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Showing 1 - 200 of 238 Journals sorted alphabetically
Acoustics     Open Access   (Followers: 4)
Actuators     Open Access   (Followers: 4)
Administrative Sciences     Open Access   (Followers: 6)
Aerospace     Open Access   (Followers: 67, SJR: 0.305, CiteScore: 1)
Agriculture     Open Access   (Followers: 9, SJR: 0.33, CiteScore: 2)
AgriEngineering     Open Access   (Followers: 1)
Agronomy     Open Access   (Followers: 18, SJR: 0.695, CiteScore: 2)
Algorithms     Open Access   (Followers: 14, SJR: 0.217, CiteScore: 1)
Allergies     Open Access   (Followers: 3)
Animals     Open Access   (Followers: 15, SJR: 0.744, CiteScore: 2)
Antibiotics     Open Access   (Followers: 10, SJR: 1.063, CiteScore: 3)
Antibodies     Open Access   (Followers: 2, SJR: 0.931, CiteScore: 3)
Antioxidants     Open Access   (Followers: 5, SJR: 0.847, CiteScore: 3)
Applied Sciences     Open Access   (Followers: 6, SJR: 0.303, CiteScore: 2)
Applied System Innovation     Open Access  
Arts     Open Access   (Followers: 9)
Atmosphere     Open Access   (Followers: 29)
Atoms     Open Access   (Followers: 1)
Axioms     Open Access   (Followers: 1)
Batteries     Open Access   (Followers: 11)
Behavioral Sciences     Open Access   (Followers: 4)
Beverages     Open Access   (Followers: 1)
Big Data and Cognitive Computing     Open Access   (Followers: 8)
Bioengineering     Open Access   (Followers: 4)
Biology     Open Access   (Followers: 4, SJR: 1.324, CiteScore: 3)
Biomedicines     Open Access   (Followers: 1)
Biomimetics     Open Access  
Biomolecules     Open Access   (Followers: 1, SJR: 2.552, CiteScore: 6)
Biosensors     Open Access   (Followers: 4, SJR: 0.829, CiteScore: 4)
Brain Sciences     Open Access   (Followers: 5, SJR: 1.047, CiteScore: 3)
Buildings     Open Access   (Followers: 9)
C - J. of Carbon Research     Open Access   (Followers: 5)
Cancers     Open Access   (Followers: 3, SJR: 2.243, CiteScore: 6)
Catalysts     Open Access   (Followers: 14)
Cells     Open Access   (Followers: 4, SJR: 2.742, CiteScore: 6)
Ceramics     Open Access  
Challenges     Open Access   (Followers: 2)
ChemEngineering     Open Access  
Chemistry     Open Access  
Chemosensors     Open Access   (Followers: 1)
Children     Open Access   (Followers: 2)
Chromatography     Open Access   (Followers: 3)
Clean Technologies     Open Access   (Followers: 1)
Climate     Open Access   (Followers: 6)
Clinics and Practice     Open Access   (SJR: 0.175, CiteScore: 1)
Clocks & Sleep     Open Access   (Followers: 2)
Coatings     Open Access   (Followers: 4)
Colloids and Interfaces     Open Access  
Computation     Open Access   (Followers: 1)
Computers     Open Access   (Followers: 2)
Condensed Matter     Open Access   (Followers: 3)
Corrosion and Materials Degradation     Open Access  
Cosmetics     Open Access   (Followers: 5)
Cryptography     Open Access   (Followers: 1)
Crystals     Open Access   (Followers: 5, SJR: 0.566, CiteScore: 2)
Current Issues in Molecular Biology     Open Access   (Followers: 3, SJR: 0.787, CiteScore: 2)
Dairy     Open Access   (Followers: 2)
Data     Open Access   (Followers: 5)
Dentistry J.     Open Access   (Followers: 6)
Designs     Open Access  
Diagnostics     Open Access   (Followers: 1, SJR: 0.669, CiteScore: 2)
Diseases     Open Access  
Diversity     Open Access   (Followers: 5)
Drones     Open Access   (Followers: 6)
Econometrics     Open Access   (Followers: 12)
Economies     Open Access   (Followers: 1)
Education     Open Access   (Followers: 13)
Electronics     Open Access   (Followers: 124, SJR: 0.548, CiteScore: 3)
Energies     Open Access   (Followers: 7, SJR: 0.67, CiteScore: 3)
Entropy     Open Access   (Followers: 8, SJR: 0.592, CiteScore: 2)
Environments     Open Access  
Epigenomes     Open Access  
European J. of Burn Care     Open Access  
European J. of Investigation in Health, Psychology and Education     Open Access   (Followers: 6)
Fermentation     Open Access   (Followers: 3)
Fibers     Open Access   (Followers: 8)
Fire     Open Access   (Followers: 2)
Fishes     Open Access  
Fluids     Open Access   (Followers: 2)
Foods     Open Access  
Forecasting     Open Access   (Followers: 1)
Forests     Open Access   (Followers: 2, SJR: 0.812, CiteScore: 2)
Fractal and Fractional     Open Access  
Future Internet     Open Access   (Followers: 188, SJR: 0.219, CiteScore: 1)
Galaxies     Open Access   (Followers: 7)
Games     Open Access   (Followers: 4, SJR: 0.242, CiteScore: 1)
Gastrointestinal Disorders     Open Access  
Gels     Open Access  
Genealogy     Open Access   (Followers: 1)
Genes     Open Access   (Followers: 2, SJR: 1.82, CiteScore: 3)
GeoHazards     Open Access   (Followers: 2)
Geosciences     Open Access   (Followers: 4, SJR: 0.451, CiteScore: 2)
Geriatrics     Open Access   (Followers: 4)
Healthcare     Open Access   (Followers: 3)
Hearts     Open Access   (Followers: 2)
Heritage     Open Access  
High-Throughput     Open Access  
Histories     Open Access   (Followers: 2)
Horticulturae     Open Access   (Followers: 3)
Humanities     Open Access   (Followers: 15)
Hydrology     Open Access   (Followers: 5)
Informatics     Open Access   (Followers: 4)
Information     Open Access   (Followers: 48, SJR: 0.222, CiteScore: 1)
Infrastructures     Open Access  
Inorganics     Open Access   (Followers: 3)
Insects     Open Access   (Followers: 2, SJR: 0.897, CiteScore: 2)
Instruments     Open Access  
Intl. J. of Environmental Research and Public Health     Open Access   (Followers: 27, SJR: 0.735, CiteScore: 2)
Intl. J. of Financial Studies     Open Access   (Followers: 5)
Intl. J. of Molecular Sciences     Open Access   (Followers: 3, SJR: 1.26, CiteScore: 4)
Intl. J. of Neonatal Screening     Open Access   (Followers: 4)
Intl. J. of Turbomachinery, Propulsion and Power     Open Access   (Followers: 18)
Inventions     Open Access  
IoT     Open Access   (Followers: 1)
ISPRS Intl. J. of Geo-Information     Open Access   (Followers: 5, SJR: 0.493, CiteScore: 2)
J : Multidisciplinary Scientific J.     Open Access  
J. of Cardiovascular Development and Disease     Open Access   (Followers: 1)
J. of Clinical Medicine     Open Access   (Followers: 3)
J. of Composites Science     Open Access   (Followers: 3)
J. of Cybersecurity and Privacy     Open Access   (Followers: 3)
J. of Developmental Biology     Open Access   (Followers: 2)
J. of Functional Biomaterials     Open Access   (Followers: 3, SJR: 0.685, CiteScore: 3)
J. of Functional Morphology and Kinesiology     Open Access  
J. of Fungi     Open Access   (Followers: 3)
J. of Imaging     Open Access   (Followers: 3)
J. of Intelligence     Open Access   (Followers: 2)
J. of Low Power Electronics and Applications     Open Access   (Followers: 9, SJR: 0.222, CiteScore: 1)
J. of Manufacturing and Materials Processing     Open Access  
J. of Marine Science and Engineering     Open Access   (Followers: 3)
J. of Nanotheranostics     Open Access   (Followers: 1)
J. of Open Innovation : Technology, Market, and Complexity     Open Access   (Followers: 1)
J. of Otorhinolaryngology, Hearing and Balance Medicine     Open Access   (Followers: 1)
J. of Personalized Medicine     Open Access   (Followers: 3, SJR: 1.269, CiteScore: 3)
J. of Risk and Financial Management     Open Access   (Followers: 9)
J. of Sensor and Actuator Networks     Open Access   (Followers: 13)
J. of Xenobiotics     Open Access  
J. of Zoological and Botanical Gardens     Open Access   (Followers: 2)
Land     Open Access   (Followers: 4)
Languages     Open Access   (Followers: 5)
Laws     Open Access   (Followers: 2)
Life     Open Access   (Followers: 2, SJR: 1.625, CiteScore: 3)
Literature     Open Access  
Logistics     Open Access   (Followers: 3)
Lubricants     Open Access   (Followers: 2)
Machine Learning and Knowledge Extraction     Open Access   (Followers: 10)
Machines     Open Access   (Followers: 3)
Magnetochemistry     Open Access  
Marine Drugs     Open Access   (Followers: 3, SJR: 0.978, CiteScore: 5)
Materials     Open Access   (Followers: 6)
Mathematical and Computational Applications     Open Access   (Followers: 3)
Mathematics     Open Access   (Followers: 3)
Medical Sciences     Open Access   (Followers: 2)
Medicina     Open Access   (Followers: 1, SJR: 0.422, CiteScore: 1)
Medicines     Open Access   (Followers: 1)
Membranes     Open Access   (Followers: 5, SJR: 0.645, CiteScore: 3)
Metabolites     Open Access   (Followers: 2, SJR: 1.026, CiteScore: 3)
Metals     Open Access   (Followers: 5, SJR: 0.55, CiteScore: 2)
Methods and Protocols     Open Access   (Followers: 1)
Microarrays     Open Access  
Micromachines     Open Access   (Followers: 3, SJR: 0.493, CiteScore: 2)
Microorganisms     Open Access   (Followers: 5)
Minerals     Open Access   (Followers: 2, SJR: 0.462, CiteScore: 2)
Molbank     Open Access   (Followers: 1, SJR: 0.12, CiteScore: 0)
Molecules     Open Access   (Followers: 7, SJR: 0.855, CiteScore: 3)
Multimodal Technologies and Interaction     Open Access  
Nanomaterials     Open Access   (Followers: 6)
Neuroglia     Open Access   (Followers: 1)
Neurology Intl.     Open Access   (Followers: 3, SJR: 0.345, CiteScore: 1)
Nitrogen     Open Access   (Followers: 2)
Non-Coding RNA     Open Access  
Nursing Reports     Open Access   (Followers: 3)
Nutrients     Open Access   (Followers: 11, SJR: 1.557, CiteScore: 4)
Oceans     Open Access  
Particles     Open Access  
Pathogens     Open Access   (Followers: 3, SJR: 1.421, CiteScore: 4)
Pharmaceuticals     Open Access   (Followers: 5, SJR: 1.293, CiteScore: 4)
Pharmaceutics     Open Access   (Followers: 4, SJR: 0.949, CiteScore: 4)
Pharmacy     Open Access   (Followers: 7)
Philosophies     Open Access  
Photonics     Open Access   (Followers: 6, SJR: 0.709, CiteScore: 2)
Physics     Open Access   (Followers: 1)
Plants     Open Access   (SJR: 1.39, CiteScore: 3)
Plasma     Open Access   (Followers: 5)
Polymers     Open Access   (Followers: 20, SJR: 0.852, CiteScore: 3)
Proceedings     Open Access   (Followers: 1)
Processes     Open Access  
Projects     Open Access   (Followers: 2)
Prosthesis     Open Access  
Proteomes     Open Access  
Psych     Open Access   (Followers: 2)
Publications     Open Access   (Followers: 7)
Quantum Beam Science     Open Access   (Followers: 1)
Quantum Reports     Open Access  
Quaternary     Open Access  
Reactions     Open Access   (Followers: 1)
Recycling     Open Access  
Religions     Open Access   (Followers: 4, SJR: 0.232, CiteScore: 1)
Remote Sensing     Open Access   (Followers: 58, SJR: 1.386, CiteScore: 4)
Reports     Open Access  
Reproductive Medicine     Open Access  

