| 1. |
- Almroth, Gabriel, 1953-, et al.
(författare)
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Detection and prevention of hepatitis C in dialysis patients and renal transplant recipients : A long-term follow up (1989–January 1997)
- 2002
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 251:2, s. 119-128
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Tidskriftsartikel (refereegranskat)abstract
- Background. Hepatitis C is frequent problem in dialysis wards.Design. A long time (1989–97) follow up of hepatitis C virus (HCV) infection in a Swedish nephrology unit was performed with anti-HCV screening, confirmatory antibody tests, viral RNA detection and molecular characterization. Case histories were reviewed with focus, onset of infection, liver morbidity and mortality.Results. In October 1991, 10% (19 of 184) of the patients in the unit (haemodialysis-, peritoneal dialysis and transplanted patients) were verified or suspected HCV carriers, whilst the number at the end of 1996 was 8% (13 of 157). Most patients were infected before 1991 but only in one case from a known HCV-infected blood donor. No new HCV infections associated with haemodialysis occurred during the study period. A total of 13 of 24 viremic patients had HCV genotype 2b, a pattern suggesting nosocomial transmission. This was further supported by phylogenetic analysis of HCV viral isolates in seven. HCV viremia was also common in patients with an incomplete anti-HCV antibody pattern as 8 of the 12 indeterminant sera were HCV-RNA positive.Conclusions. Awareness, prevention, identification of infected patients and donor testing limited transmission. Indeterminant recombinant immunoblot assays (RIBA)-results should be regarded with caution as a result of the relative immunodeficiency in uremic patients. Our data indicate nosocomial transmission in several patients.
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| 2. |
- Adamsson Eryd, Samuel, et al.
(författare)
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Blood pressure and complications in individuals with type 2 diabetes and no previous cardiovascular disease: national population based cohort study
- 2016
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Ingår i: Bmj-British Medical Journal. - : BMJ. - 1756-1833. ; 354
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES To compare the risk associated with systolic blood pressure that meets current recommendations (that is, below 140 mm Hg) with the risk associated with lower levels in patients who have type 2 diabetes and no previous cardiovascular disease. Population based cohort study with nationwide clinical registries, 2006-12. The mean follow-up was 5.0 years. 187 106 patients registered in the Swedish national diabetes register who had had type 2 diabetes for at least a year, age 75 or younger, and with no previous cardiovascular or other major disease. Clinical events were obtained from the hospital discharge and death registers with respect to acute myocardial infarction, stroke, a composite of acute myocardial infarction and stroke (cardiovascular disease), coronary heart disease, heart failure, and total mortality. Hazard ratios were estimated for different levels of baseline systolic blood pressure with clinical characteristics and drug prescription data as covariates. The group with the lowest systolic blood pressure (110-119 mm Hg) had a significantly lower risk of non-fatal acute myocardial infarction (adjusted hazard ratio 0.76, 95% confidence interval 0.64 to 0.91; P=0.003), total acute myocardial infarction (0.85, 0.72 to 0.99; P=0.04), non-fatal cardiovascular disease (0.82, 0.72 to 0.93; P=0.002), total cardiovascular disease (0.88, 0.79 to 0.99; P=0.04), and non-fatal coronary heart disease (0.88, 0.78 to 0.99; P=0.03) compared with the reference group (130-139 mm Hg). There was no indication of a J shaped relation between systolic blood pressure and the endpoints, with the exception of heart failure and total mortality. Lower systolic blood pressure than currently recommended is associated with significantly lower risk of cardiovascular events in patients with type 2 diabetes. The association between low blood pressure and increased mortality could be due to concomitant disease rather than antihypertensive treatment.
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| 3. |
- Adamsson Eryd, Samuel, et al.
