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Biomedical subjects

K Wikström

Publications and source records attributed to K Wikström.

13 recordsLinked to original sources
PubMed2005

Pro-inflammatory mediator leukotriene D4 induces transcriptional activity of potentially oncogenic genes.

The inflammatory mediator LTD4 (leukotriene D4) is present at high levels in many inflammatory conditions, and areas of chronic inflammation have an increased risk for subsequent cancer development. We demonstrate here that following LTD4 stimulation, beta-catenin is translocated to the nucleus, triggering the transcriptional activity of the TCF (T-cell factor)/LEF (lymphoid enhancer factor) family of transcription factors. These events are dependent on phosphoinositide-3 kinase activation and glycogen synthase kinase inhibition. Our data suggest that, similar to Wnt signalling, LTD4 increases free beta-catenin and targets it to the nucleus.

Gene Expression Regulation↗
PubMed2000

Leukotrienes induce cell-survival signaling in intestinal epithelial cells.

BACKGROUND & AIMS: Inflammatory bowel conditions, particularly ulcerative colitis, are associated with an increased incidence of neoplastic transformation. High levels of proinflammatory leukotrienes (LTs) and up-regulated expression of cyclooxygenase (COX)-2 are characteristic of inflammation. Moreover, COX-2 has been implicated in cell survival and early colon carcinogenesis. Other aspects of interest for intestinal cell viability are the levels of beta-catenin and the antiapoptotic protein Bcl-2. We investigated the possibility that LTs participate in the regulation of these survival factors. METHODS: We used the human intestinal epithelial cell line Int 407 and the rat intestinal epithelial cell line IEC-6. Immunoblotting was applied to ascertain protein expression and distribution, and enzyme immunoassay methodology was used to measure prostaglandin E(2) (PGE(2)) production. Apoptotic ability was assessed by trypan blue exclusion, Hoechst staining, DNA fragmentation, and a caspase-3 activity assay. RESULTS: LTD(4) and LTB(4), but not LTC(4), caused a time- and dose-dependent increase in expression and/or membrane accumulation of COX-2, beta-catenin, and Bcl-2, as well as PGE(2) production. Apoptosis assays showed that the effects of LTs on these transformation-associated proteins correlated well with the ability of these LTs to reduce programmed cell death. CONCLUSIONS: The results suggest that inflammatory conditions are associated with the expression and distribution of proteins that are characteristic of transformed cells; such conditions may involve a signaling mechanism comprising an altered rate of apoptosis.

Animals↗
PubMed1998

Characterization of protein kinase C-mediated phosphorylation of the short cytoplasmic domain isoform of C-CAM.

C-CAM is a ubiquitously expressed cell adhesion molecule belonging to the carcinoembryonic antigen family. Two co-expressed isoforms, C-CAM-L and C-CAM-S, are known, having different cytoplasmic domains both of which can be phosphorylated in vivo. Here we have characterized the PKC-mediated phosphorylation of the short cytoplasmic domain isoform, C-CAM-S. Phorbol myristyl acetate induced phosphorylation of C-CAM-S in transfected CHO cells. Using synthetic peptides and Edman degradation we identified Ser449 as the PKC-phosphorylated amino acid residue. Binding experiments with modified peptides indicated that this phosphorylation decreases the ability of the cytoplasmic domain of C-CAM-S to bind calmodulin.

Adenosine Triphosphatases↗
PubMed1997

An academic centre for gene therapy research with clinical grade manufacturing capability.

Huddinge University Hospital is a major teaching hospital affiliated with the Karolinska Institute in Southern Stockholm. For the past few years several groups have been working there in different areas of gene therapy relating to cancer, genetic and infectious diseases. However, a facility to produce clinical grade material under good manufacturing practice was lacking. To this end, Huddinge University Hospital has taken the initiative to open a Gene Therapy Research Center in 1996. This facility, which is unique of its kind in Scandinavia, is located in the Novum Research Park, Huddinge, and is a part of the existing Clinical Research Center. The newly built centre will allow clinicians and researchers to develop and produce vectors (viral and nonviral) for clinical trials and do basic research to understand the mechanisms of diseases. Although the centre will primarily serve the academic institutions it will also extend its facilities to other investigators in this field. The production unit is run in collaboration with the Faculty of Medicine, University of Lund. On-going projects include production of plasmid vectors for prevention of postangioplasty restenosis, DNA vaccine for HIV-1, cationic liposome DNA complexes for cystic fibrosis and retroviral vectors for HIV-1.