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Journal Cover
Journal Prestige (SJR): 2.742
Citation Impact (citeScore): 6
Number of Followers: 4  

  This is an Open Access Journal Open Access journal
ISSN (Online) 2073-4409
Published by MDPI Homepage  [238 journals]
  • Cells, Vol. 10, Pages 1696: Generation of a Highly Biomimetic Organoid,
           Including Vasculature, Resembling the Native Immature Testis Tissue

    • Authors: Tat-Chuan Cham, Fahar Ibtisham, Mohammad Amin Fayaz, Ali Honaramooz
      First page: 1696
      Abstract: The creation of a testis organoid (artificial testis tissue) with sufficient resemblance to the complex form and function of the innate testis remains challenging, especially using non-rodent donor cells. Here, we report the generation of an organoid culture system with striking biomimicry of the native immature testis tissue, including vasculature. Using piglet testis cells as starting material, we optimized conditions for the formation of cell spheroids, followed by long-term culture in an air–liquid interface system. Both fresh and frozen-thawed cells were fully capable of self-reassembly into stable testis organoids consisting of tubular and interstitial compartments, with all major cell types and structural details expected in normal testis tissue. Surprisingly, our organoids also developed vascular structures; a phenomenon that has not been reported in any other culture system. In addition, germ cells do not decline over time, and Leydig cells release testosterone, hence providing a robust, tunable system for diverse basic and applied applications.
      Citation: Cells
      PubDate: 2021-07-05
      DOI: 10.3390/cells10071696
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1697: Tuning IgE: IgE-Associating Molecules and
           Their Effects on IgE-Dependent Mast Cell Reactions

    • Authors: Tomoaki Ando, Jiro Kitaura
      First page: 1697
      Abstract: The recent emergence of anti-immunoglobulin E (IgE) drugs and their candidates for humans has endorsed the significance of IgE-dependent pathways in allergic disorders. IgE is distributed locally in the tissues or systemically to confer a sensory mechanism in a domain of adaptive immunity to the otherwise innate type of effector cells, namely, mast cells and basophils. Bound on the high-affinity IgE receptor FcεRI, IgE enables fast memory responses against revisiting threats of venoms, parasites, and bacteria. However, the dysregulation of IgE-dependent reactions leads to potentially life-threatening allergic diseases, such as asthma and anaphylaxis. Therefore, reactivity of the IgE sensor is fine-tuned by various IgE-associating molecules. In this review, we discuss the mechanistic basis for how IgE-dependent mast cell activation is regulated by the IgE-associating molecules, including the newly developed therapeutic candidates.
      Citation: Cells
      PubDate: 2021-07-05
      DOI: 10.3390/cells10071697
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1700: Bemisia tabaci Vesicle-Associated Membrane
           Protein 2 Interacts with Begomoviruses and Plays a Role in Virus

    • Authors: Yun-Yun Fan, Yu-Wei Zhong, Jing Zhao, Yao Chi, Sophie Bouvaine, Shu-Sheng Liu, Susan E. Seal, Xiao-Wei Wang
      First page: 1700
      Abstract: Begomoviruses cause substantial losses to agricultural production, especially in tropical and subtropical regions, and are exclusively transmitted by members of the whitefly Bemisia tabaci species complex. However, the molecular mechanisms underlying the transmission of begomoviruses by their whitefly vector are not clear. In this study, we found that B. tabaci vesicle-associated membrane protein 2 (BtVAMP2) interacts with the coat protein (CP) of tomato yellow leaf curl virus (TYLCV), an emergent begomovirus that seriously impacts tomato production globally. After infection with TYLCV, the transcription of BtVAMP2 was increased. When the BtVAMP2 protein was blocked by feeding with a specific BtVAMP2 antibody, the quantity of TYLCV in B. tabaci whole body was significantly reduced. BtVAMP2 was found to be conserved among the B. tabaci species complex and also interacts with the CP of Sri Lankan cassava mosaic virus (SLCMV). When feeding with BtVAMP2 antibody, the acquisition quantity of SLCMV in whitefly whole body was also decreased significantly. Overall, our results demonstrate that BtVAMP2 interacts with the CP of begomoviruses and promotes their acquisition by whitefly.
      Citation: Cells
      PubDate: 2021-07-05
      DOI: 10.3390/cells10071700
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1701: Phosphorylation in the Charged Linker
           Modulates Interactions and Secretion of Hsp90β

    • Authors: Weidenauer, Quadroni
      First page: 1701
      Abstract: Hsp90β is a major chaperone involved in numerous cellular processes. Hundreds of client proteins depend on Hsp90β for proper folding and/or activity. Regulation of Hsp90β is critical to coordinate its tasks and is mediated by several post-translational modifications. Here, we focus on two phosphorylation sites located in the charged linker region of human Hsp90β, Ser226 and Ser255, which have been frequently reported but whose function remains unclear. Targeted measurements by mass spectrometry indicated that intracellular Hsp90β is highly phosphorylated on both sites (>90%). The level of phosphorylation was unaffected by various stresses (e.g., heat shock, inhibition with drugs) that impact Hsp90β activity. Mutating the two serines to alanines increased the amount of proteins interacting with Hsp90β globally and increased the sensitivity to tryptic cleavage in the C-terminal domain. Further investigation revealed that phosphorylation on Ser255 and to a lesser extent on Ser226 is decreased in the conditioned medium of cultured K562 cells, and that a non-phosphorylatable double alanine mutant was secreted more efficiently than the wild type. Overall, our results show that phosphorylation events in the charged linker regulate both the interactions of Hsp90β and its secretion, through changes in the conformation of the chaperone.
      Citation: Cells
      PubDate: 2021-07-05
      DOI: 10.3390/cells10071701
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1702: Ovarian Cancer-Associated Ascites Have High
           Proportions of Cytokine-Responsive CD56bright NK Cells

    • Authors: Cláudia Rodrigues Tonetti, Caroline Natânia de Souza-Araújo, Adriana Yoshida, Rodrigo Fernandes da Silva, Paulo César Martins Alves, Taís Nitsch Mazzola, Sophie Derchain, Luís Gustavo Romani Fernandes, Fernando Guimarães
      First page: 1702
      Abstract: Ovarian cancer is the most lethal gynecological malignancy, with serous histotype as the most prevalent epithelial ovarian cancer (EOC). Peritoneal ascites is a frequent comorbidity in advanced EOC. EOC-associated ascites provide a reliable sampling source for studying lymphocytes directly from tumor environment. Herein, we carried out flow cytometry-based analysis to readdress issues on NK and T lymphocyte subsets in women with advanced EOC, additionally evaluating phenotypic modulation of their intracellular pathways involved in interleukin (IL)-2 and IL-15 signaling. Results depicted ascites as an inflammatory and immunosuppressive environment, presenting significantly (p < 0.0001) higher amounts of IL-6 and IL-10 than in the patients’ blood, as well as significantly (p < 0.05) increased expression of checkpoint inhibitory receptors (programmed death protein-1, PD-1) and ectonucleotidase (CD39) on T lymphocytes. However, NK lymphocytes from EOC-associated ascites showed higher (p < 0.05) pS6 phosphorylation compared with NK from blood. Additionally, in vitro treatment of lymphocytes with IL-2 or IL-15 elicited significantly (p < 0.001) phosphorylation of the STAT5 protein in NK, CD3 and CD8 lymphocytes, both from blood and ascites. EOC-associated ascites had a significantly (p < 0.0001) higher proportion of NK CD56bright lymphocytes than blood, which, in addition, were more responsive (p < 0.05) to stimulation by IL-2 than CD56dim NK. EOC-associated ascites allow studies on lymphocyte phenotype modulation in the tumor environment, where inflammatory profile contrasts with the presence of immunosuppressive elements and development of cellular self-regulating mechanisms.
      Citation: Cells
      PubDate: 2021-07-06
      DOI: 10.3390/cells10071702
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1703: Integrins: An Important Link between
           Angiogenesis, Inflammation and Eye Diseases

