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Article ; Online: Cellular uptake of nanoparticles

Tore Skotland / Tore Geir Iversen / Kirsten Sandvig

Precision Nanomedicine (2021)

Involvement of caveolae?

2021

Abstract: We here discuss shortly some pitfalls and challenges when investigating which endocytic mechanisms that are involved in cellular uptake of nanoparticles. We specifically discuss some common misunderstandings regarding studies claimed to demonstrate ... ...

Abstract	We here discuss shortly some pitfalls and challenges when investigating which endocytic mechanisms that are involved in cellular uptake of nanoparticles. We specifically discuss some common misunderstandings regarding studies claimed to demonstrate uptake via caveolae. Scientists in the nanomedicine field should be aware of that reduction in the membrane content of cholesterol by adding methyl-β-cyclodextrin not only removes caveolae, but inhibits other uptake mechanisms, such as macropinocytosis, as well. Furthermore, the general tyrosine kinase inhibitor genistein is not a specific inhibitor of uptake from caveolae. Moreover, one can still see that scientists in the field write that they want to direct transport of their particles to caveolae and caveosomes to avoid lysosomal degradation. However, caveosomes are artefacts caused by overexpression of caveolin-1 constructs, and ligands or particles taken up by caveolae are transported to endosomes and lysosomes as reported for other types of endocytosis.
Keywords	Medicine ; R ; Medical technology ; R855-855.5
Language	English
Publishing date	2021-04-01T00:00:00Z
Publisher	Andover House Inc.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The role of PS 18:0/18:1 in membrane function

Tore Skotland / Kirsten Sandvig

Nature Communications, Vol 10, Iss 1, Pp 1-

2019 Volume 10

Abstract: There are several lines of evidence for interactions between the two membrane leaflets in cells. In this review the authors discuss the transmembrane coupling of lipids, the involvement of phosphatidyl serine species PS 18:0/18:1, and their importance ... ...

Abstract	There are several lines of evidence for interactions between the two membrane leaflets in cells. In this review the authors discuss the transmembrane coupling of lipids, the involvement of phosphatidyl serine species PS 18:0/18:1, and their importance for various cellular processes.
Keywords	Science ; Q
Language	English
Publishing date	2019-06-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The role of PS 18:0/18:1 in membrane function

Tore Skotland / Kirsten Sandvig

Nature Communications, Vol 10, Iss 1, Pp 1-

2019 Volume 10

Abstract	There are several lines of evidence for interactions between the two membrane leaflets in cells. In this review the authors discuss the transmembrane coupling of lipids, the involvement of phosphatidyl serine species PS 18:0/18:1, and their importance for various cellular processes.
Keywords	Science ; Q
Language	English
Publishing date	2019-06-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The Protein Toxins Ricin and Shiga Toxin as Tools to Explore Cellular Mechanisms of Internalization and Intracellular Transport

Kirsten Sandvig / Simona Kavaliauskiene / Tore Skotland

Toxins, Vol 13, Iss 377, p

2021 Volume 377

Abstract: Protein toxins secreted by bacteria and found in plants can be threats to human health. However, their extreme toxicity can also be exploited in different ways, e.g., to produce hybrid toxins directed against cancer cells and to study transport ... ...

Abstract	Protein toxins secreted by bacteria and found in plants can be threats to human health. However, their extreme toxicity can also be exploited in different ways, e.g., to produce hybrid toxins directed against cancer cells and to study transport mechanisms in cells. Investigations during the last decades have shown how powerful these molecules are as tools in cell biological research. Here, we first present a partly historical overview, with emphasis on Shiga toxin and ricin, of how such toxins have been used to characterize processes and proteins of importance for their trafficking. In the second half of the article, we describe how one can now use toxins to investigate the role of lipid classes for intracellular transport. In recent years, it has become possible to quantify hundreds of lipid species using mass spectrometry analysis. Thus, it is also now possible to explore the importance of lipid species in intracellular transport. The detailed analyses of changes in lipids seen under conditions of inhibited toxin transport reveal previously unknown connections between syntheses of lipid classes and demonstrate the ability of cells to compensate under given conditions.
Keywords	endocytosis ; intracellular transport ; Golgi apparatus ; endoplasmic reticulum ; membranes ; lipids ; Medicine ; R
Subject code	612
Language	English
Publishing date	2021-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Modulation of Ricin Intoxication by the Autophagy Inhibitor EACC