(författare)
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Risk of future microvascular and macrovascular disease in people with Type 1 diabetes of very long duration : A national study with 10-year follow-up
- 2017
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Ingår i: Diabetic Medicine. - : Wiley. - 0742-3071. ; 34:3, s. 411-418
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To describe factors associated with prevalence or absence of microvascular and macrovascular complications in people with Type 1 diabetes of very long duration and to investigate the risk factors associated with the incidence of such complications. Methods: We included individuals with Type 1 diabetes who had been entered in the Swedish National Diabetes Register between 2002 and 2004 (n = 18 450). First, risk factor distribution in people with diabetes duration of ≥ 50 years was compared between people with and without complications. Second, the incidence of complications during a 10-year follow-up period was studied in all individuals who had no complications at baseline. Results: Among people with a diabetes duration of ≥ 50 years (n = 1023), 453 (44%) had macrovascular disease, 534 (52%) had microvascular disease and 319 (31%) did not have either of the diagnoses. Factors that differed significantly between people with and without macrovascular disease were gender, age, HbA1c, BMI, LDL cholesterol, HDL cholesterol, triglycerides, systolic blood pressure, albuminuria, antihypertensive medication and lipid-lowering medication. The same factors differed significantly between people with and without microvascular disease, with the exception of gender and HDL cholesterol. During the follow-up period, 6.1% of the study cohort were diagnosed with macrovascular disease and 19.6% with microvascular disease. Incidence of macrovascular disease was significantly associated with HbA1c levels. Hazard ratios decreased with longer diabetes duration. Conclusions: People with Type 1 diabetes who have survived ≥ 50 years without complications are significantly younger, and have significantly lower HbA1c levels, BMI and triglyceride levels than survivors with complications. HbA1c level is a predictor of macrovascular disease, independently of diabetes duration.
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| 4. |
- Adolfsson, Per, 1967-, et al.
(författare)
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Changes in β2-adrenoceptor expression and in adenylyl cyclase and phosphodiesterase activity in human uterine leiomyomas
- 2000
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Ingår i: Molecular human reproduction. - : Oxford University Press (OUP). - 1360-9947 .- 1460-2407. ; 6:9, s. 835-842
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Tidskriftsartikel (refereegranskat)abstract
- Uterine leiomyoma is a very common benign tumour with unclear pathophysiology in adult women. In the present study we have investigated the expression level of α2- and β2-adrenoceptors, and the adenylyl cyclase and phosphodiesterase activity in leiomyoma tissue compared with adjacent myometrium. Our results show that the α2/β2-adrenoceptor ratio is increased in leiomyoma, due to a significant decrease in β2-adrenoceptor expression. These changes were not due to an increased innervation, as the tumour tissue was completely devoid of nerve fibres. Moreover, the adenylyl cyclase activity of leiomyoma membranes was found to be ~50% lower, whereas the phosphodiesterase activity was significantly increased (by ~100%). We found that stimulating an increase in intracellular cyclic AMP, by adenylyl cyclase activity through β2-adrenoceptors (isoprenaline), by direct enzyme activation (forskolin), or by inhibition of phosphodiesterase activity (papaverine), potently blocked both protein and DNA synthesis in cultured leiomyoma smooth muscle cells. Our results imply the adrenoceptors might be involved in, or a consequence of, leiomyoma growth. The results also suggest a new interesting approach for leiomyoma pharmacotherapy.
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| 5. |
- Aifa, Sami, 1967-, et al.
(författare)
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Electrostatic interactions of peptides flanking the tyrosine kinase domain in the epidermal growth factor receptor provides a model for intracellular dimerization and autophosphorylation
- 2006
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Ingår i: Proteins. - : Wiley. - 0887-3585 .- 1097-0134. ; 62:4, s. 1036-1043
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Tidskriftsartikel (refereegranskat)abstract
- The mechanism by which ligand-activated EGFR induces autophosphorylation via dimerization is not fully understood. Structural studies have revealed an extracellular loop mediated receptor dimerization. We have previously presented experimental data showing the involvement of a positive 13 amino acid peptide (R645-R657, P13+) from the intracellular juxtamembrane domain (JM) of EGFR important for intracellular dimerization and autophosphorylation. A model was presented that suggest that P13+ interacts with a negative peptide (D979-E991, P13-) positioned distal to the tyrosine kinase domain in the opposite EGFR monomer. The present work shows additional data strengthening this model. In fact, by analyzing protein sequences of 21 annotated ErbB proteins from 9 vertebrate genomes, we reveal the high conservation of peptides P13+ and P13- with regard to their sequence as well as their position relative to the tyrosine kinase (TK) domain. Moreover in silico structure modeling of these ErbB intracellular domains supports a general electrostatic P13+/P13- interaction, implying that the C-terminal of one receptor monomer is facing the TK domain of the other monomer in the receptor dimer and vice versa. This model provides new insights into the molecular mechanism of ErbB receptor activation and suggests a new strategy to pharmacologically interfering with ErbB receptor activity. © 2005 Wiley-Liss, Inc.
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| 6. |
- Aifa, Sami, et al.