    • Authors: Małgorzata Mrugacz, Anna Bryl, Mariusz Falkowski, Katarzyna Zorena
      First page: 1703
      Abstract: Integrins belong to a group of cell adhesion molecules (CAMs) which is a large group of membrane-bound proteins. They are responsible for cell attachment to the extracellular matrix (ECM) and signal transduction from the ECM to the cells. Integrins take part in many other biological activities, such as extravasation, cell-to-cell adhesion, migration, cytokine activation and release, and act as receptors for some viruses, including severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). They play a pivotal role in cell proliferation, migration, apoptosis, tissue repair and are involved in the processes that are crucial to infection, inflammation and angiogenesis. Integrins have an important part in normal development and tissue homeostasis, and also in the development of pathological processes in the eye. This review presents the available evidence from human and animal research into integrin structure, classification, function and their role in inflammation, infection and angiogenesis in ocular diseases. Integrin receptors and ligands are clinically interesting and may be promising as new therapeutic targets in the treatment of some eye disorders.
      Citation: Cells
      PubDate: 2021-07-06
      DOI: 10.3390/cells10071703
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1704: Viscoelastic Properties in Cancer: From Cells
           to Spheroids

    • Authors: Yara Abidine, Arianna Giannetti, Jean Revilloud, Valérie M. Laurent, Claude Verdier
      First page: 1704
      Abstract: AFM-based rheology methods enable the investigation of the viscoelastic properties of cancer cells. Such properties are known to be essential for cell functions, especially for malignant cells. Here, the relevance of the force modulation method was investigated to characterize the viscoelasticity of bladder cancer cells of various invasiveness on soft substrates, revealing that the rheology parameters are a signature of malignancy. Furthermore, the collagen microenvironment affects the viscoelastic moduli of cancer cell spheroids; thus, collagen serves as a powerful proxy, leading to an increase of the dynamic moduli vs. frequency, as predicted by a double power law model. Taken together, these results shed new light on how cancer cells and tissues adapt their viscoelastic properties depending on their malignancy and the microenvironment. This method could be an attractive way to control their properties in the future, based on the similarity of spheroids with in vivo tumor models.
      Citation: Cells
      PubDate: 2021-07-06
      DOI: 10.3390/cells10071704
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1705: Deficiency in MT5-MMP Supports Branching of
           Human iPSCs-Derived Neurons and Reduces Expression of GLAST/S100 in
           iPSCs-Derived Astrocytes

    • Authors: Nikita Arnst, Pedro Belio-Mairal, Laura García-González, Laurie Arnaud, Louise Greetham, Emmanuel Nivet, Santiago Rivera, Alexander Dityatev
      First page: 1705
      Abstract: For some time, it has been accepted that the β-site APP cleaving enzyme 1 (BACE1) and the γ-secretase are two main players in the amyloidogenic processing of the β-amyloid precursor protein (APP). Recently, the membrane-type 5 matrix metalloproteinase (MT5-MMP/MMP-24), mainly expressed in the nervous system, has been highlighted as a new key player in APP-processing, able to stimulate amyloidogenesis and also to generate a neurotoxic APP derivative. In addition, the loss of MT5-MMP has been demonstrated to abrogate pathological hallmarks in a mouse model of Alzheimer’s disease (AD), thus shedding light on MT5-MMP as an attractive new therapeutic target. However, a more comprehensive analysis of the role of MT5-MMP is necessary to evaluate how its targeting affects neurons and glia in pathological and physiological situations. In this study, leveraging on CRISPR-Cas9 genome editing strategy, we established cultures of human-induced pluripotent stem cells (hiPSC)-derived neurons and astrocytes to investigate the impact of MT5-MMP deficiency on their phenotypes. We found that MT5-MMP-deficient neurons exhibited an increased number of primary and secondary neurites, as compared to isogenic hiPSC-derived neurons. Moreover, MT5-MMP-deficient astrocytes displayed higher surface area and volume compared to control astrocytes. The MT5-MMP-deficient astrocytes also exhibited decreased GLAST and S100β expression. These findings provide novel insights into the physiological role of MT5-MMP in human neurons and astrocytes, suggesting that therapeutic strategies targeting MT5-MMP should be controlled for potential side effects on astrocytic physiology and neuronal morphology.
      Citation: Cells
      PubDate: 2021-07-06
      DOI: 10.3390/cells10071705
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1706: The Role of miRNAs in Extracellular Matrix
           Repair and Chronic Fibrotic Lung Diseases

    • Authors: Kauna Usman, Aileen Hsieh, Tillie-Louise Hackett
      First page: 1706
      Abstract: The lung extracellular matrix (ECM) plays a key role in the normal architecture of the lung, from embryonic lung development to mechanical stability and elastic recoil of the breathing adult lung. The lung ECM can modulate the biophysical environment of cells through ECM stiffness, porosity, topography and insolubility. In a reciprocal interaction, lung ECM dynamics result from the synthesis, degradation and organization of ECM components by the surrounding structural and immune cells. Repeated lung injury and repair can trigger a vicious cycle of aberrant ECM protein deposition, accompanied by elevated ECM stiffness, which has a lasting effect on cell and tissue function. The processes governing the resolution of injury repair are regulated by several pathways; however, in chronic lung diseases such as asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary disease (IPF) these processes are compromised, resulting in impaired cell function and ECM remodeling. Current estimates show that more than 60% of the human coding transcripts are regulated by miRNAs. miRNAs are small non-coding RNAs that regulate gene expressions and modulate cellular functions. This review is focused on the current knowledge of miRNAs in regulating ECM synthesis, degradation and topography by cells and their dysregulation in asthma, COPD and IPF.
      Citation: Cells
      PubDate: 2021-07-06
      DOI: 10.3390/cells10071706
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1707: Impact of Repetitive DNA Elements on Snake
           Genome Biology and Evolution

    • Authors: Syed Farhan Ahmad, Worapong Singchat, Thitipong Panthum, Kornsorn Srikulnath
      First page: 1707
      Abstract: The distinctive biology and unique evolutionary features of snakes make them fascinating model systems to elucidate how genomes evolve and how variation at the genomic level is interlinked with phenotypic-level evolution. Similar to other eukaryotic genomes, large proportions of snake genomes contain repetitive DNA, including transposable elements (TEs) and satellite repeats. The importance of repetitive DNA and its structural and functional role in the snake genome, remain unclear. This review highlights the major types of repeats and their proportions in snake genomes, reflecting the high diversity and composition of snake repeats. We present snakes as an emerging and important model system for the study of repetitive DNA under the impact of sex and microchromosome evolution. We assemble evidence to show that certain repetitive elements in snakes are transcriptionally active and demonstrate highly dynamic lineage-specific patterns as repeat sequences. We hypothesize that particular TEs can trigger different genomic mechanisms that might contribute to driving adaptive evolution in snakes. Finally, we review emerging approaches that may be used to study the expression of repetitive elements in complex genomes, such as snakes. The specific aspects presented here will stimulate further discussion on the role of genomic repeats in shaping snake evolution.
      Citation: Cells
      PubDate: 2021-07-06
      DOI: 10.3390/cells10071707
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1708: Human Tissue Angiotensin Converting Enzyme
           (ACE) Activity Is Regulated by Genetic Polymorphisms, Posttranslational
           Modifications, Endogenous Inhibitors and Secretion in the Serum, Lungs and

    • Authors: Viktor Bánhegyi, Attila Enyedi, Gábor Áron Fülöp, Attila Oláh, Ivetta Mányiné Siket, Csongor Váradi, Klaudia Bottyán, Mária Lódi, Alexandra Csongrádi, Azeem J. Umar, Miklós Fagyas, Dániel Czuriga, István Édes, Miklós Pólos, Béla Merkely, Zoltán Csanádi, Zoltán Papp, Gábor Szabó, Tamás Radovits, István Takács, Attila Tóth
      First page: 1708
      Abstract: Objective: Inhibitors of the angiotensin converting enzyme (ACE) are the primarily chosen drugs to treat heart failure and hypertension. Moreover, an imbalance in tissue ACE/ACE2 activity is implicated in COVID-19. In the present study, we tested the relationships between circulating and tissue (lung and heart) ACE levels in men. Methods: Serum, lung (n = 91) and heart (n = 72) tissue samples were collected from Caucasian patients undergoing lung surgery or heart transplantation. ACE I/D genotype, ACE concentration and ACE activity were determined from serum and tissue samples. Clinical parameters were also recorded. Results: A protocol for ACE extraction was developed for tissue ACE measurements. Extraction of tissue-localized ACE was optimal in a 0.3% Triton-X-100 containing buffer, resulting in 260 ± 12% higher ACE activity over detergent-free conditions. SDS or higher Triton-X-100 concentrations inhibited the ACE activity. Serum ACE concentration correlated with ACE I/D genotype (II: 166 ± 143 ng/mL, n = 19, ID: 198 ± 113 ng/mL, n = 44 and DD: 258 ± 109 ng/mL, n = 28, p < 0.05) as expected. In contrast, ACE expression levels in the lung tissue were approximately the same irrespective of the ACE I/D genotype (II: 1423 ± 1276 ng/mg, ID: 1040 ± 712 ng/mg and DD: 930 ± 1273 ng/mg, p > 0.05) in the same patients (values are in median ± IQR). Moreover, no correlations were found between circulating and lung tissue ACE concentrations and activities (Spearman’s p > 0.05). In contrast, a significant correlation was identified between ACE activities in serum and heart tissues (Spearman’s Rho = 0.32, p < 0.01). Finally, ACE activities in lung and the serum were endogenously inhibited to similar degrees (i.e., to 69 ± 1% and 53 ± 2%, respectively). Conclusion: Our data suggest that circulating ACE activity correlates with left ventricular ACE, but not with lung ACE in human. More specifically, ACE activity is tightly coordinated by genotype-dependent expression, endogenous inhibition and secretion mechanisms.
      Citation: Cells
      PubDate: 2021-07-06
      DOI: 10.3390/cells10071708
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1709: miRNA-132/212 Gene-Deletion Aggravates the
           Effect of Oxygen-Glucose Deprivation on Synaptic Functions in the Female
           Mouse Hippocampus

