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  • 1.
    Lindelöf, Linnea
    et al.
    Uppsala University, Sweden.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Sweden.
    Lundtoft, Christian
    Uppsala University, Sweden.
    Sandling, Johanna K.
    Uppsala University, Sweden.
    Leonard, Dag
    Uppsala University, Sweden.
    Sayadi, Ahmed
    Uppsala University, Sweden.
    Rönnblom, Lars
    Uppsala University, Sweden.
    Enocsson, Helena
    Linköping University, Sweden.
    Sjöwall, Christopher
    Linköping University, Sweden.
    Jönsen, Andreas
    Lund University, Sweden;Skåne University Hospital, Sweden.
    Bengtsson, Anders A.
    Lund University, Sweden;Skåne University Hospital, Sweden.
    Hong, Mun-Gwan
    Stockholm University, Sweden;Sci Life Lab, Sweden.
    Diaz-Gallo, Lina-Marcela
    Karolinska Institutet, Sweden;Karolinska University Hospital, Sweden.
    Bianchi, Matteo
    Uppsala University, Sweden;Sci Life Lab, Sweden.
    Kozyrev, Sergey, V
    Uppsala University, Sweden;Sci Life Lab, Sweden.
    Lindblad-Toh, Kerstin
    Uppsala University, Swden;Sci Life Lab, Sweden;Broad Inst MIT & Harvard, USA.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Nilsson, Bo
    Uppsala University, Sweden.
    Gunnarsson, Iva
    Karolinska Institutet, Sweden;Karolinska University Hospital, Sweden.
    Svenungsson, Elisabet
    Karolinska Institutet, Sweden;Karolinska University Hospital, Sweden.
    Eriksson, Oskar
    Uppsala University, Sweden.
    A survey of ficolin-3 activity in Systemic Lupus Erythematosus reveals a link to hematological disease manifestations and autoantibody profile2024In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 143, article id 103166Article in journal (Refereed)
    Abstract [en]

    The complement system plays a central role in the pathogenesis of Systemic Lupus Erythematosus (SLE), but most studies have focused on the classical pathway. Ficolin-3 is the main initiator of the lectin pathway of complement in humans, but its role in systemic autoimmune disease has not been conclusively determined. Here, we combined biochemical and genetic approaches to assess the contribution of ficolin-3 to SLE risk and disease manifestations. Ficolin-3 activity was measured by a functional assay in serum or plasma samples from Swedish SLE patients (n = 786) and controls matched for age and sex (n = 566). Genetic variants in an extended 300 kb genomic region spanning the FCN3 locus were analyzed for their association with ficolin-3 activity and SLE manifestations in a Swedish multicenter cohort (n = 985). Patients with ficolin-3 activity in the highest tertile showed a strong enrichment in an SLE cluster defined by anti-Sm/DNA/nucleosome antibodies (OR 3.0, p < 0.001) and had increased rates of hematological disease (OR 1.4, p = 0.078) and lymphopenia (OR = 1.6, p = 0.039). Genetic variants associated with low ficolin-3 activity mapped to an extended haplotype in high linkage disequilibrium upstream of the FCN3 gene. Patients carrying the lead genetic variant associated with low ficolin3 activity had a lower frequency of hematological disease (OR 0.67, p = 0.018) and lymphopenia (OR 0.63, p = 0.031) and fewer autoantibodies (p = 0.0019). Loss-of-function variants in the FCN3 gene were not associated with SLE, but four (0.5 %) SLE patients developed acquired ficolin-3 deficiency where ficolin-3 activity in serum was depleted following diagnosis of SLE. Taken together, our results provide genetic and biochemical evidence that implicate the lectin pathway in hematological SLE manifestations. We also identify lectin pathway activation through ficolin-3 as a factor that contributes to the autoantibody response in SLE.

  • 2.
    Lindström, H. Jonathan G.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    de Wijn, Astrid S.
    Norwegian Univ Sci & Technol, Norway.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Faeth Therapeut Inc, USA.
    Interplay of mutations, alternate mechanisms, and treatment breaks in leukaemia: Understanding and implications studied with stochastic models2024In: Computers in Biology and Medicine, ISSN 0010-4825, E-ISSN 1879-0534, Vol. 169, article id 107826Article in journal (Refereed)
    Abstract [en]

    Bcr-Abl1 kinase domain mutations are the most prevalent cause of treatment resistance in chronic myeloid leukaemia (CML). Alternate resistance pathways nevertheless exist, and cell line experiments show certain patterns in the gain, and loss, of some of these alternate adaptations. These adaptations have clinical consequences when the tumour develops mechanisms that are beneficial to its growth under treatment, but slow down its growth when not treated. The results of temporarily halting treatment in CML have not been widely discussed in the clinic and there is no robust theoretical model that could suggest when such a pause in therapy can be tolerated. We constructed a dynamic model of how mechanisms such as Bcr-Abl1 overexpression and drug transporter upregulation evolve to produce resistance in cell lines, and investigate its behaviour subject to different treatment schedules, in particular when the treatment is paused ('drug holiday'). Our study results suggest that the presence of additional resistance mechanisms creates an environment which favours mutations that are either preexisting or occur late during treatment. Importantly, the results suggest the existence of tumour drug addiction, where cancer cells become dependent on the drug for (optimal) survival, which could be exploited through a treatment holiday. All simulation code is available at https://github.com/Sandalmoth/dual-adaptation.

  • 3.
    Kathiravan, Suppan
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Attana AB, Sweden.
    Dhillon, Prakriti
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Zhang, Tianshu
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Metal free cross-dehydrogenative N-N coupling of primary amides with Lewis basic amines2024In: Nature Communications, E-ISSN 2041-1723, Vol. 15, no 1, article id 2643Article in journal (Refereed)
    Abstract [en]

    Hydrazides, N-N containing structural motifs, are important due to their presence in a wide variety of biologically significant compounds. While the homo N-N coupling of two NH moieties to form the hydrazide N-N bond is well developed, the cross-dehydrogenative hetero N-N coupling remains very unevolved. Here we present an efficient intermolecular N-N cross-coupling of a series of primary benzamides with broad range of Lewis basic primary and secondary amines using PhI(OAc)2 as both a terminal oxidant and a cross-coupling mediator, without the need for metal catalysts, high temperatures, and inert atmospheres, and with substantial potential for use in the late-stage functionalization of drugs.

  • 4.
    Suriyanarayanan, Subramanian
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Olsson, Gustaf D.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Bioorgan & Biophys Chem Lab, SE-39182 Kalmar, Sweden..
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    On-Surface Synthesis of Porosity-Controlled Molecularly Imprinted Polymeric Receptors for the Biotinyl Moiety2024In: ACS Applied Polymer Materials, E-ISSN 2637-6105, Vol. 6, no 2, p. 1470-1482Article in journal (Refereed)
    Abstract [en]

    Controlled on-surface synthesis of polymer films using amide-based, environmentally friendly, nonionic deep eutectic solvents (ni-DESs) has been developed to regulate the porous features of the films. An appropriate combination of acetamide (A), urea (U), and their methyl derivatives (N-methylacetamide (NMA) and N-methylurea (NMU)) was used to prepare ni-DES. Polymer films were electrosynthesized using 4-aminobenzoic acid (4-ABA) and pyrrole as monomers in ni-DESs. We presumed that the flickering-cluster-like complexes and the extended H-bond networks in ni-DESs enhance the porosity of the polymer films, thus improving permeability features, as reflected in sensor performance. Electrosynthesized polymer films, imprinted with biotin templates (MIPs), have been tested as receptors for biotinylated targets. Molecular dynamics simulations of the prepolymerization mixture revealed the formed complexes between 4-ABA and biotin comprising high-frequency H-bonds. X-ray photoelectron spectroscopy (XPS) and reflection absorption infrared spectroscopy (RAIRS) studies revealed the structural integrity in the polymer films irrespective of the medium. Scanning electron microscopy (SEM) and electrochemical impedance spectroscopy (EIS) measurements showed a highly corrugated and porous nature for MIPA-U and MIPNMU-U when prepared in A-U and NMU-U ni-DESs. Atomic force microscope (AFM) studies support these observations, displaying an enhancement in the surface roughness from 1.44 nm (MIPaqueous) to 23.6 nm (MIPNMU-U). QCM analysis demonstrated a remarkable improvement in sensitivity of MIPA-U (17.99 +/- 0.72 Hz/mM) and MIPNMU-U (18.40 +/- 0.81 Hz/mM) films toward the biotin methyl ester (BtOMe, biotin derivative) than the MIPaqueous film. The chemosensor devised with the above MIP recognition films selectively recognized BtOMe (LOD = 12.5 ng/mL) and biotinylated biomolecules, as shown by the stability constant K-s values (MIPA-U = 1442 and MIPNMU-U = 1502 M-1). The porous network generated in the polymer films by the flickering-cluster-like complexes present in the ni-DES facilitates the analyte diffusion and recognition. We propose this ni-DES as an economically advantageous and environmentally friendly alternative to conventional ionic liquids and organic solvents in polymer synthesis and to influence polymer morphology for developing hierarchical materials.

  • 5.
    Kathiravan, Suppan
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Attana AB, Sweden.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Recent advances in electrochemical C–N bond formation via C–H/N–H activation with hydrogen evolution2024In: Current Research in Green and Sustainable Chemistry, E-ISSN 2666-0865, Vol. 8, article id 100405Article in journal (Refereed)
    Abstract [en]

    Electroorganic synthesis is a powerful sustainable tool for achieving greener and more efficient chemical processes across various industries. By adhering to the principles of green chemistry, atom economy, and resource efficiency, electroorganic synthesis can play a pivotal role in addressing environmental concerns and promoting a more sustainable future for chemical production. This review focuses on the latest advancements in the emerging application of electrochemistry in C-N bond formation through C-H/N-H cross-coupling. The first part of the review describes the electrochemical amination of arenes using metal catalysis (Cu, Co, Ni) with directing groups on the arene moiety. The next section addresses the same type of electrochemical C-N bond formation on arenes without directing groups, which represents a more general strategy enabling the synthesis of anilines and various heterocyclic-bound arenes in high yields. Further developments on benzylic systems are also discussed. This is followed by developments in the combination of photocatalysis and electrochemistry to activate C-H bonds in arenes, alkanes, and benzylic systems, including the use of flow reactor configurations for these reactions.

  • 6.
    Andersson, Linnea
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Sjöström, Dick J.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Quach, Huy Quang
    Mayo Clin, USA.
    Hägerström, Kim
    Region Kalmar County, Sweden.
    Hurler, Lisa
    Semmelwe Univ, Hungary.
    Kajdacsi, Erika
    Semmelwe Univ, Hungary.
    Cervenak, Laszlo
    Semmelwe Univ, Hungary.
    Prohaszka, Zoltan
    Semmelwe Univ, Hungary.
    Toonen, Erik J. M.
    Hycult Biotechnology, Netherlands.
    Mohlin, Camilla
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Mollnes, Tom Eirik
    Univ Oslo, Norway;Oslo Univ Hosp, Norway;Nordland Hosp, Norway.
    Sandgren, Per
    Karolinska Institutet, Sweden.
    Tjernberg, Ivar
    Region Kalmar County, Sweden;Linköping University, Sweden.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Storage of Transfusion Platelet Concentrates is Associated with Complement Activation and Reduced Ability of Platelets to Respond to Protease-Activated Receptor-1 and Thromboxane A2 Receptor2024In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 25, no 2, article id 1091Article in journal (Refereed)
    Abstract [en]

    Platelet activation and the complement system are mutually dependent. Here, we investigated the effects of storage time on complement activation and platelet function in routinely produced platelet concentrates. The platelet concentrates (n = 10) were stored at 22 degrees C for seven days and assessed daily for complement and platelet activation markers. Additionally, platelet function was analyzed in terms of their responsiveness to protease-activated receptor-1 (PAR-1) and thromboxane A2 receptor (TXA(2)R) activation and their capacity to adhere to collagen. Complement activation increased over the storage period for all analyzed markers, including the C1rs/C1-INH complex (fold change (FC) = 1.9; p < 0.001), MASP-1/C1-INH complex (FC = 2.0; p < 0.001), C4c (FC = 1.8, p < 0.001), C3bc (FC = 4.0; p < 0.01), and soluble C5b-9 (FC = 1.7, p < 0.001). Furthermore, the levels of soluble platelet activation markers increased in the concentrates over the seven-day period, including neutrophil-activating peptide-2 (FC = 2.5; p < 0.0001), transforming growth factor beta 1 (FC = 1.9; p < 0.001) and platelet factor 4 (FC = 2.1; p < 0.0001). The ability of platelets to respond to activation, as measured by surface expression of CD62P and CD63, decreased by 19% and 24% (p < 0.05) for PAR-1 and 69-72% (p < 0.05) for TXA(2)R activation, respectively, on Day 7 compared to Day 1. The extent of platelet binding to collagen was not significantly impaired during storage. In conclusion, we demonstrated that complement activation increased during the storage of platelets, and this correlated with increased platelet activation and a reduced ability of the platelets to respond to, primarily, TXA(2)R activation.

