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1.	Molinaro, Angela, et al. (author) Insulin-Driven PI3K-AKT Signaling in the Hepatocyte Is Mediated by Redundant PI3Kα and PI3Kβ Activities and Is Promoted by RAS. 2019 In: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 29:6 Journal article (peer-reviewed)abstract Phosphatidylinositol-3-kinase (PI3K) activity is aberrant in tumors, and PI3K inhibitors are investigated as cancer therapeutics. PI3K signaling mediates insulin action in metabolism, but the role of PI3K isoforms in insulin signaling remains unresolved. Defining the role of PI3K isoforms in insulin signaling is necessary for a mechanistic understanding of insulin action and to develop PI3K inhibitors with optimal therapeutic index. We show that insulin-driven PI3K-AKT signaling depends on redundant PI3Kα and PI3Kβ activities, whereas PI3Kδ and PI3Kγ are largely dispensable. We have also found that RAS activity promotes AKT phosphorylation in insulin-stimulated hepatocytes and that promotion of insulin-driven AKT phosphorylation by RAS depends on PI3Kα. These findings reveal the detailed mechanism by which insulin activates AKT, providing an improved mechanistic understanding of insulin signaling. This improved model for insulin signaling predicts that isoform-selective PI3K inhibitors discriminating between PI3Kα and PI3Kβ should bedosed below their hyperglycemic threshold to achieve isoform selectivity.
2.	Mondal, Tanmoy, 1981, et al. (author) Sense-antisense lncRNA pair encoded by locus 6p22.3 determines neuroblastoma susceptibility via the USP36-CHD7-SOX9 regulatory axis 2018 In: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 33:3 Journal article (peer-reviewed)abstract Trait-associated loci often map to genomic regions encoding long noncoding RNAs (lncRNAs), but the role of these lncRNAs in disease etiology is largely unexplored. We show that a pair of sense/antisense lncRNA (6p22lncRNAs) encoded by CASC15 and NBAT1 located at the neuroblastoma (NB) risk-associated 6p22.3 locus are tumor suppressors and show reduced expression in high-risk NBs. Loss of functional synergy between 6p22lncRNAs results in an undifferentiated state that is maintained by a gene-regulatory network, including SOX9 located on 17q, a region frequently gained in NB. 6p22lncRNAs regulate SOX9 expression by controlling CHD7 stability via modulating the cellular localization of USP36, encoded by another 17q gene. This regulatory nexus between 6p22.3 and 17q regions may lead to potential NB treatment strategies.
3.	Magnusson, Marie, et al. (author) A placebo-controlled study of retinal blood flow changes by pentoxifylline and metabolites in humans 2006 In: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 61:2, s. 138-147 Journal article (peer-reviewed)abstract AIM: To investigate the possible effects of pentoxifylline metabolites on retinal blood flow in humans. METHODS: A randomized, placebo-controlled, four-period cross-over study that was observer blinded and partly blinded for the eight participants. On one occasion a placebo was given as an intravenous (i.v.) infusion over 100 min. On the other three occasions pentoxifylline was administered as i.v. infusions over 100 min at a rate of 3 mg min(-1). Before two of the pentoxifylline infusions the subjects were pretreated with either ciprofloxacin or rifampicin. Retinal blood flow was measured by scanning laser doppler flowmetry (SLDF) in a selected area of the central temporal retina before, during and until 5 h after the end of infusion. Blood samples for concentration analyses of pentoxifyllin, R-M1, S-M1, M4 and M5 were taken serially and areas under the curves (AUCs) were calculated. Linear mixed models were used for the statistical analyses. RESULTS: Mean AUCs (ng h ml(-1)) were significantly increased for pentoxifylline (1964 vs. 1453) and S-M1 (5804 vs. 4227), but not R-M1 when pentoxifylline was co-administered with ciprofloxacin. The mean AUC for M5 was significantly reduced when subjects were pretreated with rifampicin (2041 vs. 3080). Pentoxifylline with and without pretreatment with rifampicin significantly increased retinal blood flow assessed as mean flow, pulsation (i.e. 1-systole/diastole), and diastolic flow (but not during systole), compared with placebo. The increases over placebo were more pronounced on diastolic flow, 9.7% (95% confidence interval 4.2, 15.5) than on mean flow, 4.6% (1.1, 8.3) after pentoxifylline administration. With pentoxifylline after rifampicin pretreatment the corresponding differences were 11.7% (5.8, 17.9) and 5.1% (1.4, 7.8) over placebo, respectively. After co-administration of pentoxifylline and ciprofloxacin we saw only a nonsignificant trend towards increased flow during diastole, but a significant decrease in pulsation. When AUCs for pentoxifylline and its metabolites were used as regressor variables to retinal mean flow we found that pentoxifylline, R-M1 and M5 had coefficients with a positive sign indicating that they enhanced the retinal blood flow. In contrast, S-M1 and M4 had coefficients with negative sign and thus appeared to decrease the blood flow in subjects treated with pentoxifylline. CONCLUSION: The R-M1 and M5 metabolites of pentoxifylline contributed significantly to the effects of pentoxifylline on retinal blood flow.
4.	Tjondro, Harry C., et al. (author) Hyper-truncated Asn355- And Asn391-glycans modulate the activity of neutrophil granule myeloperoxidase 2021 In: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 296 Journal article (peer-reviewed)abstract Myeloperoxidase (MPO) plays essential roles in neutrophil-mediated immunity via the generation of reactive oxidation products. Complex carbohydrates decorate MPO at discrete sites, but their functional relevance remains elusive. To this end, we have characterised the structure–biosynthesis–activity relationship of neutrophil MPO (nMPO). Mass spectrometry demonstrated that nMPO carries both characteristic under-processed and hyper-truncated glycans. Occlusion of the Asn355/Asn391-glycosylation sites and the Asn323-/Asn483-glycans, located in the MPO dimerisation zone, was found to affect the local glycan processing, thereby providing a molecular basis of the site-specific nMPO glycosylation. Native mass spectrometry, mass photometry and glycopeptide profiling revealed significant molecular complexity of diprotomeric nMPO arising from heterogeneous glycosylation, oxidation, chlorination and polypeptide truncation variants and a previously unreported low-abundance monoprotomer. Longitudinal profiling of maturing, mature, granule-separated and pathogen-stimulated neutrophils demonstrated that nMPO is dynamically expressed during granulopoiesis, unevenly distributed across granules and degranulated upon activation. We also show that proMPO-to-MPO maturation occurs during early/mid-stage granulopoiesis. While similar global MPO glycosylation was observed across conditions, the conserved Asn355-/Asn391-sites displayed elevated glycan hyper-truncation, which correlated with higher enzyme activities of MPO in distinct granule populations. Enzymatic trimming of the Asn355-/Asn391-glycans recapitulated the activity gain and showed that nMPO carrying hyper-truncated glycans at these positions exhibits increased thermal stability, polypeptide accessibility and ceruloplasmin-mediated inhibition potential relative to native nMPO. Finally, molecular modelling revealed that hyper-truncated Asn355-glycans positioned in the MPO-ceruloplasmin interface are critical for uninterrupted inhibition. Here, through an innovative and comprehensive approach, we report novel functional roles of MPO glycans, providing new insight into neutrophil-mediated immunity.
5.	Eriksson, Leif A., 1964-, et al. (author) Tetrazole derivatives as cytochrome p450 inhibitors 2019 Patent (pop. science, debate, etc.)abstract According to the invention there is provided a compound of formula I, wherein R1 and R2 have meanings given in the description, which compounds are useful in the treatment of skin disorders and other diseases.