(författare)
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Interactions between the juxtamembrane domain of the EGFR and calmodulin measured by surface plasmon resonance
- 2002
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Ingår i: Cellular Signalling. - 0898-6568 .- 1873-3913. ; 14:12, s. 1005-1013
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Tidskriftsartikel (refereegranskat)abstract
- One early response to epidermal growth factor receptor (EGFR) activation is an increase in intracellular calcium. We have used surface plasmon resonance (SPR) to study real-time interactions between the intracellular juxtamembrane (JM) region of EGFR and calmodulin. The EGFR-JM (Met644-Phe688) was expressed as a GST fusion protein and immobilised on a sensor chip surface. Calmodulin specifically interacts with EGFR-JM in a calcium-dependent manner with a high on and high off rate. Chemical modification of EGFR-JM by using arginine-selective phenylglyoxal or deletion of the basic segment Arg645-Arg657 inhibits the interaction. Phosphorylation of EGFR-JM by protein kinase C (PKC) or glutamate substitution of Thr654 inhibits the interaction, suggesting that PKC phosphorylation electrostatically interferes with calmodulin binding to basic arginine residues. Calmodulin binding was also inhibited by suramin. Our results suggest that EGFR-JM is essential for epidermal growth factor (EGF)-mediated calcium-calmodulin signalling and for signal integration between other signalling pathways.
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| 7. |
- Anderson, Tony, 1973-, et al.
(författare)
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Frog melanophores cultured on fluorescent microbeads : Biomimic-based biosensing
- 2005
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Ingår i: Biosensors & bioelectronics. - : Elsevier BV. - 0956-5663 .- 1873-4235. ; 21:1, s. 111-120
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Tidskriftsartikel (refereegranskat)abstract
- Melanophores are pigmented cells in lower vertebrates capable of quick color changes and thereby suitable as whole cell biosensors. In the frog dermis skin layer, the large and dark pigmented melanophore surrounds a core of other pigmented cells. Upon hormonal stimulation the black-brown pigment organelles will redistribute within the melanophore, and thereby cover or uncover the core, making complex color changes possible in the dermis. Previously, melanophores have only been cultured on flat surfaces. Here we mimic the three dimensional biological geometry in the frog dermis by culturing melanophores on fluorescent plastic microbeads. To demonstrate biosensing we use the hormones melatonin and α-melanocyte stimulating hormone (α-MSH) as lightening or darkening stimuli, respectively. Cellular responses were successfully demonstrated on single cell level by fluorescence microscopy, and in cell suspension by a fluorescence microplate reader and a previously demonstrated computer screen photo-assisted technique. The demonstrated principle is the first step towards "single well/multiple read-out" biosensor arrays based on suspensions of different selective-responding melanophores, each cultured on microbeads with distinctive spectral characteristics. By applying small amount of a clinical sample, or a candidate substance in early drug screening, to a single well containing combinations of melanophores on beads, multiple parameter read-outs will be possible. © 2004 Elsevier B.V. All rights reserved.
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| 8. |
- Andersson, Tony, 1973-, et al.
(författare)
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Phosphoinositide 3-kinase is involved in Xenopus and Labrus melanophore aggregation
- 2003
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Ingår i: Cellular Signalling. - 0898-6568 .- 1873-3913. ; 15:12, s. 1119-1127
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Tidskriftsartikel (refereegranskat)abstract
- Melanophores are pigmented cells capable of quick colour changes through coordinated transport of their intracellular pigment granules. We demonstrate the involvement of phosphoinositide 3-kinase (PI3-K) in Xenopus and Labrus aggregation by the use of the PI3-K inhibitor, LY-294002. In Xenopus, wortmannin-insensitive PI3-K was found to be essential for the aggregation, mitogen-activated protein kinase (MAPK) activation and tyrosine phosphorylation of a 280-kDa protein, and for the maintenance of low cyclic adenosine 3':5'-monophosphate (cAMP) during the aggregated state. Pre-aggregated cells disperse completely to LY-294002 at 50-100 muM, involving a transient elevation in cAMP due to adenylate cyclase (AC) stimulation or to inhibition of cyclic nucleotide phosphodiesterase (PDE). The inactive analogue LY-303511 did not induce dispersion at the same concentrations. PDE4 and/or PDE2 was found to be involved in melanosome aggregation. The similar kinetics of LY-294002 and various PDE inhibitors indicates that the elevation of cAMP might be due to inhibition of PDE. In Labrus melanophores, LY-294002 had a less dramatic effect, probably due to less dependence on PDE in regulation of cAMP levels. In Xenopus aggregation, we suggest that melatonin stimulation of the Mel1c receptor via G(betagamma) activates PI3-K that, directly or indirectly via MAPK, activates PDE. (C) 2003 Elsevier Inc. All rights reserved.
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| 9. |
- Andersson, Tony, 1973-, et al.