AIDS Vaccines↗
PubMed1996

Homophilic intercellular adhesion mediated by C-CAM is due to a domain 1-domain 1 reciprocal binding.

The cell adhesion molecule C-CAM belongs to the immunoglobulin superfamily and is expressed in epithelia, vessel endothelia, and hematopoietic cells. Differential splicing gives rise to different isoforms, of which the major two are C-CAM1 and C-CAM2, which both have four Ig-like domains in their extracellular portions, but differ in their cytoplasmic domains. Two different allelic variants of C-CAM, named a and b, occur in the rat. The adhesive binding mechanism(s) of C-CAM is not known in detail. Evidence for both homophilic and heterophilic binding has been presented, and different species and splice variants of C-CAM have shown differences in temperature and cation dependence when expressed in different cell types. Here, we have analyzed the binding mechanism of rat C-CAM2a that was expressed in CHO cells. In this system C-CAM2a-mediated adhesion was calcium- and temperature-independent. C-CAM2a-transfected cells did not adhere to nontransfected cells, demonstrating that the binding was homophilic. Cells transfected with C-CAM2a in which the N-terminal Ig-domain (D1) was deleted did not aggregate, and cells with intact C-CAM2a could not bind to these cells. This was in contrast to cells that were transfected with C-CAM2a in which the fourth Ig-like domain (D4) had been deleted; they both aggregated and bound to cells with intact C-CAM2a. Thus, C-CAM2a mediates intercellular adhesion of CHO cells by a homophilic mechanism, in which the D1 domain binds reciprocally to a D1 domain on an opposed C-CAM molecule.

Adenosine Triphosphatases↗
PubMed1995

Cell adhesion activity of the short cytoplasmic domain isoform of C-CAM (C-CAM2) in CHO cells.

C-CAM is a Ca(2+)-independent rat cell adhesion molecule belonging to the CEA gene family of the immunoglobulin superfamily. Two major isoforms that differ in the length of their cytoplasmic domains exist. In previous studies it has been reported that only the long isoform (C-CAM1) but not the short isoform (C-CAM2) can mediate adhesion. However, in the mouse, isoforms with both long and short cytoplasmic domains have been reported to have adhesive activity. In order to analyze this apparent conflict we transfected C-CAM1 or C-CAM2 into CHO Pro5 cells and examined their adhesive phenotype in an aggregation assay. We found that in this cellular system both C-CAM1 and C-CAM2 could mediate cell-cell adhesion in a Ca(2+)-independent and temperature-independent way. The results suggest that the cellular environment is important for the activity of C-CAM isoforms.

Adenosine Triphosphatases↗
PubMed1993

A bleeding model in rabbits demonstrate fresh clot selectivity for a genetically engineered variant of tissue-type plasminogen activator and for streptokinase.

The way in which three thrombolytic agents, tissue-type plasminogen activator (t-PA), streptokinase (SK) and a genetically engineered variant of t-PA composed of the second kringle and the protease domain (K2P), cause the dissolution of haemostatic plugs of differing ages was investigated in a novel rabbit model. Standardized incisions were made on the rabbit ear and the wounds were left to heal for 0.5 h or 24 h, before the thrombolytic agents were infused. In the absence of heparin, t-PA showed little discrimination between clots of different ages (36% and 28% lysis of the 0.5 h and 24 h wounds, respectively). In contrast, K2P and SK showed a pronounced fresh clot selectivity since they were significantly more effective in lysing fresh clots than old ones (68% and 4% lysis for K2P and 72% and 36% for SK, respectively). In the presence of heparin the potency of t-PA on fresh clots was considerably increased whilst the effect on old clots was not affected, a fresh clot selectivity for t-PA (64% lysis of fresh clots, 24% lysis of old clots) was thus effected. Heparin did not significantly affect the fresh clot selectivity of K2P or SK, although lysis of old clots was increased (from 4% to 36%) when it was given together with K2P. Furthermore, heparin did not affect the time to onset of bleeding nor was the bleeding time prolonged by its addition. The bleeding time observed for t-PA (20-25 min) was markedly shorter than that found for K2P or SK (40-50 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Developmental regulation of insulin like growth factor II expression in the horse.

