 0.07) based on a one-sided t-test. Conclusions: Administration of rt-PA and abciximab to AIS patients was completed without difficulty. No sICH were observed; however, 20% (1 out of 5) experienced an asymptomatic ICH. Based on our observation of five patients, there was a trend of treatment efficacy; however, these results need to be confirmed in a larger-scale placebo-controlled clinical trial. [source]

Activator protein-1 signalling pathway and apoptosis are modulated by poly(ADP-ribose) polymerase-1 in experimental colitis

IMMUNOLOGY, Issue 4 2004
Basilia Zingarelli
Summary Poly(ADP-ribose) polymerase-1 (PARP-1) is activated in response to DNA injury in the nucleus of eukaryotic cells and has been implicated in intestinal barrier dysfunction during inflammatory bowel diseases. In this study we investigated whether PARP-1 may regulate the inflammatory response of experimental colitis at the level of signal transduction mechanisms. Mice genetically deficient of PARP-1 (PARP-1,/,) and wild-type littermates were subjected to rectal instillation of trinitrobenzene sulphonic acid (TNBS). Signs of inflammation were monitored for 14 days. In wild-type mice, TNBS treatment resulted in colonic ulceration and marked apoptosis, which was associated with decreased colon content of the antiapoptotic protein Bcl-2, whereas the proapoptotic Bax was unchanged. Elevated levels of plasma nitrate/nitrite, metabolites of nitric oxide (NO), were also found. These inflammatory events were associated with activation of c-Jun-NH2 terminal kinase (JNK), phosphorylation of c-Jun and activation of the nuclear transcription factor activator protein-1 (AP-1) in the colon. In contrast, PARP-1,/, mice exhibited a significant reduction of colon damage and apoptosis, which was associated with increased colonic expression of Bcl-2 and lower levels of plasma nitrate/nitrite when compared to wild-type mice. Amelioration of colon damage was associated with a significant reduction of the activation of JNK and reduction of the DNA binding of AP-1. The data indicate that PARP-1 exerts a pathological role in colitis possibly by regulating the early stress-related transcriptional response through a positive modulation of the AP-1 and JNK pathways. [source]

Possible Involvement of I,B Kinase 2 and MKK7 in Osteoclastogenesis Induced by Receptor Activator of Nuclear Factor ,B Ligand,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 4 2002
Aiichiro Yamamoto
Abstract Recent studies have revealed the essential role of the receptor activator of nuclear factor ,B (NF-,B) ligand (RANKL) in osteoclast differentiation and activation. Adenovirus vector could efficiently transduce genes into RAW264.7 cells, which differentiate into osteoclast-like multinucleated cells in the presence of RANKL. The role of NF-,B and c- jun N-terminal kinase (JNK) activation in RANKL-induced osteoclast differentiation was investigated using an adenovirus vector carrying the dominant negative I,B kinase 2 gene (AxIKK2DN) or dominant negative MKK7 gene (AxMKK7DN). IKK2DN and MKK7DN overexpression in RAW cells specifically suppressed the NF-,B activation and JNK activation in response to RANKL, respectively, without affecting other signaling pathways. Either inhibition of NF-,B or JNK pathways dose-dependently inhibited osteoclast formation induced by RANKL. These results suggest that both NF-,B and JNK activation are independently required for osteoclast differentiation. [source]

In Vivo RANK Signaling Blockade Using the Receptor Activator of NF-,B:Fc Effectively Prevents and Ameliorates Wear Debris-Induced Osteolysis via Osteoclast Depletion Without Inhibiting Osteogenesis

