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1.
  • Hojjat-Farsangi, Mohammad (författare)
  • Small-molecule inhibitors of the receptor tyrosine kinases : promising tools for targeted cancer therapies
  • 2014
  • Ingår i: International Journal of Molecular Sciences. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1422-0067.
  • Tidskriftsartikel (refereegranskat)abstract
    • Chemotherapeutic and cytotoxic drugs are widely used in the treatment of cancer. In spite of the improvements in the life quality of patients, their effectiveness is compromised by several disadvantages. This represents a demand for developing new effective strategies with focusing on tumor cells and minimum side effects. Targeted cancer therapies and personalized medicine have been defined as a new type of emerging treatments. Small molecule inhibitors (SMIs) are among the most effective drugs for targeted cancer therapy. The growing number of approved SMIs of receptor tyrosine kinases (RTKs) i.e., tyrosine kinase inhibitors (TKIs) in the clinical oncology imply the increasing attention and application of these therapeutic tools. Most of the current approved RTK–TKIs in preclinical and clinical settings are multi-targeted inhibitors with several side effects. Only a few specific/selective RTK–TKIs have been developed for the treatment of cancer patients. Specific/selective RTK–TKIs have shown less deleterious effects compared to multi-targeted inhibitors. This review intends to highlight the importance of specific/selective TKIs for future development with less side effects and more manageable agents. This article provides an overview of: (1) the characteristics and function of RTKs and TKIs; (2) the recent advances in the improvement of specific/selective RTK–TKIs in preclinical or clinical settings; and (3) emerging RTKs for targeted cancer therapies by TKIs.
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2.
  • Barrozo, Alexandre, et al. (författare)
  • Computational Protein Engineering: Bridging the Gap between Rational Design and Laboratory Evolution
  • 2012
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 13:10, s. 12428-12460
  • Forskningsöversikt (refereegranskat)abstract
    • Enzymes are tremendously proficient catalysts, which can be used as extracellular catalysts for a whole host of processes, from chemical synthesis to the generation of novel biofuels. For them to be more amenable to the needs of biotechnology, however, it is often necessary to be able to manipulate their physico-chemical properties in an efficient and streamlined manner, and, ideally, to be able to train them to catalyze completely new reactions. Recent years have seen an explosion of interest in different approaches to achieve this, both in the laboratory, and in silico. There remains, however, a gap between current approaches to computational enzyme design, which have primarily focused on the early stages of the design process, and laboratory evolution, which is an extremely powerful tool for enzyme redesign, but will always be limited by the vastness of sequence space combined with the low frequency for desirable mutations. This review discusses different approaches towards computational enzyme design and demonstrates how combining newly developed screening approaches that can rapidly predict potential mutation “hotspots” with approaches that can quantitatively and reliably dissect the catalytic step can bridge the gap that currently exists between computational enzyme design and laboratory evolution studies.
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3.
  • Blom, Hans, et al. (författare)
  • Electrostatic Interactions of Fluorescent Molecules with Dielectric Interfaces Studied by Total Internal Reflection Fluorescence Correlation Spectroscopy
  • 2010
  • Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 11:2, s. 368-406
  • Tidskriftsartikel (refereegranskat)abstract
    • Electrostatic interactions between dielectric surfaces and different fluorophoresused in ultrasensitive fluorescence microscopy are investigated using objective-based TotalInternal Reflection Fluorescence Correlation Spectroscopy (TIR-FCS). The interfacialdynamics of cationic rhodamine 123 and rhodamine 6G, anionic/dianionic fluorescein,zwitterionic rhodamine 110 and neutral ATTO 488 are monitored at various ionic strengthsat physiological pH. As analyzed by means of the amplitude and time-evolution of theautocorrelation function, the fluorescent molecules experience electrostatic attraction orrepulsion at the glass surface depending on their charges. Influences of the electrostaticinteractions are also monitored through the triplet-state population and triplet relaxationtime, including the amount of detected fluorescence or the count-rate-per-moleculeparameter. These TIR-FCS results provide an increased understanding of how fluorophoresare influenced by the microenvironment of a glass surface, and show a promising approachfor characterizing electrostatic interactions at interfaces.
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4.
  • Fuvesi, J., et al. (författare)
  • Proteomic Analysis of Cerebrospinal Fluid in a Fulminant Case of Multiple Sclerosis
  • 2012
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 13:6, s. 7676-7693
  • Tidskriftsartikel (refereegranskat)abstract
    • Multiple Sclerosis (MS) is a chronic disease, but in rare fulminant cases rapid progression may lead to death shortly after diagnosis. Currently there is no diagnostic test to predict disease course. The aim of this study was to identify potential biomarkers/proteins related to rapid progression. We present the case history of a 15-year-old male MS patient. Cerebrospinal fluid (CSF) was taken at diagnosis and at the time of rapid progression leading to the patient's death. Using isobaric tag labeling and nanoflow liquid chromatography in conjunction with matrix assisted laser desorption/ionization time of flight tandem mass spectrometry we quantitatively analyzed the protein content of two CSF samples from the patient with fulminant MS as well as one relapsing-remitting (RR) MS patient and one control headache patient, whose CSF analysis was normal. Seventy-eight proteins were identified and seven proteins were found to be more abundant in both fulminant MS samples but not in the RR MS sample compared to the control. These proteins are involved in the immune response, blood coagulation, cell proliferation and cell adhesion. In conclusion, in this pilot study we were able to show differences in the CSF proteome of a rapidly progressing MS patient compared to a more typical clinical form of MS and a control subject.
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5.
  • Marcotuli, Ilaria, et al. (författare)
  • Non-Starch Polysaccharides in Durum Wheat : A Review
  • 2020
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 21:8, s. 2933-
  • Tidskriftsartikel (refereegranskat)abstract
    • Durum wheat is one of most important cereal crops that serves as a staple dietary component for humans and domestic animals. It provides antioxidants, proteins, minerals and dietary fibre, which have beneficial properties for humans, especially as related to the health of gut microbiota. Dietary fibre is defined as carbohydrate polymers that are non-digestible in the small intestine. However, this dietary component can be digested by microorganisms in the large intestine and imparts physiological benefits at daily intake levels of 30–35 g. Dietary fibre in cereal grains largely comprises cell wall polymers and includes insoluble (cellulose, part of the hemicellulose component and lignin) and soluble (arabinoxylans and (1,3;1,4)-β-glucans) fibre. More specifically, certain components provide immunomodulatory and cholesterol lowering activity, faecal bulking effects, enhanced absorption of certain minerals, prebiotic effects and, through these effects, reduce the risk of type II diabetes, cardiovascular disease and colorectal cancer. Thus, dietary fibre is attracting increasing interest from cereal processors, producers and consumers. Compared with other components of the durum wheat grain, fibre components have not been studied extensively. Here, we have summarised the current status of knowledge on the genetic control of arabinoxylan and (1,3;1,4)-β-glucan synthesis and accumulation in durum wheat grain. Indeed, the recent results obtained in durum wheat open the way for the improvement of these important cereal quality parameters.
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6.
  • Sommertune, Jens, et al. (författare)
  • Polymer/iron oxide nanoparticle composites—A straight forward and scalable synthesis approach
  • 2015
  • Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 16:8, s. 19752-19768
  • Tidskriftsartikel (refereegranskat)abstract
    • Magnetic nanoparticle systems can be divided into single-core nanoparticles (with only one magnetic core per particle) and magnetic multi-core nanoparticles (with several magnetic cores per particle). Here, we report multi-core nanoparticle synthesis based on a controlled precipitation process within a well-defined oil in water emulsion to trap the superparamagnetic iron oxide nanoparticles (SPION) in a range of polymer matrices of choice, such as poly(styrene), poly(lactid acid), poly(methyl methacrylate), and poly(caprolactone). Multi-core particles were obtained within the Z-average size range of 130 to 340 nm. With the aim to combine the fast room temperature magnetic relaxation of small individual cores with high magnetization of the ensemble of SPIONs, we used small (<10 nm) core nanoparticles. The performed synthesis is highly flexible with respect to the choice of polymer and SPION loading and gives rise to multi-core particles with interesting magnetic properties and magnetic resonance imaging (MRI) contrast efficacy.
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7.