The expression of the insulin like growth factor (IGF) II gene has been examined in the developing equine fetus. It was found that IGF II transcripts were present in abundant quantities in third trimester embryonic and extraembryonic tissues as for example the placenta. The expression of the IGF II gene was high in the fetal liver where two prominent transcripts--4.6 and 4.1--kB were produced. However, these transcripts could not be traced in the adult liver. Instead we found two different transcripts with the sizes of 4.0 and 2.9 kB in the adult liver. These findings taken together with the demonstration of heterologous IGF II cDNA hybridizing to equine DNA-digests suggests that the IGF II gene is under developmental control in the horse, with the possible existence of different promoters.

Animals↗
PubMed1991

Synergism between tissue-type plasminogen activator and a genetically engineered variant lacking the finger domain, the growth factor domain and the first kringle domain.

A modified variant of human tissue-type plasminogen activator (t-PA) lacking the finger domain (F), the growth factor domain (G) and the first kringle domain (K1), has an extended plasma half-life in vivo, compared to that of t-PA. When the variant (denoted K2P) was tested in vitro for its ability to lyse human plasma clots we found that the activity was characterized by a time lag phase and a sigmoidal dose-response curve. However, an attenuation of the lag phase in vitro was observed both when K2P was mixed with t-PA in a w/w ratio of 4:1 and when K2P was allowed to lyse a clot that had been pre-exposed to t-PA i.e. submitted to a limited plasmic digestion. Dosis that in vitro caused 50% lysis within 6 h were calculated from individual dose-response curves and were for K2P, t-PA and K2P/t-PA (4:1 w/w) 540 ng/ml, 360 ng/ml and 310 ng/ml, respectively. These results indicated a synergistic effect between K2P and t-PA. However, the data from individual dose-response curves showed that the effect of the K2P/t-PA mixture never was better than that of t-PA alone, and the synergistic effect in vitro is therefore considered to be of limited use. The thrombolytic activity in vivo was evaluated in a rabbit jugular vein thrombus model. Despite the lag phase observed in vitro, K2P was approximately 3 times as effective as t-PA in vivo (bolus injection). The thrombolytic effect of K2P was further potentiated when it was administered together with a small amount of t-PA (4:1 w/w).(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1985

Demonstration of galactosyltransferase activity in human seminal plasma and its relation to sperm penetration in cervical mucus.

The galactosyltransferase activity was determined in seminal plasma from 24 men with various sperm characteristics subdivided in three different groups and from 9 men subjected to vasectomy for the purpose of voluntary sterilization contributing a 4th group. The galactosyltransferase displayed an obligatory dependency on manganese ions for activity. Endogenous glycoproteins of human seminal plasma were poor acceptors for the galactosyltransferase reaction, and a more than 40-fold increase in activity was achieved in the presence of ovomucoid as exogenous acceptor. There were no significant intergroup differences with regard to galactosyltransferase activity. Hence, qualitative and quantitative discrepancies of spermatozoa were not influential on galactosyltransferase activity in a decisive way. An overall positive correlation was registered between galactosyltransferase activity and sperm penetration in cervical mucus (r = 0.53; p less than 0.01).

Cervix Mucus↗
PubMed1982

Efficacy of oral acyclovir in the treatment of initial and recurrent genital herpes.

A double-blind, randomised trial of acyclovir versus placebo was conducted in 31 patients with initial and 85 patients with recurrent genital herpes. 17 patients with initial and 42 with recurrent disease were treated with 200 mg acyclovir by mouth five times a day for 5 days, and the remaining patients received matching placebo. In patients with initial genital herpes shedding virus acyclovir significantly reduced the duration of viral shedding, itching, and pain, the time to crusting and complete healing, and new lesion formation compared with controls. In patients with recurrence disease acyclovir significantly reduced the duration of viral shedding, time to complete healing, and new lesion formation. The reported incidence of adverse events was similar in both acyclovir and placebo groups. Oral acyclovir is effective and well tolerated in patients with initial and recurrent genital herpes and can be used in outpatient therapy.

Acyclovir↗