| 31. |
- Rask-Andersen, Mathias, et al.
(författare)
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Advances in kinase targeting : current clinical use and clinical trials
- 2014
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Ingår i: TIPS - Trends in Pharmacological Sciences. - : Elsevier BV. - 0165-6147 .- 1873-3735. ; 35:11, s. 60-76
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Forskningsöversikt (refereegranskat)abstract
- Phosphotransferases, also known as kinases, are the most intensively studied protein drug target category in current pharmacological research, as evidenced by the vast number of kinase-targeting agents enrolled in active clinical trials. This development has emerged following the great success of small-molecule, orally available protein kinase inhibitors for the treatment of cancer, starting with the introduction of imatinib (Gleevec (R)) in 2003. The pharmacological utility of kinase-targeting has expanded to include treatment of inflammatory diseases, and rapid development is ongoing for kinase-targeted therapies in a broad array of indications in ophthalmology, analgesia, central nervous system (CNS) disorders, and the complications of diabetes, osteoporosis, and otology. In this review we highlight specifically the kinase drug targets and kinase-targeting agents being explored in current clinical trials. This analysis is based on a recent estimate of all established and clinical trial drug mechanisms of action, utilizing private and public databases to create an extensive dataset detailing aspects of more than 3000 approved and experimental drugs.
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| 32. |
- Arner, Anders, et al.
(författare)
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Cross-bridge cycling in smooth muscle: a short review
- 1998
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Ingår i: Acta Physiologica Scandinavica. - 0001-6772. ; 164:4, s. 363-372
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Tidskriftsartikel (refereegranskat)abstract
- This review is focused on the cross-bridge interaction of the organized contractile system of smooth muscle fibres. By using chemically skinned preparations the different enzymatic reactions of actin-myosin interaction have been associated with mechanical events. A rigor state has been identified in smooth muscle and the binding of ATP causes dissociation of rigor cross-bridges at rates slightly slower than those in skeletal muscle, but fast enough not to be rate-limiting for cross-bridge turn over in the muscle fibre. The release of inorganic phosphate (Pi) is associated with force generation, and this process is not rate-limiting for maximal shortening velocity (Vmax) in the fully activated muscle. The binding of ADP to myosin is strong in the smooth muscle contractile system, a property that might be associated with the generally slow cross-bridge turn over. Both force and Vmax are modulated by the extent of myosin light chain phosphorylation. Low levels of activation are considered to be associated with the recruitment of slowly cycling dephosphorylated cross-bridges which reduces shortening velocity. The attachment of these cross-bridge states in skinned smooth muscles can be regulated by cooperative mechanisms and thin filament associated systems. Smooth muscles exhibit a large diversity in their Vmax and the individual smooth muscle tissue can alter its Vmax under physiological conditions. The diversity and the long-term modulation of phenotype are associated with changes in myosin heavy and light chain isoform expression.
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| 33. |
- Arner, Anders, et al.
(författare)
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Effects of Ca2+ on force-velocity characteristics of normal and hypertrophic smooth muscle of the rat portal vein
- 1985
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Ingår i: Acta Physiologica Scandinavica. - 0001-6772. ; 124:4, s. 525-533
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Tidskriftsartikel (refereegranskat)abstract
- Portal hypertension was induced in rats by partial ligation of the hepatic branches of the portal vein. After 5 days of hypertension the portal veins were taken out and mounted for isometric and quick-release experiments. Portal veins from sham-operated normal rats served as controls. The ligated veins had an increased cross-sectional area, indicating smooth-muscle hypertrophy. Although the absolute magnitude of active force of these veins was increased, the active force per cross-sectional area was decreased, indicating an alteration in the properties of the contractile system. No difference in the Ca2+ concentration-response relations to K+-activated intact control and hypertrophic veins was found. In chemically skinned preparations, devoid of functional plasma membranes, the hypertrophic veins had similar Ca2+ sensitivity (in the presence of I microM calmodulin) but a lower force per cross-sectional area. Force-velocity relations were determined in K+-activated intact preparations. In control veins a reduction in extracellular Ca2+ was associated with a significant reduction in both isometric force and maximal shortening velocity (Vmax). In hypertrophic veins the decreased isometric force at maximal activation was associated with a low Vmax. A comparison between hypertrophic and submaximally stimulated control vessels showed corresponding Vmax and isometric force values. We conclude that the low isometric force of hypertrophic veins is associated with a lower rate of cross-bridge turnover. This could be an effect of alterations in the activation mechanisms or in the intrinsic properties of the contractile system itself.