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  • 7.
    Freire, Thales Souza
    et al.
    Univ Sao Paulo, Brazil.
    Zukerman-Schpector, Julio
    Univ Fed Sao Carlos, Brazil.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Caracelli, Ignez
    Univ Fed Sao Carlos, Brazil.
    Structural and thermodynamic characterization of allosteric transitions in human serum albumin with metadynamics simulations2024In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 26, no 7, p. 6436-6447Article in journal (Refereed)
    Abstract [en]

    Human serum albumin (HSA) is the most prominent protein in blood plasma, responsible for the maintenance of blood viscosity and transport of endogenous and exogenous molecules. Fatty acids (FA) are the most common ligands of HSA and their binding can modify the protein's structure. The protein can assume two well-defined conformations, referred to as 'Neutral' and 'Basic'. The Neutral (N) state occurs at pH close to 7.0 and in the absence of bound FA. The Basic (B) state occurs at pH higher than 8.0 or when the protein is bound to long-chain FA. HSA's allosteric behaviour is dependent on the number on FA bound to the structure. However, the mechanism of this allosteric regulation is not clear. To understand how albumin changes its conformation, we compared a series of HSA structures deposited in the protein data bank to identify the minimum amount of FA bound to albumin, which is enough to drive the allosteric transition. Thereafter, non-biased molecular dynamics (MD) simulations were used to track protein's dynamics. Surprisingly, running an ensemble of relatively short MD simulations, we observed rapid transition from the B to the N state. These simulations revealed differences in the mobilities of the protein's subdomains, with one domain unable to fully complete its transition. To track the transition dynamics in full, we used these results to choose good geometrical collective variables for running metadynamics simulations. The metadynamics calculations showed that there was a low energy barrier for the transition from the B to the N state, while a higher energy barrier was observed for the N to the B transition. These calculations also offered valuable insights into the transition process. Human serum albumin (HSA) is an allosteric protein that can change conformation state through low energy barriers, being the most prominent protein in blood plasma, responsible for the maintenance of blood viscosity and transport of endogenous and exogenous molecules.

  • 8.
    Yang, Jingmei
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Synergy and antagonism between azacitidine and FLT3 inhibitors2024In: Computers in Biology and Medicine, ISSN 0010-4825, E-ISSN 1879-0534, Vol. 169, p. 107889-107889, article id 107889Article in journal (Refereed)
    Abstract [en]

    Synergetic interactions between drugs can make a drug combination more effective. Alternatively, they may allow to use lower concentrations and thus avoid toxicities or side effects that not only cause discomfort but might also reduce the overall survival. Here, we studied whether synergy exists between agents that are used for treatment of acute myeloid leukaemia (AML). Azacitidine is a demethylation agent that is used in the treatment of AML patients that are unfit for aggressive chemotherapy. An activating mutation in the FLT3 gene is common in AML patients and in the absence of specific treatment makes prognosis worse. FLT3 inhibitors may be used in such cases. We sought to determine whether combination of azacitidine with a FLT3 inhibitor (gilteritinib, quizartinib, LT-850-166, FN-1501 or FF-10101) displayed synergy or antagonism. To this end, we calculated dose–response matrices of these drug combinations from experiments in human AML cells and subsequently analysed the data using a novel consensus scoring algorithm. The results show that combinations that involved non-covalent FLT3 inhibitors, including the two clinically approved drugs gilteritinib and quizartinib were antagonistic. On the other hand combinations with the covalent inhibitor FF-10101 had some range of concentrations where synergy was observed.

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  • 9.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    The Emerging Role of Molecular Dynamics Simulations in Cancer Research2024In: Comprehensive Computational Chemistry: Molecular Dynamics Simulations and Reaction Rates / [ed] Yanez, Manuel and Boyd, Russell J., Oxford. UK: Elsevier, 2024, p. 910-920Chapter in book (Refereed)
    Abstract [en]

    Cancers ultimately develop due to aberrations that involve proteins and modify their effects. Given that the structures of many proteinsinvolved in cancer pathogenesis are known, numerous studies have employed MD simulations in cancer research. In this chapter, somecauses and treatments for cancer are briefly introduced. Thereafter, systems where cancer development or therapy have been studied byMD simulations are described, focusing on contemporary subjects of interest. These include tumor cell metabolism, RAS proteins,driver mutations, allosteric inhibitors, kinetics of drug binding, activation of protein kinases and anticancer drug delivery. While notproviding a complete picture of the fields, these subjects allow the reader to understand what sorts of systems are studied, how, andwhich conclusions can be made with the help of MD simulations. This might help the interested reader to utilize such simulations forfurther studies in the field.

  • 10.
    Lindelöf, Linnea
    et al.
    Uppsala University, Sweden.
    Dahlqvist, Solbritt Rantapää
    Umeå University, Sweden.
    Lundtoft, Christian
    Uppsala University, Sweden.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Nilsson, Bo
    Uppsala University, Sweden.
    Gunnarsson, Iva
    Karolinska Institutet, Sweden;Karolinska University Hospital, Sweden.
    Svenungsson, Elisabet
    Karolinska Institutet, Sweden;Karolinska University Hospital, Sweden.
    Eriksson, Oskar
    62 Acquired ficolin-3 deficiency in patients with Systemic Lupus Erythematosus2023In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 228, no 5, p. 152515-152515, article id 62Article in journal (Refereed)
    Abstract [en]

    Background: Ficolin-3 is the main initiator of the lectin pathway in humans. Case reports of ficolin-3 deficient patients have suggested that ficolin-3 deficiency may be enriched in patients with Systemic Lupus Erythematosus (SLE), a systemic autoimmune disease where complement plays an important role. Therefore, this study aimed to investigate the activity levels of ficolin-3 and to identify potential ficolin-3 deficient individuals in two Swedish SLE cohorts.

    Methods: Serum or plasma samples from SLE patients (n=810) and matched controls (n=566) were collected from the Karolinska Institute (KI) and Umeå University Hospital. The ficolin-3 activity levels were measured by an in-house developed functional ELISA with a pooled normal human serum sample as a reference. Serial samples were analyzed for ficolin-3 deficient patients when available. Sequencing data were analyzed for FCN3 frame-shift mutation +1637delC (rs532781899) and other potential loss-of-function (LoF) variants.

    Results: This screening revealed that the level of ficolin-3 activity varies largely in patients with SLE. The activity levels also show that SLE patients seem to generally have elevated ficolin-3 activity compared to the control group (p<0.0001). Out of 810 patients with SLE, four patients were determined to be ficolin-3 deficient. For two of these patients, the ficolin-3 activity was at normal levels at the time of diagnosis and thereafter depleted over time, indicating an acquired deficiency. For deficient patients, no or very low ficolin-3 protein levels and no lectin pathway-dependent complement activation could be detected. Autoantibodies against ficolin-3 were not detectable. No patients were homozygous for the +1637delC frameshift mutation, whereas in total 10 patients were determined to be heterozygous carriers. These heterozygous patients displayed lower levels of ficolin-3 activity but did not include the deficient patients. Additional possible LoF variants were analyzed but none were enriched in either patients or controls.

    Conclusions: Contrary to the classical pathway of the complement system we show that genetic ficolin-3 deficiency is not a risk factor for SLE. Instead, acquired ficolin-3 deficiency was observed in a subgroup of SLE patients, possibly due to a potent activation of the lectin pathway that depleted ficolin-3 plasma levels in these individuals.

  • 11.
    Kokelj, Spela
    et al.
    University of Gothenburg, Sweden.
    Ostling, Jorgen
    PExA AB, Sweden.
    Fromell, Karin
    Uppsala University, Sweden.
    Vanfleteren, Lowie E. G. W.
    Sahlgrenska University Hospital, Sweden;University of Gothenburg, Sweden.
    Olsson, Henric K.
    AstraZeneca, Sweden.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Nilsson, Bo
    Uppsala University, Sweden.
    Olin, Anna-Carin
    University of Gothenburg, Sweden.
    Activation of the Complement and Coagulation Systems in the Small Airways in Asthma2023In: Respiration, ISSN 0025-7931, E-ISSN 1423-0356, Vol. 102, no 8, p. 621-631Article in journal (Refereed)
    Abstract [en]

    Background: Several studies have shown the importance of the complement and coagulation systems in the pathogenesis of asthma. Objectives: We explored whether we could detect differentially abundant complement and coagulation proteins in the samples obtained from the small airway lining fluid by collection of exhaled particles in patients with asthma and whether these proteins are associated with small airway dysfunction and asthma control. Method: Exhaled particles were obtained from 20 subjects with asthma and 10 healthy controls (HC) with the PExA method and analysed with the SOMAscan proteomics platform. Lung function was assessed by nitrogen multiple breath washout test and spirometry. Results: 53 proteins associated with the complement and coagulation systems were included in the analysis. Nine of those proteins were differentially abundant in subjects with asthma as compared to HC, and C3 was significantly higher in inadequately controlled asthma as compared to well-controlled asthma. Several proteins were associated with physiological tests assessing small airways. Conclusions: The study highlights the role of the local activation of the complement and coagulation systems in the small airway lining fluid in asthma and their association with both asthma control and small airway dysfunction. The findings highlight the potential of complement factors as biomarkers to identify different sub-groups among patients with asthma that could potentially benefit from a therapeutic approach targeting the complement system.

  • 12.
    Martin, Myriam
    et al.
    Lund University, Sweden.
    Nilsson, Sara C. C.
    Lund University, Sweden.
    Eikrem, David
    Uppsala University, Sweden.
    Fromell, Karin
    Uppsala University, Sweden.
    Scavenius, Carsten
    Aarhus Univ, Denmark.
    Vogt, Leonie M. M.
    Lund University, Sweden.
    Bielecka, Ewa
    Jagiellonian Univ, Poland.
    Potempa, Jan
    Jagiellonian Univ, Poland;Univ Louisville, USA.
    Enghild, Jan J. J.
    Aarhus Univ, Denmark.
    Nilsson, Bo
    Uppsala University, Sweden.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Kapetanovic, Meliha C. C.
    Lund University, Sweden;Skåne University Hospital, Sweden.
    Blom, Anna M. M.
    Lund University, Sweden.
    Citrullination of C1-inhibitor as a mechanism of impaired complement regulation in rheumatoid arthritis2023In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1203506Article in journal (Refereed)
    Abstract [en]

    BackgroundDysregulated complement activation, increased protein citrullination, and production of autoantibodies against citrullinated proteins are hallmarks of rheumatoid arthritis (RA). Citrullination is induced by immune cell-derived peptidyl-Arg deiminases (PADs), which are overactivated in the inflamed synovium. We characterized the effect of PAD2- and PAD4-induced citrullination on the ability of the plasma-derived serpin C1-inhibitor (C1-INH) to inhibit complement and contact system activation. MethodsCitrullination of the C1-INH was confirmed by ELISA and Western blotting using a biotinylated phenylglyoxal probe. C1-INH-mediated inhibition of complement activation was analyzed by C1-esterase activity assay. Downstream inhibition of complement was studied by C4b deposition on heat-aggregated IgGs by ELISA, using pooled normal human serum as a complement source. Inhibition of the contact system was investigated by chromogenic activity assays for factor XIIa, plasma kallikrein, and factor XIa. In addition, autoantibody reactivity to native and citrullinated C1-INH was measured by ELISA in 101 RA patient samples. ResultsC1-INH was efficiently citrullinated by PAD2 and PAD4. Citrullinated C1-INH was not able to bind the serine protease C1s and inhibit its activity. Citrullination of the C1-INH abrogated its ability to dissociate the C1-complex and thus inhibit complement activation. Consequently, citrullinated C1-INH had a decreased capacity to inhibit C4b deposition via the classical and lectin pathways. The inhibitory effect of C1-INH on the contact system components factor XIIa, plasma kallikrein, and factor XIa was also strongly reduced by citrullination. In RA patient samples, autoantibody binding to PAD2- and PAD4-citrullinated C1-INH was detected. Significantly more binding was observed in anti-citrullinated protein antibody (ACPA)-positive than in ACPA-negative samples. ConclusionCitrullination of the C1-INH by recombinant human PAD2 and PAD4 enzymes impaired its ability to inhibit the complement and contact systems in vitro. Citrullination seems to render C1-INH more immunogenic, and citrullinated C1-INH might thus be an additional target of the autoantibody response observed in RA patients.