  • Mohsenzadeh, Abas, et al. (författare)
  • The Effect of Carbon Monoxide Co-Adsorption on Ni-Catalysed Water Dissociation
  • 2013
  • Ingår i: International Journal of Molecular Sciences. - : M D P I AG. - 1661-6596 .- 1422-0067. ; 14:12, s. 23301-23314
  • Tidskriftsartikel (refereegranskat)abstract
    • The effect of carbon monoxide (CO) co-adsorption on the dissociation of water on the Ni(111) surface has been studied using density functional theory. The structures of the adsorbed water molecule and of the transition state are changed by the presence of the CO molecule. The water O–H bond that is closest to the CO is lengthened compared to the structure in the absence of the CO, and the breaking O–H bond in the transition state structure has a larger imaginary frequency in the presence of CO. In addition, the distances between the Ni surface and H2O reactant and OH and H products decrease in the presence of the CO. The changes in structures and vibrational frequencies lead to a reaction energy that is 0.17 eV less exothermic in the presence of the CO, and an activation barrier that is 0.12 eV larger in the presence of the CO. At 463 K the water dissociation rate constant is an order of magnitude smaller in the presence of the CO. This reveals that far fewer water molecules will dissociate in the presence of CO under reaction conditions that are typical for the water-gas-shift reaction.
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8.
  • Taherzadeh, M.J., et al. (författare)
  • Pretreatment of lignocellulosic wastes to improve ethanol and biogas production : A review
  • 2008
  • Ingår i: International Journal of Molecular Sciences. - : Molecular Diversity Preservation International (MDPI) AG.. - 1661-6596 .- 1422-0067. ; 9:9, s. 1621-1651
  • Tidskriftsartikel (refereegranskat)abstract
    • Lignocelluloses are often a major or sometimes the sole components of different waste streams from various industries, forestry, agriculture and municipalities. Hydrolysis of these materials is the first step for either digestion to biogas (methane) or fermentation to ethanol. However, enzymatic hydrolysis of lignocelluloses with no pretreatment is usually not so effective because of high stability of the materials to enzymatic or bacterial attacks. The present work is dedicated to reviewing the methods that have been studied for pretreatment of lignocellulosic wastes for conversion to ethanol or biogas. Effective parameters in pretreatment of lignocelluloses, such as crystallinity, accessible surface area, and protection by lignin and hemicellulose are described first. Then, several pretreatment methods are discussed and their effects on improvement in ethanol and/or biogas production are described. They include milling, irradiation, microwave, steam explosion, ammonia fiber explosion (AFEX), supercritical CO2 and its explosion, alkaline hydrolysis, liquid hot-water pretreatment, organosolv processes, wet oxidation, ozonolysis, dilute- and concentrated-acid hydrolyses, and biological pretreatments.
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9.
  • Fontes, Magnus (författare)
  • Optimal results for the nonhomogeneous initial-boundary value problem for the two-dimensional Navier-Stokes equations
  • 2010
  • Ingår i: Journal of Mathematical Fluid Mechanics. - : Springer Science and Business Media LLC. - 1422-6928 .- 1422-6952. ; 12, s. 412-434
  • Tidskriftsartikel (refereegranskat)abstract
    • In this work we study the fully nonhomogeneous initial boundary value problem for the two-dimensional time-dependent Navier–Stokes equations in a general open space domain in R2 with low regularity assumptions on the initial and the boundary value data. We show that the perturbed Navier–Stokes operator is a diffeomorphism from a suitable function space onto its own dual and as a corollary we get that the Navier–Stokes equations are uniquely solvable in these spaces and that the solution depends smoothly on all involved data. Our source data space and solution space are in complete natural duality and in this sense, without any smallness assumptions on the data, we solve the equations for data with optimally low regularity in both space and time.
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10.
  • Han, Yilin, et al. (författare)
  • Towards 3D Bioprinted Spinal Cord Organoids
  • 2022
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 23:10
  • Tidskriftsartikel (refereegranskat)abstract
    • Three-dimensional (3D) cultures, so-called organoids, have emerged as an attractive tool for disease modeling and therapeutic innovations. Here, we aim to determine if boundary cap neural crest stem cells (BC) can survive and differentiate in gelatin-based 3D bioprinted bioink scaffolds in order to establish an enabling technology for the fabrication of spinal cord organoids on a chip. BC previously demonstrated the ability to support survival and differentiation of co-implanted or co-cultured cells and supported motor neuron survival in excitotoxically challenged spinal cord slice cultures. We tested different combinations of bioink and cross-linked material, analyzed the survival of BC on the surface and inside the scaffolds, and then tested if human iPSC-derived neural cells (motor neuron precursors and astrocytes) can be printed with the same protocol, which was developed for BC. We showed that this protocol is applicable for human cells. Neural differentiation was more prominent in the peripheral compared to central parts of the printed construct, presumably because of easier access to differentiation-promoting factors in the medium. These findings show that the gelatin-based and enzymatically cross-linked hydrogel is a suitable bioink for building a multicellular, bioprinted spinal cord organoid, but that further measures are still required to achieve uniform neural differentiation.
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11.
  • Aaseth, J, et al. (författare)
  • Copper, Iron, Selenium and Lipo-Glycemic Dysmetabolism in Alzheimer's Disease
  • 2021
  • Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 22:17
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of the present review is to discuss traditional hypotheses on the etiopathogenesis of Alzheimer’s disease (AD), as well as the role of metabolic-syndrome-related mechanisms in AD development with a special focus on advanced glycation end-products (AGEs) and their role in metal-induced neurodegeneration in AD. Persistent hyperglycemia along with oxidative stress results in increased protein glycation and formation of AGEs. The latter were shown to possess a wide spectrum of neurotoxic effects including increased Aβ generation and aggregation. In addition, AGE binding to receptor for AGE (RAGE) induces a variety of pathways contributing to neuroinflammation. The existing data also demonstrate that AGE toxicity seems to mediate the involvement of copper (Cu) and potentially other metals in AD pathogenesis. Specifically, Cu promotes AGE formation, AGE-Aβ cross-linking and up-regulation of RAGE expression. Moreover, Aβ glycation was shown to increase prooxidant effects of Cu through Fenton chemistry. Given the role of AGE and RAGE, as well as metal toxicity in AD pathogenesis, it is proposed that metal chelation and/or incretins may slow down oxidative damage. In addition, selenium (Se) compounds seem to attenuate the intracellular toxicity of the deranged tau and Aβ, as well as inhibiting AGE accumulation and metal-induced neurotoxicity.
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12.
  • AbdelMageed, Manar, et al. (författare)
  • Clinical significance of stem cell biomarkers epcam, lgr5 and lgr4 mrna levels in lymph nodes of colon cancer patients
  • 2022
  • Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 23:1
  • Tidskriftsartikel (refereegranskat)abstract
    • The significance of cancer stem cells (CSCs) in initiation and progression of colon cancer (CC) has been established. In this study, we investigated the utility of measuring mRNA expression levels of CSC markers EpCAM, LGR5 and LGR4 for predicting survival outcome in surgically treated CC patients. Expression levels were determined in 5 CC cell lines, 66 primary CC tumors and 382 regional lymph nodes of 121 CC patients. Prognostic relevance was determined using Kaplan‐Meier survival and Cox regression analyses. CC patients with lymph nodes expressing high levels of EpCAM, LGR5 or LGR4 (higher than a clinical cutoff of 0.07, 0.06 and 2.558 mRNA cop-ies/18S rRNA unit, respectively) had a decreased mean survival time of 32 months for EpCAM and 42 months for both LGR5 and LGR4 at a 12‐year follow‐up (p = 0.022, p = 0.005 and p = 0.011, respec-tively). Additional patients at risk for recurrence were detected when LGR5 was combined with the biomarkers CXCL17 or CEA plus CXCL16. In conclusion, the study underscores LGR5 as a particularly useful prognostic biomarker and illustrates the strength of combining biomarkers detecting different subpopulations of cancer cells and/or cells in the tumor microenvironment for predicting recurrence.
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13.
  • AbdelMageed, Manar, et al. (författare)
  • The chemokine CXCL16 is a new biomarker for lymph node analysis of colon cancer outcome
  • 2019
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 20:22
  • Tidskriftsartikel (refereegranskat)abstract
    • Chemokines are important in the development and progression of tumors. We investigated the expression of CXCL14 and CXCL16 in colon cancer. Expression of mRNA was assessed in primary tumors and lymph nodes and CXCL16 mRNA levels were correlated to patient’s survival. Protein expression was investigated by two-color immunofluorescence and immunomorphometry. CXCL14 and CXCL16 mRNA levels and protein expression were significantly higher in colon cancer primary tumors compared to apparently normal colon tissue. Positive cells were tumor cells, as revealed by anti-CEA and anti-EpCAM staining. CXCL16, but not CXCL14, mRNA levels were significantly higher in hematoxylin and eosin positive (H&E(+)) compared to H&E(−) colon cancer lymph nodes or control nodes (P < 0.0001). CXCL16 mRNA was expressed in 5/5 colon cancer cell lines while CXCL14 was expressed significantly in only one. Kaplan-Meier analysis revealed that colon cancer patients with lymph nodes expressing high or very high levels (7.2 and 11.4 copies/18S rRNA unit, respectively) of CXCL16 mRNA had a decreased mean survival time of 30 and 46 months at the 12-year follow-up (P = 0.04, P = 0.005, respectively). In conclusion, high expression of CXCL16 mRNA in regional lymph nodes of colon cancer patients is a sign of a poor prognosis.
