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  • 1.
    Bengtsson, Sara K. S.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Sjöstedt, Jessica
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Malinina, Evgenya
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Das, Roshni
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umecrine Cognition AB, Solna, Sweden.
    Doverskog, Magnus
    Umecrine Cognition AB, Solna, Sweden.
    Johansson, Inga-Maj
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology. Umecrine Cognition AB, Solna, Sweden.
    Haage, David
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology. Department of Nursing Sciences, Mid Sweden University, Sundsvall, Sweden.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology. Umecrine Cognition AB, Solna, Sweden.
    Extra-synaptic GABAA receptor potentiation and neurosteroid-induced learning deficits are inhibited by GR3027, a GABAA modulating steroid antagonist2023In: Biomolecules, E-ISSN 2218-273X, Vol. 13, no 10, article id 1496Article in journal (Refereed)
    Abstract [en]

    Objectives In Vitro: To study the effects of GR3027 (golexanolone) on neurosteroid-induced GABA-mediated current responses under physiological GABAergic conditions with recombinant human α5β3γ2L and α1β2γ2L GABAA receptors expressed in human embryonic kidney cells, using the response patch clamp technique combined with the Dynaflow™ application system. With α5β3γ2L receptors, 0.01–3 μM GR3027, in a concentration-dependent manner, reduced the current response induced by 200 nM THDOC + 0.3 µM GABA, as well as the THDOC-induced direct gated effect. GR3027 (1 μM) alone had no effect on the GABA-mediated current response or current in the absence of GABA. With α1β2γ2L receptors, GR3027 alone had no effect on the GABA-mediated current response or did not affect the receptor by itself. Meanwhile, 1–3 µM GR3027 reduced the current response induced by 200 nM THDOC + 30 µM GABA and 3 µM GR3027 that induced by 200 nM THDOC when GABA was not present. Objectives In Vivo: GR3027 reduces allopregnanolone (AP)-induced decreased learning and anesthesia in male Wistar rats. Rats treated i.v. with AP (2.2 mg/kg) or vehicle were given GR3027 in ratios of 1:0.5 to 1:5 dissolved in 10% 2-hydroxypropyl-beta-cyclodextrin. A dose ratio of AP:GR3027 of at least 1:2.5 antagonized the AP-induced decreased learning in the Morris Water Mase (MWM) and 1:7.5 antagonized the loss of righting reflex (LoR). GR3027 treatment did not change other functions in the rat compared to the vehicle group. Conclusions: GR3027 functions in vitro as an inhibitor of GABAA receptors holding α5β3γ2L and α1β2γ2L, in vivo, in the rat, as a dose-dependent inhibitor toward AP’s negative effects on LoR and learning in the MWM.

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  • 2.
    Blomqvist, Lennart
    et al.
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Medical Radiation Physics and Nuclear Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Nordberg, Gunnar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Nurchi, Valeria M.
    Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy.
    Aaseth, Jan O.
    Department of Research, Innlandet Hospital Trust, P.O. Box 104, Brumunddal, Norway; Faculty of Health and Social Sciences, Inland Norway University of Applied Sciences, Elverum, Norway.
    Gadolinium in Medical Imaging—Usefulness, Toxic Reactions and Possible Countermeasures: A Review2022In: Biomolecules, E-ISSN 2218-273X, Vol. 12, no 6, article id 742Article, review/survey (Refereed)
    Abstract [en]

    Gadolinium (Gd) is one of the rare-earth elements. The properties of its trivalent cation (Gd3+) make it suitable to serve as the central ion in chelates administered intravenously to patients as a contrast agent in magnetic resonance imaging. Such Gd-chelates have been used for more than thirty years. During the past decades, knowledge has increased about potential harmful effects of Gd-chelates in patients with severe renal dysfunction. In such patients, there is a risk for a potentially disabling and lethal disease, nephrogenic systemic fibrosis. Restricting the use of Gd-chelates in persons with severely impaired renal function has decreased the occurrence of this toxic effect in the last decade. There has also been an increasing awareness of Gd-retention in the body, even in patients without renal dysfunction. The cumulative number of doses given, and the chemical structure of the chelate given, are factors of importance for retention in tissues. This review describes the chemical properties of Gd and its medically used chelates, as well as its toxicity and potential side effects related to injection of Gd-chelates.