6.	Lind, Marcus, et al. (author) Thrombomodulin as a marker for bleeding complications during warfarin treatment 2009 In: Archives of Internal Medicine. - : American Medical Association (AMA). - 0003-9926 .- 1538-3679. ; 169:13, s. 1210-1215 Journal article (peer-reviewed)abstract BACKGROUND: The major adverse effect of warfarin treatment is hemorrhage. Several risk factors for bleeding complications are also risk factors for thromboembolic events, making the clinical decision to initiate or withhold anticoagulant treatment difficult. Specific markers that solely identify patients at high risk of bleeding would have great clinical impact. This study aimed to test if thrombomodulin (TM) concentrations were associated with bleeding complications, cardiovascular events, or mortality in long-term anticoagulant-treated patients. METHODS: In a longitudinal cohort study we followed up 719 patients receiving warfarin treatment for a mean duration of 4.2 years. All bleeding complications causing hospitalization were registered and classified. Soluble TM antigen (sTM) concentration in plasma was measured with an enzyme-linked immunosorbent assay method. RESULTS: During the follow-up time, 113 clinically relevant bleeding events and 73 major bleeding events occurred. Increased concentration of sTM was associated with both clinically relevant bleeding and major bleeding events after adjustment for age. In the multivariable models, hazard ratios for the highest tertiles compared with the lowest were 2.29 (95% confidence interval, 1.35-3.89) and 2.33 (95% confidence interval, 1.21-4.48), respectively. No association between sTM concentration and nonfatal ischemic cardiovascular events or all-cause mortality was found. CONCLUSIONS: Increased levels of sTM are associated with bleeding complications during warfarin treatment but not with cardiovascular events or all-cause mortality. Soluble TM antigen concentration has potential as a new specific marker to identify patients at high risk of bleeding during warfarin treatment.
7.	Greiff, Lennart, et al. (author) Effects of topical platelet activating factor on the guinea-pig tracheobronchial mucosa in vivo 1997 In: Acta Physiologica Scandinavica. - 0001-6772. ; 160:4, s. 387-391 Journal article (peer-reviewed)abstract Platelet activating factor (PAF) has been reported to produce a variety of airway effects including epithelial damage and increased airway-lung absorption of hydrophilic tracers. The present study examines effects of PAF on the guinea-pig tracheobronchial mucosa in vivo. Vehicle with and without PAF (4.0 and 8.0 nmol) was superfused onto the tracheobronchial mucosa. The levels of 125I-albumin, previously given intravenously, were determined in tracheobronchial lavage fluids as an index of mucosal exudation of plasma. The mucosa was also examined by scanning electron microscopy. In separate animals, 99mTc-DTPA (a low molecular weight, 492 Da, hydrophilic tracer) was superfused onto the mucosal surface through an oro-tracheal catheter, together with vehicle or PAF (8.0 nmol). A gamma camera determined the disappearance rate of 99mTc-DTPA from the airways as an index of mucosal absorption. PAF produced dose-dependent mucosal exudation of plasma up to 20-fold greater than control (P < 0.001). However, PAF did not damage the epithelium and the absorption ability of the airway mucosa was unaffected. The results, in contrast to previous reports, suggest that PAF may not readily damage the airway mucosa even at large exudative doses of the agent. The present finding support the view that the plasticity of the epithelial junctions allows the creation of valve-like paracellular pathways for unidirectional clearance of extravasated plasma into the airway lumen. We suggest that endogenous PAF may participate in first line respiratory defence reactions by causing lumenal entry of bulk plasma without harming the epithelium.
8.	Ekman, Elisabet, et al. (author) Awareness among nurses about reporting of adverse drug reactions in Sweden 2012 In: Drug, Healthcare and Patient Safety. - 1179-1365. ; 4, s. 61-66 Journal article (peer-reviewed)abstract Background: The purpose of this study was to investigate awareness among nurses regarding their new role as reporters of adverse drug reactions in Sweden and factors that may influence reporting by nurses.Methods: In 2007, all nurses were included in the adverse drug reaction reporting scheme in Sweden. A questionnaire was sent to 753 randomly selected nurses in September 2010.Results: Of the 453 (60%) responding nurses, 265 (58%) were aware that nurses were included in the reporting of adverse drug reactions. Sixty-one nurses (14%) stated that they had reported an adverse drug reaction. Fifteen percent (n = 70) of the respondents had received training about reporting of adverse drug reactions. Almost one third of these (n = 21, 30%) had reported an adverse drug reaction on at least one occasion. Among nurses without training, a smaller proportion (n = 40, 11%, P < 0.05) had reported an adverse drug reaction on at least one occasion. The two factors considered most important by nurses for reporting were the severity of the adverse drug reaction and if the reaction was to a newly approved drug. A majority of the nurses (n = 397, 88%) were interested in a training course in pharmacology as part of their ongoing professional development. One third (32%) of all nurses stated that one reason for not reporting a suspected adverse drug reaction was that the physician responsible did not regard the reaction necessary to report.Conclusion: We found that more than half of the study population of nurses in Sweden were aware of their new role as reporters of adverse drug reactions, but few of the responding nurses had reported an adverse drug reaction. Given that training seems to be associated with high reporting frequency, we suggest more training in pharmacovigilance for nurses.
9.	Lehmann, Anders, et al. (author) Discovery of New Drugs for Weight Loss and Prevention of Weight Regain 2016 In: Neuroendocrinology of Appetite. S Dickson & J Mercer (eds.). - Chichester, UK : John Wiley & Sons, Ltd. - 9781118839324 ; , s. 247-284 Book chapter (peer-reviewed)
10.	Lai, Kuei-Hung, et al. (author) Separation and identification on stereoisomers of manoalide derivatives and their configuration-depending antileukemic effects in vitro and in vivo Other publication (other academic/artistic)
11.	Lai, Kuei-Hung (author) Studies on anti-leukemic terpenoids from medicinal mushrooms and marine sponges with ChemGPS-NP-based targets investigation of lead compounds 2017 Doctoral thesis (other academic/artistic)abstract This thesis investigates the anti-leukemic activity of terpenoids isolated from medicinal mushrooms and marine sponges, as well as their possible targets and mechanisms of action.In the first section, we focused on studying the triterpenoidal components of three triterpenoid-enriched medicinal mushrooms Antrodia cinnamomea, Ganoderma lucidum, and Poria cocos, which have been used in folk medicine for centuries and also developed into several contemporary marketed products. We isolated the major and characteristic triterpenoids from these mushrooms, together with six new lanostanoids (II-1–II-6). The anti-leukemic activity of the isolates was evaluated in vitro using MTT proliferative assay and seven of them exhibited potential anti-leukemic effect. The active lead compounds were further subjected to computational analyses utilizing the ChemGPS-NP tool. We established a database for the anti-leukemic relevant chemical space of triterpenoids isolated from these three medicinal mushrooms, which could be used as a reference database for further research on anti-leukemic triterpenoids. Our results indicated that the anti-leukemic effect of the active lead compounds was mediated not only through topoisomerases inhibition but also through inhibiting DNA polymerases.The second and third sections focused on isolation of anti-leukemic sesterterpenoids from sponges. The investigation of Carteriospongia sp. led to the isolation of two new scalarane-type sesterterpenoids (III-1 and III-2) and one known tetraprenyltoluquinol-related metabolite (III-3). All isolates exhibit an apoptotic mechanism of action against Molt 4 cells, found to be mediated through the disruption of the mitochondrial membrane potential (MMP) and inhibition of topoisomerase IIα expression. Detailed investigation of the apoptotic mechanism of action using molecular docking analysis revealed that compound III-1 might target Hsp90 protein. The apoptotic-inducing effect of III-3 was supported by in vivo experiment by suppressing the volume of xenograft tumor growth (47.58%) compared with the control.In the final section of this thesis we studied manoalide and its derivatives, sesterterpenoids isolated from the sponge Luffariella sp.. Manoalide has been studied as a potential anti-inflammatory agent for the last thirty years with more than 200 publications and 40 patents. However, the configurations at positions 24 and 25 were never revealed. In the current study, ten manoalide-type sesterterpenoids (IV-1–IV-10) were isolated from Luffariella sp. and their stereoisomers at positions 24 and 25 were identified and separated for the first time. The configuration at positions 24 and 25 showed to have a significant effect on the anti-leukemic activity of manoalide derivatives, with the 24R,25S-isomer exhibiting the most potent anti-leukemic activity. The apoptotic mechanism of action of compound IV-7 against Molt 4 cells was investigated, and the compound was found to trigger MMP disruption and intracellular reactive oxygen species (ROS) generation. Compound IV-7 also inhibited activity against both human topoisomerases, I and II. The in vivo experiment further supported the anti-leukemic effect of IV-7 with a 66.11% tumor volume suppression compared to the control.