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14.
  • Abouhmad, Adel, et al. (författare)
  • Exploring the enzymatic and antibacterial activities of novel mycobacteriophage lysin b enzymes
  • 2020
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 21:9
  • Tidskriftsartikel (refereegranskat)abstract
    • Mycobacteriophages possess different sets of lytic enzymes for disruption of the complex cell envelope of the mycobacteria host cells and release of the viral progeny. Lysin B (LysB) enzymes are mycolylarabinogalactan esterases that cleave the ester bond between the arabinogalactan and mycolic acids in the mycolylarabinogalactan-peptidoglycan (mAGP) complex in the cell envelope of mycobacteria. In the present study, four LysB enzymes were produced recombinantly and characterized with respect to their enzymatic and antibacterial activities. Examination of the kinetic parameters for the hydrolysis of para-nitrophenyl ester substrates, shows LysB-His6 enzymes to be active against a range of substrates (C4-C16), with a catalytic preference towards p-nitrophenyl laurate (C12). With p-nitrophenyl butyrate as substrate, LysB-His6 enzymes showed highest activity at 37◦C. LysB-His6 enzymes also hydrolyzed different Tween substrates with highest activity against Tween 20 and 80. Metal ions like Ca2+ and Mn2+ enhanced the enzymatic activity of LysB-His6 enzymes, while transition metal ions like Zn2+ and Cu2+ inhibited the enzymatic activity. The mycolylarabinogalactan esterase activity of LysB-His6 enzymes against mAGP complex was confirmed by LC-MS. LysB-His6 enzymes showed marginal antibacterial activity when tested alone against Mycobacterium smegmatis, however a synergetic activity was noticed when combined with outer membrane permealizers. These results confirm that LysB enzymes are lipolytic enzymes with potential application as antimycobacterials.
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15.
  • Abreha, Kibrom Berhe, et al. (författare)
  • Article leaf apoplast of field-grown potato analyzed by quantitative proteomics and activity-based protein profiling
  • 2021
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 22:21
  • Tidskriftsartikel (refereegranskat)abstract
    • Multiple biotic and abiotic stresses challenge plants growing in agricultural fields. Most molecular studies have aimed to understand plant responses to challenges under controlled conditions. However, studies on field-grown plants are scarce, limiting application of the findings in agricultural conditions. In this study, we investigated the composition of apoplastic proteomes of potato cultivar Bintje grown under field conditions, i.e., two field sites in June–August across two years and fungicide treated and untreated, using quantitative proteomics, as well as its activity using activity-based protein profiling (ABPP). Samples were clustered and some proteins showed significant intensity and activity differences, based on their field site and sampling time (June–August), indicating differential regulation of certain proteins in response to environmental or developmental factors. Peroxidases, class II chitinases, pectinesterases, and osmotins were among the proteins more abundant later in the growing season (July–August) as compared to early in the season (June). We did not detect significant differences between fungicide Shirlan treated and untreated field samples in two growing seasons. Using ABPP, we showed differential activity of serine hydrolases and β-glycosidases under greenhouse and field conditions and across a growing season. Furthermore, the activity of serine hydrolases and β-glycosidases, including proteins related to biotic stress tolerance, decreased as the season progressed. The generated proteomics data would facilitate further studies aiming at understanding mechanisms of molecular plant physiology in agricultural fields and help applying effective strategies to mitigate biotic and abiotic stresses.
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16.
  • Acevedo, Nathalie, et al. (författare)
  • DNA Methylation Levels in Mononuclear Leukocytes from the Mother and Her Child Are Associated with IgE Sensitization to Allergens in Early Life
  • 2021
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 22:2
  • Tidskriftsartikel (refereegranskat)abstract
    • DNA methylation changes may predispose becoming IgE-sensitized to allergens. We analyzed whether DNA methylation in peripheral blood mononuclear cells (PBMC) is associated with IgE sensitization at 5 years of age (5Y). DNA methylation was measured in 288 PBMC samples from 74 mother/child pairs from the birth cohort ALADDIN (Assessment of Lifestyle and Allergic Disease During INfancy) using the HumanMethylation450BeadChip (Illumina). PBMCs were obtained from the mothers during pregnancy and from their children in cord blood, at 2 years and 5Y. DNA methylation levels at each time point were compared between children with and without IgE sensitization to allergens at 5Y. For replication, CpG sites associated with IgE sensitization in ALADDIN were evaluated in whole blood DNA of 256 children, 4 years old, from the BAMSE (Swedish abbreviation for Children, Allergy, Milieu, Stockholm, Epidemiology) cohort. We found 34 differentially methylated regions (DMRs) associated with IgE sensitization to airborne allergens and 38 DMRs associated with sensitization to food allergens in children at 5Y (Sidak p <= 0.05). Genes associated with airborne sensitization were enriched in the pathway of endocytosis, while genes associated with food sensitization were enriched in focal adhesion, the bacterial invasion of epithelial cells, and leukocyte migration. Furthermore, 25 DMRs in maternal PBMCs were associated with IgE sensitization to airborne allergens in their children at 5Y, which were functionally annotated to the mTOR (mammalian Target of Rapamycin) signaling pathway. This study supports that DNA methylation is associated with IgE sensitization early in life and revealed new candidate genes for atopy. Moreover, our study provides evidence that maternal DNA methylation levels are associated with IgE sensitization in the child supporting early in utero effects on atopy predisposition.
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17.
  • Acevedo, N, et al. (författare)
  • Histone Acetylation of Immune Regulatory Genes in Human Placenta in Association with Maternal Intake of Olive Oil and Fish Consumption
  • 2019
  • Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 20:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Maternal diet modifies epigenetic programming in offspring, a potentially critical factor in the immune dysregulation of modern societies. We previously found that prenatal fish oil supplementation affects neonatal T-cell histone acetylation of genes implicated in adaptive immunity including PRKCZ, IL13, and TBX21. In this study, we measured H3 and H4 histone acetylation levels by chromatin immunoprecipitation in 173 term placentas collected in the prospective birth cohort, ALADDIN, in which information on lifestyle and diet is thoroughly recorded. In anthroposophic families, regular olive oil usage during pregnancy was associated with increased H3 acetylation at FOXP3 (p = 0.004), IL10RA (p = 0.008), and IL7R (p = 0.007) promoters, which remained significant after adjustment by offspring gender. Furthermore, maternal fish consumption was associated with increased H4 acetylation at the CD14 gene in placentas of female offspring (p = 0.009). In conclusion, prenatal olive oil intake can affect placental histone acetylation in immune regulatory genes, confirming previously observed pro-acetylation effects of olive oil polyphenols. The association with fish consumption may implicate ω-3 polyunsaturated fatty acids present in fish oil. Altered histone acetylation in placentas from mothers who regularly include fish or olive oil in their diets could influence immune priming in the newborn.
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18.
  • Adler, Dana, et al. (författare)
  • Weak Electromagnetic Fields Accelerate Fusion of Myoblasts.
  • 2021
  • Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 22:9
  • Tidskriftsartikel (refereegranskat)abstract
    • Weak electromagnetic fields (WEF) alter Ca2+ handling in skeletal muscle myotubes. Owing to the involvement of Ca2+ in muscle development, we investigated whether WEF affects fusion of myoblasts in culture. Rat primary myoblast cultures were exposed to WEF (1.75 µT, 16 Hz) for up to six days. Under control conditions, cell fusion and creatine kinase (CK) activity increased in parallel and peaked at 4-6 days. WEF enhanced the extent of fusion after one and two days (by ~40%) vs. control, but not thereafter. Exposure to WEF also enhanced CK activity after two days (almost four-fold), but not afterwards. Incorporation of 3H-thymidine into DNA was enhanced by one-day exposure to WEF (~40%), indicating increased cell replication. Using the potentiometric fluorescent dye di-8-ANEPPS, we found that exposure of cells to 150 mM KCl resulted in depolarization of the cell membrane. However, prior exposure of cells to WEF for one day followed by addition of KCl resulted in hyperpolarization of the cell membrane. Acute exposure of cells to WEF also resulted in hyperpolarization of the cell membrane. Twenty-four hour incubation of myoblasts with gambogic acid, an inhibitor of the inward rectifying K+ channel 2.1 (Kir2.1), did not affect cell fusion, WEF-mediated acceleration of fusion or hyperpolarization. These data demonstrate that WEF accelerates fusion of myoblasts, resulting in myotube formation. The WEF effect is associated with hyperpolarization but WEF does not appear to mediate its effects on fusion by activating Kir2.1 channels.
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19.
