| 1. |
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| 2. |
- Boza-Serrano, Antonio, et al.
(författare)
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Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer’s disease
- 2019
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 138:2, s. 251-273
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (Aβ) peptide, fibrillary tangles of intraneuronal tau and microglial activation are major pathological hallmarks. One of the key molecules involved in microglial activation is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimer’s disease) mice and found specifically expressed in microglia associated with Aβ plaques. Single-nucleotide polymorphisms in the LGALS3 gene, which encodes gal3, were associated with an increased risk of AD. Gal3 deletion in 5xFAD mice attenuated microglia-associated immune responses, particularly those associated with TLR and TREM2/DAP12 signaling. In vitro data revealed that gal3 was required to fully activate microglia in response to fibrillar Aβ. Gal3 deletion decreased the Aβ burden in 5xFAD mice and improved cognitive behavior. Interestingly, a single intrahippocampal injection of gal3 along with Aβ monomers in WT mice was sufficient to induce the formation of long-lasting (2 months) insoluble Aβ aggregates, which were absent when gal3 was lacking. High-resolution microscopy (stochastic optical reconstruction microscopy) demonstrated close colocalization of gal3 and TREM2 in microglial processes, and a direct interaction was shown by a fluorescence anisotropy assay involving the gal3 carbohydrate recognition domain. Furthermore, gal3 was shown to stimulate TREM2–DAP12 signaling in a reporter cell line. Overall, our data support the view that gal3 inhibition may be a potential pharmacological approach to counteract AD.
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| 3. |
- Gonzalez-Ramirez, Israel, et al.
(författare)
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On the photoproduction of DNA/RNA cyclobutane pyrimidine dimers
- 2011
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Ingår i: Theoretical Chemistry accounts. - : Springer Science and Business Media LLC. - 1432-881X .- 1432-2234. ; 128:4-6, s. 705-711
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Tidskriftsartikel (refereegranskat)abstract
- The UV photoreactivity of different pyrimidine DNA/RNA nucleobases along the singlet manifold leading to the formation of cyclobutane pyrimidine dimers has been studied by using the CASPT2 level of theory. The initially irradiated singlet state promotes the formation of excimers between pairs of properly oriented nucleobases through the overlap between the pi structures of two stacked nucleobases. The system evolves then to the formation of cyclobutane pyrimidine dimers via a shearing-type conical intersection activating a [2 + 2] photocycloaddition mechanism. The relative location of stable excimer conformations or alternative decay channels with respect to the reactive degeneracy region explains the differences in the photoproduction efficiency observed in the experiments for different nucleobases sequences. A comparative analysis of the main structural parameters and energetic profiles in the singlet manifold is carried out for thymine, uracil, cytosine, and 5-methylcytosine homodimers. Thymine and uracil dimers display the most favorable paths, in contrast to cytosine. Methylation of the nucleobases seems to increase the probability for dimerization.
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| 4. |
- Sauri, Vicenta, et al.
(författare)
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Proton/Hydrogen Transfer Mechanisms in the Guanine-€“Cytosine Base Pair : Photostability and Tautomerism
- 2013
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Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 9:1, s. 481-496
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Tidskriftsartikel (refereegranskat)abstract
- Proton/hydrogen-transfer processes have been broadly studied in the past 50 years to explain the photostability and the spontaneous tautomerism in the DNA base pairs. In the present study, the CASSCF/CASPT2 methodology is used to map the two-dimensional potential energy surfaces along the stretched NH reaction coordinates of the guanine–cytosine (GC) base pair. Concerted and stepwise pathways are explored initially in vacuo, and three mechanisms are studied: the stepwise double proton transfer, the stepwise double hydrogen transfer, and the concerted double proton transfer. The results are consistent with previous findings related to the photostability of the GC base pair, and a new contribution to tautomerism is provided. The C-based imino-oxo and imino-enol GC tautomers, which can be generated during the UV irradiation of the Watson–Crick base pair, have analogous radiationless energy-decay channels to those of the canonical base pair. In addition, the C-based imino-enol GC tautomer is thermally less stable. A study of the GC base pair is carried out subsequently taking into account the DNA surroundings in the biological environment. The most important stationary points are computed using the quantum mechanics/molecular mechanics (QM/MM) approach, suggesting a similar scenario for the proton/hydrogen-transfer phenomena in vacuo and in DNA. Finally, the static model is complemented by ab initio dynamic simulations, which show that vibrations at the hydrogen bonds can indeed originate hydrogen-transfer processes in the GC base pair. The relevance of the present findings for the rationalization of the preservation of the genetic code and mutagenesis is discussed.