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 2 2002
Lisa M. Childs
Abstract Prosthesis failure due to wear debris-induced osteolysis remains a major clinical problem and the greatest limitation for total joint arthroplasty. Based on our knowledge of osteoclast involvement in this process and the requirements of receptor activator of NF-,B (RANK) signaling in osteoclastogenesis and bone resorption, we investigated the efficacy of RANK blockade in preventing and ameliorating titanium (Ti)-induced osteolysis in a mouse calvaria model. Compared with placebo controls we found that all doses of RANK:Fc above 1 mg/kg intraperitoneally (ip) per 48 h significantly inhibited osteoclastogenesis and bone resorption in response to Ti implanted locally. Complete inhibition occurred at 10 mg/kg ip per 48 h, yielding results that were statistically equivalent to data obtained with Ti-treated RANK,/, mice. We also evaluated the effects of a single injection of RANK:Fc on day 5 on established osteolysis and found that Ti-treated were still depleted for multinucleated tartrate-resistant acid phosphatase-positive (TRAP+) cells 16 days later. More importantly, this osteoclast depletion did not affect bone formation because the bone lost from the osteolysis on day 5 was restored by day 21. An assessment of the quantity and quality of the newly formed bone in these calvariae by calcein labeling and infrared (IR) microscopy, respectively, showed no significant negative effect of RANK:Fc treatment. These studies indicate that osteoclast depletion via RANK blockade is an effective method to prevent and reverse wear debris-induced osteolysis without jeopardizing osteogenesis. [source]

Cloning, Sequencing, and Functional Characterization of the Rat Homologue of Receptor Activator of NF-,B Ligand,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 11 2000
Jiake Xu
Abstract A complementary DNA (cDNA) encoding the rat homologue of receptor activator of NF-,B ligand/osteoprotegerin ligand/osteoclast differentiation factor/tumor necrosis factor (TNF)-related activation-induced cytokine (RANKL/OPGL/ODF/TRANCE) was cloned and sequenced from tibias of ovariectomized (OVX) rats. The predicted amino acid sequence of rat RANKL (rRANKL) has 84% and 96% identity to that of human and mouse RANKL, respectively, and 35% and 37% similarity to that of human and mouse TNF-related apoptosis-inducing ligand (TRAIL), respectively. RANKL transcripts were expressed abundantly in the thymus and bone tissues of OVX rats. rRANKL has a single hydrophobic region between residues 53 and 69, which is most likely to serve as a transmembrane domain. The long C-terminal region containing ,-sheet-forming sequences of the TNF-like core is considered the extracellular region. Three truncated domains within the TNF-like core region were expressed as glutathione S-transferase (GST) fusion proteins and investigated for their ability to induce osteoclastogenesis. The results showed that GST-rRANKL (aa160-318) containing the full TNF-like core region had the highest capability to induce the formation of osteoclast-like cells from RAW264.7 cells. GST-rRANKL (aa239-318 and aa160-268) had lesser degrees of osteoclast inductivity. Furthermore, the GST-rRANKL (aa160-318) is capable of (1) inducing osteoclast formation from rat spleen cells in the presence of macrophage colony-stimulating factor (M-CSF), (2) stimulating mature rat osteoclast polarization and bone resorption ex vivo, and (3) inducing systemic hypercalcemia in vivo; thus the full TNF-like core region of rRANKL is an important regulator of calcium homeostasis and osteoclastic function. [source]

Prostaglandin E2 Induces Expression of Receptor Activator of Nuclear Factor,,B Ligand/Osteoprotegrin Ligand on Pre-B Cells: Implications for Accelerated Osteoclastogenesis in Estrogen Deficiency

