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  • 1.
    Björn, Camilla
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Medicinteknik. University of Gothenburg, Sweden; Sahlgrenska Academy, Sweden.
    Antimicrobial peptides in the treatment of infectious and inflammatory conditions: Preclinical studies of mechanism of action, efficacy, and safety2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The rapid emergence of antibiotic-resistant microbes worldwide and the urgent need of new antimicrobial agents have stimulated interest in antimicrobial peptides (AMPs) as new therapeutics for treatment of infectious diseases. AMPs are present in all living species and constitute an important part of the innate immune system in multicellular organisms, including humans. AMPs display a remarkably broad spectrum of antimicrobial activity covering both Gram-positive and Gram-negative bacteria, including many antibiotic-resistant strains, as well as fungi, viruses, and protozoa. Further, in contrast to many conventional antibiotics, AMPs rapidly kill bacteria instead of just inhibiting bacterial growth. In addition, AMPs act as modulators of the innate immune system and, importantly, bacteria seem less efficient in developing resistance towards AMPs than towards conventional antibiotics. Together these properties make AMPs highly attractive as a new class of antimicrobials, with clinical potential also extending to diseases where inflammation is part of the pathology. The aim of this thesis was to study novel AMPs with respect to their mechanism of action (MOA), antimicrobial spectrum, propensity to select for resistance, and in vivo efficacy and safety. To achieve this, we used a number of in vitro and in vivo assays, together generating a comprehensive preclinical evaluation of the peptides. The hypothesis was that the AMPs in this thesis have potential to be developed as therapeutic agents for several infectious and inflammatory conditions, including treatment of skin and soft tissue infections and prevention of postsurgical adhesion formation. The results showed that all AMPs tested (i.e. PXL03, PXL150, HLR1r, and five variants of CEN1 HC-Br) had broad antimicrobial spectra in vitro with varying sensitivity to salt and serum. Furthermore, PXL150 caused a rapid permeabilization of bacterial membrane in vitro, indicating that this is at least one part of the MOA of this peptide. Under selection pressure in vitro, bacteria did not develop resistance to the peptides tested, i.e. PXL150 and CEN1 HC. Interestingly, all peptides showed anti-inflammatory activity by inhibiting the secretion of proinflammatory mediators from stimulated human cell lines. In addition, PXL01, PXL150, and HLR1r demonstrated fibrinolytic ability in vitro by suppressing the release of plasminogen activator inhibitor-1 (PAI-1). In ex vivo and in vivo skin/wound infection models, the peptides reduced the number of viable bacteria and yeast cells. Further, PXL01 decreased postsurgical adhesion formation in vivo. Notably, nonclinical safety studies showed that PXL150 was safe and well tolerated. In conclusion, several of the peptides evaluated in this thesis demonstrated a promising preclinical efficacy and safety profile motivating further development as drug candidates for local treatment of infectious and inflammatory conditions.

  • 2.
    Fadeel, Bengt
    et al.
    Karolinska Institute, Sweden.
    Fornara, Andrea
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Material och ytteknik.
    Toprak, Muhammet S.
    KTH Royal Institute of Technology, Sweden.
    Bhattacharya, Kunal
    Karolinska Institute, Sweden.
    Keeping it real: The importance of material characterization in nanotoxicology2015In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 468, no 3, p. 498-503Article, review/survey (Refereed)
    Abstract [en]

    Nanomaterials are small and the small size and corresponding large surface area of nanomaterials confers specific properties, making these materials desirable for various applications, not least in medicine. However, it is pertinent to ask whether size is the only property that matters for the desirable or detrimental effects of nanomaterials? Indeed, it is important to know not only what the material looks like, but also what it is made of, as well as how the material interacts with its biological surroundings. It has been suggested that guidelines should be implemented on the types of information required in terms of physicochemical characterization of nanomaterials for toxicological studies in order to improve the quality and relevance of the published results. This is certainly a key issue, but it is important to keep in mind that material characterization should be fit-for-purpose, that is, the information gathered should be relevant for the end-points being studied.