  • 13.
    Yang, Jingmei
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Combination strategies to overcome drug resistance in FLT+ acute myeloid leukaemia2023In: Cancer Cell International, E-ISSN 1475-2867, Vol. 23, no 1, article id 161Article in journal (Refereed)
    Abstract [en]

    BackgroundAcute myeloid leukaemia (AML) remains difficult to treat despite the development of novel formulations and targeted therapies. Activating mutations in the FLT3 gene are common among patients and make the tumour susceptible to FLT3 inhibitors, but resistance to such inhibitors develops quickly.MethodsWe examined combination therapies aimed at FLT3(+)-AML, and studied the development of resistance using a newly developed protocol. Combinations of FLT3, CDK4/6 and PI3K inhibitors were tested for synergism.ResultsWe show that AML cells express CDK4 and that the CDK4/6 inhibitors palbociclib and abemaciclib inhibit cellular growth. PI3K inhibitors were also effective in inhibiting the growth of AML cell lines that express FLT3-ITD. Whereas resistance to quizartinib develops quickly, the combinations overcome such resistance.ConclusionsThis study suggests that a multi-targeted intervention involving a CDK4/6 inhibitor with a FLT3 inhibitor or a pan-PI3K inhibitor might be a valuable therapeutic strategy for AML to overcome drug resistance. Moreover, many patients cannot tolerate high doses of the drugs that were studied (quizartinib, palbociclib and PI3K inhibitors) for longer periods, and it is therefore of high significance that the drugs act synergistically and lower doses can be used.

  • 14.
    Mannes, Marco
    et al.
    Univ Hosp Ulm, Germany.
    Halbgebauer, Rebecca
    Univ Hosp Ulm, Germany.
    Wohlgemuth, Lisa
    Univ Hosp Ulm, Germany.
    Messerer, David Alexander Christian
    Univ Hosp Ulm, Germany;Friedrich Alexander Univ Erlangen Nurnberg, Germany;Univ Hosp Erlangen, Germany.
    Savukoski, Susa
    Univ Hosp Ulm, Germany.
    Schultze, Anke
    Univ Hosp Ulm, Germany.
    Berger, Bettina
    Univ Hosp Ulm, Germany.
    Knapp, Christiane Leonie
    Univ Hosp Ulm, Germany.
    Schmidt, Christoph Q.
    Ulm Univ, Germany.
    Fuerst, Daniel
    German Red Cross Blood Transfus Serv, Germany;Univ Hosp Ulm, Germany;Ulm Univ, Germany.
    Hillmer, Morten
    Ulm Univ, Germany;Ulm Univ Hosp Ctr, Germany.
    Siebert, Reiner
    Ulm Univ, Germany;Ulm Univ Hosp Ctr, Germany.
    Eriksson, Oskar
    Uppsala Univ, Sweden.
    Persson, Barbro
    Uppsala Univ, Sweden.
    Nilsson, Bo
    Uppsala Univ, Sweden.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala Univ, Sweden.
    Huber-Lang, Markus
    Univ Hosp Ulm, Germany.
    Combined Heterozygous Genetic Variations in Complement C2 and C8B: An Explanation for Multidimensional Immune Imbalance?2023In: Journal of Innate Immunity, ISSN 1662-811X, E-ISSN 1662-8128, Vol. 15, no 1, p. 412-427Article in journal (Refereed)
    Abstract [en]

    The complement system plays a crucial role in host defense, homeostasis, and tissue regeneration and bridges the innate and the adaptive immune systems. Although the genetic variants in complement C2 (c.839_849+17del; p.(Met280Asnfs*5)) and C8B (c.1625C>T; p.(Thr542Ile)) are known individually, here, we report on a patient carrying their combination in a heterozygous form. The patient presented with a reduced general condition and suffers from a wide variety of autoimmune diseases. While no autoimmune disease-specific autoantibodies could be detected, genetic analysis revealed abnormalities in the two complement genes C2 and C8B. Therefore, we performed a comprehensive investigation of the innate immune system on a cellular and humoral level to define the functional consequences. We found slightly impaired functionality of neutrophils and monocytes regarding phagocytosis and reactive oxygen species generation and a diminished expression of the C5aR1. An extensive complement analysis revealed a declined activation potential for the alternative and classical pathway. Reconstitution with purified C2 and C8 into patient serum failed to normalize the dysfunction, whereas the addition of C3 improved the hemolytic activity. In clinical transfer, in vitro supplementation of the patient's plasma with FFP as a complement source could fully restore full complement functionality. This study describes for the first time a combined heterozygous genetic variation in complement C2 and C8B which, however, cannot fully explain the overall dysfunctions and calls for further complement deficiency research and corresponding therapies.

  • 15.
    Nilsson, Per H.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Skattum, Lillemor
    Region Skåne, Sweden;Lund University, Sweden.
    Toonen, Erik J. M.
    Hycult Biotech, Netherlands.
    Current challenges in complement diagnostics2023In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1334050Article in journal (Other academic)
  • 16.
    Dhillon, Prakriti
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Anaspure, Prasad
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Wiklander, Jesper G.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Kathiravan, Suppan
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Diyne-steered switchable regioselectivity in cobalt(ii)-catalysed C(sp(2))-H activation of amides with unsymmetrical 1,3-diynes2023In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 21, no 9, p. 1942-1951Article in journal (Refereed)
    Abstract [en]

    The regiochemical outcome of a cobalt(ii) catalysed C-H activation reaction of aminoquinoline benzamides with unsymmetrical 1,3-diynes under relatively mild reaction conditions can be steered through the choice of diyne. The choice of diyne provides access to either 3- or 4-hydroxyalkyl isoquinolinones, paving the way for the synthesis of more highly elaborate isoquinolines.

  • 17.
    Kathiravan, Suppan
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Attana AB, Sweden.
    Anaspure, Prasad
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Electrochemical rhodium catalysed alkyne annulation with pyrazoles through anodic oxidation - a metal oxidant/additive free methodology2023In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 21, no 9, p. 2024-2033Article in journal (Refereed)
    Abstract [en]

    Pyrazole and its derivatives are important azole heteroarenes prevalent in pharmaceutical compounds and have been used as ligands for protein binding, making them valuable targets for synthetic applications. Herein we disclose an electrochemical intermolecular C-H/N-H oxidative annulation of 2-phenylpyrazoles with alkynes using a rhodium(iii) redox regime without any external metal oxidants in a water compatible solvent system. Both symmetrical and unsymmetrical alkynes were shown to be compatible with the optimized conditions.

  • 18.
    Chaban, Viktoriia
    et al.
    Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    de Boer, Eline
    Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    McAdam, Karin E.
    Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    Vaage, Jarle
    Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    Mollnes, Tom Eirik
    Univ Oslo, Norway;Oslo Univ Hosp, Norway;Nordland Hosp, Norway;Norwegian Univ Sci & Technol, Norway.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Oslo Univ Hosp, Norway.
    Piscike, Soren Erik
    Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    Islam, Rakibul
    Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    Escherichia coli-induced inflammatory responses are temperature-dependent in human whole blood ex vivo2023In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 157, p. 70-77Article in journal (Refereed)
    Abstract [en]

    Systemic inflammatory conditions are often associated with hypothermia or hyperthermia. Therapeutic hypothermia is used in post-cardiac arrest and some other acute diseases. There is a need for more knowledge concerning the effect of various temperatures on the acute inflammatory response. The complement system plays a crucial role in initiating the inflammatory response. We hypothesized that temperatures above and below the physiologic 37 & DEG;C affect complement activation and cytokine production ex vivo. Lepirudin-anticoagulated human whole blood from 10 healthy donors was incubated in the presence or absence of Escherichia coli at different temperatures (4 & DEG;C, 12 & DEG;C, 20 & DEG;C, 33 & DEG;C, 37 & DEG;C, 39 & DEG;C, and 41 & DEG;C). Complement activation was assessed by the terminal C5b-9 complement complex (TCC) and the alternative convertase C3bBbP using ELISA. Cytokines were measured using a 27-plex assay. Granulocyte and monocyte activation was evaluated by CD11b surface expression using flow cytometry. A consistent increase in complement activation was observed with rising temperature, reaching a maximum at 41 & DEG;C, both in the absence (C3bBbP p < 0.05) and presence (C3bBbP p < 0.05 and TCC p < 0.05) of E. coli. Temperature alone did not affect cytokine production, whereas incubation with E. coli significantly increased cytokine levels of IL-18, IL-2, IL-6, IL-8, IFN-& gamma;, and TNF at temperatures > 20 & DEG;C. Maximum increase occurred at 39 & DEG;C. However, a consistent decrease was observed at 41 & DEG;C, significant for IL-18 (p = 0.003). Granulocyte CD11b displayed the same temperature-dependent pattern as cytokines, with a corresponding increase in endothelial cell apoptosis and necrosis. Thus, blood temperature differentially determines the degree of complement activation and cytokine release.

  • 19.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Water.
    Estimating the Gibbs Hydration Energies of Actinium and Trans-Plutonium Actinides2023In: ChemPhysChem, ISSN 1439-4235, E-ISSN 1439-7641, Vol. 24, no 2, article id e202200516Article in journal (Refereed)
    Abstract [en]

    The use of actinides for medical, scientific and technological purposes has gained momentum in the recent years. This creates a need to understand their interactions with biomolecules, both at the interface and as they become complexed. Calculation of the Gibbs binding energies of the ions to biomolecules, i. e., the Gibbs energy change associated with a transfer of an ion from the water phase to its binding site, could help to understand the actinides' toxicities and to design agents that bind them with high affinities. To this end, there is a need to obtain accurate reference values for actinide hydration, that for most actinides are not available from experiment. In this study, a set of ionic radii is developed that enables future calculations of binding energies for Pu3+ and five actinides with renewed scientific and technological interest: Ac3+, Am3+, Cm3+, Bk3+ and Cf3+. Reference hydration energies were calculated using quantum chemistry and ion solvation theory and agree well for all ions except Ac3+, where ion solvation theory seems to underestimate the magnitude of the Gibbs hydration energy. The set of radii and reference energies that are presented here provide means to calculate binding energies for actinides and biomolecules.