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2000
Masahiro Kanematsu
Abstract Estrogen deficiency causes bone loss as a result of accelerated osteoclastic bone resorption. It also has been reported that estrogen deficiency is associated with an increase in the number of pre-B cells in mouse bone marrow. The present study was undertaken to clarify the role of altered B lymphopoiesis and of the receptor activator of nuclear factor-,B ligand (RANKL), a key molecule in osteoclastogenesis, in the bone loss associated with estrogen deficiency. In the presence of prostaglandin E2 (PGE2), the activity to form tartrate-resistant acid phosphatase (TRAP)-positive osteoclast-like cells was significantly greater in bone marrow cells derived from ovariectomized (OVX) mice than in those from sham-operated mice. Northern blot analysis revealed that PGE2 increased the amount of RANKL messenger RNA (mRNA) in bone marrow cells, not only adherent stromal cells but nonadherent hematopoietic cells; among the latter, RANKL mRNA was more abundant in OVX mice than in sham-operated mice and was localized predominantly in B220+ cells. Flow cytometry revealed that most B220+ cells in bone marrow were RANKL positive and that the percentage of RANKL-positive, B220low cells was higher in bone marrow from OVX mice than in that from sham-operated mice. The increase in the expression of RANKL and the percentage of these cells in OVX mice was abolished by the administration of indomethacin in vivo. PGE2 also markedly increased both the level of RANKL mRNA and cell surface expression of RANKL protein in the mouse pre-B cell line 70Z/3. Finally, osteoclastogenic response to PGE2 was reduced markedly by prior depletion of B220+ cells, and it was restored by adding back B220+ cells. Taken together with stimulated cyclo-oxygenase (COX)-2 activity by tumor necrosis factor , (TNF-,) and interleukin-1 (IL-1) in estrogen deficiency, these results suggest that an increase in the number of B220+ cells in bone marrow may play an important role in accelerated bone resorption in estrogen deficiency because B220+ cells exhibit RANKL on the cell surface in the presence of PGE2, thereby leading to accelerated osteoclastogenesis. [source]

Age-related differences in MAP kinase activity in VSMC in response to glucose or TNF-,

JOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2003
Muyao Li
Aortic vascular smooth muscle cells (VSMC) were used to study the effect of age on responses to high glucose concentrations or the cytokine, tumor necrosis factor-alpha (TNF-,). Activator protein-1 (AP-1) binding to DNA increased more in VSMC from old versus young rats (P,<,0.02) and was related to increased expression of its components, c-Fos, Fra-1, and JunD. The relationship to upstream signals, i.e., activities of mitogen-activated protein kinases (MAPK), was studied using antibodies to total and phosphorylated forms of extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinases (JNK) and p38. High glucose and TNF-, increased ERK phosphorylation more in old (P,<,0.05); whereas only TNF-, induced JNK activation in young (P,<,0.04). PD98059, a MEK inhibitor, attenuated AP-1 activation, lowered c-Fos and Fra-1 protein levels and reduced cell number and cells positive for proliferating cell nuclear antigen in old. We concluded that age differentially influenced activation of signaling pathways in VSMC exposed to high glucose or TNF-,. This may contribute to the increased risk for vascular disease associated with aging and diabetes mellitus (DM). J. Cell. Physiol. 197: 418,425, 2003© 2003 Wiley-Liss, Inc. [source]

Baseline Computed Tomography Changes and Clinical Outcome After Thrombolysis With Recombinant Tissue Plasminogen Activator in Acute Ischemic Stroke

JOURNAL OF NEUROIMAGING, Issue 2 2001
Jorge E. Mendizabal MD
ABSTRACT Objective. Intravenous recombinant tissue plasminogen activator (rt-PA) is the only therapy of proven value for patients with acute ischemic stroke (AIS). Controversy exists with regard to the prognostic significance of early computed tomography (CT) changes in patients receiving rt-PA for AIS. The authors retrospectively reviewed all cases of AIS who received intravenous rt-PA for AIS in University of South Alabama hospitals between January 1996 and May 1999. A neuroradiologist, blinded to clinical outcomes, reviewed all baseline CT scans for the presence of the following signs: hyperdense middle cerebral artery (HMCA), loss of gray-white differentiation (LGWD), insular ribbon sign (IRS), parenchymal hypodensity (PH), and sulcal effacement (SE). Modified Rankin Scale (mRS) score was recorded 90 days after thrombolysis, and clinical outcome was dichotomized as favorable (0,1) or unfavorable (2,6). The authors performed both univariate and multivariate analyses to investigate the relationship between early CT signs, baseline clinical variables, and functional outcome as measured by the 90-day mRS scores. Any one early CT finding was detected in 23 (64%) patients. The frequency of specific findings were as follows: SE in 13 patients (36%), LGWD in 12 patients (33%), PH in 9 patients (25%), HMCA in 4 patients (11%), and IRS in 3 patients (8%) patients. There was no statistically significant association between the occurrence of these imaging findings and subsequent functional outcome after thrombolysis. The data suggest that the presence of subtle acute CT changes in AIS patients is not predictive of clinical outcome following administration of rt-PA as per National Institute of Neurological Disorders and Stroke protocol. [source]