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  • 3.
    Bäckström, Torbjörn
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Bengtsson, Sara K. S.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Sjöstedt, Jessica
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Malinina, Evgenya
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Johansson, Inga-Maj
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Ragagnin, Gianna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Ekberg, Karin
    Asarina Pharma AB, Solna, Sweden.
    Lundgren, Per
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Isoallopregnanolone inhibits estrus cycle-dependent aggressive behavior2023In: Biomolecules, E-ISSN 2218-273X, Vol. 13, no 6, article id 1017Article in journal (Refereed)
    Abstract [en]

    Among female rats, some individuals show estrus cycle-dependent irritability/aggressive behaviors, and these individual rats may be used as a model for premenstrual dysphoric disorder (PMDD). We wanted to investigate if these behaviors are related to the estrus cycle phase containing moderately increased levels of positive GABA-A receptor-modulating steroids (steroid-PAM), especially allopregnanolone (ALLO), and if the adverse behavior can be antagonized. The electrophysiology studies in this paper show that isoallopregnanolone (ISO) is a GABA-A-modulating steroid antagonist (GAMSA), meaning that ISO can antagonize the agonistic effects of positive GABA-A receptor-modulating steroids in both α1β2γ2L and α4β3δ GABA-A receptor subtypes. In this study, we also investigated whether ISO could antagonize the estrus cycle-dependent aggressive behaviors in female Wistar rats using a resident–intruder test. Our results confirmed previous reports of estrus cycle-dependent behaviors in that 42% of the tested rats showed higher levels of irritability/aggression at diestrus compared to those at estrus. Furthermore, we found that, during the treatment with ISO, the aggressive behavior at diestrus was alleviated to a level comparable to that of estrus. We noticed an 89% reduction in the increase in aggressive behavior at diestrus compared to that at estrus. Vehicle treatment in the same animals showed a minimal effect on the diestrus-related aggressive behavior. In conclusion, we showed that ISO can antagonize Steroid-PAM both in α1β2γ2L and α4β3δ GABA-A receptor subtypes and inhibit estrus cycle-dependent aggressive behavior.

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  • 4.
    Correale, Michele
    et al.
    Cardiothoracic Department, Ospedali Riuniti University Hospital, Foggia, Italy.
    Tricarico, Lucia
    Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
    Bevere, Ester Maria Lucia
    Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
    Chirivì, Francesco
    Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
    Croella, Francesca
    Cardiothoracic Vascular Department, Division of Provincial Cardiology, Santissima Annunziata Hospital and Delta Hospital, Azienda Unità Sanitaria Locale di Ferrara, Ferrara, Italy.
    Severino, Paolo
    Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, Rome, Italy.
    Mercurio, Valentina
    Department of Translational Medical Sciences, Federico II University, Naples, Italy.
    Magrì, Damiano
    Department of Clinical and Molecular Medicine, Azienda Ospedaliera Sant’Andrea, “Sapienza” Università degli Studi di Roma, Rome, Italy.
    Dini, Frank L.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Istituto Auxologico IRCCS, Centro Medico Sant’Agostino, Via Temperanza, 6, Milan, Italy.
    Licordari, Roberto
    Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Section of Cardiology, University of Messina, Messina, Italy.
    Beltrami, Matteo
    Arrhythmia and Electrophysiology Unit, Careggi University Hospital, Florence, Italy.
    Dattilo, Giuseppe
    Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Section of Cardiology, University of Messina, Messina, Italy.
    Salzano, Andrea
    Cardiology Unit, AORN A Cardarelli, Naples, Italy.
    Palazzuoli, Alberto
    Cardiovascular Diseases Unit, Cardio-Thoracic and Vascular Department, S. Maria alle Scotte Hospital, University of Siena, Siena, Italy.
    Circulating biomarkers in pulmonary arterial hypertension: an update2024In: Biomolecules, E-ISSN 2218-273X, Vol. 14, no 5, article id 552Article, review/survey (Refereed)
    Abstract [en]