  • Ahlstedt, Jonas, et al. (författare)
  • Human Anti-Oxidation Protein A1M-A Potential Kidney Protection Agent in Peptide Receptor Radionuclide Therapy.
  • 2015
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 16:12, s. 30309-30320
  • Forskningsöversikt (refereegranskat)abstract
    • Peptide receptor radionuclide therapy (PRRT) has been in clinical use for 15 years to treat metastatic neuroendocrine tumors. PRRT is limited by reabsorption and retention of the administered radiolabeled somatostatin analogues in the proximal tubule. Consequently, it is essential to develop and employ methods to protect the kidneys during PRRT. Today, infusion of positively charged amino acids is the standard method of kidney protection. Other methods, such as administration of amifostine, are still under evaluation and show promising results. α₁-microglobulin (A1M) is a reductase and radical scavenging protein ubiquitously present in plasma and extravascular tissue. Human A1M has antioxidation properties and has been shown to prevent radiation-induced in vitro cell damage and protect non-irradiated surrounding cells. It has recently been shown in mice that exogenously infused A1M and the somatostatin analogue octreotide are co-localized in proximal tubules of the kidney after intravenous infusion. In this review we describe the current situation of kidney protection during PRRT, discuss the necessity and implications of more precise dosimetry and present A1M as a new, potential candidate for renal protection during PRRT and related targeted radionuclide therapies.
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20.
  • Ahmed, Aisha S, et al. (författare)
  • NF-κB-Associated Pain-Related Neuropeptide Expression in Patients with Degenerative Disc Disease.
  • 2019
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 20:3
  • Tidskriftsartikel (refereegranskat)abstract
    • The role of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) has been highlighted in mechanisms underlying inflammatory and neuropathic pain processes. The present study was designed to investigate whether NF-κB signaling is associated with pain-related neuropeptide expression in patients with chronic back pain related to degenerative disc disease (DDD). Intervertebral disc (IVD) tissues were collected from forty DDD patients undergoing disc replacement or fusion surgery, and from eighteen postmortem (PM) control subjects. RELA, NFKB1, CGRP, TAC1, TRPV1, and MMP-3 gene expression were analyzed by RT-qPCR, while NF-κB subunit RelA and NF-κB1⁻DNA binding in nuclear extracts and calcitonin gene related peptide (CGRP), substance P (SP), and transient receptor potential, subfamily V, member 1 (TRPV1) protein levels in cytosolic extracts of tissues were assessed by enzyme-linked immunosorbent assay (ELISA). An upregulated NF-κB1⁻DNA binding, and higher CGRP and TRPV1 protein levels were observed in DDD patients compared to PM controls. In DDD patients, NF-κB1⁻DNA binding was positively correlated with nuclear RelA levels. Moreover, NF-κB1⁻DNA binding was positively associated with TRPV1 and MMP-3 gene and SP and TRPV1 protein expression in DDD patients. Our results indicate that the expression of SP and TRPV1 in IVD tissues was associated with NF-κB activation. Moreover, NF-κB may be involved in the generation or maintenance of peripheral pain mechanisms by the regulation of pain-related neuropeptide expression in DDD patients.
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21.
  • Akula, Srinivas, et al. (författare)
  • The Evolutionary History of the Chymase Locus -a Locus Encoding Several of the Major Hematopoietic Serine Proteases
  • 2021
  • Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 22:20
  • Forskningsöversikt (refereegranskat)abstract
    • Several hematopoietic cells of the immune system store large amounts of proteases in cytoplasmic granules. The absolute majority of these proteases belong to the large family of chymotrypsin-related serine proteases. The chymase locus is one of four loci encoding these granule-associated serine proteases in mammals. The chymase locus encodes only four genes in primates, (1) the gene for a mast-cell-specific chymotryptic enzyme, the chymase; (2) a T-cell-expressed asp-ase, granzyme B; (3) a neutrophil-expressed chymotryptic enzyme, cathepsin G; and (4) a T-cell-expressed chymotryptic enzyme named granzyme H. Interestingly, this locus has experienced a number of quite dramatic expansions during mammalian evolution. This is illustrated by the very large number of functional protease genes found in the chymase locus of mice (15 genes) and rats (18 genes). A separate expansion has also occurred in ruminants, where we find a new class of protease genes, the duodenases, which are expressed in the intestinal region. In contrast, the opossum has only two functional genes in this locus, the mast cell (MC) chymase and granzyme B. This low number of genes may be the result of an inversion, which may have hindered unequal crossing over, a mechanism which may have been a major factor in the expansion within the rodent lineage. The chymase locus can be traced back to early tetrapods as genes that cluster with the mammalian genes in phylogenetic trees can be found in frogs, alligators and turtles, but appear to have been lost in birds. We here present the collected data concerning the evolution of this rapidly evolving locus, and how these changes in gene numbers and specificities may have affected the immune functions in the various tetrapod species.
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22.
  • Alexandersson, Erik, et al. (författare)
  • Plant Resistance Inducers against Pathogens in Solanaceae Species-From Molecular Mechanisms to Field Application
  • 2016
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 17
  • Forskningsöversikt (refereegranskat)abstract
    • This review provides a current summary of plant resistance inducers (PRIs) that have been successfully used in the Solanaceae plant family to protect against pathogens by activating the plant's own defence. Solanaceous species include many important crops such as potato and tomato. We also present findings regarding the molecular processes after application of PRIs, even if the number of such studies still remains limited in this plant family. In general, there is a lack of patterns regarding the efficiency of induced resistance (IR) both between and within solanaceous species. In many cases, a hypersensitivity-like reaction needs to form in order for the PRI to be efficient. "-Omics" studies have already given insight in the complexity of responses, and can explain some of the differences seen in efficacy of PRIs between and within species as well as towards different pathogens. Finally, examples of field applications of PRIs for solanaceous crops are presented and discussed. We predict that PRIs will play a role in future plant protection strategies in Solanaceae crops if they are combined with other means of disease control in different spatial and temporal combinations.
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23.
  • Alexandru, O, et al. (författare)
  • Platelet-Derived Growth Factor Receptor and Ionizing Radiation in High Grade Glioma Cell Lines
  • 2019
  • Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 20:19
  • Tidskriftsartikel (refereegranskat)abstract
    • Treatment of high grade gliomas (HGGs) has remained elusive due to their high heterogeneity and aggressiveness. Surgery followed by radiotherapy represents the mainstay of treatment for HGG. However, the unfavorable location of the tumor that usually limits total resection and the resistance to radiation therapy are the major therapeutic problems. Chemotherapy with DNA alkylating agent temozolomide is also used to treat HGG, despite modest effects on survival. Disregulation of several growth factor receptors (GFRs) were detected in HGG and receptor amplification in glioblastoma has been suggested to be responsible for heterogeneity propagation through clonal evolution. Molecularly targeted agents inhibiting these membrane proteins have demonstrated significant cytotoxicity in several types of cancer cells when tested in preclinical models. Platelet-derived growth factor receptors (PDGFRs) and associated signaling were found to be implicated in gliomagenesis, moreover, HGG commonly display a Platelet-derived growth factor (PDGF) autocrine pathway that is not present in normal brain tissues. We have previously shown that both the susceptibility towards PDGFR and the impact of the PDGFR inactivation on the radiation response were different in different HGG cell lines. Therefore, we decided to extend our investigation, using two other HGG cell lines that express PDGFR at the cell surface. Here, we investigated the effect of PDGFR inhibition alone or in combination with gamma radiation in 11 and 15 HGG cell lines. Our results showed that while targeting the PDGFR represents a good means of treatment in HGG, the combination of receptor inhibition with gamma radiation did not result in any discernable difference compared to the single treatment. The PI3K/PTEN/Akt/mTOR and Ras/Raf/MEK/ERK pathways are the major signaling pathways emerging from the GFRs, including PDGFR. Decreased sensitivity to radiation-induced cell death are often associated with redundancy in these pro-survival signaling pathways. Here we found that Phosphoinositide 3-kinases (PI3K), Extracellular-signal-regulated kinase 1/2 (ERK1/2), or c-Jun N-terminal kinase 1/2 (JNK1/2) inactivation induced radiosensitivity in HGG cells.
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24.
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25.
  • Alizadeh, E, et al. (författare)
  • The Different Facades of Retinal and Choroidal Endothelial Cells in Response to Hypoxia
  • 2018
  • Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 19:12
  • Tidskriftsartikel (refereegranskat)abstract
    • Ocular angiogenic diseases, such as proliferative diabetic retinopathy and neovascular age-related macular degeneration, are associated with severe loss of vision. These pathologies originate from different vascular beds, retinal and choroidal microvasculatures, respectively. The activation of endothelial cells (EC) plays pivotal roles in angiogenesis, often triggered by oxygen deficiency. Hypoxia-inducible factors in ECs mediate the transcription of multiple angiogenic genes, including the canonical vascular endothelial growth factors. ECs show notable heterogeneity in function, structure, and disease, therefore the understanding of retinal/choroidal ECs (REC; CEC) biochemical and molecular responses to hypoxia may offer key insights into tissue-specific vascular targeting treatments. The aim of this review is to discuss the differences spanning between REC and CEC, with focus on their response to hypoxia, which could provide innovative and sustainable strategies for site specific targeting of ocular neovascularization.