Investigation of the Reaction Between Benzophenone and Trimethylaluminium: A Source of Novel Aluminic Activator for Single-site Olefin Polymerization Catalysts

MACROMOLECULAR SYMPOSIA, Issue 1 2005
Thomas Dalet
Abstract The reaction between benzophenone and TMA was investigated in details at 20,°C for different TMA/benzophenone (r) ratios. For r,=,2, a heterodimer µ-(1,1-diphenylethoxy)-µ-methyl-tetramethyldialuminium (B) is only formed. The latter was found able to activate MeDIP(2,6-iPrPh)2FeCl2 catalyst towards ethylene polymerization. Such catalytic system leads to the formation of high molar mass polyethylene with a broad molar mass distribution, without the presence of oligomers, that is attributed to a strong reduction of the transfer reaction to TMA. [source]

The Drosophila G protein-coupled receptor, Methuselah, exhibits a promiscuous response to peptides

PROTEIN SCIENCE, Issue 11 2009
William W. Ja
Abstract Methuselah (Mth) is a G protein-coupled receptor (GPCR) associated with longevity in Drosophila melanogaster. Previously, Stunted (Sun) was identified as a peptide agonist of Mth. Here, we identify two additional activators of Mth signaling: Drosophila Sex Peptide (SP) and a novel peptide (Serendipitous Peptide Activator of Mth, SPAM). Minimal functional sequences and key residues were identified from Sun and SPAM by studying truncation and alanine-scanning mutations. These peptide agonists share little sequence homology and illustrate the promiscuity of Mth for activation. mth mutants exhibit no defects in behaviors controlled by SP, casting doubt on the biological significance of Mth activation by any of these agonists, and illustrating the difficulty in applying in vitro studies to their relevance in vivo. Future studies of Mth ligands will help further our understanding of the functional interaction of agonists and GPCRs. [source]

1141636674 Differential serine and tyrosine phosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3) in Jeg-3 choriocarcinoma cell lines

AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 6 2006
J Roediger
Background:, Signal Transducer and Activator of Transcription 3 (STAT3) is an intracellular signalling molecule, which is used by several cytokines, including leukemia inhibitory factor (LIF), epithelial growth factor (EGF), and interleukin-6 (IL-6). It induces a variety of gene transcripts and cell functions. In trophoblast cells and in tumor cells, its tyrosine phosphorylation is directly linked to their invasiveness. The regulation and function of STAT3 serine phosphorylation is still widely unclear. Material and Methods:, Jeg-3 choriocarcinoma cells were stimulated with different concentrations of EGF, IL-6 and LIF. STAT3 serine (727) and tyrosine (705) phosphorylation were analyzed 5,60 min after stimulation by SDS-PAGE electrophoresis followed by Western blotting. Results:, Jeg-3 cells display spontaneous STAT3 serine phosphorylation. 100 ng/mL EGF induces a time-dependent reduction starting 15 min after stimulation. Tyrosine phosphorylation does not occur spontaneously, but is strongly induced by EGF at all analyzed time points. LIF induces tyrosine phosphorylation, but affects serine phosphorylation only very slightly. IL-6 did not influence neither serine phosphorylation nor tyrosine phosphorylation. Discussion:, The EGF induced STAT3 tyrosine phosphorylation may be responsible for its invasion triggering capacities. The parallel reduction of serine phosphorylation may enhance this effect. LIF was formerly shown to enhance trophoblast invasion via STAT3 tyrosine phosphorylation. IL-6 displays very little effects on STAT3 and seems to use other pathways for signalling. [source]