    Pulmonary arterial hypertension (PAH) is a rare subtype of group 1 pulmonary hypertension (PH) diseases, characterized by high pulmonary artery pressure leading to right ventricular dysfunction and potential life-threatening consequences. PAH involves complex mechanisms: vasoconstriction, vascular remodeling, endothelial dysfunction, inflammation, oxidative stress, fibrosis, RV remodeling, cellular hypoxia, metabolic imbalance, and thrombosis. These mechanisms are mediated by several pathways, involving molecules like nitric oxide and prostacyclin. PAH diagnosis requires clinical evaluation and right heart catheterization, confirming a value of mPAP ≥ 20 mmHg at rest and often elevated pulmonary vascular resistance (PVR). Even if an early and accurate diagnosis is crucial, PAH still lacks effective biomarkers to assist in its diagnosis and prognosis. Biomarkers could contribute to arousing clinical suspicion and serve for prognosis prediction, risk stratification, and dynamic monitoring in patients with PAH. The aim of the present review is to report the main novelties on new possible biomarkers for the diagnosis, prognosis, and treatment monitoring of PAH.

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  • 5.
    Gharibyan, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Islam, Tohidul
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Pettersson, Nina
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Golchin, Solmaz A.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Lundgren, Johanna
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Johansson, Gabriella
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Genot, Melany
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Schultz, Nina
    Wennström, Malin
    Olofsson, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Apolipoprotein E Interferes with IAPP Aggregation and Protects Pericytes from IAPP-Induced Toxicity2020In: Biomolecules, E-ISSN 2218-273X, Vol. 10, no 1, article id 134Article in journal (Refereed)
    Abstract [en]

    Apolipoprotein E (ApoE) has become a primary focus of research after the discovery of its strong linkage to Alzheimer’s disease (AD), where the ApoE4 variant is the highest genetic risk factor for this disease. ApoE is commonly found in amyloid deposits of different origins, and its interaction with amyloid-β peptide (Aβ), the hallmark of AD, is well known. However, studies on the interaction of ApoEs with other amyloid-forming proteins are limited. Islet amyloid polypeptide (IAPP) is an amyloid-forming peptide linked to the development of type-2 diabetes and has also been shown to be involved in AD pathology and vascular dementia. Here we studied the impact of ApoE on IAPP aggregation and IAPP-induced toxicity on blood vessel pericytes. Using both in vitro and cell-based assays, we show that ApoE efficiently inhibits the amyloid formation of IAPP at highly substoichiometric ratios and that it interferes with both nucleation and elongation. We also show that ApoE protects the pericytes against IAPP-induced toxicity, however, the ApoE4 variant displays the weakest protective potential. Taken together, our results suggest that ApoE has a generic amyloid-interfering property and can be protective against amyloid-induced cytotoxicity, but there is a loss of function for the ApoE4 variant.

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  • 6.
    Gharibyan, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Jayaweera, Sanduni Wasana
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Lehmann, Manuela
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Olofsson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Endogenous Human Proteins Interfering with Amyloid Formation2022In: Biomolecules, E-ISSN 2218-273X, Vol. 12, no 3, article id 446Article, review/survey (Refereed)
    Abstract [en]

    Amyloid formation is a pathological process associated with a wide range of degenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and diabetes mellitus type 2. During disease progression, abnormal accumulation and deposition of proteinaceous material are accompanied by tissue degradation, inflammation, and dysfunction. Agents that can interfere with the process of amyloid formation or target already formed amyloid assemblies are consequently of therapeutic interest. In this context, a few endogenous proteins have been associated with an anti-amyloidogenic activity. Here, we review the properties of transthyretin, apolipoprotein E, clusterin, and BRICHOS protein domain which all effectively interfere with amyloid in vitro, as well as displaying a clinical impact in humans or animal models. Their involvement in the amyloid formation process is discussed, which may aid and inspire new strategies for therapeutic interventions.