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| 34. |
- Arner, Anders, et al.
(författare)
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Energy turnover and lactate dehydrogenase activity in detrusor smooth muscle from rats with streptozotocin-induced diabetes
- 1993
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Ingår i: Acta Physiologica Scandinavica. - 0001-6772. ; 147:4, s. 375-383
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Tidskriftsartikel (refereegranskat)abstract
- Force generation and tissue glucose metabolism were measured in the urinary bladder smooth muscle from rats with streptozotocin-induced diabetes (7-8 wk duration). Bladder wet wt was almost 4-fold higher in the diabetic animals compared with the untreated controls. Morphological analysis showed that the growth was associated with hypertrophy of the smooth muscle component in the bladder wall. Force generation of isolated bladder strip preparations was measured in vitro at different ambient oxygen tensions. Activation of intramural nerves, with electrical field stimulation, induced contractions that were unaffected by reduction of oxygen tension down to PO2 100 mmHg for both control and diabetic muscle strips. At zero PO2 force was reduced by approximately 10-20%, in both groups. High-K+ solution induced 'tonic' contractions that were slightly more inhibited by lowering PO2. At intermediate PO2 (between 100 and 20 mmHg) the diabetic muscle gave slightly higher force. At zero PO2 no significant difference could be detected between strips from control and diabetic animals. Oxygen consumption and lactate production in the preparations were determined at a PO2 of 290 mmHg and related to the volume of smooth muscle. At zero PO2, lactate formation increased 3- to 4-fold. The metabolic tension cost was lower at zero PO2. No differences in basal and contraction related metabolic rates could be detected between the two groups under normoxic and anoxic conditions. The maximal activity of lactate dehydrogenase (LDH) determined in tissue samples was about 2-fold higher in the diabetic bladder muscle.(ABSTRACT TRUNCATED AT 250 WORDS)
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| 35. |
- Arner, Anders, et al.
(författare)
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Metabolism and force in hypertrophic smooth muscle from rat urinary bladder
- 1990
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Ingår i: American Journal of Physiology: Cell Physiology. - 1522-1563. ; 258:5 Pt 1, s. 923-932
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Tidskriftsartikel (refereegranskat)abstract
- Ten days of urinary outlet obstruction in the rat induced a threefold increase in bladder weight. Active force of control and hypertrophic bladder muscle strips was measured at varying PO2 levels after high-K+, carbachol, or electrical field stimulation. Highest force output was obtained with carbachol. Force per muscle area was lower in the hypertrophic muscles. The basal rates of oxygen consumption and lactate formation were similar in the two groups. The metabolic tension cost (ATP turnover/active force) was similar in the two groups for activation with high K+ and carbachol. In anoxia the active force decreased, but this was less pronounced in the hypertrophied muscle. Hypertrophied muscle could, in contrast to the controls, maintain a sustained K+ contracture in anoxia. Basal metabolic rates and tension cost were markedly reduced in anoxia for both groups. The lower force per area with unaltered tension cost, in hypertrophic muscles under all experimental conditions, may reflect unaltered intrinsic properties of the contractile system, although the amount of contractile material has decreased relative to cell volume. The increased resistance to anoxia may reflect a metabolic adaptation to impaired oxygen supply to the hypertrophied tissue.
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| 36. |
- Arner, Anders, et al.