Kirsten Sandvig / Simona Kavaliauskiene / Anne Grethe Myrann / Tore Geir Iversen / Tore Skotland

Toxins, Vol 14, Iss 360, p

2022 Volume 360

Abstract: The compound EACC (ethyl (2-(5-nitrothiophene-2-carboxamido) thiophene-3-carbonyl) carbamate) was recently reported to inhibit fusion of autophagosomes with lysosomes in a reversible manner by inhibiting recruitment of syntaxin 17 to autophagosomes. We ... ...

Abstract	The compound EACC (ethyl (2-(5-nitrothiophene-2-carboxamido) thiophene-3-carbonyl) carbamate) was recently reported to inhibit fusion of autophagosomes with lysosomes in a reversible manner by inhibiting recruitment of syntaxin 17 to autophagosomes. We report here that this compound also provides a strong protection against the protein toxin ricin as well as against other plant toxins such as abrin and modeccin. The protection did not seem to be caused by inhibition of endocytosis and retrograde transport, but rather by inhibited release of the enzymatically active A-moiety to the cytosol. The TANK-binding kinase 1 (TBK1) has been reported to phosphorylate syntaxin 17 and be required for initiation of autophagy. The inhibitor of TBK1, MRT68601, induced in itself a strong sensitization to ricin, apparently by increasing transport to the Golgi apparatus. Importantly, MRT68601 increased Golgi transport of ricin even in the presence of EACC, but EACC was still able to inhibit intoxication, supporting the idea that EACC protects at a late step along the retrograde pathway. These results also indicate that phosphorylation of syntaxin 17 is not required for the protection observed.
Keywords	ricin ; abrin ; volkensin ; viscumin ; modeccin ; plant toxins ; Medicine ; R
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Protection against Shiga Toxins

Simona Kavaliauskiene / Anne Berit Dyve Lingelem / Tore Skotland / Kirsten Sandvig

Toxins, Vol 9, Iss 2, p

2017 Volume 44

Abstract: Shiga toxins consist of an A-moiety and five B-moieties able to bind the neutral glycosphingolipid globotriaosylceramide (Gb3) on the cell surface. To intoxicate cells efficiently, the toxin A-moiety has to be cleaved by furin and transported ... ...

Abstract	Shiga toxins consist of an A-moiety and five B-moieties able to bind the neutral glycosphingolipid globotriaosylceramide (Gb3) on the cell surface. To intoxicate cells efficiently, the toxin A-moiety has to be cleaved by furin and transported retrogradely to the Golgi apparatus and to the endoplasmic reticulum. The enzymatically active part of the A-moiety is then translocated to the cytosol, where it inhibits protein synthesis and in some cell types induces apoptosis. Protection of cells can be provided either by inhibiting binding of the toxin to cells or by interfering with any of the subsequent steps required for its toxic effect. In this article we provide a brief overview of the interaction of Shiga toxins with cells, describe some compounds and conditions found to protect cells against Shiga toxins, and discuss whether they might also provide protection in animals and humans.
Keywords	Shiga toxin ; Stx1 ; Stx2 ; hemolytic uremic syndrome ; inhibitors ; chloroquine ; fluorodeoxyglucose ; Mn2+ ; Medicine ; R
Subject code	570
Language	English
Publishing date	2017-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Cell-Penetrating Peptides

Tore Skotland / Tore Geir Iversen / Maria Lyngaas Torgersen / Kirsten Sandvig

Molecules, Vol 20, Iss 7, Pp 13313-

Possibilities and Challenges for Drug Delivery in Vitro and in Vivo

2015 Volume 13323

Abstract: In this review, we discuss how cell-penetrating peptides (CPPs) might get access to their intracellular targets. We specifically focus on the challenge of deciding whether the positively-charged CPPs are just bound to the negatively-charged cell surface ... ...