12.	Persson, Carl, et al. (author) Unbalanced research 2001 In: Trends in Pharmacological Sciences. - 0165-6147. ; 22:10, s. 538-541 Journal article (peer-reviewed)
13.	Lindén, Thomas, 1962, et al. (author) Recurrent Stroke Prevention: Diuretic and Angiotensin-Converting Enzyme Inhibitors (ACEIs)—The PROGRESS Trial. 2011 In: Hypertension and stroke - pathophysiology and management. - New York : Springer Humana Press. - 9783319291529 ; , s. 143-157 Book chapter (peer-reviewed)
14.	Nilsson, Bengt-Olof, et al. (author) Effects of polyamine synthesis inhibition on polyamines, growth and mechanical properties in hypertrophic rat urinary bladder 1998 In: Pharmacology and Toxicology. - 1600-0773. ; 82:6, s. 287-294 Journal article (peer-reviewed)abstract The polyamines putrescine, spermidine and spermine, are ubiquitous intracellular metabolites associated with growth and protein synthesis. In this study effects of polyamine synthesis inhibition on bladder growth, polyamine levels and mechanical properties were investigated in rat urinary bladder subjected to partial outflow obstruction that causes bladder hypertrophy. The S-adenosyl methionine decarboxylase inhibitor CGP-48664 (5 and 20 mg kg-1) was administered alone or in combination with the ornithine decarboxylase inhibitor DFMO (500 mg kg-1), starting one day before creation of partial outflow obstruction and then daily for 7 days. The bladder muscle level of putrescine was increased 38 times and that of spermine reduced by 4 times while spermidine was unchanged after treatment with CGP-48664 (20 mg kg-1). The increase in putrescine was abolished in animals receiving CGP-48664 in combination with DFMO. Treatment with polyamine synthesis inhibitors could not prevent or reduce the hypertrophy of the bladder as judged by bladder wet weight and protein contents. The effects on polyamine quantities were not associated with changes in Ca(2+)-force relationship or in agonist and electrically stimulated force. In summary, treatment of rats with polyamine synthesis inhibitors resulted in changes in polyamine levels in the growing urinary bladder but did not affect growth or mechanical properties.
15.	Pesonen, Erkki, et al. (author) Elevated infection parameters and infection symptoms predict an acute coronary event. 2008 In: Therapeutic Advances in Cardiovascular Disease. - : SAGE Publications. - 1753-9447 .- 1753-9455. ; 2:6, s. 419-424 Journal article (peer-reviewed)abstract BACKGROUND: The etiology and significance of flu-like symptoms often appearing before myocardial infarction should be clarified. METHODS: In a case-control study of 323 matched controls and a random sample of 110 out of 351 cases the presence of infection symptoms during the preceding four weeks before admission were asked and blood samples taken. RESULTS: Enterovirus (EV), herpes simplex virus (HSV), and Chlamydia pneumoniae IgA titers were significantly higher in cases than in controls (p<0.001, 0.008 and 0.046, respectively). Flu-like symptoms appeared significantly more often in patients than in controls the most common one being fatigue (p<0.001). In controls with fatigue, EV and HSV titers showed a trend to be higher (1.50 vs 1.45 and 4.29 vs 3.73) than in controls without fatigue but only HSV titers were statistically significantly higher (3.47 vs 3.96, p = 0.02). Even CRP and amyloid A concentrations (3.49 vs 2.08, p<0.0001 and 5.70 vs 3.77 mg/l, p = 0.003, respectively) as well as C4 (0.40 vs 0.44, p = 0.02) were higher in controls with fatigue. CONCLUSIONS: Odds ratios for a coronary event in a logistic regression model were 4.79 for fatigue and 2.72 for EV antibody levels in their fourth quartile. A linear-by-linear association test showed increasing number of single symptoms with higher EV titer quartiles (p = 0.004).
16.	Senkowski, Wojciech (author) High-throughput screening using multicellular tumor spheroids to reveal and exploit tumor-specific vulnerabilities 2017 Doctoral thesis (other academic/artistic)abstract High-throughput drug screening (HTS) in live cells is often a vital part of the preclinical anticancer drug discovery process. So far, two-dimensional (2D) monolayer cell cultures have been the most prevalent model in HTS endeavors. However, 2D cell cultures often fail to recapitulate the complex microenvironments of in vivo tumors. Monolayer cultures are highly proliferative and generally do not contain quiescent cells, thought to be one of the main reasons for the anticancer therapy failure in clinic. Thus, there is a need for in vitro cellular models that would increase predictive value of preclinical research results. The utilization of more complex three-dimensional (3D) cell cultures, such as multicellular tumor spheroids (MCTS), which contain both proliferating and quiescent cells, has therefore been proposed. However, difficult handling and high costs still pose significant hurdles for application of MCTS for HTS.In this work, we aimed to develop novel assays to apply MCTS for HTS and drug evaluation. We also set out to identify cellular processes that could be targeted to selectively eradicate quiescent cancer cells. In Paper I, we developed a novel MCTS-based HTS assay and found that nutrient-deprived and hypoxic cancer cells are selectively vulnerable to treatment with inhibitors of mitochondrial oxidative phosphorylation (OXPHOS). We also identified nitazoxanide, an FDA-approved anthelmintic agent, to act as an OXPHOS inhibitor and to potentiate the effects of standard chemotherapy in vivo. Subsequently, in Paper II we applied the high-throughput gene-expression profiling method for MCTS-based drug screening. This led to discovery that quiescent cells up-regulate the mevalonate pathway upon OXPHOS inhibition and that the combination of OXPHOS inhibitors and mevalonate pathway inhibitors (statins) results in synergistic toxicity in this cell population. In Paper III, we developed a novel spheroid-based drug combination-screening platform and identified a set of molecules that synergize with nitazoxanide to eradicate quiescent cancer cells. Finally, in Paper IV, we applied our MCTS-based methods to evaluate the effects of phosphodiesterase (PDE) inhibitors in PDE3A-expressing cell lines.In summary, this work illustrates how MCTS-based HTS yields potential to reveal and exploit previously unrecognized tumor-specific vulnerabilities. It also underscores the importance of cell culture conditions in preclinical drug discovery endeavors.
17.	Brage, M, et al. (author) Different cysteine proteinases involved in bone resorption and osteoclast formation. 2005 In: Calcified tissue international. - : Springer Science and Business Media LLC. - 0171-967X .- 1432-0827. ; 76:6, s. 439-47 Journal article (peer-reviewed)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.
18.	Belfrage, Per, et al. (author) Alterations of lipid metabolism in healthy volunteers during long-term ethanol intake 1977 In: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 7:2, s. 127-131 Journal article (peer-reviewed)abstract Nine young, healthy male volunteers were given ethanol (75 g/day) for 5 weeks. The ethanol was divided into five daily doses and taken so that blood ethanol levels never exceeded 0.04% (w/v). During the latter part of the ethanol intake period, there was a significant, transient increase of plasma triglyceride (TG) concentrations followed by reduction to normal levels. A three-fold increase of lipoprotein lipase activity (LLA) occurred in biopsy specimens of adipose tissue. An increase of alpha-lipoprotein concentrations, which correlated significantly with the decrease in plasma TG levels and the increase in adipose LLA, was also observed during the ethanol intake period. No changes were observed in plasma cholesterol and beta-lipoprotein levels. A transient, three-fold increase of TG concentrations occurred in liver biopsy specimens. Ultrastructural and cytochemical examinations of the biopsy specimens showed hyperplasia of the smooth endoplasmic reticulum, and increased canallicular activity of gamma-glutamyl transferase (gamma-GT) activity in most subjects towards the end of and after the ethanol intake period. Serum gamma-GT levels also increased significantly.
19.	Zhang, Cheng, et al. (author) Discovery of therapeutic agents targeting PKLR for NAFLD using drug repositioning 2022 In: eBioMedicine. - : Elsevier BV. - 2352-3964. ; 83 Journal article (peer-reviewed)abstract Background Non-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver pathologies. However, no medical treatment has been approved for the treatment of NAFLD. In our previous study, we found that PKLR could be a potential target for treatment of NALFD. Here, we investigated the effect of PKLR in in vivo model and performed drug repositioning to identify a drug candidate for treatment of NAFLD. Methods Tissue samples from liver, muscle, white adipose and heart were obtained from control and PKLR knock-out mice fed with chow and high sucrose diets. Lipidomics as well as transcriptomics analyses were conducted using these tissue samples. In addition, a computational drug repositioning analysis was performed and drug candidates were identified. The drug candidates were both tested in in vitro and in vivo models to evaluate their toxicity and efficacy. Findings The Pklr KO reversed the increased hepatic triglyceride level in mice fed with high sucrose diet and partly recovered the transcriptomic changes in the liver as well as in other three tissues. Both liver and white adipose tissues exhibited dysregulated circadian transcriptomic profiles, and these dysregulations were reversed by hepatic knockout of Pklr. In addition, 10 small molecule drug candidates were identified as potential inhibitor of PKLR using our drug repositioning pipeline, and two of them significantly inhibited both the PKLR expression and triglyceride level in in vitro model. Finally, the two selected small molecule drugs were evaluated in in vivo rat models and we found that these drugs attenuate the hepatic steatosis without side effect on other tissues. Interpretation In conclusion, our study provided biological insights about the critical role of PKLR in NAFLD progression and proposed a treatment strategy for NAFLD patients, which has been validated in preclinical studies. Copyright (C) 2022 The Authors. Published by Elsevier B.V.