1141638491 Hepatocyte growth factor (HGF) stimulates mammalian target of rapamycin (mTOR) in choriocarcinoma cell lines and human trophoblast cells

AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 6 2006
S Busch
Introduction:, Hepatocyte growth factor (HGF), interleukin-6 (IL-6) and insulin-like growth factor-II (IGF-II) are involved in the regulation of trophoblast cell migration and invasion. Signal Transducer and Activator of Transcription 3 (STAT3) and Mammalian Target Of Rapamycin (mTOR) signalling regulate cell invasion, growth and proliferation. mTOR plays also a key role during embryogenesis. Knock-out mice embryos die after implantation and blastocysts trophoblast outgrowth is reduced. Aim:, Stimuli which might trigger such invasive behaviour through mTOR should be defined. Methods:, The human choriocarcinoma cell lines JEG-3, JAR, the human choriocarcinoma-trophoblast hybrid AC1-M59 and human term trophoblast cells were stimulated with HGF, IL-6 or IGF-II. At several time points, the phosphorylation level of mTOR and STAT3 were tested by Western blot. STAT3 DNA-binding capacity was analyzed by Electrophorectic Mobility Shift Assay (EMSA). To examine the role of mTOR for invasion and proliferation, mTOR expression was silenced by RNA interference (RNAi). Results:, HGF, IGF-II and IL-6 did neither induce tyrosine (705) phosphorylation of STAT3 nor STAT3 DNA binding capacity as assessed by EMSA. HGF led to an increase of mTOR serine (2448) phosphorylation for all cell types after 15 and 30 min while IL-6 and IGF-II did not induce mTOR phosphorylation. Simultaneously, HGF decreased STAT3 serine (727) phosphorylation. mTOR silencing in AC1-M59 correlates with reduced proliferation and invasion. STAT3 expression was not affected by mTOR knock down. Conclusion:, HGF triggers mTOR activity in trophoblast and trophoblast-like cells. mTOR is a main regulator of crucial trophoblast functions. [source]

Recombinant Tissue-Type Plasminogen Activator in the Treatment of Acute Renal Artery Thrombosis After Kidney Transplantation

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2010
A. Garcia
Acute arterial thrombosis is an uncommon but potentially devastating consequence of kidney transplantation. Early recognition followed by thrombectomy may salvage the graft. We present a case of acute renal artery thrombosis after a living-related kidney transplant with successful treatment with operative thrombectomy and intraarterial infusion of recombinant tissue-type plasminogen activator. [source]

A collection of 11 800 single-copy Ds transposon insertion lines in Arabidopsis

THE PLANT JOURNAL, Issue 6 2004
Takashi Kuromori
Summary More than 10 000 transposon-tagged lines were constructed by using the Activator (Ac)/Dissociation (Ds) system in order to collect insertional mutants as a useful resource for functional genomics of Arabidopsis. The flanking sequences of the Ds element in the 11 800 independent lines were determined by high-throughput analysis using a semi-automated method. The sequence data allowed us to map the unique insertion site on the Arabidopsis genome in each line. The Ds element of 7566 lines is inserted in or close to coding regions, potentially affecting the function of 5031 of 25 000 Arabidopsis genes. Half of the lines have Ds insertions on chromosome 1 (Chr. 1), in which donor lines have a donor site. In the other half, the Ds insertions are distributed throughout the other four chromosomes. The intrachromosomal distribution of Ds insertions varies with the donor lines. We found that there are hot spots for Ds transposition near the ends of every chromosome, and we found some statistical preference for Ds insertion targets at the nucleotide level. On the basis of systematic analysis of the Ds insertion sites in the 11 800 lines, we propose the use of Ds -tagged lines with a single insertion in annotated genes for systematic analysis of phenotypes (phenome analysis) in functional genomics. We have opened a searchable database of the insertion-site sequences and mutated genes (http://rarge.gsc.riken.go.jp/) and are depositing these lines in the RIKEN BioResource Center as available resources (http://www.brc.riken.go.jp/Eng/). [source]