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  • 20.
    Gerogianni, Alexandra
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Baas, Laura M.
    Radboud Univ Nijmegen, Netherlands;Amalia Children’s Hospital, Netherlands.
    Sjöström, Dick J.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    van de Kar, Nicole C. A. J.
    Radboud Univ Nijmegen, Netherlands;Amalia Children’s Hospital, Netherlands.
    Pullen, Marit
    Radboud Univ Nijmegen, Netherlands.
    van de Peppel, Siem J.
    Radboud Univ Nijmegen, Netherlands;Amalia Children’s Hospital, Netherlands.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    van den Heuvel, Lambertus P.
    Radboud Univ Nijmegen, Netherlands;;Amalia Children’s Hospital, Netherlands;Univ Hosp Leuven, Belgium.
    Functional evaluation of complement factor I variants by immunoassays and SDS-PAGE2023In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1279612Article in journal (Refereed)
    Abstract [en]

    Factor I (FI) is an essential regulator of the complement system. Together with co-factors, FI degrades C3b, which inhibits further complement activation. Genetic mutations in FI are associated with pathological conditions like age-related macular degeneration and atypical hemolytic uremic syndome. Here, we evaluated eight recombinant FI genetic variants found in patients. We assessed FI's co-factor activity in the presence of two co-factors; Factor H and soluble CR1. Different analytical assays were employed; SDS-PAGE to evaluate the degradation of C3b, ELISA to measure the generation of fluid phase iC3b and the degradation of surface-bound C3b using a novel Luminex bead-based assay. We demonstrate that mutations in the FIMAC and SP domains of FI led to significantly reduced protease activity, whereas the two analyzed mutations in the LDLRA2 domain did not result in any profound changes in FI's function. The different assays employed displayed a strong positive correlation, but differences in the activity of the genetic variants Ile55Phe and Gly261Asp could only be observed by combining different methods and co-factors for evaluating FI activity. In conclusion, our results provide a new perspective regarding available diagnostic tools for assessing the impact of mutations in FI.

  • 21.
    Flockhart, M.
    et al.
    The Swedish School of Sport and Health Sciences, Sweden.
    Nilsson, L. C.
    The Swedish School of Sport and Health Sciences, Sweden.
    Tillqvist, E. N.
    The Swedish School of Sport and Health Sciences, Sweden.
    Vinge, F.
    The Swedish School of Sport and Health Sciences, Sweden.
    Millbert, F.
    The Swedish School of Sport and Health Sciences, Sweden.
    Lannerstrom, J.
    The Swedish School of Sport and Health Sciences, Sweden.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Samyn, D.
    Örebro University Hospital, Sweden;Örebro University, Sweden.
    Apro, W.
    The Swedish School of Sport and Health Sciences, Sweden.
    Sundqvist, M. L.
    The Swedish School of Sport and Health Sciences, Sweden.
    Larsen, F. J.
    The Swedish School of Sport and Health Sciences, Sweden.
    Glucosinolate-rich broccoli sprouts protect against oxidative stress and improve adaptations to intense exercise training2023In: Redox Biology, E-ISSN 2213-2317, Vol. 67, article id 102873Article in journal (Refereed)
    Abstract [en]

    Oxidative stress plays a vital role for the adaptive responses to physical training. However, excessive oxidative stress can precipitate cellular damage, necessitating protective mechanisms to mitigate this effect. Glucosinolates, found predominantly in cruciferous vegetables, can be converted into isothiocyanates, known for their antioxidative properties. These compounds activate crucial antioxidant defence pathways and support mitochondrial function and protein integrity under oxidative stress, in both Nrf2-dependent and independent manners. We here administered glucosinolate-rich broccoli sprouts (GRS), in a randomized double-blinded cross-over fashion to 9 healthy subjects in combination with daily intense exercise training for 7 days. We found that exercise in combination with GRS significantly decreased the levels of carbonylated proteins in skeletal muscle and the release of myeloperoxidase into blood. Moreover, it lowered lactate accumulation during submaximal exercise, and attenuated the severe nocturnal hypoglycaemic episodes seen during the placebo condition. Furthermore, GRS in combination with exercise improved physical performance, which was unchanged in the placebo condition.

  • 22.
    Suriyanarayanan, Subramanian
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Babu, Mohana Priya
    Indian Inst Technol Madras, India.
    Murugan, Raja
    Indian Inst Technol Madras, India.
    Muthuraj, Divyamahalakshmi
    Indian Inst Technol Madras, India.
    Ramanujam, Kothandaraman
    Indian Inst Technol Madras, India.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Indian Inst Technol Madras, India.
    Highly Efficient Recovery and Recycling of Cobalt from Spent Lithium-Ion Batteries Using an N-Methylurea-Acetamide Nonionic Deep Eutectic Solvent2023In: ACS Omega, E-ISSN 2470-1343, Vol. 8, no 7, p. 6959-6967Article in journal (Refereed)
    Abstract [en]

    The growing demand for lithium-ion batteries (LiBs) for the electronic and automobile industries combined with the limited availability of key metal components, in particular cobalt, drives the need for efficient methods for the recovery and recycling of these materials from battery waste. Herein, we introduce a novel and efficient approach for the extraction of cobalt, and other metal components, from spent LiBs using a nonionic deep eutectic solvent (ni-DES) comprised of N-methylurea and acetamide under relatively mild conditions. Cobalt could be recovered from lithium cobalt oxide-based LiBs with an extraction efficiency of >97% and used to fabricate new batteries. The N-methylurea was found to act as both a solvent component and a reagent, the mechanism of which was elucidated.

  • 23.
    Nilsson, Bo
    et al.
    Uppsala University, Sweden.
    Eriksson, Oskar
    Uppsala University, Sweden.
    Fromell, Karin
    Uppsala University, Sweden.
    Persson, Barbro
    Uppsala University, Sweden.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    How COVID-19 and other pathological conditions and medical treatments activate our intravascular innate immune system2023In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 13, article id 1030627Article in journal (Refereed)
    Abstract [en]

    COVID-19 has been shown to have a multifaceted impact on the immune system. In a recently published article in Front Immunol, we show that the intravascular innate immune system (IIIS) is strongly activated in severe COVID-19 with ARDS and appears to be one of the causes leading to severe COVID-19. In this article, we describe the IIIS and its physiological function, but also the strong pro-inflammatory effects that are observed in COVID-19 and in various other pathological conditions and treatments such as during ischemia reperfusion injury and in treatments where biomaterials come in direct contact with blood in, e.g., extracorporeal and intravasal treatments. In the present article, we describe how the IIIS, a complex network of plasma proteins and blood cells, constitute the acute innate immune response of the blood and discuss the effects that the IIIS induces in pathological disorders and treatments in modern medicine.

  • 24.
    Spiegelburg, Doreen Tabea
    et al.
    Univ Hosp Ulm, Germany.
    Mannes, Marco
    Univ Hosp Ulm, Germany.
    Schultze, Anke
    Univ Hosp Ulm, Germany.
    Scheibenberger, Frieder
    Univ Hosp Ulm, Germany.
    Mueller, Frederik
    Univ Hosp Ulm, Germany.
    Klitzing, Amadeo
    Univ Hosp Ulm, Germany.
    Messerer, David Alexander Christian
    Univ Hosp Ulm, Germany;University Hospital of Erlangen, Germany;Friedrich-Alexander University Erlangen-Nürnberg (FAU), Germany.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Nilsson, Bo
    Uppsala University, Sweden.
    Huber-Lang, Markus
    Univ Hosp Ulm, Germany.
    Braun, Christian Karl
    Univ Hosp Ulm, Germany.
    Impact of surface coating and systemic anticoagulants on hemostasis and inflammation in a human whole blood model2023In: PLOS ONE, E-ISSN 1932-6203, Vol. 18, no 1, article id e0280069Article in journal (Refereed)
    Abstract [en]

    BackgroundSurface compatibility with blood is critical both for scientific investigations on hemostasis and clinical applications. Regarding in vitro and ex vivo investigations, minimal alteration in physiological hemostasis is of particular importance to draw reliable conclusions on the human coagulation system. At the same time, artificial coagulation activation must be avoided, which is relevant for the patient, for example to prevent stent graft occlusion. The aim was to evaluate the advantages and disadvantages of antithrombotic and antifouling surface coatings in the context of their suitability for ex vivo incubation and the study of coagulation properties. MethodsWe investigated the impact of different protocols for surface coating of synthetic material and different anticoagulants on hemostasis and platelet activation in ex vivo human whole blood.Blood samples from healthy donors were incubated in coated microtubes on a rotating wheel at 37 degrees C. Two protocols for surface coating were analyzed for hemostatic parameters and metabolic status, a heparin-based coating (CHC, Corline Heparin Conjugate) without further anticoagulation and a passivating coating (MPC, 2-methacryloyloxethyl phosphorylcholine) with added anticoagulants (enoxaparin, ENOX; or fondaparinux, FPX). Employing the MPC-based coating, the anticoagulants enoxaparin and fondaparinux were compared regarding their differential effects on plasmatic coagulation by thrombelastometry and on platelet activation by flowcytometry and platelet function assays. ResultsUsing the CHC coating, significant coagulation cascade activation was observed, whereas parameters remained mostly unchanged with MPC-based protocols. Extended incubation caused significantly elevated levels of the soluble membrane attack complex. Neither ENOX nor FPX caused a relevant impairment of platelet function or activation capacity and thrombelastometric parameters remained unchanged with both protocols. For translational purposes, we additionally modeled endotoxemia with the MPC-based protocols by incubating with lipopolysaccharide plus/minus thrombin. While coagulation parameters remained unchanged, elevated Interleukin 8 and Matrix Metalloproteinase 9 demonstrated preserved immune cell responsiveness. ConclusionsThe MPC-based protocols demonstrated better hemocompatibility compared to CHC, and ENOX and FPX proved useful for additional anticoagulation. Furthermore, this simple-to-use whole blood model may be useful for experimental analyses of the early coagulatory and immunological response without decalcification.

  • 25.
    Gerogianni, Alexandra
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Bal, Melissa
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Mohlin, Camilla
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Woodruff, Trent M.
    University of Queensland, Australia.
    Lambris, John D.
    University of Pennsylvania, USA.
    Mollnes, Tom E.
    Oslo University Hospital, Norway;University of Oslo, Norway;Norwegian University of Science and Technology, Norway;Nordland Hospital, Norway.
    Sjöström, Dick J.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Oslo University Hospital, Norway;University of Oslo, Norway.
    In vitro evaluation of iron oxide nanoparticle-induced thromboinflammatory response using a combined human whole blood and endothelial cell model2023In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1101387Article in journal (Refereed)
    Abstract [en]

    Iron oxide nanoparticles (IONPs) are widely used in diagnostic and therapeutic settings. Upon systemic administration, however, they are rapidly recognized by components of innate immunity, which limit their therapeutic capacity and can potentially lead to adverse side effects. IONPs were previously found to induce the inflammatory response in human whole blood, including activation of the complement system and increased secretion of cytokines. Here, we investigated the thromboinflammatory response of 10-30 nm IONPs in lepirudin anticoagulated whole blood in interplay with endothelial cells and evaluated the therapeutic effect of applying complement inhibitors to limit adverse effects related to thromboinflammation. We found that IONPs induced complement activation, primarily at the C3-level, in whole blood incubated for up to four hours at 37°C with and without human microvascular endothelial cells. Furthermore, IONPs mediated a strong thromboinflammatory response, as seen by the significantly increased release of 21 of the 27 analyzed cytokines (p<0.05). IONPs also significantly increased cell-activation markers of endothelial cells [ICAM-1 (p<0.0001), P/E-selectin (p<0.05)], monocytes, and granulocytes [CD11b (p<0.001)], and platelets [CD62P (p<0.05), CD63 (p<0.05), NAP-2 (p<0.01), PF4 (p<0.05)], and showed cytotoxic effects, as seen by increased LDH (p<0.001) and heme (p<0.0001) levels. We found that inflammation and endothelial cell activation were partly complement-dependent and inhibition of complement at the level of C3 by compstatin Cp40 significantly attenuated expression of ICAM-1 (p<0.01) and selectins (p<0.05). We show that complement activation plays an important role in the IONPs-induced thromboinflammatory response and that complement inhibition is promising in improving IONPs biocompatibility.

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  • 26.
    Kathiravan, Suppan
    et al.
    Attana AB, Sweden.
    Zhang, Tianshu
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Iridium catalysed C2 site-selective methylation of indoles using a pivaloyl directing group through weak chelation-assistance2023In: RSC Advances, E-ISSN 2046-2069, Vol. 13, no 17, p. 11291-11295Article in journal (Refereed)
    Abstract [en]

    Here we present an iridium catalysed C2-selective methylation of indoles using methyltrifluoroborate as a source of methyl group. The iridium catalyst selectively discriminates the indole C2 and C4 C-H bonds by coordination with a pivaloyl directing group.