20.	Grubb, Anders, et al. (author) Cystatin C, a marker for successful aging and glomerular filtration rate, is not influenced by inflammation. 2011 In: Scandinavian Journal of Clinical and Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 71, s. 145-149 Journal article (peer-reviewed)abstract Abstract Background. The plasma level of cystatin C is a better marker than plasma creatinine for successful aging. It has been assumed that the advantage of cystatin C is not only due to it being a better marker for glomerular filtration rate (GFR) than creatinine, but also because an inflammatory state of a patient induces a raised cystatin C level. However, the observations of an association between cystatin C level and inflammation stem from large cohort studies. The present work concerns the cystatin C levels and degree of inflammation in longitudinal studies of individual subjects without inflammation, who undergo elective surgery. Methods. Cystatin C, creatinine, and the inflammatory markers CRP, serum amyloid A (SAA), haptoglobin and orosomucoid were measured in plasma samples from 35 patients the day before elective surgery and subsequently during seven consecutive days. Results. Twenty patients had CRP-levels below 1 mg/L before surgery and low levels of the additional inflammatory markers. Surgery caused marked inflammation with high peak values of CRP and SAA on the second day after the operation. The cystatin C level did not change significantly during the observation period and did not correlate significantly with the level of any of the four inflammatory markers. The creatinine level was significantly reduced on the first postoperative day but reached the preoperative level towards the end of the observation period. Conclusion. The inflammatory status of a patient does not influence the role of cystatin C as a marker of successful aging, nor of GFR.
21.	Korsgren, Magnus, et al. (author) Allergic eosinophil-rich inflammation develops in lungs and airways of B cell-deficient mice 1997 In: Journal of Experimental Medicine. - 1540-9538. ; 185:5, s. 885-892 Journal article (peer-reviewed)abstract Immunoglobulins (Ig), particularly IgE, are believed to be crucially involved in the pathogenesis of asthma and, equally, in allergic models of the disease. To validate this paradigm we examined homozygous mutant C57BL/6 mice, which are B cell deficient, lacking all Ig. Mice were immunized intraperitoneally with 10 micrograms ovalbumin (OVA) plus alum, followed by daily (day 14-20) 30 min exposures to OVA aerosol (OVA/OVA group). Three control groups were run: OVA intraperitoneally plus saline (SAL) aerosol (OVA/SAL group); saline intraperitoneally plus saline aerosol; saline intraperitoneally plus OVA aerosol (n = 6-7). Lung and large airway tissues obtained 24 h after the last OVA or SAL exposure were examined by light microscopy and transmission electron microscopy (TEM). The Ig-deficient mice receiving OVA/ OVA treatment had swollen and discolored lungs and exhibited marked eosinophilia both in large airway subepithelial tissue (49.2 +/- 12.0 cells/mm basement membrane [BM] versus OVA/ SAL control 1.2 +/- 0.3 cells/mm BM; P < 0.001), and perivascularly and peribronchially in the lung (49.3 +/- 9.0 cells/unit area versus OVA/SAL control 2.6 +/- 0.6 cells/unit area; P < 0.001). The eosinophilia extended to the regional lymph nodes. TEM confirmed the subepithelial and perivascular localization of eosinophils. Mucus cells in large airway epithelium increased from 1.5 +/- 0.8 (OVA/SAL mice) to 39.5 +/- 5.7 cells/mm BM in OVA/OVA treated mice (P < 0.001). OVA/SAL mice never differed from the other control groups. Corresponding experiments in wild-type mice (n = 6-7 in each group) showed qualitatively similar but less pronounced eosinophil and mucus cell changes. Macrophages and CD4+ T cells increased in lungs of all OVA/OVA-treated mice. Mast cell number did not differ but degranulation was detected only in OVA/OVA-treated wild-type mice. Immunization to OVA followed by OVA challenges thus cause eosinophil-rich inflammation in airways and lungs of mice without involvement of B cells and Ig.
22.	Persson, Carl, et al. (author) The mouse trap 1997 In: Trends in Pharmacological Sciences. - 0165-6147. ; 18:12, s. 465-467 Journal article (peer-reviewed)abstract Mouse models of asthma are now being used extensively in drug research. However, the successful unravelling of combinatorial interplays of cells and molecules in the murine airways may not be matched by equally successful demonstrations of an asthma-like pathophysiology. Here, Carl Persson, Jonas Erjefalt, Magnus Korsgren and Frank Sundler discuss the fact that major features of asthma may still need to be demonstrated in the airways of allergic mice.
23.	Uller, Lena, et al. (author) Resolution of airway disease: removal of inflammatory cells through apoptosis, egression or both? 2006 In: Trends in Pharmacological Sciences. - : Elsevier BV. - 0165-6147. ; 27:9, s. 461-466 Research review (peer-reviewed)
24.	Movahed Rad, Pouya, et al. (author) Endogenous unsaturated C18 N-acylethanolamines are vanilloid receptor (TRPV1) agonists. 2005 In: Journal of Biological Chemistry. - 1083-351X .- 0021-9258. ; 280:46, s. 38496-38504 Journal article (peer-reviewed)abstract The endogenous C18 N-acylethanolamines (NAEs) N-linolenoylethanolamine (18:3 NAE), N-linoleoylethanolamine (18:2 NAE), N-oleoylethanolamine (18:1 NAE), and N-stearoylethanolamine (18:0 NAE) are structurally related to the endocannabinoid anandamide (20:4 NAE), but these lipids are poor ligands at cannabinoid CB1 receptors. Anandamide is also an activator of the transient receptor potential (TRP) vanilloid 1 (TRPV1) on primary sensory neurons. Here we show that C18 NAEs are present in rat sensory ganglia and vascular tissue. With the exception of 18:3 NAE in rat sensory ganglia, the levels of C18 NAEs are equal to or substantially exceed those of anandamide. At submicromolar concentrations, 18:3 NAE, 18:2 NAE, and 18:1 NAE, but not 18:0 NAE and oleic acid, activate native rTRPV1 on perivascular sensory nerves. 18:1 NAE does not activate these nerves in TRPV1 gene knock-out mice. Only the unsaturated C18 NAEs elicit whole cell currents and fluorometric calcium responses in HEK293 cells expressing hTRPV1. Molecular modeling revealed a low energy cluster of U-shaped unsaturated NAE conformers, sharing several pharmacophoric elements with capsaicin. Furthermore, one of the two major low energy conformational families of anandamide also overlaps with the cannabinoid CB1 receptor ligand HU210, which is in line with anandamide being a dual activator of TRPV1 and the cannabinoid CB1 receptor. This study shows that several endogenous non-cannabinoid NAEs, many of which are more abundant than anandamide in rat tissues, activate TRPV1 and thus may play a role as endogenous TRPV1 modulators.
