| 1. |
- 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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| 2. |
- 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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| 3. |
- Bratteby, Klas, et al.
(författare)
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In Vivo Veritas : 18F-Radiolabeled Glycomimetics Allow Insights into the Pharmacological Fate of Galectin-3 Inhibitors
- 2020
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 63:2, s. 747-755
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Tidskriftsartikel (refereegranskat)abstract
- Glycomimetic drugs have attracted increasing interest as unique targeting vectors or surrogates for endogenous biomolecules. However, it is generally difficult to determine the in vivo pharmacokinetic profile of these compounds. In this work, two galectin-3 inhibitors were radiolabeled with fluorine-18 and used as surrogate PET tracers of TD139 and GB1107. Both compounds are promising drugs for clinical applications. In vivo evaluation revealed that both surrogates strongly differed with respect to their biodistribution profile. The disaccharide (TD139 surrogate) was rapidly eliminated from blood while the monosaccharide (GB1107 surrogate) showed no sign of excretion. The data obtained allowed us to infer the different in vivo fate of TD139 and GB1107 and rationalize how different administration routes could boost efficacy. Whereas the fast excretion profile of the TD139 surrogate indicated that systemic application of disaccharides is unfavorable, the extended biological half-life of the GB1107 surrogate indicated that systemic administration is possible for monosaccharides.
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| 4. |
- Burguillos Garcia, Miguel, et al.
(författare)
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Microglia-Secreted Galectin-3 Acts as a Toll-like Receptor 4 Ligand and Contributes to Microglial Activation.
- 2015
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 10:9, s. 1626-1638
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Tidskriftsartikel (refereegranskat)abstract
- Inflammatory response induced by microglia plays a critical role in the demise of neuronal populations in neuroinflammatory diseases. Although the role of toll-like receptor 4 (TLR4) in microglia's inflammatory response is fully acknowledged, little is known about endogenous ligands that trigger TLR4 activation. Here, we report that galectin-3 (Gal3) released by microglia acts as an endogenous paracrine TLR4 ligand. Gal3-TLR4 interaction was further confirmed in a murine neuroinflammatory model (intranigral lipopolysaccharide [LPS] injection) and in human stroke subjects. Depletion of Gal3 exerted neuroprotective and anti-inflammatory effects following global brain ischemia and in the neuroinflammatory LPS model. These results suggest that Gal3-dependent-TLR4 activation could contribute to sustained microglia activation, prolonging the inflammatory response in the brain.
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| 5. |
- Dominguez, Armand, et al.
(författare)
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A compact Scheimpflug lidar imaging instrument for industrial diagnostics of flames
- 2023
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Ingår i: Measurement science and technology. - : Institute of Physics. - 0957-0233 .- 1361-6501. ; 34:7
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Tidskriftsartikel (refereegranskat)abstract
- Scheimpflug lidar is a compact alternative to traditional lidar setups. With Scheimpflug lidar it is possible to make continuous range-resolved measurements. In this study we investigate the feasibility of a Scheimpflug lidar instrument for remote sensing in pool flames, which are characterized by strong particle scattering, large temperature gradients, and substantial fluctuations in particle distribution due to turbulence. An extinction coefficient can be extracted using the information about the transmitted laser power and the spatial extent of the flame. The transmitted laser power is manifested by the intensity of the ‘echo’ from a hard-target termination of the beam located behind the flame, while the information of the spatial extent of the flame along the laser beam is provided by the range-resolved scattering signal. Measurements were performed in heptane and diesel flames, respectively. © 2023 The Author(s).
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| 6. |
- Eriksson, Christer, et al.