    • Authors: Daniel Bormann, Tamara Stojanovic, Ana Cicvaric, Gabor J. Schuld, Maureen Cabatic, Hendrik Jan Ankersmit, Francisco J. Monje
      First page: 1709
      Abstract: Cerebral ischemia and its sequelae, which include memory impairment, constitute a leading cause of disability worldwide. Micro-RNAs (miRNA) are evolutionarily conserved short-length/noncoding RNA molecules recently implicated in adaptive/maladaptive neuronal responses to ischemia. Previous research independently implicated the miRNA-132/212 cluster in cholinergic signaling and synaptic transmission, and in adaptive/protective mechanisms of neuronal responses to hypoxia. However, the putative role of miRNA-132/212 in the response of synaptic transmission to ischemia remained unexplored. Using hippocampal slices from female miRNA-132/212 double-knockout mice in an established electrophysiological model of ischemia, we here describe that miRNA-132/212 gene-deletion aggravated the deleterious effect of repeated oxygen-glucose deprivation insults on synaptic transmission in the dentate gyrus, a brain region crucial for learning and memory functions. We also examined the effect of miRNA-132/212 gene-deletion on the expression of key mediators in cholinergic signaling that are implicated in both adaptive responses to ischemia and hippocampal neural signaling. miRNA-132/212 gene-deletion significantly altered hippocampal AChE and mAChR-M1, but not α7-nAChR or MeCP2 expression. The effects of miRNA-132/212 gene-deletion on hippocampal synaptic transmission and levels of cholinergic-signaling elements suggest the existence of a miRNA-132/212-dependent adaptive mechanism safeguarding the functional integrity of synaptic functions in the acute phase of cerebral ischemia.
      Citation: Cells
      PubDate: 2021-07-06
      DOI: 10.3390/cells10071709
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1710: Review: Vaspin (SERPINA12) Expression and
           Function in Endocrine Cells

    • Authors: Patrycja Kurowska, Ewa Mlyczyńska, Monika Dawid, Małgorzata Jurek, Dominika Klimczyk, Joelle Dupont, Agnieszka Rak
      First page: 1710
      Abstract: Proper functioning of the body depends on hormonal homeostasis. White adipose tissue is now known as an endocrine organ due to the secretion of multiple molecules called adipokines. These proteins exert direct effects on whole body functions, including lipid metabolism, angiogenesis, inflammation, and reproduction, whereas changes in their level are linked with pathological events, such as infertility, diabetes, and increased food intake. Vaspin-visceral adipose tissue-derived serine protease inhibitor, or SERPINA12 according to serpin nomenclature, is an adipokine discovered in 2005 that is connected to the development of insulin resistance, obesity, and inflammation. A significantly higher amount of vaspin was observed in obese patients. The objective of this review was to summarize the latest findings about vaspin expression and action in endocrine tissues, such as the hypothalamus, pituitary gland, adipose tissue, thyroid, ovary, placenta, and testis, as well as discuss the link between vaspin and pathologies connected with hormonal imbalance.
      Citation: Cells
      PubDate: 2021-07-06
      DOI: 10.3390/cells10071710
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1711: Translation Initiation Regulated by
           RNA-Binding Protein in Mammals: The Modulation of Translation Initiation
           Complex by Trans-Acting Factors

    • Authors: Akira Fukao, Takumi Tomohiro, Toshinobu Fujiwara
      First page: 1711
      Abstract: Protein synthesis is tightly regulated at each step of translation. In particular, the formation of the basic cap-binding complex, eukaryotic initiation factor 4F (eIF4F) complex, on the 5′ cap structure of mRNA is positioned as the rate-limiting step, and various cis-elements on mRNA contribute to fine-tune spatiotemporal protein expression. The cis-element on mRNAs is recognized and bound to the trans-acting factors, which enable the regulation of the translation rate or mRNA stability. In this review, we focus on the molecular mechanism of how the assembly of the eIF4F complex is regulated on the cap structure of mRNAs. We also summarize the fine-tuned regulation of translation initiation by various trans-acting factors through cis-elements on mRNAs.
      Citation: Cells
      PubDate: 2021-07-06
      DOI: 10.3390/cells10071711
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1712: Changes in Cerebrospinal Fluid Balance of TNF
           and TNF Receptors in Naïve Multiple Sclerosis Patients: Early Involvement
           in Compartmentalised Intrathecal Inflammation

    • Authors: Roberta Magliozzi, Francesco Pezzini, Mairi Pucci, Stefania Rossi, Francesco Facchiano, Damiano Marastoni, Martina Montagnana, Giuseppe Lippi, Richard Reynolds, Massimiliano Calabrese
      First page: 1712
      Abstract: An imbalance of TNF signalling in the inflammatory milieu generated by meningeal immune cell infiltrates in the subarachnoid space in multiple sclerosis (MS), and its animal model may lead to increased cortical pathology. In order to explore whether this feature may be present from the early stages of MS and may be associated with the clinical outcome, the protein levels of TNF, sTNF-R1 and sTNF-R2 were assayed in CSF collected from 122 treatment-naïve MS patients and 36 subjects with other neurological conditions at diagnosis. Potential correlations with other CSF cytokines/chemokines and with clinical and imaging parameters at diagnosis (T0) and after 2 years of follow-up (T24) were evaluated. Significantly increased levels of TNF (fold change: 7.739; p < 0.001), sTNF-R1 (fold change: 1.693; p < 0.001) and sTNF-R2 (fold change: 2.189; p < 0.001) were detected in CSF of MS patients compared to the control group at T0. Increased TNF levels in CSF were significantly (p < 0.01) associated with increased EDSS change (r = 0.43), relapses (r = 0.48) and the appearance of white matter lesions (r = 0.49). CSF levels of TNFR1 were associated with cortical lesion volume (r = 0.41) at T0, as well as with new cortical lesions (r = 0.56), whilst no correlation could be found between TNFR2 levels in CSF and clinical or MRI features. Combined correlation and pathway analysis (ingenuity) of the CSF protein pattern associated with TNF expression (encompassing elevated levels of BAFF, IFN-γ, IL-1β, IL-10, IL-8, IL-16, CCL21, haptoglobin and fibrinogen) showed a particular relationship to the interaction between innate and adaptive immune response. The CSF sTNF-R1-associated pattern (encompassing high levels of CXCL13, TWEAK, LIGHT, IL-35, osteopontin, pentraxin-3, sCD163 and chitinase-3-L1) was mainly related to altered T cell and B cell signalling. Finally, the CSF TNFR2-associated pattern (encompassing high CSF levels of IFN-β, IFN-λ2, sIL-6Rα) was linked to Th cell differentiation and regulatory cytokine signalling. In conclusion, dysregulation of TNF and TNF-R1/2 pathways associates with specific clinical/MRI profiles and can be identified at a very early stage in MS patients, at the time of diagnosis, contributing to the prediction of the disease outcome.
      Citation: Cells
      PubDate: 2021-07-06
      DOI: 10.3390/cells10071712
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1713: In Vitro Study of Human Immune Responses to
           Hyaluronic Acid Hydrogels, Recombinant Spidroins and Human Neural
           Progenitor Cells of Relevance to Spinal Cord Injury Repair

    • Authors: Lin, Ekblad-Nordberg, Michaëlsson, Götherström, Hsu, Ye, Johansson, Rising, Sundström, Åkesson
      First page: 1713
      Abstract: Scaffolds of recombinant spider silk protein (spidroin) and hyaluronic acid (HA) hydrogel hold promise in combination with cell therapy for spinal cord injury. However, little is known concerning the human immune response to these biomaterials and grafted human neural stem/progenitor cells (hNPCs). Here, we analyzed short- and long-term in vitro activation of immune cells in human peripheral blood mononuclear cells (hPBMCs) cultured with/without recombinant spidroins, HA hydrogels, and/or allogeneic hNPCs to assess potential host–donor interactions. Viability, proliferation and phenotype of hPBMCs were analyzed using NucleoCounter and flow cytometry. hPBMC viability was confirmed after exposure to the different biomaterials. Short-term (15 h) co-cultures of hPBMCs with spidroins, but not with HA hydrogel, resulted in a significant increase in the proportion of activated CD69+ CD4+ T cells, CD8+ T cells, B cells and NK cells, which likely was caused by residual endotoxins from the Escherichia coli expression system. The observed spidroin-induced hPBMC activation was not altered by hNPCs. It is resource-effective to evaluate human compatibility of novel biomaterials early in development of the production process to, when necessary, make alterations to minimize rejection risk. Here, we present a method to evaluate biomaterials and hPBMC compatibility in conjunction with allogeneic human cells.
      Citation: Cells
      PubDate: 2021-07-06
      DOI: 10.3390/cells10071713
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1714: Brain Protection after Anoxic Brain Injury: Is
           Lactate Supplementation Helpful'

    • Authors: Filippo Annoni, Lorenzo Peluso, Elisa Gouvêa Bogossian, Jacques Creteur, Elisa R. Zanier, Fabio Silvio Taccone
      First page: 1714
      Abstract: While sudden loss of perfusion is responsible for ischemia, failure to supply the required amount of oxygen to the tissues is defined as hypoxia. Among several pathological conditions that can impair brain perfusion and oxygenation, cardiocirculatory arrest is characterized by a complete loss of perfusion to the brain, determining a whole brain ischemic-anoxic injury. Differently from other threatening situations of reduced cerebral perfusion, i.e., caused by increased intracranial pressure or circulatory shock, resuscitated patients after a cardiac arrest experience a sudden restoration of cerebral blood flow and are exposed to a massive reperfusion injury, which could significantly alter cellular metabolism. Current evidence suggests that cell populations in the central nervous system might use alternative metabolic pathways to glucose and that neurons may rely on a lactate-centered metabolism. Indeed, lactate does not require adenosine triphosphate (ATP) to be oxidated and it could therefore serve as an alternative substrate in condition of depleted energy reserves, i.e., reperfusion injury, even in presence of adequate tissue oxygen delivery. Lactate enriched solutions were studied in recent years in healthy subjects, acute heart failure, and severe traumatic brain injured patients, showing possible benefits that extend beyond the role as alternative energetic substrates. In this manuscript, we addressed some key aspects of the cellular metabolic derangements occurring after cerebral ischemia-reperfusion injury and examined the possible rationale for the administration of lactate enriched solutions in resuscitated patients after cardiac arrest.
      Citation: Cells
      PubDate: 2021-07-06
      DOI: 10.3390/cells10071714
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1715: Hypoxia, Metabolic Reprogramming, and Drug
           Resistance in Liver Cancer