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26.
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27.
  • Alkhalili, Rawana N., et al. (författare)
  • Antimicrobial protein candidates from the thermophilic Geobacillus sp. Strain ZGt-1 : Production, proteomics, and bioinformatics analysis
  • 2016
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 17:8
  • Tidskriftsartikel (refereegranskat)abstract
    • A thermophilic bacterial strain, Geobacillus sp. ZGt-1, isolated from Zara hot spring in Jordan, was capable of inhibiting the growth of the thermophilic G. stearothermophilus and the mesophilic Bacillus subtilis and Salmonella typhimurium on a solid cultivation medium. Antibacterial activity was not observed when ZGt-1 was cultivated in a liquid medium; however, immobilization of the cells in agar beads that were subjected to sequential batch cultivation in the liquid medium at 60 °C showed increasing antibacterial activity up to 14 cycles. The antibacterial activity was lost on protease treatment of the culture supernatant. Concentration of the protein fraction by ammonium sulphate precipitation followed by denaturing polyacrylamide gel electrophoresis separation and analysis of the gel for antibacterial activity against G. stearothermophilus showed a distinct inhibition zone in 15-20 kDa range, suggesting that the active molecule(s) are resistant to denaturation by SDS. Mass spectrometric analysis of the protein bands around the active region resulted in identification of 22 proteins with molecular weight in the range of interest, three of which were new and are here proposed as potential antimicrobial protein candidates by in silico analysis of their amino acid sequences. Mass spectrometric analysis also indicated the presence of partial sequences of antimicrobial enzymes, amidase, and DD-carboxypeptidase.
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28.
  • Alkhalili, Rawana N., et al. (författare)
  • Identification of putative novel class-I lanthipeptides in firmicutes : A combinatorial in silico analysis approach performed on genome sequenced bacteria and a close inspection of Z-geobacillin lanthipeptide biosynthesis gene cluster of the Thermophilic geobacillus sp. strain ZGt-1
  • 2018
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 19:9
  • Tidskriftsartikel (refereegranskat)abstract
    • Lanthipeptides are ribosomally synthesized and post-translationally modified polycyclic peptides. Lanthipeptides that have antimicrobial activity are known as lantibiotics. Accordingly, the discovery of novel lantibiotics constitutes a possible solution for the problem of antibiotic resistance. We utilized the publicly available genome sequences and the bioinformatic tools tailored for the detection of lanthipeptides. We designed our strategy for screening of 252 firmicute genomes and detecting class-I lanthipeptide-coding gene clusters. The designed strategy resulted in identifying 69 class-I lanthipeptide sequences, of which more than 10% were putative novel. The identified putative novel lanthipeptides have not been annotated on the original or the RefSeq genomes, or have been annotated merely as coding for hypothetical proteins. Additionally, we identified bacterial strains that have not been previously recognized as lanthipeptide-producers. Moreover, we suggest corrections for certain firmicute genome annotations, and recommend lanthipeptide records for enriching the bacteriocin genome mining tool (BAGEL) databases. Furthermore, we propose Z-geobacillin, a putative class-I lanthipeptide coded on the genome of the thermophilic strain Geobacillus sp. ZGt-1. We provide lists of putative novel lanthipeptide sequences and of the previously unrecognized lanthipeptide-producing bacterial strains, so they can be prioritized for experimental investigation. Our results are expected to benefit researchers interested in the in vitro production of lanthipeptides.
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29.
  • Almstrand, Robert, et al. (författare)
  • Three-dimensional stratification of bacterial biofilm populations in a moving bed biofilm reactor for nitritation-anammox.
  • 2014
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 15:2, s. 2191-206
  • Tidskriftsartikel (refereegranskat)abstract
    • Moving bed biofilm reactors (MBBRs) are increasingly used for nitrogen removal with nitritation-anaerobic ammonium oxidation (anammox) processes in wastewater treatment. Carriers provide protected surfaces where ammonia oxidizing bacteria (AOB) and anammox bacteria form complex biofilms. However, the knowledge about the organization of microbial communities in MBBR biofilms is sparse. We used new cryosectioning and imaging methods for fluorescence in situ hybridization (FISH) to study the structure of biofilms retrieved from carriers in a nitritation-anammox MBBR. The dimensions of the carrier compartments and the biofilm cryosections after FISH showed good correlation, indicating little disturbance of biofilm samples by the treatment. FISH showed that Nitrosomonas europaea/eutropha-related cells dominated the AOB and Candidatus Brocadia fulgida-related cells dominated the anammox guild. New carriers were initially colonized by AOB, followed by anammox bacteria proliferating in the deeper biofilm layers, probably in anaerobic microhabitats created by AOB activity. Mature biofilms showed a pronounced three-dimensional stratification where AOB dominated closer to the biofilm-water interface, whereas anammox were dominant deeper into the carrier space and towards the walls. Our results suggest that current mathematical models may be oversimplifying these three-dimensional systems and unless the multidimensionality of these systems is considered, models may result in suboptimal design of MBBR carriers.
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30.
  • Alvarado, Gerardo, et al. (författare)
  • Heme-induced oxidation of cysteine groups of myofilament proteins leads to contractile dysfunction of permeabilized human skeletal muscle fibres
  • 2020
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 21:21
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Heme released from red blood cells targets a number of cell components including the cytoskeleton. The purpose of the present study was to determine the impact of free heme (20–300 µM) on human skeletal muscle fibres made available during orthopedic surgery. Methods: Isometric force production and oxidative protein modifications were monitored in permeabilized skeletal muscle fibre segments. Results: A single heme exposure (20 µM) to muscle fibres decreased Ca2+-activated maximal (active) force (Fo) by about 50% and evoked an approximately 3-fold increase in Ca2+-independent (passive) force (Fpassive). Oxidation of sulfhydryl (SH) groups was detected in structural proteins (e.g., nebulin, α-actinin, meromyosin 2) and in contractile proteins (e.g., myosin heavy chain and myosin-binding protein C) as well as in titin in the presence of 300 µM heme. This SH oxidation was not reversed by dithiothreitol (50 mM). Sulfenic acid (SOH) formation was also detected in the structural proteins (nebulin, α-actinin, meromyosin). Heme effects on SH oxidation and SOH formation were prevented by hemopexin (Hpx) and α1-microglobulin (A1M). Conclusions: These data suggest that free heme has a significant impact on human skeletal muscle fibres, whereby oxidative alterations in structural and contractile proteins limit contractile function. This may explain and or contribute to the weakness and increase of skeletal muscle stiffness in chronic heart failure, rhabdomyolysis, and other hemolytic diseases. Therefore, therapeutic use of Hpx and A1M supplementation might be effective in preventing heme-induced skeletal muscle alterations.
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31.
  • Alvarez-Rodriguez, Manuel, et al. (författare)
  • Does the Act of Copulation per se, without Considering Seminal Deposition, Change the Expression of Genes in the Porcine Female Genital Tract?
  • 2020
  • Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 21:15
  • Tidskriftsartikel (refereegranskat)abstract
    • Semen-through its specific sperm and seminal plasma (SP) constituents-induces changes of gene expression in the internal genital tract of pigs, particularly in the functional sperm reservoir at the utero-tubal junction (UTJ). Although seminal effects are similarly elicited by artificial insemination (AI), major changes in gene expression are registered after natural mating, a fact suggesting the act of copulation induces per se changes in genes that AI does not affect. The present study explored which pathways were solely influenced by copulation, affecting the differential expression of genes (DEGs) of the pre/peri-ovulatory genital tract (cervix, distal uterus, proximal uterus and UTJ) of estrus sows, 24 h after various procedures were performed to compare natural mating with AI of semen (control 1), sperm-free SP harvested from the sperm-peak fraction (control 2), sperm-free SP harvested from the whole ejaculate (control 3) or saline-extender BTS (control 4), using a microarray chip (GeneChip(R)porcine gene 1.0 st array). Genes related to neuroendocrine responses (ADRA1,ADRA2,GABRB2,CACNB2), smooth muscle contractility (WNT7A), angiogenesis and vascular remodeling (poFUT1,NTN4) were, among others, overrepresented with distal and proximal uterine segments exhibiting the highest number of DEGs. The findings provide novel evidence that relevant transcriptomic changes in the porcine female reproductive tract occur in direct response to the specific act of copulation, being semen-independent.
