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1.
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2.
  • Eriksson, Leif A., 1964-, et al. (författare)
  • Tetrazole derivatives as cytochrome p450 inhibitors
  • 2019
  • Patent (övrigt vetenskapligt)abstract
    • <p>According to the invention there is provided a compound of formula I, wherein R<sup>1 </sup>and R<sup>2 </sup>have meanings given in the description, which compounds are useful in the treatment of skin disorders and other diseases.</p>
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3.
  • Molinaro, Angela, et al. (författare)
  • Insulin-Driven PI3K-AKT Signaling in the Hepatocyte Is Mediated by Redundant PI3Kα and PI3Kβ Activities and Is Promoted by RAS.
  • 2019
  • Ingår i: Cell Metabolism. - 1550-4131 .- 1932-7420. ; 29:6, s. 1400-
  • Tidskriftsartikel (refereegranskat)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 be dosed below their hyperglycemic threshold to achieve isoform selectivity.
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4.
  • Mondal, Tanmoy, et al. (författare)
  • Sense-antisense lncRNA pair encoded by locus 6p22.3 determines neuroblastoma susceptibility via the USP36-CHD7-SOX9 regulatory axis
  • 2018
  • Ingår i: Cancer Cell. - 1535-6108. ; 33:3, s. 417-434.e7
  • Tidskriftsartikel (refereegranskat)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. Mondal et al. show a sense/antisense lncRNA pair expressed from the neuroblastoma (NB) risk-associated 6p22.3 locus is important for retinoic acid-induced NB differentiation gene-regulatory network by controlling CHD7 stability via modulating the cellular localization of the ubiquitin specific protease USP36.
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5.
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6.
  • Lai, Kuei-Hung (författare)
  • Studies on anti-leukemic terpenoids from medicinal mushrooms and marine sponges with ChemGPS-NP-based targets investigation of lead compounds
  • 2017
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>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.</p><p>In the first section, we focused on studying the triterpenoidal components of three triterpenoid-enriched medicinal mushrooms <em>Antrodia cinnamomea</em>, <em>Ganoderma lucidum</em>, and <em>Poria cocos</em>, 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 (<strong>II-1</strong>–<strong>II-6</strong>). The anti-leukemic activity of the isolates was evaluated <em>in vitro</em> 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.</p><p>The second and third sections focused on isolation of anti-leukemic sesterterpenoids from sponges. The investigation of<em> Carteriospongia</em><em> </em>sp. led to the isolation of two new scalarane-type sesterterpenoids (<strong>III-1 </strong>and<strong> III-2</strong>) and one known tetraprenyltoluquinol-related metabolite (<strong>III-</strong><strong>3</strong>). 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 <strong>III-1 </strong>might target<strong> </strong>Hsp90 protein. The apoptotic-inducing effect of <strong>III-3</strong> was supported by <em>in vivo</em> experiment by suppressing the volume of xenograft tumor growth (47.58%) compared with the control.</p><p>In the final section of this thesis we studied manoalide and its derivatives, sesterterpenoids isolated from the sponge <em>Luffariella</em> 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 (<strong>IV-1</strong>–<strong>IV-10</strong>) were isolated from <em>Luffariella </em>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 24<em>R</em>,25<em>S</em>-isomer exhibiting the most potent anti-leukemic activity. The apoptotic mechanism of action of compound <strong>IV-7</strong> against Molt 4 cells was investigated, and the compound was found to trigger MMP disruption and intracellular reactive oxygen species (ROS) generation. Compound <strong>IV-7 </strong>also inhibited activity against both human topoisomerases, I and II. The <em>in vivo</em> experiment further supported the anti-leukemic effect of <strong>IV-7</strong> with a 66.11% tumor volume suppression compared to the control.</p>
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7.
  • Greiff, Lennart, et al. (författare)
  • Effects of topical platelet activating factor on the guinea-pig tracheobronchial mucosa in vivo
  • 1997
  • Ingår i: Acta Physiologica Scandinavica. - Wiley-Blackwell. - 0001-6772. ; 160:4, s. 387-391
  • Tidskriftsartikel (refereegranskat)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.
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8.
  • Korsgren, Magnus, et al. (författare)
  • Allergic eosinophil-rich inflammation develops in lungs and airways of B cell-deficient mice
  • 1997
  • Ingår i: Journal of Experimental Medicine. - Rockefeller University Press. - 1540-9538. ; 185:5, s. 885-892
  • Tidskriftsartikel (refereegranskat)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.
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9.
  • Persson, Carl, et al. (författare)
  • The mouse trap
  • 1997
  • Ingår i: Trends in Pharmacological Sciences. - Elsevier. - 0165-6147. ; 18:12, s. 465-467
  • Tidskriftsartikel (refereegranskat)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.
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10.
  • Persson, Carl, et al. (författare)
  • Unbalanced research
  • 2001
  • Ingår i: Trends in Pharmacological Sciences. - Elsevier. - 0165-6147. ; 22:10, s. 538-541
  • Tidskriftsartikel (refereegranskat)
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