Browsing by Subject "BETA"

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  • Vus, Kateryna; Girych, Mykhailo; Trusova, Valeriya; Gorbenko, Galyna; Kurutos, Atanas; Vasilev, Aleksey; Gadjev, Nikolai; Deligeorgiev, Todor (2019)
    The potential of novel cyanine dyes to inhibit the insulin amyloid formation was evaluated using thioflavin T fluorescence assay, quantum-chemical calculations, molecular docking and molecular dynamics simulations. According to the ability to suppress the insulin fibrillization under physiological conditions the examined compounds were found to follow the order: trimethines > pentamethines > monomethines > heptamethines. Of these, the trimethines 3-3 and 3-5, and pentamethines 5-3 and 5-9 almost completely prevented the protein aggregation by retarding both nucleation (except 3-3) and elongation processes. The quantum-chemical calculations revealed a complex relationship between the dye structure and its inhibitory effects. The molecular docking studies showed that most cyanines bind specifically to the L17 ladder of the B chain, located at the dry steric zipper of the insulin fibril protofilament, and form the stable complexes with the helices of the insulin monomer. The molecular dynamics simulations provided evidence for the increase of insulin helicity in the presence of cyanines. Collectively, the presented findings highlight two possible mechanisms by which cyanines can inhibit the insulin fibrillization: i) stabilization of the native protein structure followed by the retardation of the protein nucleation (all dyes); and ii) blocking the lateral extension of beta-sheets via the dye-protein stacking interactions (3-3, 3-5, 5-3, 5-9). Overall, the obtained results may prove of importance for the design of small molecules capable of preventing amyloid fibril formation by insulin and other proteins. (C) 2018 Elsevier B.V. All rights reserved.
  • Rekker, Kadri; Tasa, Tonis; Saare, Merli; Samuel, Kulli; Kadastik, Ulle; Karro, Helle; Goette, Martin; Salumets, Andres; Peters, Maire (2018)
    microRNA (miRNA) expression level alterations between endometrial tissue and endometriotic lesions indicate their involvement in endometriosis pathogenesis. However, as both endometrium and endometriotic lesions consist of different cell types in various proportions, it is not clear which cells contribute to variability in miRNA levels and the overall knowledge about cell-type specific miRNA expression in ectopic cells is scarce. Therefore, we utilized fluorescence-activated cell sorting to isolate endometrial stromal cells from paired endometrial and endometrioma biopsies and combined it with high-throughput sequencing to determine miRNA alterations in endometriotic stroma. The analysis revealed 149 abnormally expressed miRNAs in endometriotic lesions, including extensive upregulation of miR-139-5p and downregulation of miR-375 compared to eutopic cells. miRNA transfection experiments in the endometrial stromal cell line ST-T1b showed that the overexpression of miR-139-5p resulted in the downregulation of homeobox A9 (HOXA9) and HOXA10 expression, whereas the endothelin 1 (EDN1) gene was regulated by miR-375. The results of this study provide further insights into the complex molecular mechanisms involved in endometriosis pathogenesis and demonstrate the necessity for cell-type-specific analysis of ectopic tissues to understand the interactions between different cell populations in disease onset and progression.
  • Äyräs, Outi; Rahkola-Soisalo, Päivi; Kaijomaa, Marja; Tikkanen, Minna; Paavonen, Jorma; Stefanovic, Vedran (2019)
    Objective: To bring new accuracy to the prognosis of outcomes of euploid fetuses with an extremely high risk in the first-trimester combined screening when compared to the low-risk group. Study design: The data included pregnancies with a trisomy 21 risk >= 1:50 in the combined first-trimester screening but normal fetal chromosomes. The control group had a risk value Results: The study comprised 483 women (161 cases and 322 controls). The mean follow-up time of children born alive was 61.4 months. An adverse outcome was detected in 11.8% of the cases and in 5.9% of the controls. After adjusting the values of mothers age, parity, and smoking habit the odds ratio for an adverse outcome was 2.1 (95% CI: 1.0-4.5, p = 0.05) for cases. When evaluating the effect of 1 SD increase in MOM of PAPP-A or 1 SD decrease in MOM of NT or beta-hCG to any adverse outcome, 1 SD increase in PAPP-A MOM decreased the risk of adverse outcome by OR 0.48 (95% CI: 0.3 - 0.8, p = 0.05) while the others were not significant. Conclusion: Euploid fetuses with a high risk in the combined first-trimester screening have a twofold risk for adverse outcomes when compared to those with a low risk. (C) 2019 Elsevier B.V. All rights reserved.