  • 27.
    Tasfaout, Aicha
    et al.
    Dublin City Univ, Ireland.
    Ibrahim, Farah
    Univ Toulon & Var, France.
    Morrin, Aoife
    Dublin City Univ, Ireland.
    Brisset, Hugues
    Univ Toulon & Var, France.
    Sorrentino, Ilaria
    CEEI Nice Cote Azur Immeuble Premium, France.
    Nanteuil, Clement
    CEEI Nice Cote Azur Immeuble Premium, France.
    Laffite, Guillaume
    CEEI Nice Cote Azur Immeuble Premium, France.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Regan, Fiona
    Dublin City Univ, Ireland.
    Branger, Catherine
    Univ Toulon & Var, France.
    Molecularly imprinted polymers for per- and polyfluoroalkyl substances enrichment and detection2023In: Talanta: The International Journal of Pure and Applied Analytical Chemistry, ISSN 0039-9140, E-ISSN 1873-3573, Vol. 258, article id 124434Article in journal (Refereed)
    Abstract [en]

    Per-and polyfluoroalkyl substances (PFAS) are highly toxic pollutants of significant concern as they are being detected in water, air, fish and soil. They are extremely persistent and accumulate in plant and animal tissues. Traditional methods of detection and removal of these substances use specialised instrumentation and require a trained technical resource for operation. Molecularly imprinted polymers (MIPs), polymeric materials with predetermined selectivity for a target molecule, have recently begun to be exploited in technologies for the selective removal and monitoring of PFAS in environmental waters. This review offers a comprehensive overview of recent developments in MIPs, both as adsorbents for PFAS removal and sensors that selectively detect PFAS at environmentally-relevant concentrations. PFAS-MIP adsorbents are classified according to their method of preparation (e.g., bulk or precipitation polymerization, surface imprinting), while PFAS-MIP sensing materials are described and discussed according to the transduction methods used (e.g., electrochemical, optical). This review aims to comprehensively discuss the PFAS-MIP research field. The efficacy and challenges facing the different applications of these materials in environmental water applications are discussed, as well as a perspective on challenges for this field that need to be overcome before exploitation of the technology can be fully realised.

  • 28.
    Meelua, Wijitra
    et al.
    Univ Phayao, Thailand.
    Wanjai, Tanchanok
    Univ Phayao, Thailand.
    Thinkumrob, Natechanok
    Univ Phayao, Thailand.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Jitonnom, Jitrayut
    Univ Phayao, Thailand.
    Multiscale QM/MM Simulations Identify the Roles of Asp239 and 1‑OH···Nucleophile in Transition State Stabilization in Arabidopsis thaliana Cell-Wall Invertase 12023In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 63, no 15, p. 4827-4838Article in journal (Refereed)
    Abstract [en]

    Arabidopsis thaliana cell-wallinvertase1 (AtCWIN1), a key enzyme in sucrose metabolism in plants, catalyzesthe hydrolysis of sucrose into fructose and glucose. AtCWIN1 belongsto the glycoside hydrolase GH-J clan, where two carboxylate residues(Asp23 and Glu203 in AtCWIN1) are well documented as a nucleophileand an acid/base catalyst. However, details at the atomic level aboutthe role of neighboring residues and enzyme-substrate interactionsduring catalysis are not fully understood. Here, quantum mechanical/molecularmechanical (QM/MM) free-energy simulations were carried out to clarifythe origin of the observed decreased rates in Asp239Ala, Asp239Asn,and Asp239Phe in AtCWIN1 compared to the wild type and delineate therole of Asp239 in catalysis. The glycosylation and deglycosylationsteps were considered in both wild type and mutants. Deglycosylationis predicted to be the rate-determining step in the reaction, witha calculated overall free-energy barrier of 15.9 kcal/mol, consistentwith the experimental barrier (15.3 kcal/mol). During the reaction,the -1 furanosyl ring underwent a conformational change correspondingto E-3 & LRARR; [E-2](&#x29e7;) & LRARR; E-1 according to the nomenclature of saccharide structures alongthe full catalytic reaction. Asp239 was found to stabilize not onlythe transition state but also the fructosyl-enzyme intermediate, whichexplains findings from previous structural and mutagenesis experiments.The 1-OH & BULL;& BULL;& BULL;nucleophile interaction has been found toprovide an important contribution to the transition state stabilization,with a contribution of & SIM;7 kcal/mol, and affected glycosylationmore significantly than deglycosylation. This study provides molecularinsights that improve the current understanding of sucrose bindingand hydrolysis in members of clan GH-J, which may benefit proteinengineering research. Finally, a rationale on the sucrose inhibitorconfiguration in chicory 1-FEH IIa, proposed a long time ago in theliterature, is also provided based on the QM/MM calculations.

  • 29.
    Månsson, Alf
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Ušaj, Marko
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Moretto, Luisa
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Matusovsky, Oleg
    McGill Univ, Canada.
    Velayuthan, Lok Priya
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Rassier, Dilson E.
    McGill Univ, Canada.
    New paradigms in actomyosin energy transduction: Critical evaluation of non-traditional models for orthophosphate release2023In: Bioessays, ISSN 0265-9247, E-ISSN 1521-1878, Vol. 45, no 9, article id 2300040Article in journal (Refereed)
    Abstract [en]

    Release of the ATP hydrolysis product ortophosphate (Pi) from the active site of myosin is central in chemo-mechanical energy transduction and closely associated with the main force-generating structural change, the power-stroke. Despite intense investigations, the relative timing between Pi-release and the power-stroke remains poorly understood. This hampers in depth understanding of force production by myosin in health and disease and our understanding of myosin-active drugs. Since the 1990s and up to today, models that incorporate the Pi-release either distinctly before or after the power-stroke, in unbranched kinetic schemes, have dominated the literature. However, in recent years, alternative models have emerged to explain apparently contradictory findings. Here, we first compare and critically analyze three influential alternative models proposed previously. These are either characterized by a branched kinetic scheme or by partial uncoupling of Pi-release and the power-stroke. Finally, we suggest critical tests of the models aiming for a unified picture.

  • 30.
    Nilsson, Per H.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Univ Oslo, Norway;Oslo Univ Hosp Rikshospitalet, Norway.
    Al-Majdoub, Mahmoud
    Attana AB, Sweden.
    Ibrahim, Ahmed
    Attana AB, Sweden.
    Aseel, Obaidullah
    Linköping University, Sweden.
    Suriyanarayanan, Subramanian
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Andersson, Linnea
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Fostock, Samir
    Attana AB, Sweden.
    Aastrup, Teodor
    Attana AB, Sweden.
    Tjernberg, Ivar
    Region Kalmar County, Sweden;Linköping University, Sweden.
    Ryden, Ingvar
    Region Kalmar County, Sweden;Linköping University, Sweden.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Quartz Crystal Microbalance Platform for SARS-CoV-2 Immuno-Diagnostics2023In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 24, no 23, article id 16705Article in journal (Refereed)
    Abstract [en]

    Rapid and accurate serological analysis of SARS-CoV-2 antibodies is important for assessing immune protection from vaccination or infection of individuals and for projecting virus spread within a population. The quartz crystal microbalance (QCM) is a label-free flow-based sensor platform that offers an opportunity to detect the binding of a fluid-phase ligand to an immobilized target molecule in real time. A QCM-based assay was developed for the detection of SARS-CoV-2 antibody binding and evaluated for assay reproducibility. The assay was cross-compared to the Roche electrochemiluminescence assay (ECLIA) Elecsys (R) Anti-SARS-CoV-2 serology test kit and YHLO's chemiluminescence immunoassay (CLIA). The day-to-day reproducibility of the assay had a correlation of r(2) = 0.99, p < 0.001. The assay linearity was r(2) = 0.96, p < 0.001, for dilution in both serum and buffer. In the cross-comparison analysis of 119 human serum samples, 59 were positive in the Roche, 52 in the YHLO, and 48 in the QCM immunoassay. Despite differences in the detection method and antigen used for antibody capture, there was good coherence between the assays, 80-100% for positive and 96-100% for negative test results. In summation, the QCM-based SARS-CoV-2 IgG immunoassay showed high reproducibility and linearity, along with good coherence with the ELISA-based assays. Still, factors including antibody titer and antigen-binding affinity may differentially affect the various assays' responses.

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  • 31.
    Adler, Anna
    et al.
    Uppsala University, Sweden.
    Fritsch, Marlene
    Uppsala University, Sweden.
    Fromell, Karin
    Uppsala University, Sweden.
    Leneweit, Gero
    ABNOBA GmbH, Germany;Assoc Promot Canc Therapy, Germany.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Nilsson, Bo
    Uppsala University, Sweden.
    Teramura, Yuji
    Uppsala University, Sweden;Cellular & Mol Biotechnol Res Inst CMB, Japan;Univ Tsukuba, Japan.
    Regulation of the innate immune system by fragmented heparin-conjugated lipids on lipid bilayered membranes in vitro2023In: Journal of materials chemistry. B, ISSN 2050-750X, E-ISSN 2050-7518, Vol. 11, no 46, p. 11121-11134Article in journal (Refereed)
    Abstract [en]

    Surface modification with heparin is a powerful biomaterial coating strategy that protects against innate immunity activation since heparin is a part of the proteoglycan heparan sulfate on cell surfaces in the body. We studied the heparinization of cellular and material surfaces via lipid conjugation to a heparin-binding peptide. In the present study, we synthesized fragmented heparin (fHep)-conjugated phospholipids and studied their regulation of the innate immune system on a lipid bilayered surface using liposomes. Liposomes have versatile applications, such as drug-delivery systems, due to their ability to carry a wide range of molecules. Owing to their morphological similarity to cell membranes, they can also be used to mimic a simple cell-membrane to study protein-lipid interactions. We investigated the interaction of complement-regulators, factor H and C4b-binding protein (C4BP), as well as the coagulation inhibitor antithrombin (AT), with fHep-lipids on the liposomal surface. Herein, we studied the ability of fHep-lipids to recruit factor H, C4BP, and AT using a quartz crystal microbalance with dissipation monitoring. With dynamic light scattering, we demonstrated that liposomes could be modified with fHep-lipids and were stable up to 60 days at 4 degree celsius. Using a capillary western blot-based method (Wes), we showed that fHep-liposomes could recruit factor H in a model system using purified proteins and assist in the degradation of the active complement protein C3b to iC3b. Furthermore, we found that fHep-liposomes could recruit factor H and AT from human plasma. Therefore, the use of fHep-lipids could be a potential coating for liposomes and cell surfaces to regulate the immune system on the lipid surface.

  • 32.
    Freire, Thales Souza
    et al.
    Univ Fed Sao Carlos, Brazil.
    Caracelli, Ignez
    Univ Fed Sao Carlos, Brazil.
    Zukerman-Schpector, Julio
    Univ Fed Sao Carlos, Brazil.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Resistance to a tyrosine kinase inhibitor mediated by changes to the conformation space of the kinase2023In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 25, no 8, p. 6175-6183Article in journal (Refereed)
    Abstract [en]

    Gilteritinib is a highly selective and effective inhibitor of the FLT3/ITD mutated protein, and is used successfully in treating acute myeloid leukaemia (AML). Unfortunately, tumour cells gradually develop resistance to gilteritinib due to mutations in the molecular drug target. The atomistic details behind this observed resistance are not clear, since the protein structure of the complex is only available in the inactive state, while the drug binds better to the active state. To overcome this limitation, we used a computer-aided approach where we docked gilteritinib to the active site of FLT3/ITD and calculated the Gibbs free energy difference between the binding energies of the parental and mutant enzymes. These calculations agreed with experimental estimations for one mutation (F691L) but not the other (D698N). To further understand how these mutations operate, we used metadynamics simulations to study the conformational landscape of the activation process. Both mutants show a lower activation energy barrier which suggests that they are more likely to adopt an active state until inhibited, making the mutant enzymes more active. This suggests that a higher efficiency of tyrosine kinases contributes to resistance not only against type 2 but also against type 1 kinase inhibitors.