(författare)
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Variant size- and glycoforms of the scavenger receptor cysteine-rich protein gp-340 with differential bacterial aggregation
- 2007
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Ingår i: Glycoconjugate Journal. - : Springer Science and Business Media LLC. - 1573-4986 .- 0282-0080. ; 24:2-3, s. 131-142
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Tidskriftsartikel (refereegranskat)abstract
- Glycoprotein gp-340 aggregates bacteria in saliva as part of innate defence at mucosal surfaces. We have detected size- and glycoforms of gp-340 between human saliva samples (n=7) and lung gp-340 from a proteinosis patient using antibodies and lectins in Western blots and ELISA measurements. Western blots of saliva samples, and of gp-340 purified, from the seven donors using a gp-340 specific antibody distinguished four gp-340 size variants, designated I to IV (n=2,2,2 and 1). While saliva gp-340 variants I to III had single bands of increasing sizes, variant IV and lung gp-340 had double bands. Purified I to IV proteins all revealed a N-terminal sequence TGGWIP upon Edman degradation. Moreover, purified gp-340 from the seven donors and lung gp-340 shared N-glycans, sialylated Gal beta 1-3GalNAc and (poly)lactosamine structures. However, the larger size gp-340 grouping II/III (n=4) and smaller size grouping I/IV correlated with a secretor, Se(+), and a non secretor, Se(-), dependent glycoform of gp-340, respectively (p=0.03). The Se(+) glycoforms contained ABH, Le(b), Le(y) and polylactosamine structures, while the Se(-) glycoforms lacked ABH antigens but expressed Lea, Lex and lactosamine structures. By contrast, lung gp- 340 completely lacked ABH, Le(a/b), Le(x/y) or sLe(x) structures. Gp-340 and secretor typing of saliva from additional donors (n=29) showed gp-340 glycoforms I to IV for 6, 16, 4 and 0 donors, respectively, and 3 non-typeable donors, and verified that gp-340 glycoforms I and II/III correlate with Se(-) and Se(+) phenotypes, respectively (p < 0.0001). The glycoforms of saliva and lung gp-340 mediated differential aggregation of Le(b)-(Helicobacter pylori), sialylpolylactosamine(Streptococcus suis) or sialic acid- (Streptococcus mutans) binding bacteria. In conclusion, variant size- and glycoforms of gp-340 are expressed by different individuals and may modulate the biological properties of gp-340 pertinent to health and disease.
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| 7. |
- Leffler, Tomas, 1962, et al.
(författare)
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Combined measurement techniques for fast detection of alkali release in fluidized bed combustion
- 2021
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Ingår i: CFB 2021 - Proceedings of the 13th International Conference on Fluidized Bed Technology. ; , s. 339-344
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Konferensbidrag (refereegranskat)abstract
- This study presents an approach combining three alkali-measuring techniques to quantitatively measure the released alkali compounds during the thermal conversion of biomass and Municipal Solid Waste (MSW) in fluidized bed reactors. The method includes measurements of alkali-containing species in the gas phase, as aerosols, or taken up by the bed material. Two techniques are used for online alkali detection in the flue gas: An In-situ Alkali Chloride Monitor (IACM), and a Surface Ionisation Detector (SID). The third technique is an Electronic Tongue (ET) used for the post-analysis of alkali content in the bed material. These three techniques form a method used to determine the alkali present in gaseous state (IACM), as aerosols (SID), and in the bed material (ET). The use of these techniques can enable the determination of optimal intervals to regenerate the bed material and to avoid bed agglomeration, slagging and fouling, as well as high-temperature corrosion.
