51.
Andersson, Karl-Erik, et al.
(författare)
CNS involvement in overactive bladder: pathophysiology and opportunities for pharmacological intervention.
2003
Ingår i: Drugs. - : Adis International. - 0012-6667. ; 63:23, s. 2595-2611
Forskningsöversikt (refereegranskat) abstract
The pathophysiology of overactive bladder (OAB) syndrome is complex, and involves both peripheral and CNS factors. Several CNS disorders are associated with OAB, e.g. stroke, spinal cord injury, Parkinson’s disease and multiple sclerosis, and in each disorder the pathophysiology of OAB can be multifactorial. Irrespective of cause or pathophysiology of OAB, antimuscarinic drugs are the first line of pharmacological treatment. However, adverse effects and limited efficacy makes alternative therapeutic principles desirable. Most alternative drugs used for the treatment of OAB have a peripheral site of action, mainly affecting efferent or afferent neurotransmission or the detrusor muscle itself. New targets for pharmacological intervention may be found in the CNS. Several CNS transmitters/transmitter systems are known to be involved in micturition control, but few drugs with a defined CNS site of action (e.g. baclofen, imipramine and duloxetine) have been used for the treatment of voiding disorders. GABA, glutamate, opioid, serotonin, noradrenaline (norepinephrine), and dopamine receptors and mechanisms are known to influence micturition, and drugs influencing these systems could potentially be developed for the treatment of OAB. Preclinical studies in different animal models have shown that modulation of normal micturition and detrusor overactivity by drugs acting within the spinal cord or supraspinally is possible. Promising results have been obtained in such models, e.g. with drugs interfering with GABA mechanisms, serotonin 5-HT1A receptors, mu-opioid receptors and alpha-adrenoreceptors. However, considering the limited predictability of existing animal models for efficacy in humans, positive proof of concept studies in humans are mandatory. Such studies are scarce and further investigations are needed.
52.
Andersson, Maria A., et al.
(författare)
Evaluation of the potential genotoxicity of chromium picolinate in mammalian cells in vivo and in vitro
2007
Ingår i: Food and Chemical Toxicology. - : Elsevier BV. - 0278-6915 .- 1873-6351. ; 45:7, s. 1097-1106
Tidskriftsartikel (refereegranskat) abstract
Chromium picolinate (CrPic) is a synthetic nutritional supplement primarily used for weight loss and muscle building. Recent studies have indicated that CrPic might be genotoxic and these findings together with the wide-spread consumer use, have increased the concern about its safety. In the present study we investigated the potential genotoxicity of CrPic in mice given a single intraperitoneal injection (up to 3 mg/kg b.wt.) by evaluating the frequency of micronucleated polychromatic erythrocytes (fMNPCE) in peripheral blood, and DNA damage in lymphocytes and hepatocytes. The fMNPCE was evaluated after 42 h and DNA damage after 16 h. Using the Comet assay DNA damage was also monitored in extended-term cultures of human lymphocytes and in L5178Y mouse lymphoma cells that had been exposed for 3 h to 500 μM CrPic under different exposure conditions.A slight, but significant CrPic-induced increase in DNA damage (P < 0.001) was observed in the human lymphocytes, but only when these cells were exposed in the absence of serum. In all other experiments CrPic was found to be without genotoxic effects, both in vivo and in vitro. Taken together, our results suggest that a high concentration of CrPic might be DNA damaging, but only under non-physiological conditions.
53.
Andersson, Maria, et al.