  • 33.
    Durall, Claudia
    et al.
    Attana AB, Sweden.
    Wallinder, Daniel
    Attana AB, Sweden.
    Ibrahim, Ahmed
    Attana AB, Sweden.
    Nolting, Andreas
    Attana AB, Sweden.
    Almajdoub, Mahmoud
    Attana AB, Sweden.
    Jones, Nicholas
    Withers and Rogers LLP, UK.
    Suriyanarayanan, Subramanian
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Aastrup, Teodor
    Attana AB, Sweden.
    Robust QCM-Based Sensing and Assay Formats in Commercialized Systems2023In: Springer Series on Chemical Sensors and Biosensors: Methods and Applications, Springer, 2023Chapter in book (Refereed)
    Abstract [en]

    Attana’s Quartz Crystal Microbalance (QCM) analytical instruments have been developed to study in vitro biological interactions, mimicking the in vivo conditions. Attana’s superior technology for kinetic interaction studies allows to perform different assays, including biochemical, crude, sera, cell, and tissue-based, in vitro diagnostic and material chemistry assays, in real time and label free. With the focus to validate, select, and optimize drug candidates prior to clinical trials, Attana has helped pharmaceutical companies to increase their efficiency and profitability. In addition, the Attana instruments and services have been used in many other applications and research as described in this chapter.

  • 34.
    Suriyanarayanan, Subramanian
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Mandal, Sudip
    Vignans Fdn Sci Technol & Res, India.
    Ramanujam, Kothandaraman
    Indian Inst Technol Madras, India.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Smart bio-nano interface derived from zein protein as receptors for biotinyl moiety2023In: Talanta: The International Journal of Pure and Applied Analytical Chemistry, ISSN 0039-9140, E-ISSN 1873-3573, Vol. 256, article id 124298Article in journal (Refereed)
    Abstract [en]

    Proteinaceous, tunable nanostructures of zein (prolamine of corn) were developed as biotinyl-specific receptors using a molecular imprinting technique. Sacrificial templates, such as latex beads (LB3) and anodized alumina membrane (AAM), have been used to control nanostructural patterns in biotin-imprinted zein (BMZ). Briefly, a methanolic solution of the zein-biotin complex was drop cast upon a self-organized LB3 and AAM templates on Au/quartz surfaces. Subsequent dissolution of these sacrificial templates affords highly oriented, predetermined, and uniformly grown hyperporous (300 nm) and nanowires (150 nm) motifs of zein (BMZ-LB3 and BMZ-AAM), as shown by scanning electron microscopy (SEM). Selective extraction of biotin molecular template cast-off site -selective biotin imprints within these zein nanostructures complementary to biotinyl moieties. Alternatively, biotin-imprinted zein nanoparticles (BMZ-Np) and thin film (BMZ-MeOH) were prepared by coacervation and drop casting methods, respectively. Density functional theoretical (DFT) studies reveal strong hydrogen-bonded interaction of biotin with serine and glutamine residues of zein. Quartz crystal microbalance (QCM) studies show remarkable sensitivity of the hyperporous-BMZ-LB3 and nanowires of BMZ-AAM towards biotin derivative (biotin methyl ester) by five (24.75 +/- 1.34 Hz/mM) and four (18.19 +/- 0.75 Hz/mM) times, respectively, higher than the BMZ-MeOH. Enhanced permeability features of the zein nanostructures, when templated with LB3, enable the QCM detection of biotin-or its derivatives down to 12.9 ng mL-1 from dairy products (Kefir). The outcome of this study shall be a key aspect in interfacing biological materials with micro-/nano-sensors and electronic devices for detecting pertinent analytes using sustainably developed biopolymer-based nanostructures.

  • 35.
    Huang, Tianwei
    et al.
    Univ Tokyo, Japan.
    Sato, Yuya
    Univ Tokyo, Japan.
    Kuramochi, Akiko
    Natl Inst Adv Ind Sci & Technol, Japan.
    Ohba, Yoshio
    Natl Inst Adv Ind Sci & Technol, Japan.
    Sano, Masayuki
    Natl Inst Adv Ind Sci & Technol, Japan.
    Miyagishi, Makoto
    Natl Inst Adv Ind Sci & Technol, Japan.
    Tateno, Hiroaki
    Natl Inst Adv Ind Sci & Technol, Japan.
    Wadhwa, Renu
    Natl Inst Adv Ind Sci & Technol, Japan;Univ Tsukuba, Japan.
    Kawasaki, Kazunori
    Natl Inst Adv Ind Sci & Technol, Japan.
    Uchida, Takeyuki
    Natl Inst Adv Ind Sci & Technol, Japan.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Nilsson, Bo
    Uppsala University, Sweden.
    Chung, Ung-il
    Univ Tokyo, Japan.
    Teramura, Yuji
    Natl Inst Adv Ind Sci & Technol, Japan;Uppsala University, Sweden;Univ Tsukuba, Japan.
    Surface modulation of extracellular vesicles with cell-penetrating peptide-conjugated lipids for improvement of intracellular delivery to endothelial cells2023In: Regenerative Therapy, ISSN 2352-3204, Vol. 22, p. 90-98Article in journal (Refereed)
    Abstract [en]

    Exosomes (diameter 30-200 nm) are a subtype of extracellular vesicles secreted by cells containing DNA, microRNA (miRNA), and proteins. Exosomes are expected to be valuable as a means of delivering drugs or functional miRNAs in treatment of diseases. However, the delivery of exosomes is not sufficiently effective, even though exosomes have intrinsic delivery functions. Cell-penetrating peptides (CPPs) are short peptide families that facilitate cellular intake of molecules and vesicles. We previously reported that the modification of cells, and liposomes with CPP-conjugated-lipids, CPPs conjugated with poly (ethylene glycol)-conjugated phospholipids (PEG-lipid), that induce adhesion by CPPs, can be useful for cell-based assays and harvesting liposomes. In this study, we aimed to modulate the exosome surface using Tat peptide (YGRKKRRQRRR)-PEG-lipids to improve intracellular delivery to endothelial cells. We isolated and characterized exosomes from the medium of HEK 293 T cell cultures. Tat conjugated PEG -lipids with different spacer molecular weights and lipid types were incorporated into exosomes using fluorescein isothiocyanate labeling to optimize the number of Tat-PEG-lipids immobilized on the exo-some surface. The exosomes modified with Tat-PEG-lipids were incubated with human umbilical vein endothelial cells (HUVECs) to study the interaction. Tat conjugated with 5 kDa PEG and C16 lipids incorporated on the exosome surface were highly detected inside HUVECs by flow cytometry. Fluores-cence was negligible in HUVECs for control groups. Thus, Tat-PEG-lipids can be modified on the exosome surface, improving the intracellular delivery of exosomes.(c) 2022, The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/).

  • 36.
    Suriyanarayanan, Subramanian
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Kandregula, Ganapathi Rao
    Indian Inst Technol Madras, India.
    Ramanujam, Kothandaraman
    Indian Inst Technol Madras, India.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Advanced Materials.
    Sustainable synthesis of hierarchically grown chloramphenicol-imprinted poly(caffeic acid) nanostructured films2023In: Journal of Applied Polymer Science, ISSN 0021-8995, E-ISSN 1097-4628, Vol. 140, no 9, article id e53560Article in journal (Refereed)
    Abstract [en]

    Hierarchically nanostructured chloramphenicol (CLP) imprinted thin polymer films have been developed using a renewable monomer, the antioxidant caffeic acid (CA), using sacrificial nanostructures to induce porosity into the films. The poly(caffeic acid) (PCA) films were synthesized on Au/quartz resonators via greener polymerization conditions (clean energy electropolymerization in aqueous buffer or a non-ionic deep eutectic solvent). The sacrificial nanostructures explored included zein-based protein nanobeads, anodized alumina membrane, and Tween 20-derived polysorbate micelles, where dissolution of the sacrificial nanostructure templates from the PCA films afforded uniform long-range hyperporous networks, nanowires and nanoparticles, respectively, as revealed by SEM studies. Selective extraction of the CLP template from PCA films, was monitored by XPS, and afforded CLP selective cavities. The CLP-imprinted PCA(zein) films demonstrated eight- to 25-fold higher sensitivity than the other nanostructures in a QCM-sensor format, the limit of detection (LOD) under optimized FIA conditions was 50 mM. Significant sensitivities for CLP in milk were observed (1.5 mu g/ml to 3 mg/ml), covering the clinically relevant concentration range. The PCA(zein) thin films selectively differentiate CLP from structurally related antibiotics and are robust. Their production from renewable feedstocks of biological origin highlights the potential of this class of nanostructured materials for applications utilizing thin films.

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  • 37.
    Fromell, Karin
    et al.
    Uppsala University, Sweden.
    Johansson, Ulrika
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Abadgar, Sophia
    Stockholm University, Sweden.
    Bourzeix, Pauline
    Uppsala University, Sweden.
    Lundholm, Lovisa
    Stockholm University, Sweden.
    Elihn, Karine
    Stockholm University, Sweden.
    The effect of airborne Palladium nanoparticles on human lung cells, endothelium and blood-A combinatory approach using three in vitro models2023In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 89, article id 105586Article in journal (Refereed)
    Abstract [en]

    A better understanding of the mechanisms behind adverse health effects caused by airborne fine particles and nanoparticles (NP) is essential to improve risk assessment and identification the most critical particle exposures. While the use of automobile catalytic converters is decreasing the exhausts of harmful gases, concentrations of fine airborne particles and nanoparticles (NPs) from catalytic metals such as Palladium (Pd) are reaching their upper safe level. Here we used a combinatory approach with three in vitro model systems to study the toxicity of Pd particles, to infer their potential effects on human health upon inhalation. The three model systems are 1) a lung system with human lung cells (ALI), 2) an endothelial cell system and 3) a human whole blood loop system. All three model systems were exposed to the exact same type of Pd NPs. The ALI lung cell exposure system showed a clear reduction in cell growth from 24 h onwards and the effect persisted over a longer period of time. In the endothelial cell model, Pd NPs induced apoptosis, but not to the same extent as the most aggressive types of NPs such as TiO2. Similarly, Pd triggered clear coagulation and contact system activation but not as forcefully as the highly thrombogenic TiO2 NPs. In summary, we show that our 3-step in vitro model of the human lung and surrounding vessels can be a useful tool for studying pathological events triggered by airborne fine particles and NPs.

  • 38.
    Nilsson Ekdahl, Kristina
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Advanced Materials. Uppsala University, Sweden.
    Fromell, Karin
    Uppsala University, Sweden.
    Mannes, Marco
    Univ Hosp Ulm, Germany.
    Grinnemo, Karl-Henrik
    Uppsala University, Sweden.
    Huber-Lang, Markus
    Univ Hosp Ulm, Germany.
    Teramura, Yuji
    Uppsala University, Sweden;National Institute of Advanced Industrial Science and Technology (AIST), Japan;Univ Tsukuba, Japan.
    Nilsson, Bo
    Uppsala University, Sweden.
    Therapeutic regulation of complement activation in extracorporeal circuits and intravascular treatments with special reference to the alternative pathway amplification loop2023In: Immunological Reviews, ISSN 0105-2896, E-ISSN 1600-065X, Vol. 313, no 1, p. 91-103Article in journal (Refereed)
    Abstract [en]

    A number of clinical treatment modalities involve contact between blood and biomaterials: these include extracorporeal circuits such as hemodialysis, cardiopulmonary bypass, plasmapheresis, and intravascular treatments. Common side effects arising from these treatments are caused by activation of the cascade systems of the blood. Many of these side effects are mediated via the complement system, including thromboinflammatory reactions and rejection of implants. Depending on the composition of the materials, complement activation is triggered via all the activation pathways but is by far mostly driven by the alternative pathway amplification loop. On biomaterial surfaces the alternative pathway amplification is totally unregulated and leads under optimal conditions to deposition of complement fragments, mostly C3b, on the surface leading to a total masking of the underlying surface. In this review, we discuss the mechanism of the complement activation, clinical consequences of the activation, and potential strategies for therapeutic regulation of the activation, using hemodialysis as demonstrator.