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  • 7. Grasso, Francesca
    et al.
    Frisan, Teresa
    Department Cell and Molecular Biology, Karolinska Institutet.
    Bacterial Genotoxins: Merging the DNA Damage Response into Infection Biology2015In: Biomolecules, E-ISSN 2218-273X, Vol. 5, no 3, p. 1762-1782Article, review/survey (Refereed)
    Abstract [en]

    Bacterial genotoxins are unique among bacterial toxins as their molecular target is DNA. The consequence of intoxication or infection is induction of DNA breaks that, if not properly repaired, results in irreversible cell cycle arrest (senescence) or death of the target cells. At present, only three bacterial genotoxins have been identified. Two are protein toxins: the cytolethal distending toxin (CDT) family produced by a number of Gram-negative bacteria and the typhoid toxin produced by Salmonella enterica serovar Typhi. The third member, colibactin, is a peptide-polyketide genotoxin, produced by strains belonging to the phylogenetic group B2 of Escherichia coli. This review will present the cellular effects of acute and chronic intoxication or infection with the genotoxins-producing bacteria. The carcinogenic properties and the role of these effectors in the context of the host-microbe interaction will be discussed. We will further highlight the open questions that remain to be solved regarding the biology of this unusual family of bacterial toxins.

  • 8.
    Hsieh, Chia-Ju
    et al.
    Division of Nuclear Medicine and Clinical Molecular Imaging, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, PA, Philadelphia, United States.
    Riad, Aladdin
    Division of Nuclear Medicine and Clinical Molecular Imaging, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, PA, Philadelphia, United States.
    Lee, Ji Youn
    Division of Nuclear Medicine and Clinical Molecular Imaging, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, PA, Philadelphia, United States.
    Sahlholm, Kristoffer
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Xu, Kuiying
    Division of Nuclear Medicine and Clinical Molecular Imaging, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, PA, Philadelphia, United States.
    Luedtke, Robert R.
    Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, TX, Fort Worth, United States.
    Mach, Robert H.
    Division of Nuclear Medicine and Clinical Molecular Imaging, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, PA, Philadelphia, United States.
    Interaction of ligands for pet with the dopamine d3 receptor: in silico and in vitro methods2021In: Biomolecules, E-ISSN 2218-273X, Vol. 11, no 4, article id 529Article in journal (Refereed)
    Abstract [en]

    [18F]Fallypride and [18F]Fluortriopride (FTP) are two different PET radiotracers that bind with sub-nanomolar affinity to the dopamine D3 receptor (D3R). In spite of their similar D3 affinities, the two PET ligands display very different properties for labeling the D3R in vivo: [18F]Fallypride is capable of binding to D3R under "baseline" conditions, whereas [18F]FTP requires the depletion of synaptic dopamine in order to image the receptor in vivo. These data suggest that [18F]Fallypride is able to compete with synaptic dopamine for binding to the D3R, whereas [18F]FTP is not. The goal of this study was to conduct a series of docking and molecular dynamic simulation studies to identify differences in the ability of each molecule to interact with the D3R that could explain these differences with respect to competition with synaptic dopamine. Competition studies measuring the ability of each ligand to compete with dopamine in the β-arrestin assay were also conducted. The results of the in silico studies indicate that FTP has a weaker interaction with the orthosteric binding site of the D3R versus that of Fallypride. The results of the in silico studies were also consistent with the IC50 values of each compound in the dopamine β-arrestin competition assays. The results of this study indicate that in silico methods may be able to predict the ability of a small molecule to compete with synaptic dopamine for binding to the D3R.

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  • 9.
    Jayaweera, Sanduni Wasana
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Surano, Solmaz
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Pettersson, Nina
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Oskarsson, Elvira
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Lettius, Lovisa
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Gharibyan, Anna L.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Olofsson, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Mechanisms of Transthyretin Inhibition of IAPP Amyloid Formation2021In: Biomolecules, E-ISSN 2218-273X, Vol. 11, no 3, article id 411Article in journal (Refereed)
    Abstract [en]

    Amyloid-formation by the islet amyloid polypeptide (IAPP), produced by the β-cells in the human pancreas, has been associated with the development of type II diabetes mellitus (T2DM). The human plasma-protein transthyretin (TTR), a well-known amyloid-inhibiting protein, is interestingly also expressed within the IAPP producing β-cells. In the present study, we have characterized the ability of TTR to interfere with IAPP amyloid-formation, both in terms of its intrinsic stability as well as with regard to the effect of TTR-stabilizing drugs. The results show that TTR can prolong the lag-phase as well as impair elongation in the course of IAPP-amyloid formation. We also show that the interfering ability correlates inversely with the thermodynamic stability of TTR, while no such correlation was observed as a function of kinetic stability. Furthermore, we demonstrate that the ability of TTR to interfere is maintained also at the low pH environment within the IAPP-containing granules of the pancreatic β-cells. However, at both neutral and low pH, the addition of TTR-stabilizing drugs partly impaired its efficacy. Taken together, these results expose mechanisms of TTR-mediated inhibition of IAPP amyloid-formation and highlights a potential therapeutic target to prevent the onset of T2DM.