(författare)
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Regulation of melanosome movement by MAP kinase
- 2003
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Ingår i: Pigment Cell Research. - : Wiley. - 0893-5785 .- 1600-0749. ; 16:3, s. 215-221
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Tidskriftsartikel (refereegranskat)abstract
- Our objectives were to further characterize the signaling pathways in melatonin-induced aggregation in Xenopus melanophores, specifically to investigate a possible role of mitogen-activated protein kinase (MAPK). By Western blotting we found that melatonin activates MAPK, which precedes melanosome aggregation measured in a microplate reader. Activation of MAPK, tyrosine phosphorylation of a previously described 280-kDa protein, and melanosome aggregation are sensitive to PD98059, a selective inhibitor of MAPK kinase. The MAPK activation is also decreased by the adenylate cyclase stimulant forskolin. In summary, we found that MAPK is activated during melatonin-induced melanosome aggregation. Activation was decreased by an inhibitor of MAPK kinase, and by forskolin. In addition to inhibition of cyclic adenosine 3′,5′-monophosphate (cAMP), reduction in protein kinase A activity (PKA), and activation of protein phosphatase 2A, we suggest that melatonin receptors activate the MAPK cascade and tyrosine phosphorylation of the 280-kDa protein. Although the cAMP/PKA signaling pathway is the most prominent, our data suggest that simultaneous activation of the MAPK cascade is of importance to obtain a completely aggregated state. This new regulatory mechanism of organelle transport by the MAPK cascade might be important in other eukaryotic cells.
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| 10. |
- Avliakulov, NK, et al.
(författare)
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Suramin blocks nucleotide triphosphate binding to ribosomal protein L3 from Trypanoplasma borreli
- 2000
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Ingår i: European Journal of Biochemistry. - : Wiley. - 0014-2956 .- 1432-1033. ; 267:6, s. 1723-1731
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Tidskriftsartikel (refereegranskat)abstract
- Ribosomal protein L3 (L3) has been demonstrated to participate in formation of the peptidyltransferase center and is essential for its catalytic activity. In the present study we show that L3 is able to bind nucleotide triphosphates with high and specific affinity in vitro. L3 was serendipitously identified by screening of a genomic phage library from a primitive kinetoplastid flagellate Trypanoplasma borreli with the ATPase domain of the topoisomerase II gene as a probe. The cloned gene was overexpressed and purified as a his-tag fusion protein in E. coli. Radioligand binding experiments, using [?-35S]ATP, showed that L3 is able to bind ATP but also GTP and UTP with similar high affinity (IC50 50-100 nM), while it has no ATPase activity. Furthermore, we showed that L3 has more than 500-fold higher affinity for nucleotide triphosphates compared to the corresponding nucleotide monophosphates and diphosphates. Molecular genetic and biochemical analyses allowed us to localize the NTP binding domain of L3 to the N-terminal 296 residues. Suramin, a polysulfonated naphthylamine derivative of urea, known for its chemotherapeutic effects completely inhibited the binding of [?-35S]ATP at subclinical levels. Results obtained with surface plasmon resonance technology showed that suramin both forms weak multimolecular complexes with L3 and bind strongly to L3 in nearly stoichiometric amounts.
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| 11. |
- Filippini, Daniel, et al.
(författare)
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Microplate based biosensing with a computer screen aided technique
- 2003
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Ingår i: Biosensors & bioelectronics. - 0956-5663 .- 1873-4235. ; 19:1, s. 35-41
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Tidskriftsartikel (refereegranskat)abstract
- Melanophores, dark pigment cells from the frog Xenopus laevis, have the ability to change light absorbance upon stimulation by different biological agents. Hormone exposure (e.g. melatonin or α-melanocyte stimulating hormone) has been used here as a reversible stimulus to test a new compact microplate reading platform. As an application, the detection of the asthma drug formoterol in blood plasma samples is demonstrated. The present system utilizes a computer screen as a (programmable) large area light source, and a standard web camera as recording media enabling even kinetic microplate reading with a versatile and broadly available platform, which suffices to evaluate numerous bioassays. Especially in the context of point of care testing or self testing applications these possibilities become advantageous compared with highly dedicated comparatively expensive commercial systems.
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| 12. |
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| 13. |
- Johansson, Fredrik, 1968-, et al.
