| 21. |
- Lindgren, Cecilia, et al.
(författare)
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Broad-Spectrum Antidote Discovery by Untangling the Reactivation Mechanism of Nerve-Agent-Inhibited Acetylcholinesterase
- 2022
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Ingår i: Chemistry - A European Journal. - : John Wiley & Sons. - 0947-6539 .- 1521-3765. ; 28:40
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Tidskriftsartikel (refereegranskat)abstract
- Reactivators are vital for the treatment of organophosphorus nerve agent (OPNA) intoxication but new alternatives are needed due to their limited clinical applicability. The toxicity of OPNAs stems from covalent inhibition of the essential enzyme acetylcholinesterase (AChE), which reactivators relieve via a chemical reaction with the inactivated enzyme. Here, we present new strategies and tools for developing reactivators. We discover suitable inhibitor scaffolds by using an activity-independent competition assay to study non-covalent interactions with OPNA-AChEs and transform these inhibitors into broad-spectrum reactivators. Moreover, we identify determinants of reactivation efficiency by analysing reactivation and pre-reactivation kinetics together with structural data. Our results show that new OPNA reactivators can be discovered rationally by exploiting detailed knowledge of the reactivation mechanism of OPNA-inhibited AChE.
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| 22. |
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| 23. |
- Lindgren, Elisabet, et al.
(författare)
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Sustainable food systems - a health perspective
- 2018
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Ingår i: Sustainability Science. - : Springer Science and Business Media LLC. - 1862-4065 .- 1862-4057. ; 13:6, s. 1505-1517
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Tidskriftsartikel (refereegranskat)abstract
- Malnutrition in all forms, ranging from undernourishment to obesity and associated diet-related diseases, is one of the leading causes of death worldwide, while food systems often have major environmental impacts. Rapid global population growth and increases in demands for food and changes in dietary habits create challenges to provide universal access to healthy food without creating negative environmental, economic, and social impacts. This article discusses opportunities for and challenges to sustainable food systems from a human health perspective by making the case for avoiding the transition to unhealthy less sustainable diets (using India as an exemplar), reducing food waste by changing consumer behaviour (with examples from Japan), and using innovations and new technologies to reduce the environmental impact of healthy food production. The article touches upon two of the challenges to achieving healthy sustainable diets for a global population, i.e., reduction on the yield and nutritional quality of crops (in particular vegetables and fruits) due to climate change; and trade-offs between food production and industrial crops. There is an urgent need to develop and implement policies and practices that provide universal access to healthy food choices for a growing world population, whilst reducing the environmental footprint of the global food system.
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| 24. |
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| 25. |
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| 26. |
- Lindgren, Hanna, et al.
(författare)
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Differential Involvement of D1 and D2 Dopamine Receptors in L-DOPA-Induced Angiogenic Activity in a Rat Model of Parkinson's Disease.
- 2009
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Ingår i: Neuropsychopharmacology. - : Springer Science and Business Media LLC. - 1740-634X .- 0893-133X. ; 34, s. 2477-2488
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Tidskriftsartikel (refereegranskat)abstract
- Angiogenesis occurs in the brains of Parkinson's disease patients, but the effects of dopamine replacement therapy on this process have not been examined. Using rats with 6-hydroxydopamine lesions, we have compared angiogenic responses induced in the basal ganglia by chronic treatment with either L-DOPA, or bromocriptine, or a selective D1 receptor agonist (SKF38393). Moreover, we have asked whether L-DOPA-induced angiogenesis can be blocked by co-treatment with either a D1- or a D2 receptor antagonist (SCH23390 and eticlopride, respectively), or by an inhibitor of extracellular signal-regulated kinases 1 and 2 (ERK1/2) (SL327). L-DOPA, but not bromocriptine, induced dyskinesia, which was associated with endothelial proliferation, upregulation of immature endothelial markers (nestin) and downregulation of endothelial barrier antigen in the striatum and its output structures. At a dose inducing dyskinesia (1.5 mg/kg/day), SKF38393 elicited angiogenic changes similar to L-DOPA. Antagonism of D1- but not D2 class receptors completely suppressed both the development of dyskinesia and the upregulation of angiogenesis markers. In fact, L-DOPA-induced endothelial proliferation was markedly exacerbated by low-dose D2 antagonism (0.01 mg/kg eticlopride). Inhibition of ERK1/2 by SL327 attenuated L-DOPA-induced dyskinesia and completely inhibited all markers of angiogenesis. These results highlight the specific link between treatment-induced dyskinesias and microvascular remodeling in the dopamine-denervated brain. L-DOPA-induced angiogenesis requires stimulation of D1 receptors and activation of ERK1/2, whereas the stimulation of D2 receptors seems to oppose this response.Neuropsychopharmacology advance online publication, 15 July 2009; doi:10.1038/npp.2009.74.
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| 27. |
- Lindgren, Hanna, et al.
(författare)
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The "motor complication syndrome" in rats with 6-OHDA lesions treated chronically with l-DOPA: Relation to dose and route of administration.
- 2007
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Ingår i: Behavioural Brain Research. - : Elsevier BV. - 0166-4328. ; 177:1, s. 150-159
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Tidskriftsartikel (refereegranskat)abstract
- l-DOPA-induced motor complications can be modelled in rats with 6-hydroxydopamine (6-OHDA) lesions by chronic injections of l-DOPA. We have compared the sensitisation and duration of rotational responses, and the occurrence of dose–failure episodes and abnormal involuntary movements (AIMs) in 6-OHDA-lesioned rats with regard to the dose and route of administration of l-DOPA. Rats were treated with either low (6 mg/kg) or high (25 mg/kg) doses of l-DOPA twice daily for 21 days whereas control animals received injections of either saline or bromocriptine (2.5 mg/kg). A dose-dependent and gradual development of AIMs and contralateral turning was observed in rats treated chronically with l-DOPA. Rats treated with bromocriptine exhibited rotational sensitisation but no AIMs. A shortening of motor response duration was not seen in any of the drug-treated groups. In contrast, dose–failure episodes occurred frequently in both l-DOPA- and bromocriptine-treated animals. Changing the route of l-DOPA administration from intraperitoneal to subcutaneous completely abolished failures in motor response without affecting the development of dyskinesia. Based on the hypothesis that higher doses of l-DOPA may be toxic to dopaminoceptive structures, we compared the total number of neurons and the levels of activated microglia in the striatum. No signs of neurodegenerative changes could be seen in any of the treatment groups. In conclusion, both body AIMs and rotations were dose-dependently evoked by l-DOPA. Only AIMs, however, provided a specific measure of dyskinesia since rotations also were induced by bromocriptine, a drug with low dyskinesiogenic potential. Dose–failure episodes were not specific to l-DOPA treatment and could be attributed to erratic drug absorption from the peritoneal route.
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