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  • 10. Karakostis, Konstantinos
    et al.
    Lopez, Ignacio
    Pena-Balderas, Ana M.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Inserm UMRS1131, Institut de Génétique Moléculaire, Université Paris 7, Hôpital St. Louis, France; Regional Centre for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Czech Republic; International Center for Cancer Vaccine Science (ICCVS), University of Gdańsk, Poland.
    Olivares-Illana, Vanesa
    Molecular and Biochemical Techniques for Deciphering p53-MDM2 Regulatory Mechanisms2021In: Biomolecules, E-ISSN 2218-273X, Vol. 11, no 1, article id 36Article, review/survey (Refereed)
    Abstract [en]

    The p53 and Mouse double minute 2 (MDM2) proteins are hubs in extensive networks of interactions with multiple partners and functions. Intrinsically disordered regions help to adopt function-specific structural conformations in response to ligand binding and post-translational modifications. Different techniques have been used to dissect interactions of the p53-MDM2 pathway, in vitro, in vivo, and in situ each having its own advantages and disadvantages. This review uses the p53-MDM2 to show how different techniques can be employed, illustrating how a combination of in vitro and in vivo techniques is highly recommended to study the spatio-temporal location and dynamics of interactions, and to address their regulation mechanisms and functions. By using well-established techniques in combination with more recent advances, it is possible to rapidly decipher complex mechanisms, such as the p53 regulatory pathway, and to demonstrate how protein and nucleotide ligands in combination with post-translational modifications, result in inter-allosteric and intra-allosteric interactions that govern the activity of the protein complexes and their specific roles in oncogenesis. This promotes elegant therapeutic strategies that exploit protein dynamics to target specific interactions.

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  • 11. Kelly, Rachel
    et al.
    Cairns, Andrew G.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ådén, Jörgen
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Bemelmans, Alexis-Pierre
    Brouillet, Emmanuel
    Patton, Tommy
    McKernan, Declan P.
    Dowd, Eilís
    The Small Molecule Alpha-Synuclein Aggregator, FN075, Enhances Alpha-Synuclein Pathology in Subclinical AAV Rat Models2021In: Biomolecules, E-ISSN 2218-273X, Vol. 11, no 11, article id 1685Article in journal (Refereed)
    Abstract [en]

    Animal models of Parkinson’s disease, in which the human α-synuclein transgene is overexpressed in the nigrostriatal pathway using viral vectors, are widely considered to be the most relevant models of the human condition. However, although highly valid, these models have major limitations related to reliability and variability, with many animals exhibiting pronounced α-synuclein expression failing to demonstrate nigrostriatal neurodegeneration or motor dysfunction. Therefore, the aim of this study was to determine if sequential intra-nigral administration of AAV-α-synuclein followed by the small α-synuclein aggregating molecule, FN075, would enhance or precipitate the associated α-synucleinopathy, nigrostriatal pathology and motor dysfunction in subclinical models. Rats were given unilateral intra-nigral injections of AAV-α-synuclein (either wild-type or A53T mutant) followed four weeks later by a unilateral intra-nigral injection of FN075, after which they underwent behavioral testing for lateralized motor functionality until they were sacrificed for immunohistological assessment at 20 weeks after AAV administration. In line with expectations, both of the AAV vectors induced widespread overexpression of human α-synuclein in the substantia nigra and striatum. Sequential administration of FN075 significantly enhanced the α-synuclein pathology with increased density and accumulation of the pathological form of the protein phosphorylated at serine 129 (pS129-α-synuclein). However, despite this enhanced α-synuclein pathology, FN075 did not precipitate nigrostriatal degeneration or motor dysfunction in these subclinical AAV models. In conclusion, FN075 holds significant promise as an approach to enhancing the α-synuclein pathology in viral overexpression models, but further studies are required to determine if alternative administration regimes for this molecule could improve the reliability and variability in these models.