  • Tayem, Raneem; Niemann, Catherin; Pesch, Monika; Morgner, Jessica; Niessen, Carien M.; Wickström, Sara A.; Aumailley, Monique (2021)
    The skin epidermis is attached to the underlying dermis by a laminin 332 (Lm332)-rich basement membrane. Consequently, loss of Lm332 leads to the severe blistering disorder epidermolysis bullosa junctionalis in humans and animals. Owing to the indispensable role of Lm332 in keratinocyte adhesion in vivo, the severity of the disease has limited research into other functions of the protein. We have conditionally disrupted Lm332 expression in basal keratinocytes of adult mice. Although blisters develop along the interfollicular epidermis, hair follicle basal cells provide sufficient anchorage of the epidermis to the dermis, making inducible deletion of the Lama3 gene compatible with life. Loss of Lm332 promoted the thickening of the epidermis and exaggerated desquamation. Global RNA expression analysis revealed major changes in the expression of keratins, cornified envelope proteins, and cellular stress markers. These modifications of the keratinocyte genetic program are accompanied by changes in cell shape and disorganization of the actin cytoskeleton. These data indicate that loss of Lm332-mediated progenitor cell adhesion alters cell fate and disturbs epidermal homeostasis.
  • Mandelin, Johanna M.; Eklund, Kari K.; Reitamo, Sakari (2010)
  • Määttä, Merita; Laurila, Henna P.; Holopainen, Saila; Aaltonen, Kaisa; Lilja-Maula, Liisa; Viitanen, Sanna; Rajamaki, Minna M. (2021)
    Background Canine idiopathic pulmonary fibrosis (CIPF) is a chronic, interstitial lung disease that mainly affects West Highland white terriers (WHWTs) and is characterized by excessive deposition of extracellular matrix (ECM) in the lung. Matrix metalloproteinases (MMPs) participate in remodeling of ECM. Objectives To compare metalloproteinase-2, -7 and -9 activities in blood or bronchoalveolar lavage fluid (BALF) samples or both of CIPF WHWTs with healthy WHWTs, healthy dogs of other breeds, and dogs with other lung diseases and determine if these MMPs could be used as diagnostic and prognostic markers for CIPF. Animals Forty-four CIPF WHWTs, 24 dogs with chronic bronchitis (CB), 17 with eosinophilic bronchopneumopathy (EBP), 10 with bacterial pneumonia, 39 healthy WHWTs, and 35 healthy dogs of other breeds. Methods Cross-sectional observational study. Pro-MMP and active MMP activities were analyzed by zymography. Results In serum, significantly higher (P <.01) pro-MMP-7 activities were observed in CIPF WHWTs compared to healthy dogs of other breeds, dogs with CB and dogs with EBP. In BALF of CIPF WHWTs, both pro-MMP-9 and pro-MMP-2 activities were significantly higher (P <.01) compared to healthy WHWTs, but these differences were not detected in plasma. The CIPF WHWTs had significantly higher (P <.05) activities of pro-MMP-9 compared to dogs with CB and of pro-MMP-2 compared to dogs with CB and EBP. No statistically significant prognostic factors were observed in CIPF WHWTs. Conclusions and clinical relevance Serum MMP-7 and BALF MMP-2 and -9 potentially may be useful diagnostic markers but not prognostic markers for CIPF.