    • Authors: Macus Hao-Ran Bao, Carmen Chak-Lui Wong
      First page: 1715
      Abstract: Hypoxia, low oxygen (O2) level, is a hallmark of solid cancers, especially hepatocellular carcinoma (HCC), one of the most common and fatal cancers worldwide. Hypoxia contributes to drug resistance in cancer through various molecular mechanisms. In this review, we particularly focus on the roles of hypoxia-inducible factor (HIF)-mediated metabolic reprogramming in drug resistance in HCC. Combination therapies targeting hypoxia-induced metabolic enzymes to overcome drug resistance will also be summarized. Acquisition of drug resistance is the major cause of unsatisfactory clinical outcomes of existing HCC treatments. Extra efforts to identify novel mechanisms to combat refractory hypoxic HCC are warranted for the development of more effective treatment regimens for HCC patients.
      Citation: Cells
      PubDate: 2021-07-06
      DOI: 10.3390/cells10071715
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1716: Cardiac Fibrosis and Fibroblasts

    • Authors: Kurose
      First page: 1716
      Abstract: Cardiac fibrosis is the excess deposition of extracellular matrix (ECM), such as collagen. Myofibroblasts are major players in the production of collagen, and are differentiated primarily from resident fibroblasts. Collagen can compensate for the dead cells produced by injury. The appropriate production of collagen is beneficial for preserving the structural integrity of the heart, and protects the heart from cardiac rupture. However, excessive deposition of collagen causes cardiac dysfunction. Recent studies have demonstrated that myofibroblasts can change their phenotypes. In addition, myofibroblasts are found to have functions other than ECM production. Myofibroblasts have macrophage-like functions, in which they engulf dead cells and secrete anti-inflammatory cytokines. Research into fibroblasts has been delayed due to the lack of selective markers for the identification of fibroblasts. In recent years, it has become possible to genetically label fibroblasts and perform sequencing at single-cell levels. Based on new technologies, the origins of fibroblasts and myofibroblasts, time-dependent changes in fibroblast states after injury, and fibroblast heterogeneity have been demonstrated. In this paper, recent advances in fibroblast and myofibroblast research are reviewed.
      Citation: Cells
      PubDate: 2021-07-06
      DOI: 10.3390/cells10071716
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1717: In Vitro Cell Toxicity and Intracellular
           Uptake of Doxorubicin Exposed as a Solution or Liposomes: Implications for
           Treatment of Hepatocellular Carcinoma

    • Authors: Kullenberg, Degerstedt, Calitz, Pavlović, Balgoma, Gråsjö, Sjögren, Hedeland, Heindryckx, Lennernäs
      First page: 1717
      Abstract: Cytostatic effects of doxorubicin in clinically applied doses are often inadequate and limited by systemic toxicity. The main objective of this in vitro study was to determine the anti-tumoral effect (IC50) and intracellular accumulation of free and liposomal doxorubicin (DOX) in four human cancer cell lines (HepG2, Huh7, SNU449 and MCF7). The results of this study showed a correlation between longer DOX exposure time and lower IC50 values, which can be attributed to an increased cellular uptake and intracellular exposure of DOX, ultimately leading to cell death. We found that the total intracellular concentrations of DOX were a median value of 230 times higher than the exposure concentrations after exposure to free DOX. The intracellular uptake of DOX from solution was at least 10 times higher than from liposomal formulation. A physiologically based pharmacokinetic model was developed to translate these novel quantitative findings to a clinical context and to simulate clinically relevant drug concentration–time curves. This showed that a liver tumor resembling the liver cancer cell line SNU449, the most resistant cell line in this study, would not reach therapeutic exposure at a standard clinical parenteral dose of doxorubicin (50 mg/m2), which is serious limitation for this drug. This study emphasizes the importance of in-vitro to in-vivo translations in the assessment of clinical consequence of experimental findings.
      Citation: Cells
      PubDate: 2021-07-06
      DOI: 10.3390/cells10071717
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1718: Epigenetic Drifts during Long-Term Intestinal
           Organoid Culture

    • Authors: Torsten Thalheim, Susann Siebert, Marianne Quaas, Maria Herberg, Michal R. Schweiger, Gabriela Aust, Joerg Galle
      First page: 1718
      Abstract: Organoids retain the morphological and molecular patterns of their tissue of origin, are self-organizing, relatively simple to handle and accessible to genetic engineering. Thus, they represent an optimal tool for studying the mechanisms of tissue maintenance and aging. Long-term expansion under standard growth conditions, however, is accompanied by changes in the growth pattern and kinetics. As a potential explanation of these alterations, epigenetic drifts in organoid culture have been suggested. Here, we studied histone tri-methylation at lysine 4 (H3K4me3) and 27 (H3K27me3) and transcriptome profiles of intestinal organoids derived from mismatch repair (MMR)-deficient and control mice and cultured for 3 and 20 weeks and compared them with data on their tissue of origin. We found that, besides the expected changes in short-term culture, the organoids showed profound changes in their epigenomes also during the long-term culture. The most prominent were epigenetic gene activation by H3K4me3 recruitment to previously unmodified genes and by H3K27me3 loss from originally bivalent genes. We showed that a long-term culture is linked to broad transcriptional changes that indicate an ongoing maturation and metabolic adaptation process. This process was disturbed in MMR-deficient mice, resulting in endoplasmic reticulum (ER) stress and Wnt activation. Our results can be explained in terms of a mathematical model assuming that epigenetic changes during a long-term culture involve DNA demethylation that ceases if the metabolic adaptation is disturbed.
      Citation: Cells
      PubDate: 2021-07-07
      DOI: 10.3390/cells10071718
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1719: Contribution of Adventitia-Derived Stem and
           Progenitor Cells to New Vessel Formation in Tumors

    • Authors: Berin Upcin, Erik Henke, Florian Kleefeldt, Helene Hoffmann, Andreas Rosenwald, Ster Irmak-Sav, Huseyin Bertal Aktas, Uwe Rückschloß, Süleyman Ergün
      First page: 1719
      Abstract: Blocking tumor vascularization has not yet come to fruition to the extent it was hoped for, as angiogenesis inhibitors have shown only partial success in the clinic. We hypothesized that under-appreciated vascular wall-resident stem and progenitor cells (VW-SPCs) might be involved in tumor vascularization and influence effectiveness of anti-angiogenic therapy. Indeed, in patient samples, we observed that vascular adventitia-resident CD34+ VW-SPCs are recruited to tumors in situ from co-opted vessels. To elucidate this in detail, we established an ex vivo model using concomitant embedding of multi-cellular tumor spheroids (MCTS) and mouse aortic rings (ARs) into collagen gels, similar to the so-called aortic ring assay (ARA). Moreover, ARA was modified by removing the ARs’ adventitia that harbors VW-SPCs. Thus, this model enabled distinguishing the contribution of VW-SPCs from that of mature endothelial cells (ECs) to new vessel formation. Our results show that the formation of capillary-like sprouts is considerably delayed, and their number and network formation were significantly reduced by removing the adventitia. Substituting iPSC-derived neural spheroids for MCTS resulted in distinct sprouting patterns that were also strongly influenced by the presence or absence of VW-SPCs, also underlying the involvement of these cells in non-pathological vascularization. Our data suggest that more comprehensive approaches are needed in order to block all of the mechanisms contributing to tumor vascularization.
      Citation: Cells
      PubDate: 2021-07-07
      DOI: 10.3390/cells10071719
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1720: Role of Alternative Splicing in Regulating
           Host Response to Viral Infection

    • Authors: Kuo-Chieh Liao, Mariano A. Garcia-Blanco
      First page: 1720
      Abstract: The importance of transcriptional regulation of host genes in innate immunity against viral infection has been widely recognized. More recently, post-transcriptional regulatory mechanisms have gained appreciation as an additional and important layer of regulation to fine-tune host immune responses. Here, we review the functional significance of alternative splicing in innate immune responses to viral infection. We describe how several central components of the Type I and III interferon pathways encode spliced isoforms to regulate IFN activation and function. Additionally, the functional roles of splicing factors and modulators in antiviral immunity are discussed. Lastly, we discuss how cell death pathways are regulated by alternative splicing as well as the potential role of this regulation on host immunity and viral infection. Altogether, these studies highlight the importance of RNA splicing in regulating host–virus interactions and suggest a role in downregulating antiviral innate immunity; this may be critical to prevent pathological inflammation.
      Citation: Cells
      PubDate: 2021-07-08
      DOI: 10.3390/cells10071720
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1721: Cardiolipin, Non-Bilayer Structures and
           Mitochondrial Bioenergetics: Relevance to Cardiovascular Disease

    • Authors: Edward S. Gasanoff, Lev S. Yaguzhinsky, Győző Garab
      First page: 1721
      Abstract: The present review is an attempt to conceptualize a contemporary understanding about the roles that cardiolipin, a mitochondrial specific conical phospholipid, and non-bilayer structures, predominantly found in the inner mitochondrial membrane (IMM), play in mitochondrial bioenergetics. This review outlines the link between changes in mitochondrial cardiolipin concentration and changes in mitochondrial bioenergetics, including changes in the IMM curvature and surface area, cristae density and architecture, efficiency of electron transport chain (ETC), interaction of ETC proteins, oligomerization of respiratory complexes, and mitochondrial ATP production. A relationship between cardiolipin decline in IMM and mitochondrial dysfunction leading to various diseases, including cardiovascular diseases, is thoroughly presented. Particular attention is paid to the targeting of cardiolipin by Szeto–Schiller tetrapeptides, which leads to rejuvenation of important mitochondrial activities in dysfunctional and aging mitochondria. The role of cardiolipin in triggering non-bilayer structures and the functional roles of non-bilayer structures in energy-converting membranes are reviewed. The latest studies on non-bilayer structures induced by cobra venom peptides are examined in model and mitochondrial membranes, including studies on how non-bilayer structures modulate mitochondrial activities. A mechanism by which non-bilayer compartments are formed in the apex of cristae and by which non-bilayer compartments facilitate ATP synthase dimerization and ATP production is also presented.
      Citation: Cells
      PubDate: 2021-07-08
      DOI: 10.3390/cells10071721
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1722: How Influenza Virus Uses Host Cell Pathways
           during Uncoating