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  • 12.
    Mallikarjuna, Pramod
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Zhou, Yang
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Landström, Maréne
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    The Synergistic Cooperation between TGF-Cancer and Fibrosis2022In: Biomolecules, E-ISSN 2218-273X, Vol. 12, no 5, article id 635Article, review/survey (Refereed)
    Abstract [en]

    Transforming growth factor β (TGF-β) is a multifunctional cytokine regulating homeostasis and immune responses in adult animals and humans. Aberrant and overactive TGF-β signaling promotes cancer initiation and fibrosis through epithelial–mesenchymal transition (EMT), as well as the invasion and metastatic growth of cancer cells. TGF-β is a key factor that is active during hypoxic conditions in cancer and is thereby capable of contributing to angiogenesis in various types of cancer. Another potent role of TGF-β is suppressing immune responses in cancer patients. The strong tumor-promoting effects of TGF-β and its profibrotic effects make it a focus for the development of novel therapeutic strategies against cancer and fibrosis as well as an attractive drug target in combination with immune regulatory checkpoint inhibitors. TGF-β belongs to a family of cytokines that exert their function through signaling via serine/threonine kinase transmembrane receptors to intracellular Smad proteins via the canonical pathway and in combination with co-regulators such as the adaptor protein and E3 ubiquitin ligases TRAF4 and TRAF6 to promote non-canonical pathways. Finally, the outcome of gene transcription initiated by TGF-β is context-dependent and controlled by signals exerted by other growth factors such as EGF and Wnt. Here, we discuss the synergistic cooperation between TGF-β and hypoxia in development, fibrosis and cancer.

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  • 13.
    Marinovíc, Mila
    et al.
    Department of Microbiology, Faculty of Agriculture and Forestry, University of Helsinki, Helsinki, Finland.
    Di Falco, Marcos
    Centre for Structural and Functional Genomics, Concordia University, QC, Montréal, Canada.
    Aguilar Pontes, Maria Victoria
    Fungal Physiology, Westerdijk Fungal Biodiversity Institute Fungal Molecular Physiology, Utrecht University, Uppsalalaan 8, Utrecht, Netherlands.
    Gorzsás, András
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Tsang, Adrian
    Centre for Structural and Functional Genomics, Concordia University, QC, Montréal, Canada.
    de Vries, Ronald P.
    Fungal Physiology, Westerdijk Fungal Biodiversity Institute Fungal Molecular Physiology, Utrecht University, Uppsalalaan 8, Utrecht, Netherlands.
    Mäkelä, Miia R.
    Department of Microbiology, Faculty of Agriculture and Forestry, University of Helsinki, Helsinki, Finland.
    Hildén, Kristiina
    Department of Microbiology, Faculty of Agriculture and Forestry, University of Helsinki, Helsinki, Finland.
    Comparative Analysis of Enzyme Production Patterns of Lignocellulose Degradation of Two White Rot Fungi: Obba rivulosa and Gelatoporia subvermispora2022In: Biomolecules, E-ISSN 2218-273X, Vol. 12, no 8, article id 1017Article in journal (Refereed)
    Abstract [en]

    The unique ability of basidiomycete white rot fungi to degrade all components of plant cell walls makes them indispensable organisms in the global carbon cycle. In this study, we analyzed the proteomes of two closely related white rot fungi, Obba rivulosa and Gelatoporia subvermispora, during eight-week cultivation on solid spruce wood. Plant cell wall degrading carbohydrate-active enzymes (CAZymes) represented approximately 5% of the total proteins in both species. A core set of orthologous plant cell wall degrading CAZymes was shared between these species on spruce suggesting a conserved plant biomass degradation approach in this clade of basidiomycete fungi. However, differences in time-dependent production of plant cell wall degrading enzymes may be due to differences among initial growth rates of these species on solid spruce wood. The obtained results provide insight into specific enzymes and enzyme sets that are produced during the degradation of solid spruce wood in these fungi. These findings expand the knowledge on enzyme production in nature-mimicking conditions and may contribute to the exploitation of white rot fungi and their enzymes for biotechnological applications.