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  • 39.
    Xu, Yuan
    et al.
    Xiamen Univ, China.
    Zhang, Shu
    Xiamen Univ, China.
    Lindahl, Erik
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Advanced Materials. Linnaeus University, Linnaeus Knowledge Environments, Water.
    Wu, Wei
    Xiamen Univ, China.
    Su, Peifeng
    Xiamen Univ, China.
    A general tight-binding based energy decomposition analysis scheme for intermolecular interactions in large molecules2022In: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 157, no 3, article id 034104Article in journal (Refereed)
    Abstract [en]

    In this work, a general tight-binding based energy decomposition analysis (EDA) scheme for intermolecular interactions is proposed. Different from the earlier version [Xu et al., J. Chem. Phys. 154, 194106 (2021)], the current tight-binding based density functional theory (DFTB)-EDA is capable of performing interaction analysis with all the self-consistent charge (SCC) type DFTB methods, including SCC-DFTB2/3 and GFN1/2-xTB, despite their different formulas and parameterization schemes. In DFTB-EDA, the total interaction energy is divided into frozen, polarization, and dispersion terms. The performance of DFTB-EDA with SCC-DFTB2/3 and GFN1/2-xTB for various interaction systems is discussed and assessed. Published under an exclusive license by AIP Publishing.

  • 40.
    Adler, Anna
    et al.
    Uppsala University, Sweden.
    Manivel, Vivek Anand
    Uppsala University, Sweden.
    Fromell, Karin
    Uppsala University, Sweden.
    Teramura, Yuji
    Uppsala University, Sweden;Cellular & Mol Biotechnol Res Inst CMB, Japan.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Nilsson, Bo
    Uppsala University, Sweden.
    A Robust Method to Store Complement C3 With Superior Ability to Maintain the Native Structure and Function of the Protein2022In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 13, article id 891994Article in journal (Refereed)
    Abstract [en]

    Complement components have a reputation to be very labile. One of the reasons for this is the spontaneous hydrolysis of the internal thioester that is found in both C3 and C4 (but not in C5). Despite the fact that approximate to 20,000 papers have been published on human C3 there is still no reliable method to store the protein without generating C3(H2O), a fact that may have affected studies of the conformation and function of C3, including recent studies on intracellular C3(H2O). The aim of this work was to define the conditions for storage of native C3 and to introduce a robust method that makes C3 almost resistant to the generation of C3(H2O). Here, we precipitated native C3 at the isoelectric point in low ionic strength buffer before freezing the protein at -80 degrees C. The formation of C3(H2O) was determined using cation exchange chromatography and the hemolytic activity of the different C3 preparations was determined using a hemolytic assay for the classical pathway. We show that freezing native C3 in the precipitated form is the best method to avoid loss of function and generation of C3(H2O). By contrast, the most efficient way to consistently generate C3(H2O) was to incubate native C3 in a buffer at pH 11.0. We conclude that we have defined the optimal storage conditions for storing and maintaining the function of native C3 without generating C3(H2O) and also the conditions for consistently generating C3(H2O).

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  • 41.
    Oruganti, Baswanth
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Lindahl, Erik
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Yang, Jingmei
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Amiri, Wahid
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Rahimullah, Rezwan
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Allosteric enhancement of the BCR-Abl1 kinase inhibition activity of nilotinib by cobinding of asciminib2022In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 298, no 8, article id 102238Article in journal (Refereed)
    Abstract [en]

    Inhibitors that bind competitively to the ATP binding pocket in the kinase domain of the oncogenic fusion protein BCR-Abl1 are used successfully in targeted therapy of chronic myeloid leukemia (CML). Such inhibitors provided the first proof of concept that kinase inhibition can succeed in a clinical setting. However, emergence of drug resistance and dose-dependent toxicities limit the effectiveness of these drugs. Therefore, treatment with a combination of drugs without overlapping resistance mechanisms appears to be an appropriate strategy. In the present work, we explore the effectiveness of combination therapies of the recently developed allosteric inhibitor asciminib with the ATP-competitive inhibitors nilotinib and dasatinib in inhibiting the BCR-Abl1 kinase activity in CML cell lines. Through these experiments, we demonstrate that asciminib significantly enhances the inhibition activity of nilotinib, but not of dasatinib. Exploring molecular mechanisms for such allosteric enhancement via systematic computational investigation incorporating molecular dynamics, metadynamics simulations, and density functional theory calculations, we found two distinct contributions. First, binding of asciminib triggers conformational changes in the inactive state of the protein, thereby making the activation process less favorable by similar to 4 kcal/mol. Second, the binding of asciminib decreases the binding free energies of nilotinib by similar to 3 and similar to 7 kcal/mol for the wildtype and T315I-mutated protein, respectively, suggesting the possibility of reducing nilotinib dosage and lowering risk of developing resistance in the treatment of CML.

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  • 42.
    Mollnes, Tom E.
    et al.
    Nordland Hosp, Norway;Oslo Univ Hosp, Norway;Norwegian Univ Sci & Technol, Norway;Nordland Hosp, Norway.
    Storm, Benjamin S.
    Nordland Hosp, Norway;UiT Arctic Univ Norway, Norway;Nord Univ, Norway.
    Brekke, Ole L.
    Nordland Hosp, Norway;UiT Arctic Univ Norway, Norway;Nordland Hosp, Norway.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Advanced Materials. Oslo Univ Hosp, Norway.
    Lambris, John D.
    Univ Penn, USA.
    Application of the C3 inhibitor compstatin in a human whole blood model designed for complement research-20 years of experience and future perspectives2022In: Seminars in Immunology, ISSN 1044-5323, E-ISSN 1096-3618, Vol. 59, article id 101604Article, review/survey (Refereed)
    Abstract [en]

    The complex molecular and cellular biological systems that maintain host homeostasis undergo continuous crosstalk. Complement, a component of innate immunity, is one such system. Initially regarded as a system to protect the host from infection, complement has more recently been shown to have numerous other functions, including involvement in embryonic development, tissue modeling, and repair. Furthermore, the complement system plays a major role in the pathophysiology of many diseases. Through interactions with other plasma cascades, including hemostasis, complement activation leads to the broad host-protective response known as thromboinflammation. Most complement research has been limited to reductionistic models of purified components and cells and their interactions in vitro. However, to study the pathophysiology of complement-driven diseases, including the interaction between the complement system and other inflammatory systems, holistic models demonstrating only minimal interference with complement activity are needed. Here we describe two such models; whole blood anticoagulated with either the thrombin inhibitor lepirudin or the fibrin polymerization peptide blocker GPRP, both of which retain complement activity and preserve the ability of complement to be mutually reactive with other inflammatory systems. For instance, to examine the relative roles of C3 and C5 in complement activation, it is possible to compare the effects of the C3 inhibitor compstatin effects to those of inhibitors of C5 and C5aR1. We also discuss how complement is activated by both pathogen-associated molecular patterns, inducing infectious inflammation caused by organisms such as Gram-negative and Gram-positive bacteria, and by sterile damage-associated molecular patterns, including cholesterol crystals and artificial materials used in clinical medicine. When C3 is inhibited, it is important to determine the mechanism by which inflammation is attenuated, i.e., whether the attenuation derives directly from C3 activation products or via downstream activation of C5, since the mechanism involved may determine the appropriate choice of inhibitor under various conditions. With some exceptions, most inflammatory responses are dependent on C5 and C5aR1; one exception is venous air embolism, in which air bubbles enter the blood circulation and trigger a mainly C3-dependent thromboembolism, with the formation of an active C3 convertase, without a corresponding C5 activation. Under such conditions, an inhibitor of C3 is needed to attenuate the inflammation. Our holistic blood models will be useful for further studies of the inhibition of any complement target, not just C3 or C5. The focus here will be on targeting the critical complement component, activation product, or receptor that is important for the pathophysiology in a variety of disease conditions.

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  • 43.
    Weber, Florian
    et al.
    Univ Oslo, Norway.
    Quach, Huy Quang
    Univ Oslo, Norway.
    Reiersen, Mathias
    Univ Oslo, Norway.
    Sarraj, Sadaf Yosef
    Univ Oslo, Norway.
    Bakir, Dyala Nidal
    Univ Oslo, Norway.
    Jankowski, Victor Aleksander
    Univ Oslo, Norway.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Advanced Materials. Univ Oslo, Norway.
    Tiainen, Hanna
    Univ Oslo, Norway.
    Characterization of the foreign body response of titanium implants modified with polyphenolic coatings2022In: Journal of Biomedical Materials Research. Part A, ISSN 1549-3296, E-ISSN 1552-4965, Vol. 110, no 7, p. 1341-1355Article in journal (Refereed)
    Abstract [en]

    The foreign body response is dictating the outcome of wound healing around any implanted materials. Patients who suffer from chronic inflammatory diseases and impaired wound healing often face a higher risk for implant failure. Therefore, functional surfaces need to be developed to improve tissue integration. For this purpose, we evaluated the impact of surface coatings made of antioxidant polyphenolic molecules tannic acid (TA) and pyrogallol (PG) on the host response in human blood. Our results showed that although the polyphenolic surface modifications impact the initial blood protein adsorption compared to Ti, the complement and coagulation systems are triggered. Despite complement activation, monocytes and granulocytes remained inactivated, which was manifested in a low pro-inflammatory cytokine expression. Under oxidative stress, both coatings were able to reduce intracellular reactive oxygen species in human gingival fibroblasts (hGFs). However, no anti-inflammatory effects of polyphenolic coatings could be verified in hGFs stimulated with lipopolysaccharide and IL-1 beta. Although polyphenols reportedly inhibit the NF-kappa B signaling pathway, phosphorylation of NF-kappa B p65 was observed. In conclusion, our results indicated that TA and PG coatings improved the hemocompatibility of titanium surfaces and have the potential to reduce oxidative stress during wound healing.

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  • 44.
    Mannes, Marco
    et al.
    Univ Hosp Ulm, Germany.
    Mastellos, Dimitrios C.
    Natl Ctr Sci Res Demokritos, Greece.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Nilsson, Bo
    Uppsala University, Sweden.
    Yancopoulou, Despina
    Amyndas Pharmaceut, Greece.
    Lambris, John D.
    Univ Penn, USA.
    Huber-Lang, Markus
    Univ Hosp Ulm, Germany.
    Complement C3 activation in the ICU: Disease and therapy as Bonnie and Clyde2022In: Seminars in Immunology, ISSN 1044-5323, E-ISSN 1096-3618, Vol. 60, article id 101640Article, review/survey (Refereed)
    Abstract [en]

    Patients in the intensive care unit (ICU) often straddle the divide between life and death. Understanding the complex underlying pathomechanisms relevant to such situations may help intensivists select broadly acting treatment options that can improve the outcome for these patients. As one of the most important defense mechanisms of the innate immune system, the complement system plays a crucial role in a diverse spectrum of diseases that can necessitate ICU admission. Among others, myocardial infarction, acute lung injury/acute respiratory distress syndrome (ARDS), organ failure, and sepsis are characterized by an inadequate complement response, which can potentially be addressed via promising intervention options. Often, ICU monitoring and existing treatment options rely on massive intervention strategies to maintain the function of vital organs, and these approaches can further contribute to an unbalanced complement response. Artificial surfaces of extracorporeal organ support devices, transfusion of blood products, and the application of anticoagulants can all trigger or amplify undesired complement activation. It is, therefore, worth pursuing the evaluation of complement inhibition strategies in the setting of ICU treatment. Recently, clinical studies in COVID-19-related ARDS have shown promising effects of central inhibition at the level of C3 and paved the way for prospective investigation of this approach. In this review, we highlight the fundamental and often neglected role of complement in the ICU, with a special focus on targeted complement inhibition. We will also consider complement substitution therapies to temporarily counteract a disease/treatment-related complement consumption.