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| 5. |
- Bouchard, Ron A., et al.
(författare)
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Structure-Function Analysis of Global Pharmaceutical Linkage Regulations
- 2011
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Ingår i: Minnesota Journal of Law, Science & Technology. - Minneapolis : University of Minnesota. - 1552-9533. ; 12:2, s. 391-456
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Tidskriftsartikel (refereegranskat)abstract
- Prompt and affordable access to essential medicines is a component of almost all domestic and global public health models. As is now well known, the availability and costs of both brand and generic drugs is a function of traditional patent law incentives. What is less known, however, is that generic entry is controlled increasingly through an emerging form of intellectual property law referred to as "linkage regulations". Linkage regulations tie generic drug approval, and thus access to essential medications, to existing drug patents through potentially long and costly litigation. The linkage regime is in the process of rapidly spreading worldwide through international free trade agreements. Even so, very little is known about how the regulations work in developed nations let alone how they impact on public health systems across international borders. The authors constitute a new consortium of eleven health policy experts and practicing lawyers in nine countries including those with mature linkage regulations, those with new regulations, those without regulations but with practices that parallel linkage, and those where regulations are currently subject to intense public debate and litigation. Here, we propose a novel framework to conduct a comparative legal analysis of global pharmaceutical linkage, with the aim of obtaining critical information about the costs and benefits of tying pharmaceutical innovation and generic drug availability to drug patenting. A major goal of the research is to investigate the structural and functional aspects of global linkage regulations as they relate to drug availability, costs and expenditures on the one hand and incentives for innovation and protection of rights on the other. The structural and functional aspects we discuss here include: assessment in each jurisdiction of the original policy intent underpinning linkage; the manner in which public health policy and economic policy is perceived by governments and the courts to converge or diverge through linkage; the specific legal checks and balances designed specifically to maintain balance between the interests of brand and generic firms; the growing expansion of linkage beyond the drug approval-drug patenting nexus to encompass drug pricing and reimbursement; and the role of empirical studies to establish the legal legitimacy of linkage regulations. A second major goal of our work is to assist domestic and global governments and legal systems working with linkage regimes to stimulate the production of new and innovative drugs while at the same time lowering public health costs and increasing access to essential medicines.
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| 6. |
- Boza-Serrano, Antonio, et al.