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  • 14.
    Nordberg, Monica
    et al.
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Nordberg, Gunnar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Metallothionein and Cadmium Toxicology - Historical Review and Commentary2022In: Biomolecules, E-ISSN 2218-273X, Vol. 12, no 3, article id 360Article, review/survey (Refereed)
    Abstract [en]

    More than one and a half centuries ago, adverse human health effects were reported after use of a cadmium-containing silver polishing agent. Long-term cadmium exposure gives rise to kidney or bone disease, reproductive toxicity and cancer in animals and humans. At present, high human exposures to cadmium occur in small-scale mining, underlining the need for preventive measures. This is particularly urgent in view of the growing demand for minerals and metals in global climate change mitigation. This review deals with a specific part of cadmium toxicology that is important for understanding when toxic effects appear and, thus, is crucial for risk assessment. The discovery of the low-molecular-weight protein metallothionein (MT) in 1957 was an important milestone because, when this protein binds cadmium, it modifies cellular cadmium toxicity. The present authors contributed evidence in the 1970s concerning cadmium binding to MT and synthesis of the protein in tissues. We showed that binding of cadmium to metallothionein in tissues prevented some toxic effects, but that metallothionein can increase the transport of cadmium to the kidneys. Special studies showed the importance of the Cd/Zn ratio in MT for expression of toxicity in the kidneys. We also developed models of cadmium toxicokinetics based on our MT-related findings. This model combined with estimates of tissue levels giving rise to toxicity, made it possible to calculate expected risks in relation to exposure. Other scientists developed these models further and international organizations have successfully used these amended models in recent publications. Our contributions in recent decades included studies in humans of MT-related biomarkers showing the importance of MT gene expression in lymphocytes and MT autoantibodies for risks of Cd-related adverse effects in cadmium-exposed population groups. In a study of the impact of zinc status on the risk of kidney dysfunction in a cadmium-exposed group, the risks were low when zinc status was good and high when zinc status was poor. The present review summarizes this evidence in a risk assessment context and calls for its application in order to improve preventive measures against adverse effects of cadmium exposures in humans and animals.

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  • 15.
    Padariya, Monikaben
    et al.
    International Centre for Cancer Vaccine Science, University of Gdansk, ul. Kładki 24, Gdansk, Poland.
    Sznarkowska, Alicja
    International Centre for Cancer Vaccine Science, University of Gdansk, ul. Kładki 24, Gdansk, Poland.
    Kote, Sachin
    International Centre for Cancer Vaccine Science, University of Gdansk, ul. Kładki 24, Gdansk, Poland.
    Gómez-Herranz, Maria
    International Centre for Cancer Vaccine Science, University of Gdansk, ul. Kładki 24, Gdansk, Poland.
    Mikac, Sara
    International Centre for Cancer Vaccine Science, University of Gdansk, ul. Kładki 24, Gdansk, Poland.
    Pilch, Magdalena
    International Centre for Cancer Vaccine Science, University of Gdansk, ul. Kładki 24, Gdansk, Poland.
    Alfaro, Javier
    International Centre for Cancer Vaccine Science, University of Gdansk, ul. Kładki 24, Gdansk, Poland; Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. International Centre for Cancer Vaccine Science, University of Gdansk, ul. Kładki 24, Gdansk, Poland; Inserm UMRS1131, Institut de Génétique Moléculaire, Université Paris 7, Hôpital St. Louis, Paris, France; RECAMO, Masaryk Memorial Cancer Institute, Zlutykopec 7, Brno, Czech Republic.
    Hupp, Ted
    International Centre for Cancer Vaccine Science, University of Gdansk, ul. Kładki 24, Gdansk, Poland; Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
    Kalathiya, Umesh
    International Centre for Cancer Vaccine Science, University of Gdansk, ul. Kładki 24, Gdansk, Poland.
    Functional interfaces, biological pathways, and regulations of interferon-related dna damage resistance signature (Irds) genes2021In: Biomolecules, E-ISSN 2218-273X, Vol. 11, no 5, article id 622Article, review/survey (Refereed)
    Abstract [en]