25.	Malm, Johan, et al. (author) Lipopolysaccharide-binding protein is produced in the epididymis and associated with spermatozoa and prostasomes. 2005 In: Journal of Reproductive Immunology. - : Elsevier BV. - 1872-7603 .- 0165-0378. ; 66:1, s. 33-43 Journal article (peer-reviewed)
26.	Björn, Niclas, et al. (author) Genes and variants in hematopoiesis-related pathways are associated with gemcitabine/carboplatin-induced thrombocytopenia 2020 In: The Pharmacogenomics Journal. - : Nature Publishing Group. - 1470-269X .- 1473-1150. ; 20:2, s. 179-191 Journal article (peer-reviewed)abstract Chemotherapy-induced myelosuppression, including thrombocytopenia, is a recurrent problem during cancer treatments that may require dose alterations or cessations that could affect the antitumor effect of the treatment. To identify genetic markers associated with treatment-induced thrombocytopenia, we whole-exome sequenced 215 non-small cell lung cancer patients homogeneously treated with gemcitabine/carboplatin. The decrease in platelets (defined as nadir/baseline) was used to assess treatment-induced thrombocytopenia. Association between germline genetic variants and thrombocytopenia was analyzed at single-nucleotide variant (SNV) (based on the optimal false discovery rate, the severity of predicted consequence, and effect), gene, and pathway levels. These analyses identified 130 SNVs/INDELs and 25 genes associated with thrombocytopenia (P-value < 0.002). Twenty-three SNVs were validated in an independent genome-wide association study (GWAS). The top associations include rs34491125 in JMJD1C (P-value = 9.07 × 10−5), the validated variants rs10491684 in DOCK8 (P-value = 1.95 × 10−4), rs6118 in SERPINA5 (P-value = 5.83 × 10−4), and rs5877 in SERPINC1 (P-value = 1.07 × 10−3), and the genes CAPZA2 (P-value = 4.03 × 10−4) and SERPINC1 (P-value = 1.55 × 10−3). The SNVs in the top-scoring pathway “Factors involved in megakaryocyte development and platelet production” (P-value = 3.34 × 10−4) were used to construct weighted genetic risk score (wGRS) and logistic regression models that predict thrombocytopenia. The wGRS predict which patients are at high or low toxicity risk levels, for CTCAE (odds ratio (OR) = 22.35, P-value = 1.55 × 10−8), and decrease (OR = 66.82, P-value = 5.92 × 10−9). The logistic regression models predict CTCAE grades 3–4 (receiver operator characteristics (ROC) area under the curve (AUC) = 0.79), and large decrease (ROC AUC = 0.86). We identified and validated genetic variations within hematopoiesis-related pathways that provide a solid foundation for future studies using genetic markers for predicting chemotherapy-induced thrombocytopenia and personalizing treatments.
27.	Ericsson, Peter, et al. (author) ECL Cell Histamine Mobilization Studied byGastric Submucosal Microdialysis in Awake Rats:Methodological Considerations. 2003 In: Pharmacology and Toxicology. - : Wiley. - 1600-0773 .- 0901-9928. ; 93:2, s. 57-65 Journal article (peer-reviewed)abstract The ECL cells are endocrine/paracrine cells in the acid-producing part of the stomach. They secrete histamine in response to circulating gastrin. Gastric submucosal microdialysis has been used to study ECL-cell histamine mobilization in awake rats. In the present study we assess the usefulness and limitations of the technique. Microdialysis probes were implanted in the gastric submucosa. Histological analysis of the stomach wall around the probe revealed a moderate, local inflammatory reaction 1-2 days after implantation; the inflammation persisted for at least 10 days. Experiments were conducted 3 days after the implantation. The "true" submucosal histamine concentration was determined by perfusing at different rates (the zero flow method) or with different concentrations of histamine at a constant rate (the no-net-flux method): in fasted rats it was calculated to be 87±5 (means±S.E.M.) nmol/l and 76±9 nmol/l, respectively. The corresponding histamine concentrations in fed rats were 93±5 and 102±8 nmol/l, respectively. With a perfusion rate of 74 mul/hr the recovery of submucosal histamine was 49%, at 34 mul/hr the recovery increased to 83%. At a perfusion rate below 20 mul/hr the microdialysate histamine concentration was close to the actual concentration in the submucosa. The ECL-cell histamine mobilization was independent of the concentrations of Ca2+ in the perfusion medium (0-3.4 mmol/l Ca2+). In one experiment, histamine mobilization in response to gastrin (10 nmol/kg/hr subcutaneously) was monitored in rats pretreated with prednisolone (60 mg/kg) or indomethacin (15 mg/kg). The two antiinflammatory agents failed to affect the concentration of histamine in the microdialysate either before or during the gastrin challenge, which was in accord with the observation that the inflammatory reaction was modest and that inflammatory cells were relatively few around the probe and in the wall of the probe. In another experiment, rats were given aminoguanidine (10 mg/kg) or metoprine (10 mg/kg) 4 hr before the start of gastrin infusion (5 nmol/kg/hr intravenously). Metoprine (inhibitor of histamine N-methyl transferase) did not affect the microdialysate histamine concentration, while aminoguanidine (inhibitor of diamine oxidase) raised both basal and gastrin-stimulated histamine concentrations. We conclude that microdialysis can be used to monitor changes in the concentration of histamine in the submucosa of the stomach, and that the inflammatory reaction to the probe is moderate and does not affect the submucosal histamine mobilization.
28.	Hansson, Ola, et al. (author) Inflammatory response in white adipose tissue in the non-obese hormone-sensitive lipase null mouse model. 2006 In: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 5:7, s. 1701-1710 Journal article (peer-reviewed)
29.	Johansson, Staffan, 1976, et al. (author) Mechanistic Proposal for the Formation of Specific Immunogenic Complexes via a Radical Pathway: A Key Step in Allergic Contact Dermatitis to Olefinic Hydroperoxides 2009 In: Chem. Res. Toxicol.. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 22:11, s. 1774-1781 Journal article (peer-reviewed)abstract The widespread use of scented products causes an increase of allergic contact dermatitis to fragrance compounds in Western countries today. Many fragrance compounds are prone to autoxidation, forming hydroperoxides as their primary oxidation products. Hydroperoxides are known to be strong allergens and to form specific immunogenic complexes. However, the mechanisms for the formation of the immunogenic complexes are largely unknown. We have investigated this mechanism for (5R)-5-isopropenyl-2-methyl-2-cyclohexene-1-hydroperoxide (Lim-2-OOH) by studying the formation of adducts in the reaction between this hydroperoxide and 5,10,15,20-tetraphenyl-21H,23H-porphine iron(III) chloride (Fe(III)TPPCl) in the presence of protected cysteine (NAc-Cys-OMe) or glutathione (GSH). Isolated adducts originate from the addition of the thiol group of NAc-Cys-OMe over the carbon−carbon double bonds of carvone. Furthermore, adducts between NAc-Cys-OMe and carveol as well as between GSH and carvone have been identified. The formation of these adducts most likely proceeds via the radical thiol−ene mechanism. The addition of a terpene moiety to cysteine offers an explanation of the specificity of the immune response to structurally different hydroperoxides. These results also explain the lack of cross-reactivity between carvone and Lim-2-OOH. In conclusion, we propose that immunogenic complexes of olefinic hydroperoxides can be formed via the radical thiol−ene mechanism. These complexes will be specific for the individual olefinic hydroperoxides due to the inclusion of a terpene moiety derived from the hydroperoxide.
30.	Karlsson, Isabella, 1980, et al. (author) Photodegradation of Dibenzoylmethanes: Potential Cause of Photocontact Allergy to Sunscreens 2009 In: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 22:11, s. 1881-1892 Journal article (peer-reviewed)abstract One of the most frequently observed photoallergens today is the sunscreen agent 4-tert-butyl-4′-methoxy dibenzoylmethane (1a). The structurally similar compound, 4-isopropyldibenzoylmethane (1b), was a common cause of sunscreen allergy in the eighties and early nineties but was removed from the market in 1993 and replaced with dibenzoylmethane 1a. We have studied the photodegradation of the dibenzoylmethane 1a, to better understand how these substances cause an immune reaction. Several expected degradation products were formed and identified. Of these, arylglyoxals and benzils were of particular interest because they were unexplored as potential contact allergens. The allergenic potential of photodegraded 1a was evaluated by screening the formed arylglyoxals and benzils for their sensitizing capacity in the murine local lymph node assay. The arylglyoxals were found to be strong sensitizers. They were also found to be highly reactive toward the nucleophile arginine, which indicates that the immunogenic hapten-protein complex could be formed via an electrophilic-nucleophilic pathway. By varying the electron-withdrawing or -donating capacity of the substituent in the para position of the arylglyoxal, the electronic effects were shown to have no significant impact on either the sensitizing or the electrophilic power of arylglyoxals. Thus, a change in the substitution pattern of the parent dibenzoylmethane will not influence the sensitizing capacity of the products formed from them upon photodegradation. Furthermore, the combined studies of benzils, using the local lymph node assay and a cell proliferation assay, indicate that the benzils are cytotoxic rather than allergenic. Taken together, this study presents strong indication that photocontact allergy to dibenzoylmethanes is caused by the arylglyoxals that are formed upon photodegradation.