(författare)
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The role of Galectin-3 in α-synuclein-induced microglial activation
- 2014
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Ingår i: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 2
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Forskningsöversikt (refereegranskat)abstract
- Background: Parkinson's disease (PD) is the most prevalent neurodegenerative motor disorder. The neuropathology is characterized by intraneuronal protein aggregates of α-synuclein and progressive degeneration of dopaminergic neurons within the substantia nigra. Previous studies have shown that extracellular α-synuclein aggregates can activate microglial cells, induce inflammation and contribute to the neurodegenerative process in PD. However, the signaling pathways involved in α-synuclein-mediated microglia activation are poorly understood. Galectin-3 is a member of a carbohydrate-binding protein family involved in cell activation and inflammation. Therefore, we investigated whether galectin-3 is involved in the microglia activation triggered by α-synuclein. Results: We cultured microglial (BV2) cells and induced cell activation by addition of exogenous α-synuclein monomers or aggregates to the cell culture medium. This treatment induced a significant increase in the levels of proinflammatory mediators including the inducible Nitric Oxide Synthase (iNOS), interleukin 1 Beta (IL-1β) and Interleukin-12 (IL-12). We then reduced the levels of galectin-3 expression using siRNA or pharmacologically targeting galectin-3 activity using bis-(3-deoxy-3-(3-fluorophenyl-1H-1,2,3-triazol-1-yl)-β-D-galactopyranosyl)-sulfane. Both approaches led to a significant reduction in the observed inflammatory response induced by α-synuclein. We confirmed these findings using primary microglial cells obtained from wild-type and galectin-3 null mutant mice. Finally, we performed injections of α-synuclein in the olfactory bulb of wild type mice and observed that some of the α-synuclein was taken up by activated microglia that were immunopositive for galectin-3. Conclusions: We show that α-synuclein aggregates induce microglial activation and demonstrate for the first time that galectin-3 plays a significant role in microglia activation induced by α-synuclein. These results suggest that genetic down-regulation or pharmacological inhibition of galectin-3 might constitute a novel therapeutic target in PD and other synucleinopathies.
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| 7. |
- Fernández-Calle, Rosalía, et al.
(författare)
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APOE in the bullseye of neurodegenerative diseases : impact of the APOE genotype in Alzheimer’s disease pathology and brain diseases
- 2022
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Ingår i: Molecular Neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 17:1
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Forskningsöversikt (refereegranskat)abstract
- ApoE is the major lipid and cholesterol carrier in the CNS. There are three major human polymorphisms, apoE2, apoE3, and apoE4, and the genetic expression of APOE4 is one of the most influential risk factors for the development of late-onset Alzheimer's disease (AD). Neuroinflammation has become the third hallmark of AD, together with Amyloid-β plaques and neurofibrillary tangles of hyperphosphorylated aggregated tau protein. This review aims to broadly and extensively describe the differential aspects concerning apoE. Starting from the evolution of apoE to how APOE's single-nucleotide polymorphisms affect its structure, function, and involvement during health and disease. This review reflects on how APOE's polymorphisms impact critical aspects of AD pathology, such as the neuroinflammatory response, particularly the effect of APOE on astrocytic and microglial function and microglial dynamics, synaptic function, amyloid-β load, tau pathology, autophagy, and cell-cell communication. We discuss influential factors affecting AD pathology combined with the APOE genotype, such as sex, age, diet, physical exercise, current therapies and clinical trials in the AD field. The impact of the APOE genotype in other neurodegenerative diseases characterized by overt inflammation, e.g., alpha- synucleinopathies and Parkinson's disease, traumatic brain injury, stroke, amyotrophic lateral sclerosis, and multiple sclerosis, is also addressed. Therefore, this review gathers the most relevant findings related to the APOE genotype up to date and its implications on AD and CNS pathologies to provide a deeper understanding of the knowledge in the APOE field.
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| 8. |
- García-Revilla, Juan, et al.