    Interferon (IFN)-related DNA damage resistant signature (IRDS) genes are a subgroup of interferon-stimulated genes (ISGs) found upregulated in different cancer types, which promotes resistance to DNA damaging chemotherapy and radiotherapy. Along with briefly discussing IFNs and signalling in this review, we highlighted how different IRDS genes are affected by viruses. On the contrary, different strategies adopted to suppress a set of IRDS genes (STAT1, IRF7, OAS family, and BST2) to induce (chemo-and radiotherapy) sensitivity were deliberated. Significant biological pathways that comprise these genes were classified, along with their frequently associated genes (IFIT1/3, IFITM1, IRF7, ISG15, MX1/2 and OAS1/3/L). Major upstream regulators from the IRDS genes were identified, and different IFN types regulating these genes were outlined. Functional interfaces of IRDS proteins with DNA/RNA/ATP/GTP/NADP biomolecules featured a well-defined pharmacophore model for STAT1/IRF7-dsDNA and OAS1/OAS3/IFIH1-dsRNA complexes, as well as for the genes binding to GDP or NADP+. The Lys amino acid was found commonly interacting with the ATP phosphate group from OAS1/EIF2AK2/IFIH1 genes. Considering the premise that targeting IRDS genes mediated resistance offers an efficient strategy to resensitize tumour cells and enhances the outcome of anti-cancer treatment, this review can add some novel insights to the field.

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  • 16.
    Rani, Alka
    et al.
    Department of Botany, School of Basic and Applied Sciences, Central University of Punjab, Ghudda, Bathinda, Punjab, India.
    Saini, Khem Chand
    Department of Botany, School of Basic and Applied Sciences, Central University of Punjab, Ghudda, Bathinda, Punjab, India.
    Bast, Felix
    Department of Botany, School of Basic and Applied Sciences, Central University of Punjab, Ghudda, Bathinda, Punjab, India.
    Varjani, Sunita
    Gujarat Pollution Control Board, Gandhinagar, Gujarat, India.
    Mehariya, Sanjeet
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Bhatia, Shashi Kant
    Department of Biological Engineering, College of Engineering, Konkuk University, Seoul, South Korea.
    Sharma, Neeta
    ENEA, Italian National Agency for New Technologies, Energy and Sustainable Economic Development, Department of Sustainability-CR Trisaia, Rotondella, Italy.
    Funk, Christiane
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    A review on microbial products and their perspective application as antimicrobial agents2021In: Biomolecules, E-ISSN 2218-273X, Vol. 11, no 12, article id 1860Article, review/survey (Refereed)
    Abstract [en]

    Microorganisms including actinomycetes, archaea, bacteria, fungi, yeast, and microalgae are an auspicious source of vital bioactive compounds. In this review, the existing research regard-ing antimicrobial molecules from microorganisms is summarized. The potential antimicrobial compounds from actinomycetes, particularly Streptomyces spp.; archaea; fungi including endophytic, filamentous, and marine-derived fungi, mushroom; and microalgae are briefly described. Further-more, this review briefly summarizes bacteriocins, halocins, sulfolobicin, etc., that target multiple-drug resistant pathogens and considers next-generation antibiotics. This review highlights the pos-sibility of using microorganisms as an antimicrobial resource for biotechnological, nutraceutical, and pharmaceutical applications. However, more investigations are required to isolate, separate, purify, and characterize these bioactive compounds and transfer these primary drugs into clinically approved antibiotics.

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  • 17.
    Sundin, Charlotta
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Saleeb, Michael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Spjut, Sara
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Qin, Liena
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Identification of small molecules blocking the Pseudomonas aeruginosa type III secretion system protein PcrV2021In: Biomolecules, E-ISSN 2218-273X, Vol. 11, no 1, article id 55Article in journal (Refereed)
    Abstract [en]

    Pseudomonas aeruginosa is an opportunistic bacterial pathogen that employs its type III secretion system (T3SS) during the acute phase of infection to translocate cytotoxins into the host cell cytoplasm to evade the immune system. The PcrV protein is located at the tip of the T3SS, facilitates the integration of pore-forming proteins into the eukaryotic cell membrane, and is required for translocation of cytotoxins into the host cell. In this study, we used surface plasmon resonance screening to identify small molecule binders of PcrV. A follow-up structure-activity relationship analysis resulted in PcrV binders that protect macrophages in a P. aeruginosa cell-based infection assay. Treatment of P. aeruginosa infections is challenging due to acquired, intrinsic, and adaptive resistance in addition to a broad arsenal of virulence systems such as the T3SS. Virulence blocking molecules targeting PcrV constitute valuable starting points for development of next generation antibacterials to treat infections caused by P. aeruginosa. 

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