31.	Mitra, Sanhita, et al. (author) Subcellular distribution of p53 by the p53-responsive lncRNA NBAT1 determines chemotherapeutic response in neuroblastoma. 2021 In: Cancer research. - 1538-7445. ; 81:6, s. 1457-1471 Journal article (peer-reviewed)abstract Neuroblastoma has a low mutation rate for the p53 gene. Alternative ways of p53 inactivation have been proposed in neuroblastoma, such as abnormal cytoplasmic accumulation of wild-type p53. However, mechanisms leading to p53 inactivation via cytoplasmic accumulation are not well investigated. Here we show that the neuroblastoma risk-associated locus 6p22.3-derived tumor suppressor NBAT1 is a p53-responsive lncRNA that regulates p53 subcellular levels. Low expression of NBAT1 provided resistance to genotoxic drugs by promoting p53 accumulation in cytoplasm and loss from mitochondrial and nuclear compartments. Depletion of NBAT1 altered CRM1 function and contributed to the loss of p53-dependent nuclear gene expression during genotoxic drug treatment. CRM1 inhibition rescued p53-dependent nuclear functions and sensitized NBAT1-depleted cells to genotoxic drugs. Combined inhibition of CRM1 and MDM2 was even more effective in sensitizing aggressive neuroblastoma cells with p53 cytoplasmic accumulation. Thus, our mechanistic studies uncover an NBAT1-dependent CRM1/MDM2-based potential combination therapy for high-risk neuroblastoma patients.
32.	Midlöv, Patrik, et al. (author) Medication report reduces number of medication errors when elderly patients are discharged from hospital 2008 In: PHARMACY WORLD & SCIENCE. - : Springer Science and Business Media LLC. - 0928-1231 .- 1573-739X. ; 30:1, s. 92-98 Journal article (peer-reviewed)abstract Objective To investigate whether a Medication Report can reduce the number of medication errors when elderly patients are discharged from hospital. Method We conducted a prospective intervention with retrospective controls on patients at three departments at Lund University Hospital, Sweden that where transferred to primary care. The intervention group, where patients received a Medication Report at discharge, was compared with a control group with patients of the same age, who were not given a Medication Report when discharged from the same ward one year earlier. Main outcome measures The main outcome measure was the number of medication errors when elderly patients were discharged from hospital. Results Among 248 patients in the intervention group 79 (32%) had at least one medication error as compared with 118 (66%) among the 179 patients in the control group. In the intervention group 15% of the patients had errors that were considered to have moderate or high risk of clinical consequences compared with 32% in the control group. The differences were statistically significant (P < 0.001). Conclusion Medication errors are common when elderly patients are discharged from hospital. The Medication Report is a simple tool that reduces the number of medication errors.
33.	Björk, Jonas, et al. (author) A new tool for predicting the probability of chronic kidney disease from a specific value of estimated GFR. 2010 In: Scandinavian Journal of Clinical and Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; Jul 1, s. 327-333 Journal article (peer-reviewed)abstract Abstract Objective. To demonstrate how patients' probability of having chronic kidney disease (CKD) stage 3-5 (measured GFR <60 mL/min/1.73 m(2)) can be predicted from a specific value of estimated glomerular filtration rate (eGFR). Material and methods. The probability of CKD stage 3-5 was predicted from a logistic regression model (n = 850) using three different eGFR prediction equations: Lund-Malmö, MDRD and CKD-EPI. Population weighting was used to illustrate how this probability varies in three different populations: original sample (55% true prevalence of CKD stage 3-5), a screening (6.7% prevalence) and a CKD population (84% prevalence). Results. All three eGFR-equations had high classification ability (area under the receiver-operating-characteristic curve = 97%). The probability of CKD stage 3-5 increased with decreasing eGFR, varied substantially among the populations studied and to some extent between the eGFR-equations. Using the Lund-Malmö equation as illustration, the probability of CKD stage 3-5 is > 90% only when eGFR is <38 mL/min/1.73 m(2) in a screening population, whereas it is > 90% already when eGFR is <51 mL/min/1.73 m(2) in a CKD population. Conversely, the probability of CKD stage 3-5 is <10% if eGFR > 59 mL/min/1.73 m(2) in a screening population, whereas it is <10% only when eGFR is > 88 mL/min/1.73 m(2) in a CKD population. Conclusion. Instead of reporting diagnostic accuracy as sensitivity, specificity, and predictive values, actual eGFR supplemented with the probability that it represents a true GFR <60 mL/min/1.73 m(2) may be more valuable for physicians. Clinical (pre-test) probability in the population must be considered when predicting this probability.
34.	Björk, Jonas, et al. (author) Revised equations for estimating glomerular filtration rate based on the Lund-Malmö Study cohort. 2011 In: Scandinavian Journal of Clinical and Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 71, s. 232-239 Journal article (peer-reviewed)abstract Abstract Objective. To increase the accuracy of estimated GFR (eGFR) from creatinine overall and at measured GFR ≥90 mL/min per 1.73 m(2) by revising the Lund-Malmö (LM) equations, to elaborate on more complex forms to improve the LM and CKD-EPI equations further, and to assess benefits of adding lean body mass (LBM). Material and methods. Swedish Caucasians (n = 850, 376 women; median 60, range 18-95 years) referred for GFR measurement (plasma iohexol-clearance: median 55, range 5-173 mL/min/1.73 m(2)) constituted the Lund-Malmö Study cohort. Bias, precision, accuracy, expressed as median absolute percentage difference and percentage of estimates ±10% (P(10)) and ±30% (P(30)) of measured GFR, and classification ability with respect to five GFR stages were compared with the original LM, CKD-EPI and MDRD equations. Results. LM Revised overall performed better than LM Original without LBM due to increased accuracy at measured GFR ≥90 mL/min/1.73 m(2). Further extensions of the CKD-EPI or LM equations did not substantially improve overall performance. In particular, the performance of LM Revised at measured GFR ≥90 mL/min/1.73 m(2) could not be improved further without decreasing accuracy and classification ability at lower GFR-levels. Adding LBM to the equations had no strong effect on accuracy. Conclusion. Comparisons with the CKD-EPI and MDRD equations suggest that the LM equations are superior for the present Swedish population, due to markedly higher accuracy of the LM equations at measured GFR <30 mL/min/1.73 m(2). However, the LM equations cannot be recommended for use in general clinical practice until validated in other populations.
35.	Karlsson, Oskar, et al. (author) MALDI imaging delineates hippocampal glycosphingolipid changes associated with neurotoxin induced proteopathy following neonatal BMAA exposure. 2017 In: Biochimica et Biophysica Acta. - : Elsevier BV. - 0006-3002 .- 1878-2434. ; 1865:7, s. 740-746 Journal article (peer-reviewed)abstract The environmental toxin β-N-methylamino-L-alanine (BMAA) has been proposed to contribute to neurodegenerative diseases. We have previously shown that neonatal exposure to BMAA results in dose-dependent cognitive impairments, proteomic alterations and progressive neurodegeneration in the hippocampus of adult rats. A high BMAA dose (460mg/kg) also induced intracellular fibril formation, increased protein ubiquitination and enrichment of proteins important for lipid transport and metabolism. The aim of this study was therefore to elucidate the role of neuronal lipids in BMAA-induced neurodegeneration. By using matrix assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS), we characterized the spatial lipid profile in the hippocampus of six month-old rats that were treated neonatally (postnatal days 9-10) with 460mg/kg BMAA. Multivariate statistical analysis revealed long-term changes in distinct ganglioside species (GM, GD, GT) in the dentate gyrus. These changes could be a consequence of direct effects on ganglioside biosynthesis through the b-series (GM3-GD3-GD2-GD1b-GT1b) and may be linked to astrogliosis. Complementary immunohistochemistry experiments towards GFAP and S100β further verified the role of increased astrocyte activity in BMAA-induced brain damage. This highlights the potential of imaging MS for probing chemical changes associated with neuropathological mechanisms in situ. This article is part of a Special Issue entitled: MALDI Imaging, edited by Dr. Corinna Henkel and Prof. Peter Hoffmann.