Thrombolytic Therapy with Tissue Plasminogen Activator for the Treatment of Nonstructural Malfunction of Bileaflet Cardiac Valve Prostheses

ARTIFICIAL ORGANS, Issue 5 2002
Hideki Teshima
Abstract: This study was conducted to determine the effect of thrombolytic therapy with tissue plasminogen activator (t-PA) for nonstructural malfunction of bileaflet cardiac valve prostheses. Twenty-seven patients with bileaflet prosthetic valve malfunction diagnosed by a combination of cineradiography and transthoracic echocardiography were treated with the administration of intravenous t-PA. The treatment resulted in complete success in 55.6% (15 of 27), partial success in 22.2% (6 of 27), and no change in 22.2% (6 of 27). In the complete success and partial success groups, the condition of the patients in 85.7% (18 of 21) of the cases improved within 24 h after the administration of t-PA. Six cases in whom thrombolytic therapy was instituted more than 1 month (ranged from 1 to 38 months, mean 14.7 months) after the diagnosis of prosthetic valve malfunction showed significantly less effectiveness of thrombolytic therapy with t-PA. Only one patient (3.7%) had a major complication (thromboembolism) after t-PA treatment. The results suggest that thrombolytic therapy with t-PA in patients with nonstructural malfunction of bileaflet cardiac valve prostheses is effective with low incidence of complication when the treatment is instituted early after the diagnosis. [source]

Insulin-like growth factor-I receptor signal transduction and the Janus Kinase/Signal Transducer and Activator of Transcription (JAK-STAT) pathway

BIOFACTORS, Issue 1 2009
Eddy Himpe
Abstract The insulin-like growth factor IGF-I is an important fetal and postnatal growth factor, which is also involved in tissue homeostasis via regulation of proliferation, differentiation, and cell survival. To understand the role of IGF-I in the pathophysiology of a variety of disorders, including growth disorders, cancer, and neurodegenerative diseases, a detailed knowledge of IGF-I signal transduction is required. This knowledge may also contribute to the development of new therapies directed at the IGF-I receptor or other signaling molecules. In this review, we will address IGF-I receptor signaling through the JAK/STAT pathway in IGF-I signaling and the role of cytokine-induced inhibitors of signaling (CIS) and suppressors of cytokine signaling (SOCS). It appears that, in addition to the canonical IGF-I signaling pathways through extracellular-regulated kinase (ERK) and phosphatidylinositol-3 kinase (PI3K)-Akt, IGF-I also signals through the JAK/STAT pathway. Activation of this pathway may lead to induction of SOCS molecules, well-known feedback inhibitors of the JAK/STAT pathway, which also suppress of IGF-I-induced JAK/STAT signaling. Furthermore, other IGF-I-induced signaling pathways may also be modulated by SOCS. It is conceivable that the effect of these classical inhibitors of cytokine signaling directly affect IGF-I receptor signaling, because they are able to associate to the intracellular part of the IGF-I receptor. These observations indicate that CIS and SOCS molecules are key to cross-talk between IGF-I receptor signaling and signaling through receptors belonging to the hematopoietic/cytokine receptor superfamily. Theoretically, dysregulation of CIS or SOCS may affect IGF-I-mediated effects on body growth, cell differentiation, proliferation, and cell survival. © 2009 International Union of Biochemistry and Molecular Biology, Inc. [source]

Role of selenium in regulation of spermatogenesis: Involvement of activator protein 1