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32.
  • Alvarez-Rodriguez, Manuel, 1983-, et al. (författare)
  • Expression of Immune Regulatory Genes in the Porcine Internal Genital Tract Is Differentially Triggered by Spermatozoa and Seminal Plasma
  • 2019
  • Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 20:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Mating or cervical deposition of spermatozoa or seminal plasma (SP) modifies the expression of genes affecting local immune defense processes at the oviductal sperm reservoir in animals with internal fertilization, frequently by down-regulation. Such responses may occur alongside sperm transport to or even beyond the reservoir. Here, immune-related gene expression was explored with cDNA microarrays on porcine cervix-to-infundibulum tissues, pre-/peri-ovulation. Samples were collected 24 h post-mating or cervical deposition of sperm-peak spermatozoa or SP (from the sperm-peak fraction or the whole ejaculate). All treatments of this interventional study affected gene expression. The concerted action of spermatozoa and SP down-regulated chemokine and cytokine (P00031), interferon-gamma signaling (P00035), and JAK/STAT (P00038) pathways in segments up to the sperm reservoir (utero-tubal junction (UTJ)/isthmus). Spermatozoa in the vanguard sperm-peak fraction (P1-AI), uniquely displayed an up-regulatory effect on these pathways in the ampulla and infundibulum. Sperm-free SP, on the other hand, did not lead to major effects on gene expression, despite the clinical notion that SP mitigates reactivity by the female immune system after mating or artificial insemination.
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33.
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34.
  • Alvarez-Rodriguez, Manuel, et al. (författare)
  • The Transcriptome of Pig Spermatozoa, and Its Role in Fertility
  • 2020
  • Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 21:5
  • Tidskriftsartikel (refereegranskat)abstract
    • In the study presented here we identified transcriptomic markers for fertility in the cargo of pig ejaculated spermatozoa using porcine-specific micro-arrays (GeneChip((R)) miRNA 4.0 and GeneChip((R)) Porcine Gene 1.0 ST). We report (i) the relative abundance of the ssc-miR-1285, miR-16, miR-4332, miR-92a, miR-671-5p, miR-4334-5p, miR-425-5p, miR-191, miR-92b-5p and miR-15b miRNAs, and (ii) the presence of 347 up-regulated and 174 down-regulated RNA transcripts in high-fertility breeding boars, based on differences of farrowing rate (FS) and litter size (LS), relative to low-fertility boars in the (Artificial Insemination) AI program. An overrepresentation analysis of the protein class (PANTHER) identified significant fold-increases for C-C chemokine binding (GO:0019957): CCR7, which activates B- and T-lymphocytes, 8-fold increase), XCR1 and CXCR4 (with ubiquitin as a natural ligand, 1.24-fold increase), cytokine receptor activity (GO:0005126): IL23R receptor of the IL23 protein, associated to JAK2 and STAT3, 3.4-fold increase), the TGF-receptor (PC00035) genes ACVR1C and ACVR2B (12-fold increase). Moreover, two micro-RNAs (miR-221 and mir-621) were down- and up-regulated, respectively, in high-fertility males. In conclusion, boars with different fertility performance possess a wide variety of differentially expressed RNA present in spermatozoa that would be attractive targets as non-invasive molecular markers for predicting fertility.
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35.
  • Ameer, SS, et al. (författare)
  • Epigenetics and Heart Failure
  • 2020
  • Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 21:23
  • Tidskriftsartikel (refereegranskat)abstract
    • Epigenetics refers to changes in phenotypes without changes in genotypes. These changes take place in a number of ways, including via genomic DNA methylation, DNA interacting proteins, and microRNAs. The epigenome is the second dimension of the genome and it contains key information that is specific to every type of cell. Epigenetics is essential for many fundamental processes in biology, but its importance in the development and progression of heart failure, which is one of the major causes of morbidity and mortality worldwide, remains unclear. Our understanding of the underlying molecular mechanisms is incomplete. While epigenetics is one of the most innovative research areas in modern biology and medicine, compounds that directly target the epigenome, such as epidrugs, have not been well translated into therapies. This paper focuses on epigenetics in terms of genomic DNA methylation, such as 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) modifications. These appear to be more dynamic than previously anticipated and may underlie a wide variety of conditions, including heart failure. We also outline possible new strategies for the development of novel therapies.
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36.
  • Amirkavei, M, et al. (författare)
  • Induction of Heat Shock Protein 70 in Mouse RPE as an In Vivo Model of Transpupillary Thermal Stimulation
  • 2020
  • Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 21:6
  • Tidskriftsartikel (refereegranskat)abstract
    • The induction of heat shock response in the macula has been proposed as a useful therapeutic strategy for retinal neurodegenerative diseases by promoting proteostasis and enhancing protective chaperone mechanisms. We applied transpupillary 1064 nm long-duration laser heating to the mouse (C57Bl/6J) fundus to examine the heat shock response in vivo. The intensity and spatial distribution of heat shock protein (HSP) 70 expression along with the concomitant probability for damage were measured 24 h after laser irradiation in the mouse retinal pigment epithelium (RPE) as a function of laser power. Our results show that the range of heating powers for producing heat shock response while avoiding damage in the mouse RPE is narrow. At powers of 64 and 70 mW, HSP70 immunostaining indicates 90 and 100% probability for clearly elevated HSP expression while the corresponding probability for damage is 20 and 33%, respectively. Tunel staining identified the apoptotic regions, and the estimated 50% damaging threshold probability for the heating (ED50) was ~72 mW. The staining with Bestrophin1 (BEST1) demonstrated RPE cell atrophy with the most intense powers. Consequently, fundus heating with a long-duration laser provides an approachable method to develop heat shock-based therapies for the RPE of retinal disease model mice.
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37.
  • Ammendola, M., et al. (författare)
  • Mast Cells Density Positive to Tryptase Correlate with Microvascular Density in both Primary Gastric Cancer Tissue and Loco-Regional Lymph Node Metastases from Patients That Have Undergone Radical Surgery
  • 2016
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 17:11
  • Tidskriftsartikel (refereegranskat)abstract
    • Mast Cells (MCs) play a role in immune responses and more recently MCs have been involved in tumoral angiogenesis. In particular MCs can release tryptase, a potent in vivo and in vitro pro-angiogenic factor via proteinase-activated receptor-2 (PAR-2) activation and mitogen-activated protein kinase (MAPK) phosphorylation. MCs can release tryptase following c-Kit receptor activation. Nevertheless, no data are available concerning the relationship among MCs Density Positive to Tryptase (MCDPT) and Microvascular Density (MVD) in both primary gastric cancer tissue and loco-regional lymph node metastases. A series of 75 GC patients with stage T2-3N2-3M0 (by AJCC for Gastric Cancer Seventh Edition) undergone to radical surgery were selected for the study. MCDPT and MVD were evaluated by immunohistochemistry and by image analysis system and results were correlated each to other in primary tumor tissue and in metastatic lymph nodes harvested. Furthermore, tissue parameters were correlated with important clinico-pathological features. A significant correlation between MCDPT and MVD was found in primary gastric cancer tissue and lymph node metastases. Pearson t-test analysis (r ranged from 0.74 to 0.79; p-value ranged from 0.001 to 0.003). These preliminary data suggest that MCDPT play a role in angiogenesis in both primary tumor and in lymph node metastases from GC. We suggest that MCs and tryptase could be further evaluated as novel targets for anti-angiogenic therapies.
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38.
  • Anastacio, A, et al. (författare)
  • Ovarian Follicles Rescued 3 Days after Cyclophosphamide Treatment in Adolescent Mice: An Experimental Study Aiming at Maximizing Methods for Fertility Preservation through In Vitro Follicle Culture
  • 2019
  • Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 20:24
  • Tidskriftsartikel (refereegranskat)abstract
    • There is currently a lack of knowledge about the feasibility of performing procedures for fertility preservation after chemotherapy treatment has been initiated. In this experimental controlled study using adolescent mice, we aimed to investigate if the chance of rescuing and growing in vitro secondary follicles (SeF) would be affected three days after a single injection of cyclophosphamide (CPA). The main outcomes included were: (1) The number of SeF with good morphologic quality obtained per ovary 3 days after CPA injection, (2) SeF development in culture, (3) small follicle density (SFD) on histology, and (4) apoptosis markers, including terminal deoxynucleotidyl transferase dUTP nick end-labelling (TUNEL), mRNA expression, and distribution of p 53 upregulated modulator of apoptosis (Puma) and phosphatase and tensin homolog (Pten). We found a 60% reduction of SeF obtained per ovary in all CPA-treated groups vs. controls. However, in vitro survival rates at culture day 12 and antrum formation were similar among all groups. On histology, SFD was only significantly reduced in the high CPA dose group. Apoptotic cells were mainly found in large growing follicles of CPA groups. Our study indicates the feasibility of SeF isolation and in vitro follicle culture 3 days following CPA treatment and a still preserved SFD, particularly following a low-dose CPA treatment.