  • 3.
    Hedberg, Y. S.
    et al.
    KTH Royal Institute of Technology, Sweden; Karolinska Institute, Sweden.
    Pradhan, S.
    KTH Royal Institute of Technology, Sweden.
    Cappellini, F.
    Karolinska Institute, Sweden.
    Karlsson, M. -E
    KTH Royal Institute of Technology, Sweden.
    Blomberg, Eva
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Life Science. KTH Royal Institute of Technology, Sweden.
    Karlsson, H. L.
    Karolinska Institute, Sweden.
    Odnevall Wallinder, I.
    KTH Royal Institute of Technology, Sweden.
    Hedberg, J. F.
    KTH Royal Institute of Technology, Sweden.
    Electrochemical surface oxide characteristics of metal nanoparticles (Mn, Cu and Al) and the relation to toxicity2016In: Electrochimica Acta, ISSN 0013-4686, E-ISSN 1873-3859, Vol. 212, p. 360-371Article in journal (Refereed)
    Abstract [en]

    Most metal nanoparticles (NPs), except noble metal NPs, rapidly form a thin surface oxide in ambient conditions. The protective properties of these oxides improve or worsen depending on the environment, e.g., the human lung. Several properties, including the chemical/electrochemical stability and defect density, determine the capacity of these surface oxides to hinder the bulk metal from further oxidation (corrosion). The aim of this study was to investigate whether electrochemical surface oxide characterization of non-functionalized base metal NPs of different characteristics (Al, Mn and Cu) can assist in understanding their bioaccessibility (metal release) in cell media (DMEM+) and their cytotoxic properties following exposure in lung epithelial (A549) cells. The composition and valence states of surface oxides of metal NPs and their electrochemical activity were investigated using an electrochemical technique based on a graphite paste electrode to perform cyclic voltammetry in buffer solutions and open circuit potential measurements in DMEM+. The electrochemical surface oxide characterization was complemented and verified by Raman spectroscopy, X-ray diffraction, and X-ray photoelectron spectroscopy. The open circuit potential trends in DMEM+ correlated well with metal release results in the same solution, and provided information on the kinetics of oxide dissolution in the case of Cu NPs. Extensive particle agglomeration in cell medium (DMEM+) was observed by means of photon-cross correlation spectroscopy for all metal NPs, with sedimentation taking place very quickly. As a consequence, measurements of the real dose of added non-functionalized metal NPs to cell cultures for cytotoxicity testing from a sonicated stock solution were shown necessary. The cytotoxic response was found to be strongly correlated to changes in physico-chemical and electrochemical properties of the surface oxides of the metal NPs, the most potent being Cu NPs, followed by Mn NPs. No cytotoxicity was observed for Al NPs. The electrochemical surface oxide characterization corresponded well with other tools commonly used for nanotoxicological characterization and provided additional information.

  • 4.
    Kuna, V K
    et al.
    University of Gothenburg, Sweden.
    Padma, A M
    University of Gothenburg, Sweden.
    Håkansson, Joakim
    RISE - Research Institutes of Sweden, Bioscience and Materials, Chemistry and Materials.
    Nygren, J
    TATAA Biocenter, Sweden.
    Sjöback, R
    TATAA Biocenter, Sweden.
    Petronis, Sarunas
    RISE - Research Institutes of Sweden, Bioscience and Materials, Chemistry and Materials.
    Sumitran-Holgersson, S
    University of Gothenburg, Sweden.
    Significantly accelerated wound healing of full-thickness skin using a novel composite gel of porcine acellular dermal matrix and human peripheral blood cells2017In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 26, no 2, p. 293-307Article in journal (Refereed)
    Abstract [en]

    Herein, we report the fabrication of a novel composite gel from decellularized gal-gal-knockout porcine skin and human peripheral blood mononuclear cells (hPBMC) for full-thickness skin wound healing. Decellularized skin extracellular matrix (ECM) powder was prepared via chemical treatment, freeze-drying and homogenization. The powder was mixed with culture medium containing hyaluronic acid to generate a pig skin gel (PSG). The effect of the gel in regeneration of full-thickness wound was studied in nude mice. We found significantly accelerated wound closure already on day 15 in animals treated with PSG only or PSG+hPBMC as compared to untreated and hyaluronic acid treated controls (p<0.05). Addition of the hPBMC to the gel resulted in marked increase of host blood vessels as well as the presence of human blood vessels. At day 25, histologically, the wounds in animals treated with PSG only or PSG+hPBMC were completely closed as compared to controls. Thus, the gel facilitated generation of new skin with well arranged epidermal cells and restored bilayer structure of the epidermis and dermis. These results suggest that porcine skin ECM gel together with human cells may be a novel and promising biomaterial for medical applications especially for patients with acute and chronic skin wounds.