BIOFACTORS, Issue 3 2005
Sonia Shalini
Abstract Selenium (Se) is involved in the process of male reproduction. Several studies have been carried out to find the mechanism of Se action through identified selenoproteins. Especially selenoenzyme phospholipid glutathione peroxidase (PHGPx, GPx-4) plays a pivotal role in regulating spermatogenesis. However, the action of selenium is best known as an antioxidant which acts through various selenoproteins viz. glutathione peroxidase, thioredoxin reductase and selenoprotein P. Oxidative stress is currently being considered a leading cause of male infertility. Presently, the involvement of redox active transcription factor, AP1 (Activator protein1) in testicular function was studied. AP1 is redox sensitive and also controls cell proliferation. The effects of Se might be mediated through it. Different Se status - deficient, adequate and excess Se - were generated in male Balb/c mice by feeding yeast based selenium deficient diet and deficient diet supplemented with Se as sodium selenite (0.2 and 1 ppm Se), respectively, for a period of 4 and 8 weeks. Se status was checked by measuring the Se levels and glutathione peroxidase (GSH-Px) activity in testis and liver. The reproductive potential of mice was affected at these changed Se levels. Changes in the activity of superoxide dismutase (SOD), levels of reduced glutathione (GSH) and oxidized glutathione (GSSG) were observed indicating increased oxidative stress at both the levels. Further, changes in the mRNA expression of GSH-Px, ,-glutamylcysteine synthetase ,GCS) and Mn superoxide dismutase (MnSOD) were observed. Decrease in cjun and cfos mRNA levels were observed at both the Se status (deficient and excess) which might be responsible for decreased germ cell number, differentiation and reduced fertility observed at the altered Se levels. [source]

Ras and Signal Transducer and Activator of Transcription (STAT) Are Essential and Sufficient Downstream Components of Janus Kinases in Cell Proliferation

CANCER SCIENCE, Issue 5 2000
Rumiko Mizuguchi
Cytokines exert their activities in cell growth and differentiation by binding specific cell membrane receptors. Janus kinases (JAKs) are cytoplasmic protein tyrosine kinases that physically interact with intracellular domains of the cytokine receptors and they play crucial roles in transducing signals triggered by the cytokine-receptor interaction. We have previously shown that conditional activation of JAK through membrane-proximal dimerization confers cytokine-independence on interleukin-3 (IL-3)-dependent Ba/F3 lymphoid cells and that the cytokine-independent proliferation is completely inhibited by dominant negative Ras. In this work, we demonstrate that ectopic expression of a dominant negative form of Stat5, a major signal transducer and activator of transcription (STAT) expressed in Ba/F3 cells, also inhibits JAK-triggered mitogenesis. In contrast, overexpression of constitutively active Ras or conditional activation of Stat5 by chemical dimerization fails to confer cytokine-independence. However, concomitant activation of ectopic Ras and Stat5 molecules in Ba/F3 cells suffices for cell proliferation in the absence of IL-3. Our results indicate that Ras and STAT are essential and sufficient components of JAK-triggered mitogenesis. Our findings further indicate that the cytokine signal bifurcates into Ras and STAT pathways following JAK activation. [source]

ChemInform Abstract: Evaluation of Pyrrolin-2-one Derivatives Synthesized by a New Practical Method as Inhibitors of Plasminogen Activator inhibitor-1 (PAI-1).

CHEMINFORM, Issue 25 2010
Hiroshi Miyazaki
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source]

Achiral Benzophenone Ligand,Rhodium Complex with Chiral Diamine Activator for High Enantiocontrol in Asymmetric Transfer Hydrogenation.

CHEMINFORM, Issue 41 2006
Koichi Mikami
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF. [source]

Palladium(II)-Catalyzed Oxidative Transformation of Allylic Alcohols and Vinyl Ethers into 2-Alkoxytetrahydrofurans: Catechol as an Activator of Catalyst.

CHEMINFORM, Issue 18 2006
Kimi Minami
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF. [source]

Aqueous Ammonia as a New Activator for Sonogashira Coupling.

CHEMINFORM, Issue 21 2005
Mohamed S. Mohamed Ahmed
Abstract For Abstract see ChemInform Abstract in Full Text. [source]

Facile Method for the Preparation of Triarylsulfonium Bromides Using Grignard Reagents and Chlorotrimethylsilane as an Activator.