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39.
  • Andersson, Daniel, 1979, et al. (författare)
  • Preamplification with dUTP and cod UNG enables elimination of contaminating amplicons
  • 2018
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 19:10
  • Tidskriftsartikel (refereegranskat)abstract
    • Analyzing rare DNA and RNA molecules in limited sample sizes, such as liquid biopsies and single cells, often requires preamplification, which makes downstream analyses particularly sensitive to polymerase chain reaction (PCR) generated contamination. Herein, we assessed the feasibility of performing Cod uracil-DNA N-glycosylase (Cod UNG) treatment in combination with targeted preamplification, using deoxyuridine triphosphate (dUTP) to eliminate carry-over DNA. Cod UNG can be completely and irreversibly heat inactivated, a prerequisite in preamplification methods, where any loss of amplicons is detrimental to subsequent quantification. Using 96 target assays and quantitative real-time PCR, we show that replacement of deoxythymidine triphosphate (dTTP) with dUTP in the preamplification reaction mix results in comparable dynamic range, reproducibility, and sensitivity. Moreover, Cod UNG essentially removes all uracil-containing template of most assays, regardless of initial concentration, without affecting downstream analyses. Finally, we demonstrate that the use of Cod UNG and dUTP in targeted preamplification can easily be included in the workflow for single-cell gene expression profiling. In summary, Cod UNG treatment in combination with targeted preamplification using dUTP provides a simple and efficient solution to eliminate carry-over contamination and the generation of false positives and inaccurate quantification.
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40.
  • Andersson, Madelene, et al. (författare)
  • Development of an experimental ex vivo wound model to evaluate antimicrobial efficacy of topical formulations
  • 2021
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 22:9
  • Tidskriftsartikel (refereegranskat)abstract
    • Wound infections are considered a major cause for wound-associated morbidity. There is a high demand for alternative, robust, and affordable methods that can provide relatable and repro-ducible results when testing topical treatments, both in research and in the pharmaceutical industry. Here we present an ex vivo wound infection model using porcine skin and a burn wounding method, allowing for the efficacy evaluation of topical antimicrobial formulations. Utilizing this model, we demonstrate the potential of topical treatments after infecting the wounds with clinically significant bacteria, P. aeruginosa and S. aureus. We show that the method is compatible with several analytical tools used to analyze infection and antimicrobial effects. Both bacterial strains success-fully infected the wound surface, as well as deeper regions of the tissue. Quantification of viable bacteria on the wound surface and in the tissue, longitudinal measurements of bioluminescence, fluorescence microscopy, and scanning electron microscopy were used to confirm the effects of an-tibacterial treatments. Furthermore, we show that biofilms are formed on the wound surface, indi-cating that the demonstrated method mirrors typical in vivo infections.
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41.
  • Andersson, Marlene, et al. (författare)
  • Silk Spinning in Silkworms and Spiders
  • 2016
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 17
  • Forskningsöversikt (refereegranskat)abstract
    • Spiders and silkworms spin silks that outcompete the toughness of all natural and manmade fibers. Herein, we compare and contrast the spinning of silk in silkworms and spiders, with the aim of identifying features that are important for fiber formation. Although spiders and silkworms are very distantly related, some features of spinning silk seem to be universal. Both spiders and silkworms produce large silk proteins that are highly repetitive and extremely soluble at high pH, likely due to the globular terminal domains that flank an intermediate repetitive region. The silk proteins are produced and stored at a very high concentration in glands, and then transported along a narrowing tube in which they change conformation in response primarily to a pH gradient generated by carbonic anhydrase and proton pumps, as well as to ions and shear forces. The silk proteins thereby convert from random coil and alpha helical soluble conformations to beta sheet fibers. We suggest that factors that need to be optimized for successful production of artificial silk proteins capable of forming tough fibers include protein solubility, pH sensitivity, and preservation of natively folded proteins throughout the purification and initial spinning processes.
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42.
  • Andersson, Richard L., et al. (författare)
  • Antibacterial Properties of Tough and Strong Electrospun PMMA/PEO Fiber Mats Filled with Lanasol-A Naturally Occurring Brominated Substance
  • 2014
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 15:9, s. 15912-15923
  • Tidskriftsartikel (refereegranskat)abstract
    • A new type of antimicrobial, biocompatible and toughness enhanced ultra-thin fiber mats for biomedical applications is presented. The tough and porous fiber mats were obtained by electrospinning solution-blended poly (methyl methacrylate) (PMMA) and polyethylene oxide (PEO), filled with up to 25 wt % of Lanasol-a naturally occurring brominated cyclic compound that can be extracted from red sea algae. Antibacterial effectiveness was tested following the industrial Standard JIS L 1902 and under agitated medium (ASTM E2149). Even at the lowest concentrations of Lanasol, 4 wt %, a significant bactericidal effect was seen with a 4-log (99.99%) reduction in bacterial viability against S. aureus, which is one of the leading causes of hospital-acquired (nosocomial) infections in the world. The mechanical fiber toughness was insignificantly altered up to the maximum Lanasol concentration tested, and was for all fiber mats orders of magnitudes higher than electrospun fibers based on solely PMMA. This antimicrobial fiber system, relying on a dissolved antimicrobial agent (demonstrated by X-ray diffraction and Infrared (IR)-spectroscopy) rather than a dispersed and "mixed-in" solid antibacterial particle phase, presents a new concept which opens the door to tougher, stronger and more ductile antimicrobial fibers.
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43.
  • Andjus, Pavle, et al. (författare)
  • Extracellular Vesicles as Innovative Tool for Diagnosis, Regeneration and Protection against Neurological Damage
  • 2020
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 21:18
  • Forskningsöversikt (refereegranskat)abstract
    • Extracellular vesicles (EVs) have recently attracted a great deal of interest as they may represent a new biosignaling paradigm. According to the mode of biogenesis, size and composition, two broad categories of EVs have been described, exosomes and microvesicles. EVs have been shown to carry cargoes of signaling proteins, RNA species, DNA and lipids. Once released, their content is selectively taken up by near or distant target cells, influencing their behavior. Exosomes are involved in cell-cell communication in a wide range of embryonic developmental processes and in fetal-maternal communication. In the present review, an outline of the role of EVs in neural development, regeneration and diseases is presented. EVs can act as regulators of normal homeostasis, but they can also promote either neuroinflammation/degeneration or tissue repair in pathological conditions, depending on their content. Since EV molecular cargo constitutes a representation of the origin cell status, EVs can be exploited in the diagnosis of several diseases. Due to their capability to cross the blood-brain barrier (BBB), EVs not only have been suggested for the diagnosis of central nervous system disorders by means of minimally invasive procedures, i.e., "liquid biopsies", but they are also considered attractive tools for targeted drug delivery across the BBB. From the therapeutic perspective, mesenchymal stem cells (MSCs) represent one of the most promising sources of EVs. In particular, the neuroprotective properties of MSCs derived from the dental pulp are here discussed.
  •  
44.
  • Andreasson, M, et al. (författare)
  • MCEE Mutations in an Adult Patient with Parkinson's Disease, Dementia, Stroke and Elevated Levels of Methylmalonic Acid
  • 2019
  • Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 20:11
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Methylmalonic aciduria (MMA-uria) is seen in several inborn errors of metabolism (IEM) affecting intracellular cobalamin pathways. Methylmalonyl-CoA epimerase (MCE) is an enzyme involved in the mitochondrial cobalamin-dependent pathway generating succinyl-CoA. Homozygous mutations in the corresponding MCEE gene have been shown in children to cause MCE deficiency with isolated MMA-uria and a variable clinical phenotype. We describe a 78-year-old man with Parkinson’s disease, dementia and stroke in whom elevated serum levels of methylmalonic acid had been evident for many years. Metabolic work-up revealed intermittent MMA-uria and increased plasma levels of propionyl-carnitine not responsive to treatment with high-dose hydroxycobalamin. Whole genome sequencing was performed, with data analysis targeted towards genes known to cause IEM. Compound heterozygous mutations were identified in the MCEE gene, c.139C>T (p.Arg47X) and c.419delA (p.Lys140fs), of which the latter is novel. To our knowledge, this is the first report of an adult patient with MCEE mutations and MMA-uria, thus adding novel data to the possible phenotypical spectrum of MCE deficiency. Although clinical implications are uncertain, it can be speculated whether intermittent hyperammonemia during episodes of metabolic stress could have precipitated the patient’s ongoing neurodegeneration attributed to Parkinson’s disease.
  •  
45.