36.	Gustafsson, Anna, et al. (author) Gas6 and the receptor tyrosine kinase Axl in clear cell renal cell carcinoma. 2009 In: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 4:10, s. e7575- Journal article (peer-reviewed)abstract BACKGROUND: The molecular biology of renal cell carcinoma (RCC) is complex and not fully understood. We have recently found that the expression of the receptor tyrosine kinase Axl in the RCC tumors independently correlates with survival of the patients. PRINCIPAL FINDINGS: Here, we have investigated the role of Axl and its ligand Gas6, the vitamin-K dependent protein product of the growth arrest-specific gene 6, in clear cell RCC (ccRCC) derived cells. The Axl protein was highly expressed in ccRCC cells deficient in functional von Hippel-Lindau (VHL) protein, a tumor suppressor gene often inactivated in ccRCC. VHL reconstituted cells expressed decreased levels of Axl protein, but not Axl mRNA, suggesting VHL to regulate Axl expression. Gas6-mediated activation of Axl in ccRCC cells resulted in Axl phosphorylation, receptor down-regulation, decreased cell-viability and migratory capacity. No effects of the Gas6/Axl system could be detected on invasion. Moreover, in ccRCC tumor tissues, Axl was phosphorylated and Gas6 gamma-carboxylated, suggesting these molecules to be active in vivo. SIGNIFICANCE: These results provide novel information regarding the complex function of the Gas6/Axl system in ccRCC.
37.	Greiff, Lennart, et al. (author) Effects of hydrogen peroxide on the guinea-pig tracheobronchial mucosa in vivo 1999 In: Acta Physiologica Scandinavica. - : Wiley. - 0001-6772 .- 1365-201X. ; 165:4, s. 415-420 Journal article (peer-reviewed)abstract Lumenal entry of plasma (mucosal exudation) is a key feature of airway inflammation. In airways challenged with histamine-type mediators and allergen the mucosal exudation response occurs without causing epithelial derangement and without increased airway absorption. In contrast, reactive oxygen metabolites may cause mucosal damage. In this study, involving guinea-pig airways, we have examined effects of H2O2 on airway exudation and absorption in vivo. Vehicle or H2O2 (0.1 and 0.5 M) was superfused onto the tracheobronchial mucosal surface through an oro-tracheal catheter. 125I-albumin, given intravenously, was determined in tracheobronchial tissue and in lavage fluids 10 min after challenge as an index of mucosal exudation of plasma. The tracheobronchial mucosa was also examined by scanning electron microscopy. In separate animals, 99mTc-DTPA was superfused 20 min after vehicle or H2O2 (0.1 and 0.5 M) had been given. A gamma camera determined the disappearance rate of 99mTc-DTPA from the airways as an index of airway absorption. The high dose of H2O2 (0.5 M) produced epithelial damage, increased the absorption of 99mTc-DTPA (P < 0.001), and increased the exudation of plasma (P < 0.001). Notably, it appeared that all extravasated plasma had entered the airway lumen within 10 min. These data demonstrate that H2O2 differs from exudative autacoids such as histamine by causing both epithelial damage and plasma exudation responses. These data also agree with the view that the epithelial lining determines the rate of absorption and is responsible for the valve-like function that allows lumenal entry of extravasated bulk plasma without any increased inward perviousness.
38.	Arner, Anders, et al. (author) Effects of Ca2+ on force-velocity characteristics of normal and hypertrophic smooth muscle of the rat portal vein 1985 In: Acta Physiologica Scandinavica. - 0001-6772. ; 124:4, s. 525-533 Journal article (peer-reviewed)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.
39.	Arner, Anders, et al. (author) Energy turnover and lactate dehydrogenase activity in detrusor smooth muscle from rats with streptozotocin-induced diabetes 1993 In: Acta Physiologica Scandinavica. - 0001-6772. ; 147:4, s. 375-383 Journal article (peer-reviewed)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)
40.	Arner, Anders, et al. (author) Metabolism and force in hypertrophic smooth muscle from rat urinary bladder 1990 In: American Journal of Physiology: Cell Physiology. - 1522-1563. ; 258:5 Pt 1, s. 923-932 Journal article (peer-reviewed)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.
41.	Arner, Anders, et al. (author) Structural and mechanical adaptations in rat aorta in response to sustained changes in arterial pressure 1984 In: Acta Physiologica Scandinavica. - 0001-6772. ; 122:2, s. 119-126 Journal article (peer-reviewed)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).
42.	Chen, Y, et al. (author) Increase in insulin-like growth factor I in hypertrophying smooth muscle 1994 In: American Journal of Physiology - Endocrinology and Metabolism. - 1522-1555. ; 266:2 Pt 1, s. 224-229 Journal article (peer-reviewed)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.
43.	Lindqvist, Anders, et al. (author) Long-term effects of Ca(2+) on structure and contractility of vascular smooth muscle 1999 In: American Journal of Physiology: Cell Physiology. - 1522-1563. ; 277:1, s. 64-73 Journal article (peer-reviewed)abstract Culture of dispersed smooth muscle cells is known to cause rapid modulation from the contractile to the synthetic cellular phenotype. However, organ culture of smooth muscle tissue, with maintained extracellular matrix and cell-cell contacts, may facilitate maintenance of the contractile phenotype. To test the influence of culture conditions, structural, functional, and biochemical properties of rat tail arterial rings were investigated after culture. Rings were cultured for 4 days in the absence and presence of 10% FCS and then mounted for physiological experiments. Intracellular Ca(2+) concentration ([Ca(2+)](i)) after stimulation with norepinephrine was similar in rings cultured with and without FCS, whereas force development after FCS was decreased by >50%. The difference persisted after permeabilization with beta-escin. These effects were associated with the presence of vasoconstrictors in FCS and were dissociated from its growth-stimulatory action. FCS treatment increased lactate production but did not affect ATP, ADP, or AMP contents. The contents of actin and myosin were decreased by culture but similar for all culture conditions. There was no effect of FCS on calponin contents or myosin SM1/SM2 isoform composition, nor was there any appearance of nonmuscle myosin. FCS-stimulated rings showed evidence of cell degeneration not found after culture without FCS or with FCS + verapamil (1 microM) to lower [Ca(2+)](i). The decreased force-generating ability after culture with FCS is thus associated with increased [Ca(2+)](i) during culture and not primarily caused by growth-associated modulation of cells from the contractile to the synthetic phenotype.
44.	Malmqvist, Ulf, et al. (author) Contractile and cytoskeletal proteins in smooth muscle during hypertrophy and its reversal 1991 In: American Journal of Physiology: Cell Physiology. - 1522-1563. ; 260:5, s. 1085-1093 Journal article (peer-reviewed)abstract Hypertrophy of rat urinary bladder smooth muscle was induced by partial urethral obstruction. Bladder weight increased from 70 to 240 mg after 10 days and to 700 mg after 7 wk. Removal of the obstruction after 10 days caused a regression of bladder weight to 130 mg. The relative volume of smooth muscle in the bladder wall increased during hypertrophy. The concentration of myosin in the smooth muscle cells decreased in 10-day hypertrophied bladders, whereas the concentration of actin was unchanged. The actin-myosin ratio was 2.3 in controls, 3.3 in 10-day obstructed bladders, and 2.9 in 7-wk obstructed bladders. After removal of obstruction, the ratio was normalized. Two isoforms of myosin heavy chains were identified (SM1 and SM2). The relative amount of SM2 decreased during hypertrophy. The relative proportion of actin isoforms (alpha, beta, and gamma) was altered toward more gamma and less alpha. These changes were reversible upon removal of the obstruction. Desmin was the dominating intermediate filament protein. The concentration of desmin and filamin increased in the hypertrophic bladders. The increased desmin-actin and filamin-actin ratios in obstructed bladders were normalized after removal of the obstruction. The results suggest that the turnover of contractile and cytoskeletal proteins is fast and can be regulated in response to changes in the functional demands in smooth muscle.
45.	Malmqvist, Ulf, et al. (author) Cytoskeletal and contractile proteins in detrusor smooth muscle from bladders with outlet obstruction--a comparative study in rat and man 1991 In: Scandinavian Journal of Urology and Nephrology. - : Informa UK Limited. - 0036-5599 .- 1651-2065. ; 25:4, s. 261-267 Journal article (peer-reviewed)abstract Detrusor biopsies were obtained from patients with urinary outlet obstruction due to prostatic enlargement and from age-matched control patients. The relative amounts of actin and myosin and their isoforms, as well as desmin and filamin were determined and compared with corresponding results from bladders from control rats and rats with 10 days of experimental outlet obstruction of the urinary bladder. In the human control detrusor the actin/myosin ratio was similar to that in the control rat. The isoform distribution of the myosin heavy chains differed between man and rat. In the biopsies from the patients with outlet obstruction and in the obstructed rat bladders the actin/myosin ratio was increased. A change in the myosin heavy chain distribution in the obstructed bladders was observed for both species. The filamin/actin ratio increased significantly in the obstructed rat bladders and tended to increase in the obstructed human bladders. Desmin was the dominating intermediate filament protein. The desmin/actin ratio increased in obstructed bladders in man and in rat.