(författare)
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An indomethacin-sensitive contraction induced by β-antagonists in guinea pig airways
- 2004
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Ingår i: Canadian Journal of Physiology and Pharmacology. - : Canadian Science Publishing. - 0008-4212 .- 1205-7541. ; 82:6, s. 393-401
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Tidskriftsartikel (refereegranskat)abstract
- β-adrenergic receptor (β-AR) antagonists have been associated with increased airway reactivity in asthmatics and potentiation of contractile stimuli in animal models. In the present study, using an in vitro model of tracheal preparations from guinea pigs, we show that the β-AR antagonists propranolol and pindolol induce a smooth muscle contraction. A prerequisite for this contraction is that the airway preparations have been pre-treated with an β-AR agonist. Our data show that the contractile effect of β-AR antagonists is not a simple consequence of reversing the agonist-induced relaxation. Furthermore, the effect seems to be mediated through interaction with β2-ARs since the response is stereo-selective, and the selective β1-AR receptor antagonist atenolol did not induce any contractile response. SQ 29,546, a thromboxane A2 antagonist; MK 886, a lipoxygenase inhibitor; and indomethacin, a cyclooxygenase inhibitor significantly inhibited the contractions of the tracheal preparations induced with propranolol or pindolol. We put forward the hypothesis that the contractile effect of the β-AR antagonist is a consequence of their inverse agonist activity, which is only evident when the receptor population have a higher basal activity. Our results indicate a novel additional explanation for the known side effect, bronchoconstriction, of β-AR antagonist.Key words: beta antagonist, guinea pig trachea, propranolol, formoterol, pindolol, indomethacin.
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| 14. |
- Nilsson, Harriet M., et al.
(författare)
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L-NAME-induced dispersion of melanosomes in melanophores activates PKC, MEK and ERK1
- 2001
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Ingår i: Pigment Cell Research. - : Wiley. - 0893-5785 .- 1600-0749. ; 14:6, s. 450-455
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Tidskriftsartikel (refereegranskat)abstract
- Melanosome movement represents a good model of cytoskeleton-mediated transport of organelles in eukaryotic cells. We recently observed that inhibiting nitric oxide synthase (NOS) with Nω-nitro-l-arginine methyl ester (l-NAME) induced dispersion in melanophores pre-aggregated with melatonin. Activation of cyclic adenosine 3′,5′-monophosphate (cAMP)-dependent protein kinase (PKA) or calcium-dependent protein kinase (PKC) is known to cause dispersion. Also, PKC and NO have been shown to regulate the mitogen/extracellular signal-regulated kinase (MEK)-ERK pathway. Accordingly, our objective was to further characterize the signaling pathway of l-NAME-induced dispersion. We found that the dispersion was decreased by staurosporine and PD98059, which respectively inhibit PKC and MEK, but not by the PKA inhibitor H89. Furthermore, Western blotting revealed that ERK1 kinase was phosphorylated in l-NAME-dispersed melanophores. l-NAME also caused dispersion in latrunculin-B-treated cells, suggesting that this effect is not due to inhibition of the melatonin signaling pathway. Summarizing, we observed that PKC and MEK inhibitors decreased the l-NAME-induced dispersion, which caused phosphorylation of ERK1. Our results also suggest that NO is a negative regulator of phosphorylations that leads to organelle transport.
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| 15. |
- Nilsson, Isabelle, 1971-, et al.
(författare)
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Molecular cloning of a putative Ciona intestinalis cionin receptor, a new member of the CCK/gastrin receptor family
- 2003
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Ingår i: Gene. - : Elsevier BV. - 0378-1119 .- 1879-0038. ; 323:1-2, s. 79-88
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Tidskriftsartikel (refereegranskat)abstract
- Cionin, a peptide showing similarities with cholecystokinin and gastrin has been shown to be expressed in the gut and neural ganglion of the protochordate Ciona intestinalis. The present report describes the cloning of a putative cionin receptor (CioR), a new member of the CCK/gastrin family from the gastrointestinal tract of C. intestinalis. mRNA from the stomach of C. intestinalis was isolated using a modified RNA extraction procedure and, subsequently, reverse-transcribed into single-stranded cDNA by means of rapid amplification of 5′- and 3′-cDNA ends (RACE-PCR), followed by full-length PCR amplification. The cloned full-length PCR amplicons contained a short upstream open-reading frame (uORF) coding for a putative 16 amino acid long peptide, followed by a long open reading frame encoding a 526 amino acid putative CioR protein. At the amino acid level, the putative CioR protein shared 35–40% homology with cloned mammalian, chicken, and Xenopus laevis CCK receptors. Phylogenetic analysis revealed that the chicken and X. laevis CCK receptors are orthologues of the mammalian CCK2 receptors whereas CioR protein forms a clade with vertebrate cholecystokinin receptors. Moreover, we found that the CioR cDNA and deduced amino acid sequences were found to correspond to the annotated CCK/gastrin-like receptor gene on Scaffold 117 (C. intestinalis draft genome project, Joint Genome Institute database; http://www.jgi.doe.gov).