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| 8. |
- Leffler, Tomas
(författare)
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Development and Application of Optical Diagnostics of Alkali Vapours for Solid Fuel Combustion
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: High amounts of alkali in the fuel, such as potassium and sodium in combination with high amounts of chlorine increase the chances of high-temperature corrosion, deposit growth and slagging and fouling. These risks need to be reduced to avoid losses in revenue due to unplanned stops and costs related to increased maintenance. Aims:This research targets the development of a new cell to produce calibration spectra of good quality that render accurately-determined alkali chloride concentrations. Similarly, it aims to develop new measurement techniques that can be used to determine the concentration and formation of alkali. Methods:UV absorption measurement on sublimated vapour from potassium chloride under well-defined conditions, which subsequently can be converted into an accurate calibration spectrum. Differential Absorption Light Detection and Ranging technique adapted to measurements in the combustion environment using one optical access port. Laser-induced Photofragmentation Fluorescence imaging for formation studies of alkali compounds. Results:This work has resulted in a calibration cell able to provide alkali vapour of well-controlled conditions and Laser-induced Photofragmentation Fluorescence imaging set-up for the formation studies of alkali compounds. It has been shown in the laboratory environment that the Differential Absorption Light Detection and Ranging technique can be used for alkali chloride measurements. Discussion:Prospectively the work aims at contributing to the development of more efficient combustors with low levels of emission and reduced operational problems and also increase the academic knowledge of alkali compound formation during biomass combustion.
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| 9. |
- Leffler, Tomas, et al.
(författare)
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Experimental investigations of potassium chemistry in premixed flames
- 2017
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Ingår i: Fuel. - : Elsevier BV. - 0016-2361. ; 203, s. 802-810
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Tidskriftsartikel (refereegranskat)abstract
- Quantitative potassium species concentrations have been measured in alkali-seeded premixed methane-air flames of different stoichiometry. Potassium chloride (KCl) and hydroxide (KOH) were measured by broadband UV absorption spectroscopy and laser-induced photofragmentation fluorescence, while atomic potassium was measured using tuneable diode-laser spectroscopy. In addition, laser Rayleigh scattering was employed for temperature measurements. Investigations were made for different alkali-seeding levels and chlorine loads resulting in KCl/KOH concentrations up to ∼30 ppm and concentrations of K atoms at ppm levels. Experimental results were compared with predictions from a chemical mechanism used in a homogenous reactor model. The observed trends, decrease in KCl and KOH concentrations and increase in K-atom concentrations with flame equivalence ratio, were well reproduced in simulations and are compared with results reported in literature. In addition, possibilities using the experimental methods for further investigations of alkali-related combustion phenomena and detailed model validation of alkali chemistry are discussed.
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| 10. |
- Leffler, Tomas, et al.
(författare)
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Laser-Induced Photofragmentation Fluorescence Imaging of Alkali Compounds in Flames
- 2017
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Ingår i: Applied Spectroscopy. - : SAGE Publications. - 0003-7028 .- 1943-3530. ; 71:6, s. 1289-1299
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Tidskriftsartikel (refereegranskat)abstract
- Laser-induced photofragmentation fluorescence has been investigated for the imaging of alkali compounds in premixed laminar methane–air flames. An ArF excimer laser, providing pulses of wavelength 193 nm, was used to photodissociate KCl, KOH, and NaCl molecules in the post-flame region and fluorescence from the excited atomic alkali fragment was detected. Fluorescence emission spectra showed distinct lines of the alkali atoms allowing for efficient background filtering. Temperature data from Rayleigh scattering measurements together with simulations of potassium chemistry presented in literature allowed for conclusions on the relative contributions of potassium species KOH and KCl to the detected signal. Experimental approaches for separate measurements of these components are discussed. Signal power dependence and calculated fractions of dissociated molecules indicate the saturation of the photolysis process, independent on absorption cross-section, under the experimental conditions. Quantitative KCl concentrations up to 30 parts per million (ppm) were evaluated from the fluorescence data and showed good agreement with results from ultraviolet absorption measurements. Detection limits for KCl photofragmentation fluorescence imaging of 0.5 and 1.0 ppm were determined for averaged and single-shot data, respectively. Moreover, simultaneous imaging of KCl and NaCl was demonstrated using a stereoscope with filters. The results indicate that the photofragmentation method can be employed for detailed studies of alkali chemistry in laboratory flames for validation of chemical kinetic mechanisms crucial for efficient biomass fuel utilization.
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