(författare)
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Structural and mechanical adaptations in rat aorta in response to sustained changes in arterial pressure
- 1984
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Ingår i: Acta Physiologica Scandinavica. - 0001-6772. ; 122:2, s. 119-126
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Tidskriftsartikel (refereegranskat)abstract
- Structural and mechanical adaptations in response to sustained changes in arterial pressure were studied on abdominal aorta of the male rat. Two models were used: 1. Aortic ligature (L), immediately below the renal arteries producing hypotension distal to the knot (duration before sacrifice 6 weeks or 3 months). 2. One-clip renal hypertensive rats (H) (duration 6 weeks). Normotensive sham-operated rats (C) served as controls. At sacrifice mean tail artery pressure was L: 58 +/- 1, C: 110 +/- 3, and H: 163 +/- 5 mmHg (SE, N=6). Segments of abdominal aorta were mounted in vitro for determination of their length-tension relations (activation: High-K+ solution with 2.5 mM Ca2+). At end of experiments the vessels were supramaximally stimulated at optimal circumference (1o) for active force (activation: High-K+ solution with 10 mM Ca2+, and 10(-5) M noradrenaline), and then fixated for light and electron microscopy. Passive and active length-tension relations were shifted towards lower and higher circumference values for hypo- and hypertensive vessels, respectively. The 1o values were L: 3.60 +/- 0.13, C: 4.44 +/- 0.19, and H: 4.91 +/- 0.29 mm. The media thickness at 1o was reduced in L: 56.0 +/- 3.3, and increased in H: 81.3 +/- 2.4 compared to C: 73.4 +/- 1.8 micron. Maximal active wall stress was L: 46.6 +/- 9.8, C: 74.2 +/- 7.0, and H: 83.8 +/- 7.7 mN/mm2. Intracellular volume (ICV) in the media was L: 30 +/- 2, C: 45 +/- 3, and H: 44 +/- 1% (n=4 for each).
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| 37. |
- Brage, M, et al.
(författare)
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Different cysteine proteinases involved in bone resorption and osteoclast formation.
- 2005
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Ingår i: Calcified tissue international. - : Springer Science and Business Media LLC. - 0171-967X .- 1432-0827. ; 76:6, s. 439-47
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Tidskriftsartikel (refereegranskat)abstract
- Cysteine proteinases, especially cathepsin K, play an important role in osteoclastic degradation of bone matrix proteins and the process can, consequently, be significantly inhibited by cysteine proteinase inhibitors. We have recently reported that cystatin C and other cysteine proteinase inhibitors also reduce osteoclast formation. However, it is not known which cysteine proteinase(s) are involved in osteoclast differentiation. In the present study, we compared the relative potencies of cystatins C and D as inhibitors of bone resorption in cultured mouse calvariae, osteoclastogenesis in mouse bone marrow cultures, and cathepsin K activity. Inhibition of cathepsin K activity was assessed by determining equilibrium constants for inhibitor complexes in fluorogenic substrate assays. The data demonstrate that whereas human cystatins C and D are equipotent as inhibitors of bone resorption, cystatin D is 10-fold less potent as an inhibitor of osteoclastogenesis and 200-fold less potent as an inhibitor of cathepsin K activity. A recombinant human cystatin C variant with Gly substitutions for residues Arg8, Leu9, Val10, and Trp106 did not inhibit bone resorption, had 1,000-fold decreased inhibitory effect on cathepsin K activity compared to wildtype cystatin C, but was equipotent with wildtype cystatin C as an inhibitor of osteoclastogenesis. It is concluded that (i) different cysteine proteinases are likely to be involved in bone resorption and osteoclast formation, (ii) cathepsin K may not be an exclusive target enzyme in any of the two systems, and (iii) the enzyme(s) involved in osteoclastogenesis might not be a typical papain-like cysteine proteinase.
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| 38. |
- Chen, Y, et al.
(författare)
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Increase in insulin-like growth factor I in hypertrophying smooth muscle
- 1994
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Ingår i: American Journal of Physiology - Endocrinology and Metabolism. - 1522-1555. ; 266:2 Pt 1, s. 224-229
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Tidskriftsartikel (refereegranskat)abstract
- The present study focuses on the role of the insulin-like growth factor (IGF) system in the development of smooth muscle hypertrophy. Hypertrophy was initiated by partial ligation of portal vein or urethra in female Sprague-Dawley rats weighing approximately 220 g. Levels of mRNA were analyzed by solution hybridization. Seven days after ligation, the wet weight of the portal vein was increased about threefold and the concentration of IGF-I mRNA was increased fourfold. The bladder wet weight was increased twofold 3 days after ligation and fourfold 10 days after ligation. IGF-I mRNA in the bladder was elevated 3-fold after 3 days and 2.5-fold after 10 days, whereas IGF binding protein 2 mRNA was increased approximately 2-fold after 3 days and 5-fold after 10 days. IGF-I receptor mRNA in the hypertrophying bladder remained unchanged. Increased levels of IGF-I were demonstrated with immunohistochemistry in both hypertrophying portal vein and urinary bladder. The results show a specific increase in IGF-I mRNA as well as an increased IGF-I immunoreactivity during hypertrophy of smooth muscle, which suggests that the local IGF-system may play a role in smooth muscle hypertrophy.