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| 16. |
- Nilsson, Isabelle, 1971-, et al.
(författare)
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Molecular cloning of an unusual bicistronic cholecystokinin receptor mRNA expressed in chicken brain : a structural and functional expression study
- 2003
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Ingår i: Regulatory Peptides. - 0167-0115 .- 1873-1686. ; 114:1, s. 37-43
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Tidskriftsartikel (refereegranskat)abstract
- This report describes the molecular cloning and pharmacological characterization of a transiently expressed chicken brain cholecystokinin receptor (CCK-CHR) in COS-7 cells. A polymerase chain reaction (PCR)-based cloning strategy was applied using: (1) an initial PCR with deoxyinosine-containing primers designed to target conserved regions in CCK receptors, followed by (2) rapid amplification of cDNA ends (RACE), and (3) full-length PCR of the CCK-CHR cDNA. The full-length cloned bicistronic CCK-CHR cDNA contained a short upstream open reading frame (uORF) coding for a putative six-amino-acid-long peptide of unknown function, followed by a long open reading frame (lORF) encoding the 436-amino-acid-long CCK-CHR receptor protein. At the amino acid level, the CCK-CHR shared ∼50% homology with mammalian and Xenopus laevis CCK receptors. The pharmacological profile of CCK-CHR resembled that of CCK-B receptors using agonists (CCK-8, CCK-4, gastrin-17), whereas CCK-CHR showed higher affinity for the CCK-A receptor antagonist, devazepide, than for the CCK-B receptor antagonist, l-365,260. To the best of our knowledge, this is the first description and functional expression study of a cloned chicken CCK receptor cDNA.
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| 17. |
- Nilsson, Isabelle, 1971-, et al.
(författare)
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Pharmacological analysis of CCK2 receptor ligands using COS-7 and SK-N-MC cells, expressing the human CCK2 receptor
- 2002
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Ingår i: Regulatory Peptides. - 1873-1686 .- 0167-0115. ; 103:1, s. 29-37
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Tidskriftsartikel (refereegranskat)abstract
- A series of CCK2 receptor ligands were analysed with respect to their interaction with binding sites in the membranes of COS-7 cells and SK-N-MC cells transiently expressing the human CCK2 receptor (short isoform). The ligands were YF476, YM022, AG041R, L-740,093, JB93182, PD134308, and PD136450. Their binding was analysed by radioligand competition using [H-3]L-365,260 as the labelled ligand. Saturation binding analysis indicated that [H-3]L-365,260 interacted with a single class of binding sites. In competition binding experiments using COS-7-cell membranes, all seven ligands were incubated together with 2 nM [H-3]L-365,260. The data for four of the compounds fitted a one-site model (pK(i) values: YM022: 9.2 +/- 0.02, YF476: 9.6 +/- 0.04; L-740,093: 9.2 +/- 0.01, and AG041R: 8.3 +/- 0.06), while the data for the three others fitted a two-site model (pK(i) values: JB93182: 8.8 +/- 0.04 and 6.0 +/- 0.15; PD 134308: 9.0 +/- 0.04 and 6.1 +/- 0.15; and PD 136450: 9.0 +/- 0.02 and 5.4 +/- 0.41). SK-N-MC cell membranes and 2 nM [H-3]L-365,260 were incubated together with YM022, YF476, JB93182, and PD134308. The data for YM022 and YF476 fitted a one-site model (pKi values: YM022: 9.3 +/- 0.06, YF476: 9.4 +/- 0.02), while the data for JB93182 and PD134308 fitted a two-site model (pK(i) values: JB93182: 8.7 +/- 0.06 and 6.2 +/- 0.06; PD134308: 9.1 +/- 0.06 and 7.0 +/- 0.17). Competition binding experiments in the presence of the GTP-analogue guanylylimidodiphosphate, using either of the two cell types, produced similar binding data for PD 134308 and JB93182 as in the absence of GTP-analogue. The human receptor seems to exist in a low and/or high affinity state. The shift from low to high affinity does not seem to reflect the degree of G protein coupling.
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| 18. |
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| 19. |
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| 20. |
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| 21. |
- Strömberg, H, et al.