(författare)
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Galectin-3 shapes toxic alpha-synuclein strains in Parkinson’s disease
- 2023
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Ingår i: Acta Neuropathologica. - 0001-6322. ; 146:1, s. 51-75
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Tidskriftsartikel (refereegranskat)abstract
- Parkinson’s Disease (PD) is a neurodegenerative and progressive disorder characterised by intracytoplasmic inclusions called Lewy bodies (LB) and degeneration of dopaminergic neurons in the substantia nigra (SN). Aggregated α-synuclein (αSYN) is known to be the main component of the LB. It has also been reported to interact with several proteins and organelles. Galectin-3 (GAL3) is known to have a detrimental function in neurodegenerative diseases. It is a galactose-binding protein without known catalytic activity and is expressed mainly by activated microglial cells in the central nervous system (CNS). GAL3 has been previously found in the outer layer of the LB in post-mortem brains. However, the role of GAL3 in PD is yet to be elucidated. In post-mortem samples, we identified an association between GAL3 and LB in all the PD subjects studied. GAL3 was linked to less αSYN in the LB outer layer and other αSYN deposits, including pale bodies. GAL3 was also associated with disrupted lysosomes. In vitro studies demonstrate that exogenous recombinant Gal3 is internalised by neuronal cell lines and primary neurons where it interacts with endogenous αSyn fibrils. In addition, aggregation experiments show that Gal3 affects spatial propagation and the stability of pre-formed αSyn fibrils resulting in short, amorphous toxic strains. To further investigate these observations in vivo, we take advantage of WT and Gal3KO mice subjected to intranigral injection of adenovirus overexpressing human αSyn as a PD model. In line with our in vitro studies, under these conditions, genetic deletion of GAL3 leads to increased intracellular αSyn accumulation within dopaminergic neurons and remarkably preserved dopaminergic integrity and motor function. Overall, our data suggest a prominent role for GAL3 in the aggregation process of αSYN and LB formation, leading to the production of short species to the detriment of larger strains which triggers neuronal degeneration in a mouse model of PD.
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| 9. |
- Garcia-Revilla, Juan, et al.
(författare)
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Hyperinflammation and Fibrosis in Severe COVID-19 Patients : Galectin-3, a Target Molecule to Consider
- 2020
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- COVID-19 disease have become so far the most important sanitary crisis in the XXI century. In light of the events, any clinical resource should be considered to alleviate this crisis. Severe COVID-19 cases present a so-called cytokine storm as the most life-threatening symptom accompanied by lung fibrosis. Galectin-3 has been widely described as regulator of both processes. Hereby, we present compelling evidences on the potential role of galectin-3 in COVID-19 in the regulation of the inflammatory response, fibrosis and infection progression. Moreover, we provide a strong rationale of the utility of measuring plasma galectin-3 as a prognosis biomarker for COVID-19 patients and propose that inhibition of galectin-3 represents a feasible and promising new therapeutical approach.
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| 10. |
- Ortigoza-Escobar, Juan Darío, et al.
(författare)
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Free-thiamine is a potential biomarker of thiamine transporter-2 deficiency: a treatable cause of Leigh syndrome.
- 2016
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 139:Pt 1, s. 31-8
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Tidskriftsartikel (refereegranskat)abstract
- Thiamine transporter-2 deficiency is caused by mutations in the SLC19A3 gene. As opposed to other causes of Leigh syndrome, early administration of thiamine and biotin has a dramatic and immediate clinical effect. New biochemical markers are needed to aid in early diagnosis and timely therapeutic intervention. Thiamine derivatives were analysed by high performance liquid chromatography in 106 whole blood and 38 cerebrospinal fluid samples from paediatric controls, 16 cerebrospinal fluid samples from patients with Leigh syndrome, six of whom harboured mutations in the SLC19A3 gene, and 49 patients with other neurological disorders. Free-thiamine was remarkably reduced in the cerebrospinal fluid of five SLC19A3 patients before treatment. In contrast, free-thiamine was slightly decreased in 15.2% of patients with other neurological conditions, and above the reference range in one SLC19A3 patient on thiamine supplementation. We also observed a severe deficiency of free-thiamine and low levels of thiamine diphosphate in fibroblasts from SLC19A3 patients. Surprisingly, pyruvate dehydrogenase activity and mitochondrial substrate oxidation rates were within the control range. Thiamine derivatives normalized after the addition of thiamine to the culture medium. In conclusion, we found a profound deficiency of free-thiamine in the CSF and fibroblasts of patients with thiamine transporter-2 deficiency. Thiamine supplementation led to clinical improvement in patients early treated and restored thiamine values in fibroblasts and cerebrospinal fluid.
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