Abstract	In this review, we discuss how cell-penetrating peptides (CPPs) might get access to their intracellular targets. We specifically focus on the challenge of deciding whether the positively-charged CPPs are just bound to the negatively-charged cell surface and subsequently endocytosed or actually transported into the cytosol, either by direct plasma membrane penetration or after endocytosis. This discussion includes comments about pitfalls when using pharmacological inhibitors in such studies. The possibility of exploiting CPPs as carriers for the delivery of drugs of different sizes in vitro is discussed, as is the use of CPPs as carriers for therapeutic drugs or contrast agents in vivo. We conclude that in many cases, more studies are needed to demonstrate conclusively whether increased delivery of a substance attached to CPPs is due to a membrane-penetrating property or whether the increase is a consequence of just changing the charge of the substance to be delivered. Finally, the expected dose needed for the use of such conjugates in vivo is discussed, including aspects to consider in order to bring potential products into clinical use.
Keywords	cell-penetrating peptides ; cellular uptake ; endocytosis ; drug delivery ; in vivo dose ; pharmaceutical development ; Organic chemistry ; QD241-441
Subject code	610
Language	English
Publishing date	2015-07-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Biodistribution of Poly(alkyl cyanoacrylate) Nanoparticles in Mice and Effect on Tumor Infiltration of Macrophages into a Patient-Derived Breast Cancer Xenograft

Abhilash D. Pandya / Tore-Geir Iversen / Siver Moestue / Maria T. Grinde / Ýrr Mørch / Sofie Snipstad / Andreas K. O. Åslund / Geir F. Øy / Wanja Kildal / Olav Engebråten / Kirsten Sandvig / Tore Skotland / Gunhild M. Mælandsmo

Nanomaterials, Vol 11, Iss 1140, p

2021 Volume 1140

Abstract: We have investigated the biodistribution and tumor macrophage infiltration after intravenous injection of the poly(alkyl cyanoacrylate) nanoparticles (NPs): PEBCA (poly(2-ethyl-butyl cyanoacrylate), PBCA (poly(n-butyl cyanoacrylate), and POCA (poly(octyl ...

Abstract	We have investigated the biodistribution and tumor macrophage infiltration after intravenous injection of the poly(alkyl cyanoacrylate) nanoparticles (NPs): PEBCA (poly(2-ethyl-butyl cyanoacrylate), PBCA (poly(n-butyl cyanoacrylate), and POCA (poly(octyl cyanoacrylate), in mice. These NPs are structurally similar, have similar PEGylation, and have previously been shown to give large variations in cellular responses in vitro. The PEBCA NPs had the highest uptake both in the patient-derived breast cancer xenograft MAS98.12 and in lymph nodes, and therefore, they are the most promising of these NPs for delivery of cancer drugs. High-resolution magic angle spinning magnetic resonance (HR MAS MR) spectroscopy did not reveal any differences in the metabolic profiles of tumors following injection of the NPs, but the PEBCA NPs resulted in higher tumor infiltration of the anti-tumorigenic M1 macrophages than obtained with the two other NPs. The PEBCA NPs also increased the ratio of M1/M2 (anti-tumorigenic/pro-tumorigenic) macrophages in the tumors, suggesting that these NPs might be used both as a vehicle for drug delivery and to modulate the immune response in favor of enhanced therapeutic effects.
Keywords	poly(alkyl cyanoacrylate) nanoparticles ; breast cancer ; biodistribution ; macrophage infiltration ; magnetic resonance spectroscopy ; Chemistry ; QD1-999
Subject code	500
Language	English
Publishing date	2021-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Data including GROMACS input files for atomistic molecular dynamics simulations of mixed, asymmetric bilayers including molecular topologies, equilibrated structures, and force field for lipids compatible with OPLS-AA parameters

Tomasz Róg / Adam Orłowski / Alicia Llorente / Tore Skotland / Tuulia Sylvänne / Dimple Kauhanen / Kim Ekroos / Kirsten Sandvig / Ilpo Vattulainen

Data in Brief, Vol 7, Iss , Pp 1171-

2016 Volume 1174

Abstract: In this Data in Brief article we provide a data package of GROMACS input files for atomistic molecular dynamics simulations of multicomponent, asymmetric lipid bilayers using the OPLS-AA force field. These data include 14 model bilayers composed of 8 ... ...