(författare)
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Distribution of the transcription factor Signal Transducer and Activator of Transcription 3 in the rat central nervous system and dorsal root ganglia
- 2000
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Ingår i: Brain Research. - 0006-8993 .- 1872-6240. ; 853:1, s. 105-114
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Tidskriftsartikel (refereegranskat)abstract
- Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor that acts as an intracellular signalling molecule after receptor activation by several cytokines, e.g., interleukin-6, leptin and ciliary neurotrophic factor. We have investigated the localization of STAT3 in the rat central nervous system and dorsal root ganglia. Light microscopic immunohistochemistry showed that STAT3-like immunoreactivity (STAT3-LI) was present in the nucleus and cytoplasm of neurons. STAT3-LI was seen both in cell bodies and in proximal and distal dendrites. Many structures involved in motor functions, such as the ventral horn of the spinal cord, the motor cranial nerve nuclei, the red nucleus and the Purkinje cells of the cerebellum showed STAT3-LI. STAT3-LI was also present in many regions involved in autonomic regulation, such as the intermediolateral cell column of the spinal cord, the nucleus of the solitary tract, the dorsal motor nucleus of the vagus nerve, the area postrema, the locus coeruleus, the Barrington's nucleus and the arcuate, the lateral, the dorsomedial, the ventromedial, and the paraventricular hypothalamic nuclei. Other structures showing STAT3-LI were the dorsal root ganglia, the thalamus (the anterodorsal and paraventricular nucleus), the cerebral neocortex (layer 5) and the olfactory bulb. The wide distribution of STAT3-LI in the nervous system is consistent with reports of cytokine actions in the brain, but the present findings further suggest novel roles for STAT3 in mediating influences of cytokines on specific neuronal circuits regulating motor, sensory and autonomic functions.
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| 22. |
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| 23. |
- Svensson, Samuel, 1962-, et al.
(författare)
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Melanin inhibits cytotoxic effects of doxorubicin and daunorubicin in MOLT 4 cells
- 2003
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Ingår i: Pigment Cell Research. - : Wiley. - 0893-5785 .- 1600-0749. ; 16:4, s. 351-354
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Tidskriftsartikel (refereegranskat)abstract
- In the present study we have developed a simple method to elucidate the melanin binding ability of different chemotherapeutic agents. The anthracyclines, doxorubicin and daunorubicin, or the alkylating agent cisplatin were preincubated with melanin (Sepia). Melanin and free drug was then separated through centrifugation and the cytotoxic effects of corresponding drug were evaluated in a MTT (3-(4,5-dimetyltiazol-2-yl)-2,5-difenyl-tetrazoliumbromide) assay using MOLT-4 cells. Our results show that melanin pretreatment shifted the IC50 value for doxorubicin from 0.06 to 0.97 ╡M and for daunorubicin from 0.04 to 0.80 pM. In contrast, the IC50 values of cisplatin was not influenced by melanin pretreatment indicating that cisplatin does not bind to melanin. By comparing equi-active concentrations from concentration-response curves with or without melanin pretreatment an approximate binding capacity of melanin could be estimated. Our results show that melanin binds about 900 nmol/mg doxorubicin and 760 nmol/mg daunorubicin. Chloroquine, which is known to bind to melanin with high affinity, was found to inhibit melanin binding of both daunorubicin and doxorubicin, thereby leading to an increased sensitivity of the anthracyclines. The clinical implications of melanin binding regarding unwanted accumulation of anthracyclines in the skin as well as chemoprotective effects against chemotherapy are discussed.
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| 24. |
- Svensson, Samuel, 1962-
(författare)
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Melanophore a2-Adrenoceptors.
- 1993
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The present study provides new insight into the pharmacology, the signal transduction mechanisms and the molecular biology of a2-adrenoceptors (a2-ARs) in black pigment cells (melanophores) of a teleost fish, the cuckoo wrasse (Labrus ossifagus L.). Stimulation of these receptors leads to an aggregation of intracellular pigment granules, which is the cellular mechanism underlying the ability of fishes to change color.The pharmacology of the melanophore a2-AR is very similar to its mammalian counterparts. However, the melanophore a2-AR is unique in one respect, UK 14,304, a potent agonist at mammalian a2-ARs, is an antagonist in melanophores.Noradrenaline and the selective a2-AR agonist B-HT 920 are pharmacologically heterogeneous regarding their ability to induce pigment aggregation. This may reflect that B-HT 920 and noradrenaline interact with different a2-AR sites.Pigment aggregation induced by a2-ARs seems to involve multiplesignaling pathways. Attenuation of intracellular cAMP production and a subsequent reduction of protein kinase A activity may serve as one mechanism, and an additional signal mechanism may involve activation of a phosphatase.An a2-adrenoceptor (a2p) from L. ossifagus skin mRNA was cloned. The deduced amino acid sequence showed significant homology with the human a2-ARs. When expressed in a mammalian cell line, the pharmacology of the Melanin-concentrating hormone (MCH) induces pigment aggregationthrough a unique receptor. However, MCH receptors and a2-ARs might share a common signal transduction mechanism, namely attenuation of cAMP production.When melanophores are maintained in tissue culture media, the sensitivity to noradrenaline is increased and the sensitivity to MCH is decreased. This reciprocal change in sensitivity may be due to an increase in a2-AR coupling at the expense of MCH receptor couplingand/or to a down regulation of MCH receptors.