  • Ivaska, Lotta E.; Silvoniemi, Antti; Palomares, Oscar; Turunen, Riitta; Mikola, Emilia; Puhakka, Tuomo; Söderlund-Venermo, Maria; Akdis, Mübeccel; Akdis, Cezmi A.; Jartti, Tuomas (2021)
    Background Persistent human bocavirus 1 (HBoV1) infection is a common finding in patients suffering from chronic tonsillar disease. However, the associations between HBoV1 infection and specific immune reactions are not completely known. We aimed to compare in vivo expression of T-cell cytokines, transcription factors, and type I/III interferons in human tonsils between HBoV1-positive and -negative tonsillectomy patients. Methods Tonsil tissue samples, nasopharyngeal aspirate (NPA), and serum samples were obtained from 143 immunocompetent adult and child tonsillectomy patients. HBoV1 and 14 other respiratory viruses were detected in NPAs and tonsil tissues by polymerase chain reaction (PCR). Serology and semi-quantitative PCR were used for diagnosing HBoV1 infections. Expression of 14 cytokines and transcription factors (IFN-alpha, IFN-beta, IFN-gamma, IL-10, IL-13, IL-17, IL-28, IL-29, IL-37, TGF-beta, FOXP3, GATA3, RORC2, Tbet) was analyzed by quantitative reverse-transcription (RT)-PCR in tonsil tissues. Results HBoV1 was detected by PCR in NPA and tonsils from 25 (17%) study patients. Serology results indicated prior nonacute infections in 81% of cases. Tonsillar cytokine responses were affected by HBoV1 infection. The suppression of two transcription factors, RORC2 and FOXP3, was associated with HBoV1 infection (p < 0.05). Furthermore, intratonsillar HBoV1-DNA loads correlated negatively with IFN-lambda family cytokines and IL-13. Conclusions Our study shows distinctively decreased T-helper(17) and T-regulatory type immune responses in local lymphoid tissue in HBoV1-positive tonsillectomy patients. HBoV1 may act as a suppressive immune modulator.
  • Konttinen, Henna; Cabral-da-Silva, Mauricio e Castro; Ohtonen, Sohvi; Wojciechowski, Sara; Shakirzyanova, Anastasia; Caligola, Simone; Giugno, Rosalba; Ishchenko, Yevheniia; Hernández, Damián; Fazaludeen, Mohammad Feroze; Eamen, Shaila; Budia, Mireia Gómez; Fagerlund, Ilkka; Scoyni, Flavia; Korhonen, Paula; Huber, Nadine; Haapasalo, Annakaisa; Hewitt, Alex W.; Vickers, James; Smith, Grady C.; Oksanen, Minna; Graff, Caroline; Kanninen, Katja M.; Lehtonen, Sarka; Propson, Nicholas; Schwartz, Michael P.; Pébay, Alice; Koistinaho, Jari; Ooi, Lezanne; Malm, Tarja (2019)
    Summary Here we elucidate the effect of Alzheimer disease (AD)-predisposing genetic backgrounds, APOE4, PSEN1ΔE9, and APPswe, on functionality of human microglia-like cells (iMGLs). We present a physiologically relevant high-yield protocol for producing iMGLs from induced pluripotent stem cells. Differentiation is directed with small molecules through primitive erythromyeloid progenitors to re-create microglial ontogeny from yolk sac. The iMGLs express microglial signature genes and respond to ADP with intracellular Ca2+ release distinguishing them from macrophages. Using 16 iPSC lines from healthy donors, AD patients and isogenic controls, we reveal that the APOE4 genotype has a profound impact on several aspects of microglial functionality, whereas PSEN1ΔE9 and APPswe mutations trigger minor alterations. The APOE4 genotype impairs phagocytosis, migration, and metabolic activity of iMGLs but exacerbates their cytokine secretion. This indicates that APOE4 iMGLs are fundamentally unable to mount normal microglial functionality in AD.