(författare)
Evaluation of catechol-induced DNA damage in human lymphocytes : A comparison between freshly isolated lymphocytes and T-lymphocytes from extended-term cultures
2007
Ingår i: Toxicology in Vitro. - : Elsevier BV. - 0887-2333 .- 1879-3177. ; 21:4, s. 716-722
Tidskriftsartikel (refereegranskat) abstract
Extended-term cultures of proliferating human T-lymphocytes (ETC) may be a practical alternative to freshly isolated non-proliferating peripheral blood lymphocytes (PBL) when studying genotoxicity in vitro. To investigate if the pattern of DNA damage differs between the two in vitro systems, catechol-induced DNA damage was evaluated in PBL and ETC derived from the same blood sample, using three different donors. DNA damage was monitored using the comet assay. Whereas 3 h of exposure to 0.5 mM catechol was found to be without DNA damaging effects, 3 mM was found to induce significant damage both in the PBL and the ETC (the latter being clearly less sensitive). The level of reactive oxygen species (ROS) was also measured in the ETC using the fluorescent probe carboxy-H2DCFA. ROS was found to be considerably increased both at 0.5 and 3 mM catechol. The demonstrated difference in sensitivity towards catechol-induced DNA damage between PBL and ETC may be due to their different proliferative status, but despite this difference both in vitro systems were able to identify catechol as a DNA damaging agent at the same concentration.
54.
Andersson, Maria, et al.
(författare)
Interindividual differences in initial DNA repair capacity when evaluating H2O2-induced DNA damage in extended-term cultures of human lymphocytes using the comet assay
2007
Ingår i: Cell Biology and Toxicology. - : Springer Science and Business Media LLC. - 0742-2091 .- 1573-6822. ; 23:6, s. 401-411
Tidskriftsartikel (refereegranskat) abstract
It has been suggested that extended-term cultures of human lymphocytes could be used as a complement to cell lines based on transformed cells when testing the genotoxicity of chemicals. To investigate whether the pattern of induced DNA damage and its subsequent repair differs significantly between cultures based on different blood donors, hydrogen peroxide (H2O2)-induced DNA damage was measured in cultures from four different subjects using the comet assay. The DNA damage was significantly increased in all cultures after 10 min exposure to 0.25 mmol/L H2O2, and there was a significant decrease in the H2O2-induced DNA damage in all cultures after 30 min of DNA repair. The level of damage varied between the different donors, especially after the repair. Using PCR and DNA sequencing, exon 5 of the p53 gene was sequenced in the lymphocytes from the donors with the lowest and highest residual damage. No such mutation was found. Mouse lymphoma L5178Y cells carrying the p53 mutation in exon 5 were included as a reference. These cells were found to be less sensitive toward the H2O2-induced DNA damage, and they were also found to have a rather low DNA repair capacity. The demonstrated variation in H2O2-induced DNA damage and DNA repair capacity between the cultures from the different subjects may be important from a risk assessment perspective, but is obviously not of decisive importance when it comes to the development of a routine assay for genotoxicity.
55.
Andersson, Roland, et al.
(författare)
Treatment of acute pancreatitis: focus on medical care.
2009
Ingår i: Drugs. - : Adis International. - 0012-6667. ; 69:5, s. 505-514
Tidskriftsartikel (refereegranskat) abstract
Acute pancreatitis has an incidence of about 300 per 1 million individuals per year, of which 10-15% of patients develop the severe form of the disease. Novel management options, which have the potential to improve outcome, include initial proper fluid resuscitation, which maintains microcirculation and thereby potentially decreases ischaemia and reperfusion injury. The traditional treatment concept in acute pancreatitis, fasting and parenteral nutrition, has been challenged and early initiation of enteral feeding in severe pancreatitis and oral intake in mild acute pancreatitis is both feasible and provides some benefits. There are at present no data supporting immunonutritional supplements and probiotics should be avoided in patients with acute pancreatitis. There is also no evidence of any benefits provided by prophylactic antibacterials in patients with predicted severe acute pancreatitis. A variety of specific medical interventions have been investigated (e.g. intense blood glucose monitoring by insulin) but none has become clinically useful. Lessons can probably be learned from critical care in general, but studies are needed to verify these interventions in acute pancreatitis.
56.
57.
Annas, Anita, et al.