CHEMINFORM, Issue 45 2004
Shigeaki Imazeki
Abstract For Abstract see ChemInform Abstract in Full Text. [source]

Selective Urokinase-Type Plasminogen Activator (uPA) Inhibitors.

CHEMINFORM, Issue 40 2004
Part 3.
Abstract For Abstract see ChemInform Abstract in Full Text. [source]

ChemInform Abstract: Use of PyBOP as a Convenient Activator for the Synthesis of Nitriles from Primary Amides.

CHEMINFORM, Issue 28 2001
D. Subhas Bose
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source]

Molecular Approaches towards the Inhibition of the Signal Transducer and Activator of Transcription 3 (Stat3) Protein

CHEMMEDCHEM, Issue 8 2008
Steven Fletcher Dr.
Molecular approaches towards Stat3 inhibition: Stat3 inhibition represents an exciting new approach to the treatment of cancer. The advances in the direct molecular inhibition of Stat3 are highlighted through discussion of the various inhibitors currently under investigation, including peptide sequences, peptidomimetics, small molecules and platinum-based agents. [source]

AMPK activators , potential therapeutics for metabolic and other diseases

ACTA PHYSIOLOGICA, Issue 1 2009
G. Zhou
Abstract AMP-activated protein kinase (AMPK)-mediated cellular metabolic responses to tissue-specific and whole-body stimuli play a vital role in the control of energy homeostasis. As a cellular energy-sensing mechanism, AMPK activation stimulates glucose uptake and fat oxidation, while it suppresses lipogenesis and gluconeogenesis. The cumulative effects of AMPK activation lead to beneficial metabolic states in liver, muscle and other peripheral tissues that are critical in the pathogenesis of obesity, type 2 diabetes and related metabolic disorders. Activators of AMPK that target selected tissues hold potential as novel therapeutics for diseases in which altered energy metabolism contributes to aetiology. [source]

Increased Bone Formation in Mice Lacking Plasminogen Activators,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2003
E Daci
Abstract Plasminogen activators tPA and uPA are involved in tissue remodeling, but their role in bone growth is undefined. Mice lacking tPA and uPA show increased bone formation and bone mass. The noncollagenous components of bone matrix are also increased, probably from defective degradation. This study underlines the importance of controlled bone matrix remodeling for normal endochondral ossification. Introduction: Proteolytic pathways are suggested to play a role in endochondral ossification. To elucidate the involvement of the plasminogen activators tPA and uPA in this process, we characterized the long bone phenotype in mice deficient in both tPA and uPA (tPA,/,:uPA,/,). Materials and Methods: Bones of 2- to 7-day-old tPA,/,:uPA,/, and wild-type (WT) mice were studied using bone histomorphometry, electron microscopy analysis, and biochemical assessment of bone matrix components. Cell-mediated degradation of metabolically labeled bone matrix, osteoblast proliferation, and osteoblast differentiation, both at the gene and protein level, were studied in vitro using cells derived from both genotypes. Results: Deficiency of the plasminogen activators led to elongation of the bones and to increased bone mass (25% more trabecular bone in the proximal tibial metaphysis), without altering the morphology of the growth plate. In addition, the composition of bone matrix was modified in plasminogen activator deficient mice, because an increased amount of proteoglycans (2×), osteocalcin (+45%), and fibronectin (+36%) was detected. Matrix degradation assays showed that plasminogen activators, by generating plasmin, participate in osteoblast-mediated degradation of the noncollagenous components of bone matrix. In addition, proliferation of primary osteoblasts derived from plasminogen activator-deficient mice was increased by 35%. Finally, osteoblast differentiation and formation of a mineralized bone matrix were enhanced in osteoblast cultures derived from tPA,/,:uPA,/, mice. Conclusions: The data presented indicate the importance of the plasminogen system in degradation of the noncollagenous components of bone matrix and suggest that the accumulation of these proteins in bone matrix,as occurs during plasminogen activator deficiency,may in turn stimulate osteoblast function, resulting in increased bone formation. [source]