    • Authors: Etori Aguiar Moreira, Yohei Yamauchi, Patrick Matthias
      First page: 1722
      Abstract: Influenza is a zoonotic respiratory disease of major public health interest due to its pandemic potential, and a threat to animals and the human population. The influenza A virus genome consists of eight single-stranded RNA segments sequestered within a protein capsid and a lipid bilayer envelope. During host cell entry, cellular cues contribute to viral conformational changes that promote critical events such as fusion with late endosomes, capsid uncoating and viral genome release into the cytosol. In this focused review, we concisely describe the virus infection cycle and highlight the recent findings of host cell pathways and cytosolic proteins that assist influenza uncoating during host cell entry.
      Citation: Cells
      PubDate: 2021-07-08
      DOI: 10.3390/cells10071722
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1723: Salivary Gland Tissue Engineering Approaches:
           State of the Art and Future Directions

    • Authors: Lindsay R. Piraino, Danielle S. W. Benoit, Lisa A. DeLouise
      First page: 1723
      Abstract: Salivary gland regeneration is important for developing treatments for radiation-induced xerostomia, Sjögren’s syndrome, and other conditions that cause dry mouth. Culture conditions adopted from tissue engineering strategies have been used to recapitulate gland structure and function to study and regenerate the salivary glands. The purpose of this review is to highlight current trends in the field, with an emphasis on soluble factors that have been shown to improve secretory function in vitro. A PubMed search was conducted to identify articles published in the last 10 years and articles were evaluated to identify the most promising approaches and areas for further research. Results showed increasing use of extracellular matrix mimetics, such as Matrigel®, collagen, and a variety of functionalized polymers. Soluble factors that provide supportive cues, including fibroblast growth factors (FGFs) and neurotrophic factors, as well as chemical inhibitors of Rho-associated kinase (ROCK), epidermal growth factor receptor (EGFR), and transforming growth factor β receptor (TGFβR) have shown increases in important markers including aquaporin 5 (Aqp5); muscle, intestine, and stomach expression 1 (Mist1); and keratin (K5). However, recapitulation of tissue function at in vivo levels is still elusive. A focus on identification of soluble factors, cells, and/or matrix cues tested in combination may further increase the maintenance of salivary gland secretory function in vitro. These approaches may also be amenable for translation in vivo to support successful regeneration of dysfunctional glands.
      Citation: Cells
      PubDate: 2021-07-08
      DOI: 10.3390/cells10071723
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1724: ACE2 Is Expressed in Immune Cells That
           Infiltrate the Placenta in Infection-Associated Preterm Birth

    • Authors: Phetcharawan Lye, Caroline E. Dunk, Jianhong Zhang, Yanxing Wei, Jittanan Nakpu, Hirotaka Hamada, Guinever E. Imperio, Enrrico Bloise, Stephen G. Matthews, Stephen J. Lye
      First page: 1724
      Abstract: COVID-19 is associated with increased incidence of preterm birth (PTB). We assessed pathways by which SARS-CoV-2 could access the placenta. Placentae, from PTB with or without chorioamnionitis (ChA), or from term pregnancies (n = 12/13/group) were collected. Peripheral blood was collected from healthy pregnant women (n = 6). Second trimester placental explants (16–20 weeks, n = 5/group) were treated with lipopolysaccharide (LPS, to mimic bacterial infection) and ACE2, CCL2, IL-6/8 and TNFα mRNA was assessed. ChA-placentae exhibited increased ACE2 and CCL2 mRNA expression (p < 0.05). LPS increased cytokine and ACE2 mRNA in placental explants. Placental ACE2 protein localized to syncytiotrophoblast, fetal endothelium, extravillous trophoblast and in immune cells-subsets (M1/M2 macrophage and neutrophils) within the villous stroma. Significantly increased numbers of M1 macrophage and neutrophils were present in the ChA-placenta (p < 0.001). Subsets of peripheral immune cells from pregnant women express the ACE2 mRNA and protein. A greater fraction of granulocytes was positive for ACE2 protein expression compared to lymphocytes or monocytes. These data suggest that in pregnancies complicated by ChA, ACE2 positive immune cells in the maternal circulation have the potential to traffic SARS-CoV-2 virus to the placenta and increase the risk of vertical transmission to the placenta/fetus.
      Citation: Cells
      PubDate: 2021-07-08
      DOI: 10.3390/cells10071724
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1725: Use of Synchrotron Phase-Sensitive Imaging for
           the Investigation of Magnetopriming and Solar UV-Exclusion Impact on
           Soybean (Glycine max) Leaves

    • Authors: Anis Fatima, Sunita Kataria, Ashish Kumar Agrawal, Balwant Singh, Yogesh Kashyap, Meeta Jain, Marian Brestic, Suleyman I. Allakhverdiev, Anshu Rastogi
      First page: 1725
      Abstract: The combined response of exclusion of solar ultraviolet radiation (UV-A+B and UV-B) and static magnetic field (SMF) pre-treatment of 200 mT for 1 h were studied on soybean (Glycine max) leaves using synchrotron imaging. The seeds of soybean with and without SMF pre-treatment were sown in nursery bags kept in iron meshes where UV-A+B (280–400 nm) and UV-B (280–315 nm) from solar radiation were filtered through a polyester filters. Two controls were planned, one with polythene filter controls (FC)- which allows all the UV (280–400 nm); the other control had no filter used (open control-OC). Midrib regions of the intact third trifoliate leaves were imaged using the phase-contrast imaging technique at BL-4, Indus-2 synchrotron radiation source. The solar UV exclusion results suggest that ambient UV caused a reduction in leaf growth which ultimately reduced the photosynthesis in soybean seedlings, while SMF treatment caused enhancement of leaf growth along with photosynthesis even under the presence of ambient UV-B stress. The width of midrib and second-order veins, length of the second-order veins, leaf vein density, and the density of third-order veins obtained from the quantitative image analysis showed an enhancement in the leaves of plants that emerged from SMF pre-treated seeds as compared to untreated ones grown in open control and filter control conditions (in the presence of ambient UV stress). SMF pre-treated seeds along with UV-A+B and UV-B exclusion also showed significant enhancements in leaf parameters as compared to the UV excluded untreated leaves. Our results suggested that SMF-pretreatment of seeds diminishes the ambient UV-induced adverse effects on soybean.
      Citation: Cells
      PubDate: 2021-07-08
      DOI: 10.3390/cells10071725
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1726: Modeling Hepatotropic Viral Infections: Cells
           vs. Animals

    • Authors: Niloofar Khoshdel-Rad, Ensieh Zahmatkesh, Polina Bikmulina, Maria Peshkova, Nastasia Kosheleva, Evgeny A. Bezrukov, Roman B. Sukhanov, Anna Solovieva, Anastasia Shpichka, Peter Timashev, Massoud Vosough
      First page: 1726
      Abstract: The lack of an appropriate platform for a better understanding of the molecular basis of hepatitis viruses and the absence of reliable models to identify novel therapeutic agents for a targeted treatment are the two major obstacles for launching efficient clinical protocols in different types of viral hepatitis. Viruses are obligate intracellular parasites, and the development of model systems for efficient viral replication is necessary for basic and applied studies. Viral hepatitis is a major health issue and a leading cause of morbidity and mortality. Despite the extensive efforts that have been made on fundamental and translational research, traditional models are not effective in representing this viral infection in a laboratory. In this review, we discuss in vitro cell-based models and in vivo animal models, with their strengths and weaknesses. In addition, the most important findings that have been retrieved from each model are described.
      Citation: Cells
      PubDate: 2021-07-08
      DOI: 10.3390/cells10071726
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1727: M2 Muscarinic Receptor Activation Impairs
           Mitotic Progression and Bipolar Mitotic Spindle Formation in Human
           Glioblastoma Cell Lines

    • Authors: Maria Di Bari, Vanessa Tombolillo, Francesco Alessandrini, Claudia Guerriero, Mario Fiore, Italia Anna Asteriti, Emilia Castigli, Miriam Sciaccaluga, Giulia Guarguaglini, Francesca Degrassi, Ada Maria Tata
      First page: 1727
      Abstract: Background: Glioblastoma multiforme (GBM) is characterized by several genetic abnormalities, leading to cell cycle deregulation and abnormal mitosis caused by a defective checkpoint. We previously demonstrated that arecaidine propargyl ester (APE), an orthosteric agonist of M2 muscarinic acetylcholine receptors (mAChRs), arrests the cell cycle of glioblastoma (GB) cells, reducing their survival. The aim of this work was to better characterize the molecular mechanisms responsible for this cell cycle arrest. Methods: The arrest of cell proliferation was evaluated by flow cytometry analysis. Using immunocytochemistry and time-lapse analysis, the percentage of abnormal mitosis and aberrant mitotic spindles were assessed in both cell lines. Western blot analysis was used to evaluate the modulation of Sirtuin2 and acetylated tubulin—factors involved in the control of cell cycle progression. Results: APE treatment caused arrest in the M phase, as indicated by the increase in p-HH3 (ser10)-positive cells. By immunocytochemistry, we found a significant increase in abnormal mitoses and multipolar mitotic spindle formation after APE treatment. Time-lapse analysis confirmed that the APE-treated GB cells were unable to correctly complete the mitosis. The modulated expression of SIRT2 and acetylated tubulin in APE-treated cells provides new insights into the mechanisms of altered mitotic progression in both GB cell lines. Conclusions: Our data show that the M2 agonist increases aberrant mitosis in GB cell lines. These results strengthen the idea of considering M2 acetylcholine receptors a novel promising therapeutic target for the glioblastoma treatment.
      Citation: Cells
      PubDate: 2021-07-08
      DOI: 10.3390/cells10071727
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1728: Phagocytic Activities of Reactive Microglia
           and Astrocytes Associated with Prion Diseases Are Dysregulated in Opposite