(författare)
Differential response of cultured human umbilical vein and artery endothelial cells to Ah receptor agonist treatment : CYP-dependent activation of food and environmental mutagens
2000
Ingår i: Toxicology and Applied Pharmacology. - : Elsevier BV. - 0041-008X .- 1096-0333. ; 169:1, s. 94-101
Tidskriftsartikel (refereegranskat) abstract
In the present study, 7-ethoxyresorufin O-deethylase (EROD), 7,12-dimethylbenz[a]anthracene (DMBA)-hydroxylase, and covalent binding of H-3-labeled 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (H-3-Trp-P-1) and H-3-DMBA were examined in human umbilical vein endothelial cells (HUVEC) and human umbilical artery endothelial cells (HUAEC) exposed to the aryl hydrocarbon (Ah) receptor agonist beta -naphthoflavone (BNF) or vehicle only. The results revealed a marked induction of enzymatic activity in BNF-treated HUVEC compared with vehicle-treated cells, whereas no similar response was observed in BNF-treated HUAEC. EROD, DMBA hydroxylase, and covalent binding of H-3-Trp-P-1 and H-3-DMBA in BNF-treated HUVEC were reduced in the presence of the CYP1A inhibitor ellipticine. Addition of other CYP1A inhibitors ru-naphthoflavone, miconazole, 1-ethynylpyrene, 1-(1-propynyl)pyrene, or the CYP1A substrate ethoyresorufin to the incubation buffer of BNF-treated HUVEC reduced covalent binding of H-3-Trp-P-1 by 93-98%. Western blot analysis confirmed an induction of CYP1A1 in BNF-treated HUVEC, but not in BNF-treated HUAEC. CYP1A1 was, however, detected in both vehicle- and BNF-treated HUAEC. The results showed that BNF exposure induced CYP1A1 and metabolic activation of xenobiotics in HUVEC, whereas the catalytic activity remained low in BNF-treated HUAEC. Our results suggest that endothelial lining of human veins may be a target for adverse effects of xenobiotics activated into reactive metabolites by Ah receptor-regulated enzymes. Several studies have detected CYP1A1 in endothelial linings, whereas expression of CYP1A2 and CYP1B1 seems to be negligible at this site. This suggests that the metabolic activation and covalent binding of H-3-Trp-P-1 and H-3-DMBA in HUVEC are most likely mediated by CYP1A1.
58.
Annas, Anita
(författare)
Metabolism-dependent activation of food and environmental mutagens in endothelial cells
2000
Doktorsavhandling (övrigt vetenskapligt) abstract
The endothelial cells of blood vessels have been proposed as a target for toxic effects ofxenobiotics in the cardiovascular system. In the present studies, induction of cytochromeP450 1A (CYP1A) enzymes and metabolic activation of food and environmentalmutagens were examined in endothelial cells of rodents, birds, and humans. Theheterocyclic amine 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and thepolycyclic aromatic hydrocarbons 7,12-dimethylbenz[a]anthracene (DMBA) andbenzo[a]pyrene were used as models for food and environmental mutagens.The results showed that Trp-P-1 was activated into tissue-binding metabolites in endothelial cells, preferentially of capillaries and veins, in rodents pretreated with the aryl hydrocarbon (Ah) receptor agonist β-naphthoflavone (BNF), whereas similar activationdid not occur in vehicle-treated animals. Similarly, exposure to BNF increased the tissue-binding of Trp-P-1 and DMBA in cultured human umbilical vein endothelial cells (HUVEC), as compared with vehicle-treated cells. In contrast, exposure to BNF did not increase the binding of the mutagens in human umbilical artery endothelial cells (HUAEC). The formation of reactive metabolites of Trp-P-1 and DMBA correlated with induction of CYP1A1 protein and/or CYP1A-dependent catalytic activities, such as 7-ethoxyresorufin O-deethylase (EROD) and DMBA hydroxylase, in endothelial cells of rodents and cultured HUVEC. Moreover, exposure to BNF increased the activation ofbenzo[a]pyrene into genotoxic metabolites in HUVEC as compared with vehicle-treated cells.In chicken and eider duck embryos, BNF induced EROD and activation of Trp-P-1 to tissue binding metabolites in the endothelial linings, preferentially of capillaries and veins, in heart and chorioallantoic membrane (CAM). In vehicle-treated embryos, these activities were low.Overall, the present studies show that CYP1A-dependent activation of xenobiotics into tissue binding or genotoxic metabolites can be induced in blood vessel endothelia in various species following exposure to Ah receptor agonists. The results also show that there is a differential response to Ah receptor agonists within the vascular tree; CYP1A and enzymatic activities are preferentially induced in endothelial cells of veins and capillaries, and to lesser extent in arteries. The results suggest that certain endothelial cellsmay be targets for CYP1A-dependent activation of xenobiotics in individuals exposed to Ah receptor agonists.