  • 5.
    Moodie, Lindon W. K.
    et al.
    UiT The Arctic University of Norway, Norway.
    Žužek, Monika C.
    University of Ljubljana, Slovenia.
    Frangež, Robert
    University of Ljubljana, Slovenia.
    Andersen, Jeanette H.
    UiT The Arctic University of Norway, Norway.
    Hansen, Espen
    UiT The Arctic University of Norway, Norway.
    Olsen, Elisabeth K.
    UiT The Arctic University of Norway, Norway.
    Cergolj, Marija
    University of Ljubljana, Slovenia; University of Rijeka, Croatia.
    Sepčić, Kristina
    University of Ljubljana, Slovenia.
    Hansen, Kine Ø
    UiT The Arctic University of Norway, Norway.
    Svenson, Johan
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor, Medicinteknik. UiT The Arctic University of Norway, Norway.
    Synthetic analogs of stryphnusin isolated from the marine sponge: Stryphnus fortis inhibit acetylcholinesterase with no effect on muscle function or neuromuscular transmission2016In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 14, no 47, p. 11220-11229Article in journal (Refereed)
    Abstract [en]

    The marine secondary metabolite stryphnusin (1) was isolated from the boreal sponge Stryphnus fortis, collected off the Norwegian coast. Given its resemblance to other natural acetylcholinesterase antagonists, it was evaluated against electric eel acetylcholinesterase and displayed inhibitory activity. A library of twelve synthetic phenethylamine analogs, 2a-7a and 2b-7b, containing tertiary and quaternary amines respectively were synthesized to investigate the individual structural contributions to the activity. Compound 7b was the strongest competitive inhibitor of both acetylcholinesterase and butyrylcholinesterase with IC50 values of 57 and 20 μM, respectively. This inhibitory activity is one order of magnitude higher than the positive control physostigmine, and is comparable with several other marine acetylcholinesterase inhibitors. The physiological effect of compound 7b on muscle function and neuromuscular transmission was studied and revealed a selective mode of action at the investigated concentration. This data is of importance as the interference of therapeutic acetylcholinesterase inhibitors with neuromuscular transmission can be problematic and lead to unwanted side effects. The current findings also provide additional insights into the structure-activity relationship of both natural and synthetic acetylcholinesterase inhibitors.

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  • 6.
    Svensson, C. R.
    et al.
    Lund University, Sweden.
    Ameer, S. S.
    Lund University, Sweden.
    Ludvigsson, L.
    Lund University, Sweden.
    Ali, N.
    Lund University, Sweden.
    Alhamdow, A.
    Lund University, Sweden; Karolinska Institute, Sweden.
    Messing, M. E.
    Lund University, Sweden.
    Pagels, J.
    Lund University, Sweden.
    Gudmundsson, A.
    Lund University, Sweden.
    Bohgard, M.
    Lund University, Sweden.
    Sanfins, E.
    Institute of Emerging Diseases and Innovative Therapies, France.
    Kåredal, M.
    Lund University, Sweden.
    Broberg, K.
    Lund University, Sweden; Karolinska Institute, Sweden.
    Rissler, Jenny
    RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Kemi Material och Ytor. Lund University, Sweden.
    Validation of an air–liquid interface toxicological set-up using Cu, Pd, and Ag well-characterized nanostructured aggregates and spheres2016In: Journal of nanoparticle research, ISSN 1388-0764, E-ISSN 1572-896X, Vol. 18, no 4, article id 86Article in journal (Refereed)
    Abstract [en]

    Systems for studying the toxicity of metal aggregates on the airways are normally not suited for evaluating the effects of individual particle characteristics. This study validates a set-up for toxicological studies of metal aggregates using an air–liquid interface approach. The set-up used a spark discharge generator capable of generating aerosol metal aggregate particles and sintered near spheres. The set-up also contained an exposure chamber, The Nano Aerosol Chamber for In Vitro Toxicity (NACIVT). The system facilitates online characterization capabilities of mass mobility, mass concentration, and number size distribution to determine the exposure. By dilution, the desired exposure level was controlled. Primary and cancerous airway cells were exposed to copper (Cu), palladium (Pd), and silver (Ag) aggregates, 50–150 nm in median diameter. The aggregates were composed of primary particles &lt;10 nm in diameter. For Cu and Pd, an exposure of sintered aerosol particles was also produced. The doses of the particles were expressed as particle numbers, masses, and surface areas. For the Cu, Pd, and Ag aerosol particles, a range of mass surface concentrations on the air–liquid interface of 0.4–10.7, 0.9–46.6, and 0.1–1.4 µg/cm2, respectively, were achieved. Viability was measured by WST-1 assay, cytokines (Il-6, Il-8, TNF-a, MCP) by Luminex technology. Statistically significant effects and dose response on cytokine expression were observed for SAEC cells after exposure to Cu, Pd, or Ag particles. Also, a positive dose response was observed for SAEC viability after Cu exposure. For A549 cells, statistically significant effects on viability were observed after exposure to Cu and Pd particles. The set-up produced a stable flow of aerosol particles with an exposure and dose expressed in terms of number, mass, and surface area. Exposure-related effects on the airway cellular models could be asserted.

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