    • Authors: Anshuman Sinha, Rajesh Kushwaha, Kara Molesworth, Olga Mychko, Natallia Makarava, Ilia V. Baskakov
      First page: 1728
      Abstract: Phagocytosis is one of the most important physiological functions of the glia directed at maintaining a healthy, homeostatic environment in the brain. Under a homeostatic environment, the phagocytic activities of astrocytes and microglia are tightly coordinated in time and space. In neurodegenerative diseases, both microglia and astrocytes contribute to neuroinflammation and disease pathogenesis, however, whether their phagocytic activities are up- or downregulated in reactive states is not known. To address this question, this current study isolated microglia and astrocytes from C57BL/6J mice infected with prions and tested their phagocytic activities in live-cell imaging assays that used synaptosomes and myelin debris as substrates. The phagocytic uptake by the reactive microglia was found to be significantly upregulated, whereas that of the reactive astrocytes was strongly downregulated. The up- and downregulation of phagocytosis by the two cell types were observed irrespective of whether disease-associated synaptosomes, normal synaptosomes, or myelin debris were used in the assays, indicating that dysregulations are dictated by cell reactive states, not substrates. Analysis of gene expression confirmed dysregulation of phagocytic functions in both cell types. Immunostaining of animal brains infected with prions revealed that at the terminal stage of disease, neuronal cell bodies were subject to engulfment by reactive microglia. This study suggests that imbalance in the phagocytic activities of the reactive microglia and astrocytes, which are dysregulated in opposite directions, is likely to lead to excessive microglia-mediated neuronal death on the one hand, and the inability of astrocytes to clear cell debris on the other hand, contributing to the neurotoxic effects of glia as a whole.
      Citation: Cells
      PubDate: 2021-07-08
      DOI: 10.3390/cells10071728
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1729: The Role of MSC in Wound Healing, Scarring and

    • Authors: Raquel Guillamat-Prats
      First page: 1729
      Abstract: Tissue repair and regeneration after damage is not completely understood, and current therapies to support this process are limited. The wound healing process is associated with cell migration and proliferation, extracellular matrix remodeling, angiogenesis and re-epithelialization. In normal conditions, a wound will lead to healing, resulting in reparation of the tissue. Several risk factors, chronic inflammation, and some diseases lead to a deficient wound closure, producing a scar that can finish with a pathological fibrosis. Mesenchymal stem/stromal cells (MSCs) are widely used for their regenerative capacity and their possible therapeutically potential. Derived products of MSCs, such as exosomes or extravesicles, have shown a therapeutic potential similar to MSCs, and these cell-free products may be interesting in clinics. MSCs or their derivative products have shown paracrine beneficial effects, regulating inflammation, modifying the fibroblast activation and production of collagen and promoting neovascularization and re-epithelialization. This review describes the effects of MSCs and their derived products in each step of the wound repair process. As well, it reviews the pre-clinical and clinical use of MSCs to benefit in skin wound healing in diabetic associated wounds and in pathophysiological fibrosis.
      Citation: Cells
      PubDate: 2021-07-08
      DOI: 10.3390/cells10071729
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1730: Pathophysiological Effects of Overactive STIM1
           on Murine Muscle Function and Structure

    • Authors: Roberto Silva-Rojas, Anne-Laure Charles, Sarah Djeddi, Bernard Geny, Jocelyn Laporte, Johann Böhm
      First page: 1730
      Abstract: Store-operated Ca2+ entry (SOCE) is a ubiquitous mechanism regulating extracellular Ca2+ entry to control a multitude of Ca2+-dependent signaling pathways and cellular processes. SOCE relies on the concerted activity of the reticular Ca2+ sensor STIM1 and the plasma membrane Ca2+ channel ORAI1, and dysfunctions of these key factors result in human pathologies. STIM1 and ORAI1 gain-of-function (GoF) mutations induce excessive Ca2+ influx through SOCE over-activation, and cause tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK), two overlapping disorders characterized by muscle weakness, and additional multi-systemic signs affecting growth, platelets, spleen, skin, and intellectual abilities. In order to investigate the pathophysiological effect of overactive SOCE on muscle function and structure, we combined transcriptomics with morphological and functional studies on a TAM/STRMK mouse model. Muscles from Stim1R304W/+ mice displayed aberrant expression profiles of genes implicated in Ca2+ handling and excitation-contraction coupling (ECC), and in vivo investigations evidenced delayed muscle contraction and relaxation kinetics. We also identified signs of reticular stress and abnormal mitochondrial activity, and histological and respirometric analyses on muscle samples revealed enhanced myofiber degeneration associated with reduced mitochondrial respiration. Taken together, we uncovered a molecular disease signature and deciphered the pathomechanism underlying the functional and structural muscle anomalies characterizing TAM/STRMK.
      Citation: Cells
      PubDate: 2021-07-08
      DOI: 10.3390/cells10071730
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1731: Group V Phospholipase A2 Mediates Endothelial
           Dysfunction and Acute Lung Injury Caused by Methicillin-Resistant
           Staphylococcus Aureus

    • Authors: Yu Maw Htwe, Huashan Wang, Patrick Belvitch, Lucille Meliton, Mounica Bandela, Eleftheria Letsiou, Steven M. Dudek
      First page: 1731
      Abstract: Lung endothelial dysfunction is a key feature of acute lung injury (ALI) and clinical acute respiratory distress syndrome (ARDS). Previous studies have identified the lipid-generating enzyme, group V phospholipase A2 (gVPLA2), as a mediator of lung endothelial barrier disruption and inflammation. The current study aimed to determine the role of gVPLA2 in mediating lung endothelial responses to methicillin-resistant Staphylococcus aureus (MRSA, USA300 strain), a major cause of ALI/ARDS. In vitro studies assessed the effects of gVPLA2 inhibition on lung endothelial cell (EC) permeability after exposure to heat-killed (HK) MRSA. In vivo studies assessed the effects of intratracheal live or HK-MRSA on multiple indices of ALI in wild-type (WT) and gVPLA2-deficient (KO) mice. In vitro, HK-MRSA increased gVPLA2 expression and permeability in human lung EC. Inhibition of gVPLA2 with either the PLA2 inhibitor, LY311727, or with a specific monoclonal antibody, attenuated the barrier disruption caused by HK-MRSA. LY311727 also reduced HK-MRSA-induced permeability in mouse lung EC isolated from WT but not gVPLA2-KO mice. In vivo, live MRSA caused significantly less ALI in gVPLA2 KO mice compared to WT, findings confirmed by intravital microscopy assessment in HK-MRSA-treated mice. After targeted delivery of gVPLA2 plasmid to lung endothelium using ACE antibody-conjugated liposomes, MRSA-induced ALI was significantly increased in gVPLA2-KO mice, indicating that lung endothelial expression of gVPLA2 is critical in vivo. In summary, these results demonstrate an important role for gVPLA2 in mediating MRSA-induced lung EC permeability and ALI. Thus, gVPLA2 may represent a novel therapeutic target in ALI/ARDS caused by bacterial infection.
      Citation: Cells
      PubDate: 2021-07-08
      DOI: 10.3390/cells10071731
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1732: Obesity-Induced Dysbiosis Exacerbates IFN-γ
           Production and Pulmonary Inflammation in the Mycobacterium tuberculosis

    • Authors: Sandra Patricia Palma Albornoz, Thais Fernanda de Campos Fraga-Silva, Ana Flávia Gembre, Rômulo Silva de Oliveira, Fernanda Mesquita de Souza, Tamara Silva Rodrigues, Isis do Carmo Kettelhut, Camila Sanches Manca, Alceu Afonso Jordao, Leandra Naira Zambelli Ramalho, Paulo Eduardo Martins Ribolla, Daniela Carlos, Vânia Luiza Deperon Bonato
      First page: 1732
      Abstract: The microbiota of the gut–lung axis affects local and far-reaching immune responses and might also trigger chronic and inflammatory diseases. We hypothesized that gut dysbiosis induced by obesity, which coexists in countries with a high tuberculosis burden, aggravates the host susceptibility and the pulmonary damage tolerance. To assess our hypothesis, we used a model of high-fat diet (HFD)-induced obesity, followed by infection of C57BL/6 mice with Mycobacterium tuberculosis. We showed that obesity increased the susceptibility, the pulmonary inflammation and IFN-γ levels in M. tuberculosis-infected mice. During the comorbidity obesity and tuberculosis, there is an increase of Bacteroidetes and Firmicutes in the lungs, and an increase of Firmicutes and butyrate in the feces. Depletion of gut microbiota by antibiotic treatment in the obese infected mice reduced the frequencies of CD4+IFN-γ+IL-17− cells and IFN-γ levels in the lungs, associated with an increase of Lactobacillus. Our findings reinforce the role of the gut–lung axis in chronic infections and suggest that the gut microbiota modulation may be a potential host-directed therapy as an adjuvant to treat TB in the context of IFN-γ-mediated immunopathology.
      Citation: Cells
      PubDate: 2021-07-08
      DOI: 10.3390/cells10071732
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1733: Extracellular Vesicles in Multiple Sclerosis:
           Role in the Pathogenesis and Potential Usefulness as Biomarkers and
           Therapeutic Tools