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| 25. |
- Svensson, Sara, et al.
(författare)
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Merged testing for colorectal cancer syndromes and re-evaluation of genetic variants improve diagnostic yield: Results from a nationwide prospective cohort
- 2022
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Ingår i: Genes Chromosomes & Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 61:10, s. 585-591
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Tidskriftsartikel (refereegranskat)abstract
- Approximately 5% of patients with colorectal cancer (CRC) have a Mendelian predisposition for the disease. Identification of the disease-causing genetic variant enables carrier testing and tailored cancer prevention within affected families. To determine the panorama and genetic variation of Mendelian CRC syndromes among referrals at the cancer genetics clinics in Sweden, 850 patients clinically selected for CRC genetic investigation were included in a prospective study that tested for all major hereditary polyposis and nonpolyposis CRC conditions. Genetically defined syndromes were diagnosed in 11% of the patients. Lynch syndrome was predominant (n = 73) followed by familial adenomatous polyposis (n = 12) and MUTYH-associated polyposis (n = 8); the latter of which two patients presented with CRC before polyposis was evident. One patient with a history of adolescent-onset CRC and polyposis had biallelic disease-causing variants diagnostic for constitutional mismatch repair deficiency syndrome. Post-study review of detected variants of unknown clinical significance (n = 129) resulted in the reclassification of variants as likely benign (n = 59) or as diagnostic for Lynch syndrome (n = 2). Our results reveal the panorama of Mendelian CRC syndromes at the cancer genetics clinics in Sweden and show that unified testing for polyposis and nonpolyposis CRC conditions as well as regular reexamination of sequence data improve the diagnostic yield.
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| 26. |
- Testorf, Martin, 1972-, et al.
(författare)
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A model for switch-like phenomena in biological systems
- 2001
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Ingår i: Biophysical Chemistry. - 0301-4622 .- 1873-4200. ; 94:1-2, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- We present a model for the activity of protein clusters based on a simultaneous desorption of an activator (agonist, substrate molecule, etc.) and an inactivator (antagonist, inhibitor, etc.) caused by the collision or interaction between two effector molecules (e.g. receptors, enzymes). This model gives rise to switch-like dose–response curves, which are difficult to explain by ordinary co-operativity. It fits with recent experimental results obtained on single cells. Some other interesting aspects of the model are also pointed out. The model is similar to the model used to explain steep ‘dose–response curves’ in heterogeneous catalysis, caused by the reaction between two different molecules or atoms on the surface of the catalyst.
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| 27. |
- Testorf, Martin, 1972-, et al.
(författare)
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Volume changes of individual melanosomes measured by scanning force microscopy
- 2001
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Ingår i: Pigment Cell Research. - : Wiley. - 0893-5785 .- 1600-0749. ; 14:6, s. 445-449
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Tidskriftsartikel (refereegranskat)abstract
- Black pigment cells, melanophores, e.g. located in the epidermis and dermis of frogs, are large flat cells having intracellular black pigment granules, called melanosomes. Due to a large size, high optical contrast, and quick response to drugs, melanophores are attractive as biosensors as well as for model studies of intracellular processes; e.g. organelle transport and G-protein coupled receptors. The geometry of melanosomes from African clawed toad, Xenopus laevis, has been measured using scanning force microscopy (SFM). Three-dimensional images from SFM were used to measure height, width, and length of the melanosomes (100 from aggregated cells and 100 from dispersed cells). The volumes of melanosomes isolated from aggregated and dispersed melanophores were significantly different (P<0.05, n=200). The average ellipsoidal volume was 0.14±0.01 (aggregated) and 0.17±0.01 μm3 (dispersed), a difference of 18%. The average major diameter was 810±20 and 880±20 nm for aggregated and dispersed melanosomes, respectively. To our knowledge, this is the first time SFM has been used to study melanosomes. This may provide an alternative non-destructive technique that may be particularly suitable for studying morphological aspects of various melanin granules.
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