59.
Appukkuttan, Prasad, et al.
(författare)
Microwave-assisted transition-metal-catalyzed synthesis of N-shifted and ring-expanded buflavine analogues
2007
Ingår i: Chemistry - A European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 13:22, s. 6452-6460
Tidskriftsartikel (övrigt vetenskapligt) abstract
Two novel and efficient strategies for the synthesis of hitherto unknown N-shifted and ring-expanded buflavine analogues are presented. Construction of the medium-sized ring system of the title molecules, a difficult task due to the high activation energy needed for the ring-closure with the additional rigidity imposed by the biaryl skeleton, was achieved by using Suzuki-Miyaura biaryl coupling and a ring-closing metathesis reaction as the key steps. The combination of a second-generation Grubbs catalyst and microwave irradiation proved to be highly useful in generating the otherwise difficult to obtain medium-sized ring system of the buflavine analogues.
60.
Araya, Zufan, et al.
(författare)
Metabolism of 25-hydroxyvitamin D3 by microsomal and mitochondrial vitamin D3 25-hydroxylases (CYP2D25 and CYP27A1) : a novel reaction by CYP27A1
2003
Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - 1388-1981 .- 1879-2618. ; 1632:1-21-3, s. 40-47
Tidskriftsartikel (refereegranskat) abstract
The metabolism of 25-hydroxyvitamin D(3) was studied with a crude mitochondrial cytochrome P450 extract from pig kidney and with recombinant human CYP27A1 (mitochondrial vitamin D(3) 25-hydroxylase) and porcine CYP2D25 (microsomal vitamin D(3) 25-hydroxylase). The kidney mitochondrial cytochrome P450 catalyzed the formation of 1alpha,25-dihydroxyvitamin D(3), 24,25-dihydroxyvitamin D(3) and 25,27-dihydroxyvitamin D(3). An additional metabolite that was separated from the other hydroxylated products on HPLC was also formed. The formation of this 25-hydroxyvitamin D(3) metabolite was dependent on NADPH and the mitochondrial electron transferring protein components. A monoclonal antibody directed against purified pig liver CYP27A1 immunoprecipitated the 1alpha- and 27-hydroxylase activities towards 25-hydroxyvitamin D(3) as well as the formation of the unknown metabolite. These results together with substrate inhibition experiments indicate that CYP27A1 is responsible for the formation of the unknown 25-hydroxyvitamin D(3) metabolite in kidney. Recombinant human CYP27A1 was found to convert 25-hydroxyvitamin D(3) into 1alpha,25-dihydroxyvitamin D(3), 25,27-dihydroxyvitamin D(3) and a major metabolite with the same retention time on HPLC as that formed by kidney mitochondrial cytochrome P450. Gas chromatography-mass spectrometry (GC-MS) analysis of the unknown enzymatic product revealed it to be a triol different from other known hydroxylated 25-hydroxyvitamin D(3) metabolites such as 1alpha,25-, 23,25-, 24,25-, 25,26- or 25,27-dihydroxyvitamin D(3). The product had the mass spectrometic properties expected for 4beta,25-dihydroxyvitamin D(3). Recombinant porcine CYP2D25 converted 25-hydroxyvitamin D(3) into 1alpha,25-dihydroxyvitamin D(3) and 25,26-dihydroxyvitamin D(3). It can be concluded that both CYP27A1 and CYP2D25 are able to carry out multiple hydroxylations of 25-hydroxyvitamin D(3).
