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- Ristivojevic, MK, et al.
(författare)
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Alpha-Gal on the Protein Surface Hampers Transcytosis through the Caco-2 Monolayer
- 2020
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Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 21:16
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Tidskriftsartikel (refereegranskat)abstract
- Transepithelial transport of proteins is an important step in the immune response to food allergens. Mammalian meat allergy is characterized by an IgE response against the carbohydrate moiety galactosyl-α-1,3-galactose (α-Gal) present on mammalian glycoproteins and glycolipids, which causes severe allergic reactions several hours after red meat consumption. The delayed reaction may be related to the processing of α-Gal carrying proteins in the gastrointestinal tract. The aim of this study was to investigate how protein glycosylation by α-Gal affects the susceptibility to gastric digestion and transport through the Caco-2 cell monolayer. We found that α-Gal glycosylation altered protein susceptibility to gastric digestion, where large protein fragments bearing the α-Gal epitope remained for up to 2 h of digestion. Furthermore, α-Gal glycosylation of the protein hampered transcytosis of the protein through the Caco-2 monolayer. α-Gal epitope on the intact protein could be detected in the endosomal fraction obtained by differential centrifugation of Caco-2 cell lysates. Furthermore, the level of galectin-3 in Caco-2 cells was not affected by the presence of α-Gal glycosylated BSA (bovine serum albumin) (BSA-α-Gal). Taken together, our data add new knowledge and shed light on the digestion and transport of α-Gal glycosylated proteins.
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| 11. |
- Maximyuk, O., et al.
(författare)
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Plasma membrane poration by opioid neuropeptides : a possible mechanism of pathological signal transduction
- 2015
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Ingår i: Cell Death and Disease. - : Nature Publishing Group. - 2041-4889. ; 6:3
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Tidskriftsartikel (refereegranskat)abstract
- Neuropeptides induce signal transduction across the plasma membrane by acting through cell-surface receptors. The dynorphins, endogenous ligands for opioid receptors, are an exception; they also produce non-receptor-mediated effects causing pain and neurodegeneration. To understand non-receptor mechanism(s), we examined interactions of dynorphins with plasma membrane. Using fluorescence correlation spectroscopy and patch-clamp electrophysiology, we demonstrate that dynorphins accumulate in the membrane and induce a continuum of transient increases in ionic conductance. This phenomenon is consistent with stochastic formation of giant (~2.7 nm estimated diameter) unstructured non-ion-selective membrane pores. The potency of dynorphins to porate the plasma membrane correlates with their pathogenic effects in cellular and animal models. Membrane poration by dynorphins may represent a mechanism of pathological signal transduction. Persistent neuronal excitation by this mechanism may lead to profound neuropathological alterations, including neurodegeneration and cell death.
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| 14. |
- Ristivojevic, MK, et al.
(författare)
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α-Gal on the protein surface affects uptake and degradation in immature monocyte derived dendritic cells
- 2018
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 12684-
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Tidskriftsartikel (refereegranskat)abstract
- Red meat allergy is characterized by an IgE response against the carbohydrate galactose-α-1,3-galactose (α-Gal), which is abundantly expressed on glycoproteins from non-primate mammals. The mechanisms of how α-Gal is processed and presented to the immune system to initiate an allergic reaction are still unknown. The aim of this study was to reveal whether the presence of α-Gal epitopes on the protein surface influence antigen uptake and processing in immature monocyte-derived dendritic cells (iMDDCs). Immature MDDCs were prepared from healthy blood donors and red meat allergic patients. We found an increased internalization of α-Gal carrying proteins over time in iMDDCs by flow cytometric analysis, which was independent of the donor allergic status. The uptake of α-Gal carrying proteins was significantly higher than the uptake of non-α-Gal carrying proteins. Confocal microscopy revealed α-Gal carrying proteins scattered around the cytoplasm in most iMDDCs while detection of proteins not carrying α-Gal was negligible. Fluorescent detection of protein on SDS-PAGE showed that degradation of α-Gal carrying proteins was slower than degradation of non-α-Gal carrying proteins. Thus, the presence of α-Gal on the protein surface affects both uptake and degradation of the protein, and the results add new knowledge of α-Gal as a clinically relevant food allergen.
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- Aksnes, M, et al.
(författare)
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Comparison of Cerebrospinal Fluid Amyloidogenic Nanoplaques With Core Biomarkers of Alzheimer's Disease
- 2021
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Ingår i: Frontiers in aging neuroscience. - : Frontiers Media SA. - 1663-4365. ; 12, s. 608628-
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Tidskriftsartikel (refereegranskat)abstract
- Accurate biomarkers of Alzheimer’s disease (AD) are essential for early diagnosis and intervention. Available biomarkers are not sufficient to permit the monitoring of AD progression over time, and additional biomarkers are required. Measures of aggregated amyloid-β (Aβ) could be useful biomarkers for AD. Here, we investigate whether levels of Thioflavin-T (ThT) positive amyloid aggregates, i.e., nanoplaques, in cerebrospinal fluid (CSF) could serve as useful biomarkers for AD. One-hundred and eighteen memory clinic patients were AT(N) classified, and CSF nanoplaque concentrations were compared between patients on the “Alzheimer’s continuum” (A+ patients) and patients with “Normal AD biomarkers” or “Non-AD pathologic change” (A− patients). CSF nanoplaque concentrations and sizes were quantified using the novel ThT-Fluorescence Correlation Spectroscopy (ThT-FCS) assay, and core biomarkers (Aβ42, total tau and phosphorylated tau) were determined by enzyme-linked immunosorbent assays. We investigated the association between nanoplaque concentrations and core biomarkers, and the diagnostic value of nanoplaque levels. Nanoplaque levels were increased in A+ patients compared to A− patients. Nanoplaque concentrations were negatively associated with Aβ42, but not related to total tau or phosphorylated tau measures. Quantification of nanoplaques did not improve the classification of patients on the Alzheimer’s continuum compared to the core biomarkers alone. Dynamic changes in nanoplaques concentration and size throughout AD stages should be explored in longitudinal studies.
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- Auer, JMT, et al.
(författare)
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Of numbers and movement - understanding transcription factor pathogenesis by advanced microscopy
- 2020
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Ingår i: Disease models & mechanisms. - : The Company of Biologists. - 1754-8411 .- 1754-8403. ; 13:12
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Tidskriftsartikel (refereegranskat)abstract
- Transcription factors (TFs) are life-sustaining and, therefore, the subject of intensive research. By regulating gene expression, TFs control a plethora of developmental and physiological processes, and their abnormal function commonly leads to various developmental defects and diseases in humans. Normal TF function often depends on gene dosage, which can be altered by copy-number variation or loss-of-function mutations. This explains why TF haploinsufficiency (HI) can lead to disease. Since aberrant TF numbers frequently result in pathogenic abnormalities of gene expression, quantitative analyses of TFs are a priority in the field. In vitro single-molecule methodologies have significantly aided the identification of links between TF gene dosage and transcriptional outcomes. Additionally, advances in quantitative microscopy have contributed mechanistic insights into normal and aberrant TF function. However, to understand TF biology, TF-chromatin interactions must be characterised in vivo, in a tissue-specific manner and in the context of both normal and altered TF numbers. Here, we summarise the advanced microscopy methodologies most frequently used to link TF abundance to function and dissect the molecular mechanisms underlying TF HIs. Increased application of advanced single-molecule and super-resolution microscopy modalities will improve our understanding of how TF HIs drive disease.
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