  • Lehikoinen, Anni; Voutilainen, Raimo; Romppanen, Jarkko; Heinonen, Seppo (2020)
    Background: The purpose of this study was to determine whether first trimester trisomy screening (FTS) parameters are affected by alcohol and drug use. Methods: A routine combined FTS including measurements of maternal serum levels of free beta-human chorionic gonadotropin subunit (free beta-hCG) and pregnancy-associated plasma protein A (PAPP-A) were measured at 9-11 weeks of gestation, and fetal nuchal translucency thickness (NTT) at 11-13 weeks of gestation. In total 544 women with singleton pregnancies [71 alcohol and drug abusers, 88 smokers, 168 non-smokers delivering a small for gestational age (SGA) child, and 217 unexposed control women] were assessed. Results: Free beta-hCG levels were higher in alcohol and drug abusing than in unexposed pregnant women [mean 1.5 vs. 1.2 multiples of medians (MoM); P=0.013]. However, stepwise multiple linear regression analyses suggested that smoking could explain increased free beta-hCG. Additionally, we observed lower PAPP-A levels in the smoking mothers (0.9 vs. 1.2 MoM; P=0.045) and in those giving birth to an SGA child compared to the controls (1.1 vs.. 1.2 MoM; P Conclusions: The present study shows increased free beta-hCG levels in alcohol and drug abusers, but maternal smoking may explain the result. Maternal serum PAPP-A levels were lower in smoking than non-smoking mothers, and in mothers delivering an SGA child. However, FTS parameters (PAPP-A, free beta-hCG and NTT) seem not to be applicable for the use as alcohol biomarkers because of their clear overlap between alcohol abusers and healthy controls.
  • Ezzat, Kariem; Pernemalm, Maria; Palsson, Sandra; Roberts, Thomas C.; Järver, Peter; Dondalska, Aleksandra; Bestas, Burcu; Sobkowiak, Michal J.; Levänen, Bettina; Sköld, Magnus; Thompson, Elizabeth A.; Saher, Osama; Kari, Otto K.; Lajunen, Tatu; Ekstrom, Eva Sverremark; Nilsson, Caroline; Ishchenko, Yevheniia; Malm, Tarja; Wood, Matthew J. A.; Power, Ultan F.; Masich, Sergej; Linden, Anders; Sandberg, Johan K.; Lehtiö, Janne; Spetz, Anna-Lena; EL Andaloussi, Samir (2019)
    Artificial nanoparticles accumulate a protein corona layer in biological fluids, which significantly influences their bioactivity. As nanosized obligate intracellular parasites, viruses share many biophysical properties with artificial nanoparticles in extracellular environments and here we show that respiratory syncytial virus (RSV) and herpes simplex virus type 1 (HSV-1) accumulate a rich and distinctive protein corona in different biological fluids. Moreover, we show that corona pre-coating differentially affects viral infectivity and immune cell activation. In addition, we demonstrate that viruses bind amyloidogenic peptides in their corona and catalyze amyloid formation via surface-assisted heterogeneous nucleation. Importantly, we show that HSV-1 catalyzes the aggregation of the amyloid beta-peptide (A beta(42)), a major constituent of amyloid plaques in Alzheimer's disease, in vitro and in animal models. Our results highlight the viral protein corona as an acquired structural layer that is critical for viral-host interactions and illustrate a mechanistic convergence between viral and amyloid pathologies.
  • Gershony, Liza C.; Belanger, Janelle M.; Hytönen, Marjo K.; Lohi, Hannes; Oberbauer, Anita M. (2021)
    In dogs, symmetrical lupoid onychodystrophy (SLO) results in nail loss and an abnormal regrowth of the claws. In Bearded Collies, an autoimmune nature has been suggested because certain dog leukocyte antigen (DLA) class II haplotypes are associated with the condition. A genome-wide association study of the Bearded Collie revealed two regions of association that conferred risk for disease: one on canine chromosome (CFA) 12 that encompasses the DLA genes, and one on CFA17. Case-control association was employed on whole genome sequencing data to uncover putative causative variants in SLO within the CFA12 and CFA17 associated regions. Genotype imputation was then employed to refine variants of interest. Although no SLO-associated protein-coding variants were identified on CFA17, multiple variants, many with predicted damaging effects, were identified within potential candidate genes on CFA12. Furthermore, many potentially damaging alleles were fully correlated with the presence of DLA class II risk haplotypes for SLO, suggesting that the variants may reflect DLA class II haplotype association with disease or vice versa. Strong linkage disequilibrium in the region precluded the ability to isolate and assess the individual or combined effect of variants on disease development. Nonetheless, all were predictive of risk for SLO and, with judicious assessment, their application in selective breeding may prove useful to reduce the incidence of SLO in the breed.