  • 45.
    Landsem, Anne
    et al.
    Nordland Hosp Trust, Norway.
    Emblem, Ase
    Nordland Hosp Trust, Norway.
    Lau, Corinna
    Nordland Hosp Trust, Norway.
    Christiansen, Dorte
    Nordland Hosp Trust, Norway.
    Gerogianni, Alexandra
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Nordland Hosp Trust, Norway.
    Karlsen, Bard Ove
    Nordland Hosp Trust, Norway.
    Mollnes, Tom Eirik
    Nordland Hosp Trust, Norway;Norwegian Univ Sci & Technol, Norway;Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Advanced Materials. Nordland Hosp Trust, Norway;Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    Brekke, Ole-Lars
    Nordland Hosp Trust, Norway;UiT Arctic Univ Norway, Norway.
    Complement C3b contributes to Escherichia coli-induced platelet aggregation in human whole blood2022In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 13, article id 1020712Article in journal (Refereed)
    Abstract [en]

    Introduction: Platelets have essential functions as first responders in the immune response to pathogens. Activation and aggregation of platelets in bacterial infections can lead to life-threatening conditions such as arterial thromboembolism or sepsis-associated coagulopathy. Methods: In this study, we investigated the role of complement in Escherichia coli (E. coli)-induced platelet aggregation in human whole blood, using Multiplate(R) aggregometry, flow cytometry, and confocal microscopy. Results and Discussion: We found that compstatin, which inhibits the cleavage of complement component C3 to its components C3a and C3b, reduced the E. coli-induced platelet aggregation by 42%-76% (p = 0.0417). This C3-dependent aggregation was not C3a-mediated as neither inhibition of C3a using a blocking antibody or a C3a receptor antagonist, nor the addition of purified C3a had any effects. In contrast, a C3b-blocking antibody significantly reduced the E. coli-induced platelet aggregation by 67% (p = 0.0133). We could not detect opsonized C3b on platelets, indicating that the effect of C3 was not dependent on C3b-fragment deposition on platelets. Indeed, inhibition of glycoprotein IIb/IIIa (GPIIb/IIIa) and complement receptor 1 (CR1) showed that these receptors were involved in platelet aggregation. Furthermore, aggregation was more pronounced in hirudin whole blood than in hirudin platelet-rich plasma, indicating that E. coli-induced platelet aggregation involved other blood cells. In conclusion, the E. coli-induced platelet aggregation in human whole blood is partly C3b-dependent, and GPIIb/IIIa and CR1 are also involved in this process.

  • 46.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Water.
    Computational studies of protein–drug binding affinity changes upon mutations in the drug target2022In: Wiley Interdisciplinary Reviews. Computational Molecular Science, ISSN 1759-0876, E-ISSN 1759-0884, Vol. 12, no 1, article id e1563Article in journal (Refereed)
    Abstract [en]

    Mutations that lead to drug resistance limit the efficacy of antibiotics, antiviral drugs, targeted cancer therapies, and other treatments. Accurately calculating protein–drug binding affinity changes upon mutations in the drug target is of high interest as this can yield a better understanding into how such mutations drive drug-resistance, especially when the mutation in question does not directly interfere with binding of the drug. The main aim of this article is to provide an up-to-date reference on the computational tools that are available for the calculation of Gibbs energy (free energy) changes upon mutation, their strengths, and limitations. The methods that are discussed include free energy calculations (free energy perturbation, thermodynamic integration, multistate Bennett acceptance ratio), analysis of molecular dynamics simulations (linear interaction energy, molecular mechanics [MM]/Poisson–Boltzmann solvated area, and MM/generalized Born solvated area), and methods that involve quantum mechanical calculations (including QM/MM). The possibility to use machine learning is also introduced. Given that the benefit of accurately calculating binding affinity changes upon mutation depends on comparing calculated values with experimental measurements, a brief survey on experimental methods and observables is provided. Examples of computational studies that go beyond calculating the Gibbs energy changes are given. Factors that need to be addressed by the computational chemist and potential pitfalls are discussed at length.

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  • 47.
    Adler, Anna
    et al.
    Uppsala University, Sweden.
    Inoue, Yuuki
    The University of Tokyo, Japan.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Baba, Teruhiko
    National Institute of Advanced Industrial Science and Technology, Japan.
    Ishihara, Kazuhiko
    The University of Tokyo, Japan.
    Nilsson, Bo
    Uppsala University, Sweden.
    Teramura, Yuji
    Uppsala University, Sweden;National Institute of Advanced Industrial Science and Technology, Japan.
    Effect of liposome surface modification with water-soluble phospholipid polymer chain-conjugated lipids on interaction with human plasma proteins2022In: Journal of materials chemistry. B, ISSN 2050-750X, E-ISSN 2050-7518, Vol. 10, no 14, p. 2512-2522Article in journal (Refereed)
    Abstract [en]

    Alternative liposome surface coatings for PEGylation to evade the immune system, particularly the complement system, have garnered significant interest. We previously reported poly(2-methacryloyloxyethyl phosphorylcholine) (MPC)-based lipids (PMPC-lipids) and investigated the surface modification of liposomes. In this study, we synthesize PMPC-lipids with polymerization degrees of 10 (MPC10-lipid), 20 (MPC20-lipid), 50 (MPC50-lipid), and 100 (MPC100-lipid), and coated liposomes with 1, 5, or 10 mol% PMPC-lipids (PMPC-liposomes). Non-modified and PEGylated liposomes are used as controls. We investigate the liposome size, surface charge, polydispersity index, and adsorption of plasma proteins to the liposomes post incubation in human plasma containing N,N,N′,N′-ethylenediamine tetraacetic acid (EDTA) or lepirudin by some methods such as sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), western blotting, and automated capillary western blot, with emphasis on the binding of complement protein C3. It is shown that the coating of liposome PMPC-lipids can suppress protein adsorption more effectively with an increase in the molecular weight and molar ratio (1-10 mol%). Apolipoprotein A-I is detected on PMPC-liposomes with a higher molecular weight and higher molar ratio of PMPC-lipids, whereas α2-macroglobulin is detected on non-modified, PEGylated, and PMPC-liposomes with a shorter polymer chain. In addition, a correlation is shown among the PMPC molecular weight, molar ratio, and C3 binding. The MPC10-lipid cannot inhibit C3 binding efficiently, whereas surface modifications with 10 mol% MPC20-lipid and 5 mol% and 10 mol% MPC50-lipid suppress both total protein and C3 binding. Hence, liposome modification with PMPC-lipids can be a possible strategy for avoiding complement activation.

  • 48.
    Hultström, Michael
    et al.
    Uppsala University, Sweden;McGill Univ, Canada;Jewish Gen Hosp, Canada.
    Frithiof, Robert
    Uppsala University, Sweden.
    Grip, Jonathan
    Karolinska University Hospital, Sweden;Karolinska Institutet, Sweden.
    Lindelöf, Linnea
    Uppsala University, Sweden.
    Rooijackers, Olav
    Karolinska University Hospital, Sweden;Karolinska Institutet, Sweden.
    Pigazzini, Sara
    Univ Helsinki, Finland.
    Niemi, Mari
    Univ Helsinki, Finland.
    Cordioli, Mattia
    Univ Helsinki, Finland.
    Nkambule, Lindo
    Univ Helsinki, Finland.
    Maricic, Tomislav
    Max Planck Inst Evolutionary Anthropol, Germany.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Nilsson, Bo
    Uppsala University, Sweden.
    Lipcsey, Miklos
    Uppsala University, Sweden.
    Zeberg, Hugo
    Max Planck Inst Evolutionary Anthropol, Germany;Karolinska Institutet, Sweden.
    Eriksson, Oskar
    Uppsala University, Sweden.
    Genetic determinants of mannose-binding lectin activity predispose to thromboembolic complications in critical COVID-192022In: Nature Immunology, ISSN 1529-2908, E-ISSN 1529-2916, Vol. 23, p. 861-864Article in journal (Refereed)
  • 49.
    Ndugire, William
    et al.
    Univ Massachusetts, USA.
    Raviranga, N. G. Hasitha
    Univ Massachusetts, USA.
    Lao, Jingzhe
    Univ Massachusetts, USA.
    Ramström, Olof
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Univ Massachusetts, USA.
    Yan, Mingdi
    Univ Massachusetts, USA.
    Gold Nanoclusters as Nanoantibiotic Auranofin Analogues2022In: Advanced Healthcare Materials, ISSN 2192-2640, E-ISSN 2192-2659, Vol. 11, no 9, article id 2101032Article in journal (Refereed)
    Abstract [en]

    Auranofin, a gold(I)-complex with tetraacetylated thioglucose (Ac(4)GlcSH) and triethylphosphine ligands, is an FDA-approved drug used as an anti-inflammatory aid in the treatment of rheumatoid arthritis. In repurposing auranofin for other diseases, it was found that the drug showed significant activity against Gram-positive but was inactive against Gram-negative bacteria. Herein, the design and synthesis of gold nanoclusters (AuNCs) based on the structural motif of auranofin are reported. Phosphine-capped AuNCs are synthesized and glycosylated, yielding auranofin analogues with mixed triphenylphosphine monosulfonate (TPPMS)/Ac(4)GlcSH ligand shells. These AuNCs are active against both Gram-negative and Gram-positive bacteria, including multidrug-resistant pathogens. Notably, an auranofin analogue, a mixed-ligand 1.6 nm AuNC 4b, is more active than auranofin against Pseudomonas aeruginosa, while exhibiting lower toxicity against human A549 cells. The enhanced antibacterial activity of these AuNCs is characterized by a greater uptake of Au by the bacteria compared to Au-I complexes. Additional factors include increased oxidative stress, moderate inhibition of thioredoxin reductase (TrxR), and DNA damage. Most intriguingly, the uptake of AuNCs are not affected by the bacterial outer membrane (OM) barrier or by binding with the extracellular proteins. This contrasts with Au-I complexes like auranofin that are susceptible to protein binding and hindered by the OM barrier.

  • 50.
    Gerogianni, Alexandra
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Dimitrov, Jordan D.
    Sorbonne Univ, France.
    Zarantonello, Alessandra
    Sorbonne Univ, France.
    Poillerat, Victoria
    Sorbonne Univ, France.
    Chonat, Satheesh
    Childrens Healthcare Atlanta, USA;Emory Univ, USA.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    McAdam, Karin E.
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Mollnes, Tom E.
    Oslo Univ Hosp, Norway;Univ Oslo, Norway;Norwegian Univ Sci & Technol, Norway;Norwegian Univ Sci & Technol, Norway;Nordland Hosp, Norway.
    Mohlin, Camilla
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Roumenina, Lubka T.
    Sorbonne Univ, France.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Advanced Materials. Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Heme Interferes With Complement Factor I-Dependent Regulation by Enhancing Alternative Pathway Activation2022In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 13, article id 901876Article in journal (Refereed)
    Abstract [en]

    Hemolysis, as a result of disease or exposure to biomaterials, is characterized by excess amounts of cell-free heme intravascularly and consumption of the protective heme-scavenger proteins in plasma. The liberation of heme has been linked to the activation of inflammatory systems, including the complement system, through alternative pathway activation. Here, we investigated the impact of heme on the regulatory function of the complement system. Heme dose-dependently inhibited factor I-mediated degradation of soluble and surface-bound C3b, when incubated in plasma or buffer with complement regulatory proteins. Inhibition occurred with factor H and soluble complement receptor 1 as co-factors, and the mechanism was linked to the direct heme-interaction with factor I. The heme-scavenger protein hemopexin was the main contaminant in purified factor I preparations. This led us to identify that hemopexin formed a complex with factor I in normal human plasma. These complexes were significantly reduced during acute vasoocclusive pain crisis in patients with sickle cell disease, but the complexes were normalized at their baseline outpatient clinic visit. Hemopexin exposed a protective function of factor I activity in vitro, but only when it was present before the addition of heme. In conclusion, we present a mechanistic explanation of how heme promotes uncontrolled complement alternative pathway amplification by interfering with the regulatory capacity of factor I. Reduced levels of hemopexin and hemopexin-factor I complexes during an acute hemolytic crisis is a risk factor for heme-mediated factor I inhibition.

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