Abstract	In this Data in Brief article we provide a data package of GROMACS input files for atomistic molecular dynamics simulations of multicomponent, asymmetric lipid bilayers using the OPLS-AA force field. These data include 14 model bilayers composed of 8 different lipid molecules. The lipids present in these models are: cholesterol (CHOL), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylethanolamine (POPE), 1-stearoyl-2-oleoyl-sn-glycero-3-phosphatidyl-ethanolamine (SOPE), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylserine (POPS), 1-stearoyl-2-oleoyl-sn-glycero-3-phosphatidylserine (SOPS), N-palmitoyl-D-erythro-sphingosyl-phosphatidylcholine (SM16), and N-lignoceroyl-D-erythro-sphingosyl-phosphatidylcholine (SM24). The bilayers׳ compositions are based on lipidomic studies of PC-3 prostate cancer cells and exosomes discussed in Llorente et al. (2013) [1], showing an increase in the section of long-tail lipid species (SOPS, SOPE, and SM24) in the exosomes. Former knowledge about lipid asymmetry in cell membranes was accounted for in the models, meaning that the model of the inner leaflet is composed of a mixture of PC, PS, PE, and cholesterol, while the extracellular leaflet is composed of SM, PC and cholesterol discussed in Van Meer et al. (2008) [2]. The provided data include lipids׳ topologies, equilibrated structures of asymmetric bilayers, all force field parameters, and input files with parameters describing simulation conditions (md.mdp). The data is associated with the research article “Interdigitation of Long-Chain Sphingomyelin Induces Coupling of Membrane Leaflets in a Cholesterol Dependent Manner” (Róg et al., 2016) [3]. Keywords: Molecular dynamics simulations, Force field, Topology, Lipidomics, Lipid, GROMACS
Keywords	Computer applications to medicine. Medical informatics ; R858-859.7 ; Science (General) ; Q1-390
Subject code	612
Language	English
Publishing date	2016-06-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The ether lipid precursor hexadecylglycerol causes major changes in the lipidome of HEp-2 cells.

Jonas Bergan / Tore Skotland / Tuulia Sylvänne / Helena Simolin / Kim Ekroos / Kirsten Sandvig

PLoS ONE, Vol 8, Iss 9, p e

2013 Volume 75904

Abstract: The ether-lipid precursor sn-1-O-hexadecylglycerol (HG) can be used to compensate for early metabolic defects in ether-lipid biosynthesis. To investigate a possible metabolic link between ether-linked phospholipids and the rest of the cellular lipidome, ... ...

Abstract	The ether-lipid precursor sn-1-O-hexadecylglycerol (HG) can be used to compensate for early metabolic defects in ether-lipid biosynthesis. To investigate a possible metabolic link between ether-linked phospholipids and the rest of the cellular lipidome, we incubated HEp-2 cells with HG. Mass spectrometry analysis revealed major changes in the lipidome of HG-treated cells compared to that of untreated cells or cells treated with palmitin, a control substance for HG containing an acyl group instead of the ether group. We present quantitative data for a total of 154 species from 17 lipid classes. These species are those constituting more than 2% of their lipid class for most lipid classes, but more than 1% for the ether lipids and glycosphingolipids. In addition to the expected ability of HG to increase the levels of ether-linked glycerophospholipids with 16 carbon atoms in the sn-1 position, this precursor also decreased the amounts of glycosphingolipids and increased the amounts of ceramide, phosphatidylinositol and lysophosphatidylinositol. However, incubation with palmitin, the fatty acyl analogue of HG, also increased the amounts of ceramide and phosphatidylinositols. Thus, changes in these lipid classes were not ether lipid-dependent. No major effects were observed for the other lipid classes, and cellular functions such as growth and endocytosis were unaffected. The data presented clearly demonstrate the importance of performing detailed quantitative lipidomic studies to reveal how the metabolism of ether-linked glycerophospholipids is coupled to that of glycosphingolipids and ester-linked glycerophospholipids, especially phosphatidylinositols.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2013-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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