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- Dahlstrom, M, et al.
(författare)
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Identification of Novel Positive Allosteric Modulators of Neurotrophin Receptors for the Treatment of Cognitive Dysfunction
- 2021
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 10:8
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is the most common neurodegenerative disorder and results in severe neurodegeneration and progressive cognitive decline. Neurotrophins are growth factors involved in the development and survival of neurons, but also in underlying mechanisms for memory formation such as hippocampal long-term potentiation. Our aim was to identify small molecules with stimulatory effects on the signaling of two neurotrophins, the nerve growth factor (NGF) and the brain derived neurotrophic factor (BDNF). To identify molecules that could potentiate neurotrophin signaling, 25,000 molecules were screened, which led to the identification of the triazinetrione derivatives ACD855 (Ponazuril) and later on ACD856, as positive allosteric modulators of tropomyosin related kinase (Trk) receptors. ACD855 or ACD856 potentiated the cellular signaling of the neurotrophin receptors with EC50 values of 1.9 and 3.2 or 0.38 and 0.30 µM, respectively, for TrkA or TrkB. ACD855 increased acetylcholine levels in the hippocampus by 40% and facilitated long term potentiation in rat brain slices. The compounds acted as cognitive enhancers in a TrkB-dependent manner in several different behavioral models. Finally, the age-induced cognitive dysfunction in 18-month-old mice could be restored to the same level as found in 2-month-old mice after a single treatment of ACD856. We have identified a novel mechanism to modulate the activity of the Trk-receptors. The identification of the positive allosteric modulators of the Trk-receptors might have implications for the treatment of Alzheimer’s diseases and other diseases characterized by cognitive impairment.
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- Delkash, Madjid, et al.
(författare)
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Impacts of Anthropogenic Land Use Changes on Nutrient Concentrations in Surface Waterbodies : A Review
- 2018
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Ingår i: Clean - Soil, Air, Water. - : Wiley. - 1863-0650 .- 1863-0669. ; 46:5
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Tidskriftsartikel (refereegranskat)abstract
- Increased population leads to land use (LU) changes from natural to urban and agricultural LU. These disturbances not only decrease the natural treatment potential but they also worsen surface water quality (SWQ). The aim of this review is to assess studies about impacts of anthropogenic LU changes on levels of nutrient concentrations in surface waterbodies, highlighting the important parameters needed for an integrated simulation. The results reported in the literature are not always fully consistent. These contradictory results can sometimes be explained by field measurements under different climatic conditions, different features of landscapes, air deposition rates on ground surfaces, and groundwater flow interactions with surface water. Integrated modelling has been suggested to overcome these inconsistencies. Physical-based and empirical models are the most popular approaches for LU-SWQ studies. Generally, anthropogenic LU such as agricultural and urban areas usually enhances nutrient concentrations much more than natural lands such as forest and barren. Developing sustainable metropolitan areas instead of rural areas, establishing high-standard wastewater treatment plants, and practicing efficient fertiliser application would ameliorate the poor nutrient conditions in SWQ. Riparian vegetation, grassed swales, and construction of artificial wetlands as buffer zones are the most promising natural water quality control measures.
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