46.	Malmqvist, Ulf, et al. (author) Mechanics and Ca(2+)-sensitivity of human detrusor muscle bundles studied in vitro 1991 In: Acta Physiologica Scandinavica. - 0001-6772. ; 143:4, s. 373-380 Journal article (peer-reviewed)abstract Mechanical properties of isolated smooth muscle strips from human urinary bladder were investigated in vitro. Bladder tissue was obtained from tumour-free wall regions of bladders from male patients undergoing cystectomy for bladder carcinoma. In intact muscle strips, activated with high-K+ solution, half-maximal force occurred at about 0.9 mM extracellular [Ca2+]. The length-active force relation was determined and the muscle strips were fixed for light and electron microscopy at optimal length for active force (1o). The maximal active force per unit smooth muscle cross-sectional area was 208 +/- 49 mN/mm2, n = 6. Chemically skinned preparations were obtained by treatment with triton X-100. These preparations had a steep [Ca2+]-force relation in the micromolar range which was influenced by calmodulin. The skinned preparations could be maximally activated by irreversible thiophosphorylation of the regulatory light chains. The force-velocity relation was determined in the maximally activated skinned muscle at 22 degrees C at 0.51o. When the muscle was shortened by 10%, force was reduced by 35% whereas the maximal shortening velocity was little affected.
47.	Hellström, Lina, et al. (author) Impact of the Lund Integrated Medicines Management (LIMM) model on medication appropriateness and drug-related hospital revisits. 2011 In: European Journal of Clinical Pharmacology. - : Springer Science and Business Media LLC. - 0031-6970 .- 1432-1041. ; 67:7, s. 741-752 Journal article (peer-reviewed)abstract PurposeTo examine the impact of systematic medication reconciliations when admitted to hospital, and medication review while in hospital, on the number of inappropriate medications and unscheduled drug-related hospital revisits in elderly patients.MethodsA prospective, controlled study in 210 patients, aged 65 years or older, who were admitted to one of three internal medicine wards at a University Hospital in Sweden. Patients received either standard care or care according to the Lund Integrated Medicines Management (LIMM) model. A multi-professional team, including a clinical pharmacist, provided medication reconciliations on admission and medication reviews during the hospital stay for the LIMM group. Blinded reviewers evaluated the appropriateness of the prescribing (using the Medication Appropriateness Index) on admission and discharge, and assessed the probability that a drug-related problem was the reason for any patient readmitted to hospital or visiting the emergency department within three months of discharge (using WHO causality criteria).ResultsThere was a greater decrease in the number of inappropriate drugs in the intervention group than in the control group for both the intention-to-treat population (51% [95% CI 43-58%] versus 39% [95% CI 30-48%], p=0.0446) and the per-protocol population (60% [95% CI 51-67%] versus 44% [95% CI 34-52 %], p=0.0106). There were 6 revisits to hospital in the intervention group which were judged as ‘possibly, probably or certainly drug-related’, compared with 12 in the control group (p=0.0469).ConclusionIn this study, medication reconciliation and reviews provided by a clinical pharmacist in a multi-professional team significantly reduced the number of inappropriate drugs and unscheduled drug-related hospital revisits for elderly patients.
48.	Olafsson, Isleifur, et al. (author) Production, characterization and use of monoclonal antibodies against the major extracellular human cysteine proteinase inhibitors cystatin C and kininogen 1988 In: Scandinavian Journal of Clinical & Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 48:6, s. 573-582 Journal article (peer-reviewed)abstract Murine monoclonal antibodies against the major cysteine proteinase inhibitors of human biological fluids, cystatin C and kininogen, were produced. The cystatin C antibody, HCC3, with a Ka of 2times107 l/mol, increased the inhibition of papain by cystatin C and was suitable for use in immunoblotting, immunohistochemistry and in the construction of a sensitive sandwich enzyme immunoassay for quantification of cystatin C. It recognized not only free cystatin C but also cystatin C in complexes with cysteine proteinases. The kininogen antibody, HK4, was directed against the third, cysteine proteinase inhibitory domain of the heavy chain of kininogen (Ka=1times107 l/mol), but did not influence the papain inhibitory activity of kininogen. It reacted with free kininogen as well as kininogen in complex with cysteine proteinases. Both antibodies could be used for the production of specific immunosorbents.
49.	Strålberg, Fredrik, et al. (author) Inhibition of lipopolysaccharide-induced osteoclast formation and bone resorption in vitro and in vivo by cysteine proteinase inhibitors 2017 In: Journal of Leukocyte Biology. - : FEDERATION AMER SOC EXP BIOL. - 0741-5400 .- 1938-3673. ; 101:5, s. 1233-1243 Journal article (peer-reviewed)abstract Inflammation-induced bone destruction is a major treatment target in many inflammatory skeletal diseases. The aim of this study was to investigate if the cysteine proteinase inhibitors cystatin C, fungal cysteine proteinase inhibitor (E-64), and N-benzyloxycarbonyl-arginylleucyl-valyl-glycyl-diazomethane acetate (Z-RLVG-CHN2) can inhibit LPS-induced osteoclast formation. Mouse bone marrow macrophages (BMMs) were isolated and primed with receptor activator of NF-kappa B ligand (RANKL) for 24 h, followed by stimulation with LPS, with and without inhibitors. Adult mice were injected locally with LPS and then treated with E-64 and osteoclast formation assessed by the number of cathepsin K+ multinucleated cells. Cystatin C inhibited LPS-induced osteoclast formation time and concentration dependently (IC50 = 0.3 mu M). The effect was associated with decreased mRNA and protein expression of tartrate-resistant acid phosphatase (TRAP) and cathepsin K and of the osteoclastogenic transcription factors c-Fos and NFATc1. LPS-induced osteoclast formation on bone slices was also inhibited by cystatin C, resulting in decreased pit formation and release of bone matrix proteins. Similar data were obtained with E-64 and Z-RLVG-CHN2. Cystatin C was internalized in BMMs stimulated by LPS but not in unstimulated BMMs. Osteoclast formation induced by LPS was dependent on TNF-alpha, and the 3 inhibitors abolished LPS-induced TNF superfamily 2 (gene encoding TNF-alpha; Tnfsf2) mRNA expression without affecting Il1b, Il6, or oncostatin M (Osm) expression. Formation of osteoclasts in the skull bones after local LPS stimulation was inhibited by E-64. It is concluded that cysteine proteinase inhibitors effectively inhibit LPS-induced osteoclast formation in vivo and in vitro by inhibition of TNF-alpha expression. The targeting of cysteine proteinases might represent a novel treatment modality for prevention of inflammatory bone loss. RAHAMSON M, 1988, FEBS LETTERS, V236, P14 RAHAMSON M, 1990, BIOCHEMICAL JOURNAL, V268, P287
50.	Holmér, Andreas, et al. (author) The factor H variant associated with age-related macular degeneration (H384) and the non-disease associated form bind differentially to C-reactive protein, fibromodulin, DNA and necrotic cells. 2007 In: Journal of Biological Chemistry. - 1083-351X. ; 282:15, s. 10894-10900 Journal article (peer-reviewed)abstract Recently, a polymorphism in the complement regulator factor H (FH) gene has been associated with age-related macular degeneration. When histidine instead of tyrosine is present at position 384 in the seventh complement control protein (CCP) domain of FH, the risk for age-related macular degeneration is increased. It was recently shown that these allotypic variants of FH, in the context of a recombinant construct corresponding to CCPs 6 - 8, recognize polyanionic structures differently, which may lead to altered regulation of the alternative pathway of complement. We show now that His-384, corresponding to the risk allele, binds C-reactive protein (CRP) poorly compared with the Tyr-384 form. We also found that C1q and phosphorylcholine do not compete with FH for binding to C-reactive protein. The interaction with extracellular matrix protein fibromodulin, which we now show to be mediated, at least in part, by CCP6 - 8 of FH, occurs via the polypeptide of fibromodulin and not through its glycosaminoglycan modifications. The Tyr-384 variant of FH bound fibromodulin better than the His-384 form. Furthermore, we find that CCP6 - 8 is able to interact with DNA and necrotic cells, but in contrast the His-384 allotype binds these ligands more strongly than the Tyr-384 variant. The variations in binding affinity of the two alleles indicate that complement activation and local inflammation in response to different targets will differ between His/His and Tyr/Tyr homozygotes.

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