| 1. |
- Blomgren, Fredrik, et al.
(författare)
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Two statins and cromolyn as possible drugs against the cytotoxicity of A beta(31-35) and A beta(25-35) peptides: a comparative study by advanced computer simulation methods
- 2022
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Ingår i: RSC Advances. - : Royal Society of Chemistry (RSC). - 2046-2069. ; 12:21, s. 13352-13366
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Tidskriftsartikel (refereegranskat)abstract
- In this work, possible effective mechanisms of cromolyn, atorvastatin and lovastatin on the cytotoxicity of A beta(31-35) and A beta(25-35) peptides were investigated by classical molecular dynamics and well-tempered metadynamics simulations. The results demonstrate that all the drugs affect the behavior of the peptides, such as their ability to aggregate, and alter their secondary structures and their affinity to a particular drug. Our findings from the computed properties suggest that the best drug candidate is lovastatin. This medicine inhibits peptide aggregation, adsorbs the peptides on the surface of the drug clusters, changes the secondary structure and binds to MET35, which has been seen as the reason for the toxicity of the studied peptide sequences. Moreover, lovastatin is the drug which previously has demonstrated the strongest ability to penetrate the blood-brain barrier and makes lovastatin the most promising medicine among the three investigated drugs. Atorvastatin is also seen as a potential candidate if its penetration through the blood-brain barrier could be improved. Otherwise, its properties are even better than the ones demonstrated by lovastatin. Cromolyn appears to be less interesting as an anti-aggregant from the computational data, in comparison to the two statins.
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| 2. |
- Chrobak, Wojciech, et al.
(författare)
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Component of cannabis, cannabidiol, as a possible drug against the cytotoxicity of Aβ(31-35) and Aβ(25-35) peptides: An investigation by molecular dynamics and well-tempered metadynamics simulations
- 2021
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Ingår i: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 12:4, s. 660-674
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Tidskriftsartikel (refereegranskat)abstract
- In this work cannabidiol (CBD) was investigated as a possible drug against the cytotoxicity of Aβ(31-35) and Aβ(25-35) peptides with the help of atomistic molecular dynamics (MD) and well-tempered metadynamics simulations. Four interrelated mechanisms of possible actions of CBD are proposed from our computations. This implies that one mechanism can be a cause or/and a consequence of another. CBD is able to decrease the aggregation of peptides at certain concentrations of compounds in water. This particular action is more prominent for Aβ(25-35), since originally Aβ(31-35) did not exhibit aggregation properties in aqueous solutions. Interactions of CBD with the peptides affect secondary structures of the latter ones. Clusters of CBD are seen as possible adsorbents of Aβ(31-35) and Aβ(25-35) since peptides are tending to aggregate around them. And last but not least, CBD exhibits binding to MET35. All four mechanisms of actions can possibly inhibit the Aβ-cytotoxicity as discussed in this paper. Moreover, the amount of water also played a role in peptide clustering: with a growing concentration of peptides in water without a drug, the aggregation of both Aβ(31-35) and Aβ(25-35) increased. The number of hydrogen bonds between peptides and water was significantly higher for simulations with Aβ(25-35) at the higher concentration of peptides, while for Aβ(31-35) that difference was rather insignificant. The presence of CBD did not substantially affect the number of hydrogen bonds in the simulated systems.
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| 3. |
- Doeser, Fredrik, 1975-, et al.
(författare)
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Vad kännetecknar en de facto-stat?
- 2013
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Ingår i: Utan röst och status. - Stockholm : Utrikespolitiska institutet. - 9789175072272 ; , s. 2-9
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 4. |
- Moudio, Serge, et al.
(författare)
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Exposure of alpha-Synuclein Aggregates to Organotypic Slice Cultures Recapitulates Key Molecular Features of Parkinsons Disease
- 2022
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Ingår i: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- The accumulation of proteinaceous deposits comprised largely of the alpha-synuclein protein is one of the main hallmarks of Parkinsons disease (PD) and related synucleinopathies. Their progressive development coincides with site-specific phosphorylation, oxidative stress and eventually, compromised neuronal function. However, modeling protein aggregate formation in animal or in vitro models has proven notably difficult. Here, we took advantage of a preclinical organotypic brain slice culture model to study alpha-synuclein aggregate formation ex vivo. We monitored the progressive and gradual changes induced by alpha-synuclein such as cellular toxicity, autophagy activation, mitochondrial dysfunction, cellular death as well as alpha-synuclein modification including site-specific phosphorylation. Our results demonstrate that organotypic brain slice cultures can be cultured for long periods of time and when cultured in the presence of aggregated alpha-synuclein, the molecular features of PD are recapitulated. Taken together, this ex vivo model allows for detailed modeling of the molecular features of PD, thus enabling studies on the cumulative effects of alpha-synuclein in a complex environment. This provides a platform to screen potential disease-modifying therapeutic candidates aimed at impeding alpha-synuclein aggregation and/or cellular transmission. Moreover, this model provides a robust replacement for in vivo studies that do not include behavioral experiments, thus providing a way to reduce the number of animals used in an accelerated timescale.
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