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| 39. |
- Cheng, Fang, et al.
(författare)
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Differences in the uptake and nuclear localization of anti-proliferative heparan sulfate between human lung fibroblasts and human lung carcinoma cells
- 2001
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Ingår i: Journal of Cellular Biochemistry. - : Wiley. - 0730-2312 .- 1097-4644. ; 83:4, s. 597-606
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Tidskriftsartikel (refereegranskat)abstract
- Heparan sulfate inhibits the proliferation of normal human lung fibroblasts (HFL-1) but not of a human lung carcinoma cell-line (A549). in this study we investigated possible mechanisms and structural requirements by which anti proliferative heparan sulfates exerts its effects on binding, uptake and subcellular localisation. Both HFL-1 and A549 cells were incubated with I-125- or rhodamine-labeled L-iduronate-rich antiproliferative heparan sulfate species as well as L-iduronate-poor inactive ones. The anti proliferative heparan sulfate was bound to the cell surface on both HFL-1 and A549 cells, but to a lesser extent and with less affinity to A549 cells. Both cell types bound the anti proliferative heparan sulfate with one high- and with one low affinity site. The L-iduronate-poor heparan sulfate bound to a lesser extent and with less affinity to both cell types compared to the anti proliferative heparan sulfate. The antiproliferative heparan sulfate accumulated in the cytoplasm of HFL-1 cells after 24 h incubation, but after 72 h it was found evenly distributed in the nucleus. The time-scale for anti proliferative activity correlated with nuclear localization. In contrast, in A549 cells it was only found near the nuclear membrane. The inactive heparan sulfate was taken up in considerably smaller amounts compared to the antiproliferative heparan sulfate and could not be detected in the nucleus of either HFL-1 or A549 cells. Our data suggest that the anti proliferative activity of L-iduronate-rich heparan sulfate on normal fibroblasts may be due to direct effects on nuclear processes, such as gene transcription.
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| 40. |
- De Basso, Rachel, et al.
(författare)
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Increased carotid plaque burden in men with the fibrillin-1 2/3 genotype
- 2014
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Ingår i: Clinical and Experimental Pharmacology and Physiology. - : Wiley. - 1440-1681 .- 0305-1870. ; 41:9, s. 637-642
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Tidskriftsartikel (refereegranskat)abstract
- Fibrillin-1 (FBN1) is an important constituent of the vascular wall and earlier studies have indicated an effect of the FBN1 2/3 genotype on blood pressure as well as aortic stiffness in men. The aim of the present study was to determine whether the FBN1 2/3 genotype was associated with the presence of carotid plaque and incident cardiovascular morbidity and mortality in middle-aged subjects. The FBN1 genotype was characterized in 5765 subjects (2424 men, 3341 women; age 45-69years) recruited from the Malmo Diet and Cancer Study Cardiovascular Cohort, Sweden. Plaque occurrence and intima-media thickness (IMT) of the carotid artery were assessed by ultrasound. The incidence of first cardiovascular events (myocardial infarction and stroke) and cause-specific mortality were monitored over a mean follow-up period of 13.2years. The most common FBN1 genotypes were 2/2, 2/3 and 2/4, which accounted for 92.2% (n=5317) of subjects. There were no differences between the three genotypes regarding age, blood pressure, glucose, lipids, smoking habits, common carotid artery diameter and intima-media thickness in men and women. The presence of plaque in the carotid artery was higher in men with the 2/3 genotype compared with the 2/2 and 2/4 genotypes (55% vs 46% and 50%, respectively; P=0.007). No similar differences were observed in women. No significant relationship was observed between FBN1 genotypes and the incidence of cardiovascular disease or all-cause mortality. The increased prevalence of plaque in the carotid artery of middle-aged men with the FBN1 2/3 genotype indicates pathological arterial wall remodelling with a more pronounced atherosclerotic burden.
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