  • Anerillas, Luis Oliveros, et al. (författare)
  • Three-dimensional osteogenic differentiation of bone marrow mesenchymal stem cells promotes matrix metallopeptidase 13 (Mmp13) expression in type i collagen hydrogels
  • 2021
  • Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 22:24
  • Tidskriftsartikel (refereegranskat)abstract
    • Autologous bone transplantation is the principal method for reconstruction of large bone defects. This technique has limitations, such as donor site availability, amount of bone needed and morbidity. An alternative to this technique is tissue engineering with bone marrow-derived mesenchymal stem cells (BMSCs). In this study, our aim was to elucidate the benefits of culturing BMSCs in 3D compared with the traditional 2D culture. In an initial screening, we combined BMSCs with four different biogels: unmodified type I collagen (Col I), type I collagen methacrylate (ColMa), an alginate and cellulose-based bioink (CELLINK) and a gelatin-based bioink containing xanthan gum (GelXA-bone). Col I was the best for structural integrity and maintenance of cell morphology. Osteogenic, adipogenic, and chondrogenic differentiations of the BMSCs in 2D versus 3D type I collagen gels were investigated. While the traditional pellet culture for chondrogenesis was superior to our tested 3D culture, Col I hydrogels (i.e., 3D) favored adipogenic and osteogenic differentiation. Further focus of this study on osteogenesis were conducted by comparing 2D and 3D differentiated BMSCs with Osteoimage® (stains hydroxyapatite), von Kossa (stains anionic portion of phosphates, carbonates, and other salts) and Alizarin Red (stains Ca2+ deposits). Multivariate gene analysis with various covariates showed low variability among donors, successful osteogenic differentiation, and the identification of one gene (matrix metallopeptidase 13, MMP13) significantly differentially expressed in 2D vs. 3D cultures. MMP13 protein expression was confirmed with immunohistochemistry. In conclusion, this study shows evidence for the suitability of type I collagen gels for 3D osteogenic differentiation of BMSCs, which might improve the production of tissue-engineered constructs for treatment of bone defects.
  •  
46.
  • Ankarloo, Jonas, et al. (författare)
  • Escherichia coli mar and acrAB Mutants Display No Tolerance to Simple Alcohols
  • 2010
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 11:4, s. 1403-1412
  • Tidskriftsartikel (refereegranskat)abstract
    • The inducible Mar phenotype of Escherichia coli is associated with increased tolerance to multiple hydrophobic antibiotics as well as some highly hydrophobic organic solvents such as cyclohexane, mediated mainly through the AcrAB/TolC efflux system. The influence of water miscible alcohols ethanol and 1-propanol on a Mar constitutive mutant and a mar deletion mutant of E. coli K-12, as well as the corresponding strains carrying the additional acrAB deletion, was investigated. In contrast to hydrophobic solvents, all strains were killed in exponential phase by 1-propanol and ethanol at rates comparable to the parent strain. Thus, the Mar phenotype does not protect E. coli from killing by these more polar solvents. Surprisingly, AcrAB does not contribute to an increased alcohol tolerance. In addition, sodium salicylate, at concentrations known to induce the mar operon, was unable to increase 1-propanol or ethanol tolerance. Rather, the toxicity of both solvents was increased in the presence of sodium salicylate. Collectively, the results imply that the resilience of E. coli to water miscible alcohols, in contrast to more hydrophobic solvents, does not depend upon the AcrAB/TolC efflux system, and suggests a lower limit for substrate molecular size and functionality. Implications for the application of microbiological systems in environments containing high contents of water miscible organic solvents, e. g., phage display screening, are discussed.
  •  
47.
  • Arabuli, Lili, et al. (författare)
  • Co-aggregation of S100A9 with DOPA and cyclen-based compounds manifested in amyloid fibril thickening without altering rates of self-assembly
  • 2021
  • Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 22:16
  • Tidskriftsartikel (refereegranskat)abstract
    • The amyloid cascade is central for the neurodegeneration disease pathology, including Alzheimer’s and Parkinson’s, and remains the focus of much current research. S100A9 protein drives the amyloid-neuroinflammatory cascade in these diseases. DOPA and cyclen-based compounds were used as amyloid modifiers and inhibitors previously, and DOPA is also used as a precursor of dopamine in Parkinson’s treatment. Here, by using fluorescence titration experiments we showed that five selected ligands: DOPA-D-H-DOPA, DOPA-H-H-DOPA, DOPA-D-H, DOPA-cyclen, and H-E-cyclen, bind to S100A9 with apparent Kd in the sub-micromolar range. Ligand docking and molecular dynamic simulation showed that all compounds bind to S100A9 in more than one binding site and with different ligand mobility and H-bonds involved in each site, which all together is consistent with the apparent binding determined in fluorescence experiments. By using amyloid kinetic analysis, monitored by thioflavin-T fluorescence, and AFM imaging, we found that S100A9 co-aggregation with these compounds does not hinder amyloid formation but leads to morphological changes in the amyloid fibrils, manifested in fibril thickening. Thicker fibrils were not observed upon fibrillation of S100A9 alone and may influence the amyloid tissue propagation and modulate S100A9 amyloid assembly as part of the amyloid-neuroinflammatory cascade in neurodegenerative diseases.
  •  
48.
  • Ardalan, Maryam, 1979, et al. (författare)
  • Sex-Dependent Effects of Perinatal Inflammation on the Brain: Implication for Neuro-Psychiatric Disorders
  • 2019
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 20:9
  • Tidskriftsartikel (refereegranskat)abstract
    • Individuals born preterm have higher rates of neurodevelopmental disorders such as schizophrenia, autistic spectrum, and attention deficit/hyperactivity disorders. These conditions are often sexually dimorphic and with different developmental trajectories. The etiology is likely multifactorial, however, infections both during pregnancy and in childhood have emerged as important risk factors. The association between sex- and age-dependent vulnerability to neuropsychiatric disorders has been suggested to relate to immune activation in the brain, including complex interactions between sex hormones, brain transcriptome, activation of glia cells, and cytokine production. Here, we will review sex-dependent effects on brain development, including glia cells, both under normal physiological conditions and following perinatal inflammation. Emphasis will be given to sex-dependent effects on brain regions which play a role in neuropsychiatric disorders and inflammatory reactions that may underlie early-life programming of neurobehavioral disturbances later in life.
  •  
49.
  • Arvidsson, G, et al. (författare)
  • A Protein Intrinsic Disorder Approach for Characterising Differentially Expressed Genes in Transcriptome Data: Analysis of Cell-Adhesion Regulated Gene Expression in Lymphoma Cells
  • 2018
  • Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 19:10
  • Tidskriftsartikel (refereegranskat)abstract
    • Conformational protein properties are coupled to protein functionality and could provide a useful parameter for functional annotation of differentially expressed genes in transcriptome studies. The aim was to determine whether predicted intrinsic protein disorder was differentially associated with proteins encoded by genes that are differentially regulated in lymphoma cells upon interaction with stromal cells, an interaction that occurs in microenvironments, such as lymph nodes that are protective for lymphoma cells during chemotherapy. Intrinsic disorder protein properties were extracted from the Database of Disordered Protein Prediction (D2P2), which contains data from nine intrinsic disorder predictors. Proteins encoded by differentially regulated cell-adhesion regulated genes were enriched in intrinsically disordered regions (IDRs) compared to other genes both with regard to IDR number and length. The enrichment was further ascribed to down-regulated genes. Consistently, a higher proportion of proteins encoded by down-regulated genes contained at least one IDR or were completely disordered. We conclude that down-regulated genes in stromal cell-adherent lymphoma cells encode proteins that are characterized by elevated levels of intrinsically disordered conformation, indicating the importance of down-regulating functional mechanisms associated with intrinsically disordered proteins in these cells. Further, the approach provides a generally applicable and complementary alternative to classification of differentially regulated genes using gene ontology or pathway enrichment analysis.
  •  
50.
  • Aryal, Bibek, et al. (författare)
  • Xyloglucan Remodeling Defines Auxin-Dependent Differential Tissue Expansion in Plants
  • 2021
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 22
  • Tidskriftsartikel (refereegranskat)abstract
    • Size control is a fundamental question in biology, showing incremental complexity in plants, whose cells possess a rigid cell wall. The phytohormone auxin is a vital growth regulator with central importance for differential growth control. Our results indicate that auxin-reliant growth programs affect the molecular complexity of xyloglucans, the major type of cell wall hemicellulose in eudicots. Auxin-dependent induction and repression of growth coincide with reduced and enhanced molecular complexity of xyloglucans, respectively. In agreement with a proposed function in growth control, genetic interference with xyloglucan side decorations distinctly modulates auxin-dependent differential growth rates. Our work proposes that auxin-dependent growth programs have a spatially defined effect on xyloglucan's molecular structure, which in turn affects cell wall mechanics and specifies differential, gravitropic hypocotyl growth.
  •  
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