    • Authors: Marianna D’Anca, Chiara Fenoglio, Francesca Romana Buccellato, Caterina Visconte, Daniela Galimberti, Elio Scarpini
      First page: 1733
      Abstract: Although extracellular vesicles (EVs) were initially relegated to a waste disposal role, nowadays, they have gained multiple fundamental functions working as messengers in intercellular communication as well as exerting active roles in physiological and pathological processes. Accumulating evidence proves the involvement of EVs in many diseases, including those of the central nervous system (CNS), such as multiple sclerosis (MS). Indeed, these membrane-bound particles, produced in any type of cell, carry and release a vast range of bioactive molecules (nucleic acids, proteins, and lipids), conferring genotypic and phenotypic changes to the recipient cell. This means that not only EVs per se but their content, especially, could reveal new candidate disease biomarkers and/or therapeutic agents. This review is intended to provide an overview regarding current knowledge about EVs’ involvement in MS, analyzing the potential versatility of EVs as a new therapeutic tool and source of biomarkers.
      Citation: Cells
      PubDate: 2021-07-08
      DOI: 10.3390/cells10071733
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1734: Self-Assembled Permanent Micro-Magnets in a
           Polymer-Based Microfluidic Device for Magnetic Cell Sorting

    • Authors: Lucie Descamps, Marie-Charlotte Audry, Jordyn Howard, Samir Mekkaoui, Clément Albin, David Barthelemy, Léa Payen, Jessica Garcia, Emmanuelle Laurenceau, Damien Le Roy, Anne-Laure Deman
      First page: 1734
      Abstract: Magnetophoresis-based microfluidic devices offer simple and reliable manipulation of micro-scale objects and provide a large panel of applications, from selective trapping to high-throughput sorting. However, the fabrication and integration of micro-scale magnets in microsystems involve complex and expensive processes. Here we report on an inexpensive and easy-to-handle fabrication process of micrometer-scale permanent magnets, based on the self-organization of NdFeB particles in a polymer matrix (polydimethylsiloxane, PDMS). A study of the inner structure by X-ray tomography revealed a chain-like organization of the particles leading to an array of hard magnetic microstructures with a mean diameter of 4 µm. The magnetic performance of the self-assembled micro-magnets was first estimated by COMSOL simulations. The micro-magnets were then integrated into a microfluidic device where they act as micro-traps. The magnetic forces exerted by the micro-magnets on superparamagnetic beads were measured by colloidal probe atomic force microscopy (AFM) and in operando in the microfluidic system. Forces as high as several nanonewtons were reached. Adding an external millimeter-sized magnet allowed target magnetization and the interaction range to be increased. Then, the integrated micro-magnets were used to study the magnetophoretic trapping efficiency of magnetic beads, providing efficiencies of 100% at 0.5 mL/h and 75% at 1 mL/h. Finally, the micro-magnets were implemented for cell sorting by performing white blood cell depletion.
      Citation: Cells
      PubDate: 2021-07-09
      DOI: 10.3390/cells10071734
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1735: Leukocytes in Inflammation, Resolution of
           Inflammation, Autoimmune Diseases and Cancer

    • Authors: János G. Filep
      First page: 1735
      Abstract: Inflammation is a double-edged sword [...]
      Citation: Cells
      PubDate: 2021-07-09
      DOI: 10.3390/cells10071735
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1736: In Silico Analysis of the Longevity and
           Timeline of Individual Germinal Center Reactions in a Primary Immune

    • Authors: Theinmozhi Arulraj, Sebastian C. Binder, Michael Meyer-Hermann
      First page: 1736
      Abstract: Germinal centers (GCs) are transient structures in the secondary lymphoid organs, where B cells undergo affinity maturation to produce high affinity memory and plasma cells. The lifetime of GC responses is a critical factor limiting the extent of affinity maturation and efficiency of antibody responses. While the average lifetime of overall GC reactions in a lymphoid organ is determined experimentally, the lifetime of individual GCs has not been monitored due to technical difficulties in longitudinal analysis. In silico analysis of the contraction phase of GC responses towards primary immunization with sheep red blood cells suggested that if individual GCs had similar lifetimes, the data would be consistent only when new GCs were formed until a very late phase after immunization. Alternatively, there could be a large variation in the lifetime of individual GCs suggesting that both long and short-lived GCs might exist in the same lymphoid organ. Simulations predicted that such differences in the lifetime of GCs could arise due to variations in antigen availability and founder cell composition. These findings identify the potential factors limiting GC lifetime and contribute to an understanding of overall GC responses from the perspective of individual GCs in a primary immune response.
      Citation: Cells
      PubDate: 2021-07-09
      DOI: 10.3390/cells10071736
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1737: The Role of Voltage-Dependent Anion Channel in
           Mitochondrial Dysfunction and Human Disease

    • Authors: Joyce T. Varughese, Susan K. Buchanan, Ashley S. Pitt
      First page: 1737
      Abstract: The voltage-dependent anion channel (VDAC) is a β-barrel membrane protein located in the outer mitochondrial membrane (OMM). VDAC has two conductance states: an open anion selective state, and a closed and slightly cation-selective state. VDAC conductance states play major roles in regulating permeability of ATP/ADP, regulation of calcium homeostasis, calcium flux within ER-mitochondria contact sites, and apoptotic signaling events. Three reported structures of VDAC provide information on the VDAC open state via X-ray crystallography and nuclear magnetic resonance (NMR). Together, these structures provide insight on how VDAC aids metabolite transport. The interaction partners of VDAC, together with the permeability of the pore, affect the molecular pathology of diseases including Parkinson’s disease (PD), Friedreich’s ataxia (FA), lupus, and cancer. To fully address the molecular role of VDAC in disease pathology, major questions must be answered on the structural conformers of VDAC. For example, further information is needed on the structure of the closed state, how binding partners or membrane potential could lead to the open/closed states, the function and mobility of the N-terminal α-helical domain of VDAC, and the physiological role of VDAC oligomers. This review covers our current understanding of the various states of VDAC, VDAC interaction partners, and the roles they play in mitochondrial regulation pertaining to human diseases.
      Citation: Cells
      PubDate: 2021-07-09
      DOI: 10.3390/cells10071737
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1738: Dietary Fatty Acids at the Crossroad between
           Obesity and Colorectal Cancer: Fine Regulators of Adipose Tissue
           Homeostasis and Immune Response

    • Authors: Manuela Del Cornò, Rosaria Varì, Beatrice Scazzocchio, Barbara Varano, Roberta Masella, Lucia Conti
      First page: 1738
      Abstract: Colorectal cancer (CRC) is among the major threatening diseases worldwide, being the third most common cancer, and a leading cause of death, with a global incidence expected to increase in the coming years. Enhanced adiposity, particularly visceral fat, is a major risk factor for the development of several tumours, including CRC, and represents an important indicator of incidence, survival, prognosis, recurrence rates, and response to therapy. The obesity-associated low-grade chronic inflammation is thought to be a key determinant in CRC development, with the adipocytes and the adipose tissue (AT) playing a significant role in the integration of diet-related endocrine, metabolic, and inflammatory signals. Furthermore, AT infiltrating immune cells contribute to local and systemic inflammation by affecting immune and cancer cell functions through the release of soluble mediators. Among the factors introduced with diet and enriched in AT, fatty acids (FA) represent major players in inflammation and are able to deeply regulate AT homeostasis and immune cell function through gene expression regulation and by modulating the activity of several transcription factors (TF). This review summarizes human studies on the effects of dietary FA on AT homeostasis and immune cell functions, highlighting the molecular pathways and TF involved. The relevance of FA balance in linking diet, AT inflammation, and CRC is also discussed. Original and review articles were searched in PubMed without temporal limitation up to March 2021, by using fatty acid as a keyword in combination with diet, obesity, colorectal cancer, inflammation, adipose tissue, immune cells, and transcription factors.
      Citation: Cells
      PubDate: 2021-07-09
      DOI: 10.3390/cells10071738
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1739: Characterization of RIN Isoforms and Their
           Expression in Tomato Fruit Ripening

    • Authors: Maria A. Slugina, Gleb I. Efremov, Anna V. Shchennikova, Elena Z. Kochieva
      First page: 1739
      Abstract: Ripening of tomato fleshy fruit is coordinated by transcription factor RIN, which triggers ethylene and carotenoid biosynthesis, sugar accumulation, and cell wall modifications. In this study, we identified and characterized complete sequences of the RIN chromosomal locus in two tomato Solanum lycopersicum cultivars, its rin/RIN genotype, and three wild green-fruited species differing in fruit color and composition. The results reveal that S. lycopersicum cultivars and some wild species (S. pennellii, S. habrochaites, and S. huaylasense) had a 3′-splicing site enabling the transcription of RIN1i and RIN2i isoforms. The other wild species (S. arcanum, S. chmielewskii, S. neorickii, and S. peruvianum) had a 3′-splicing site only for RIN2i, which was consistent with RIN1i and RIN2i expression patterns. The genotype rin/RIN, which had an extended 3′-terminal deletion in the rin allele, mainly expressed the chimeric RIN–MC transcript, which was also found in cultivars (RIN/RIN). The RIN1, but not RIN2, protein is able to induce the transcription of the reporter gene in the Y2H system, which positively correlated with the transcription profile of RIN1i and RIN target genes. We suggest that during fruit ripening, RIN1 activates ripening-related genes, whereas RIN2 and RIN–MC act as modulators by competing for RIN-binding sites in gene promoters, which should be confirmed by further studies on the association between RIN-splicing mechanisms and tomato fruit ripening.
      Citation: Cells
      PubDate: 2021-07-09
      DOI: 10.3390/cells10071739
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1740: The Emergence of Senescent Surface Biomarkers
           as Senotherapeutic Targets

    • Authors: Martina Rossi, Kotb Abdelmohsen
      First page: 1740
      Abstract: Senescence is linked to a wide range of age-associated diseases and physiological declines. Thus, senotherapeutics are emerging to suppress the detrimental effects of senescence either by senomorphics or senolytics. Senomorphics suppress the traits associated with senescence phenotypes, while senolytics aim to clear senescent cells by suppressing their survival and enhancing the apoptotic pathways. The main goal of these approaches is to suppress the proinflammatory senescence-associated secretory phenotype (SASP) and to promote the immune recognition and elimination of senescent cells. One increasingly attractive approach is the targeting of molecules or proteins specifically present on the surface of senescent cells. These proteins may play roles in the maintenance and survival of senescent cells and hence can be targeted for senolysis. In this review, we summarize the recent knowledge regarding senolysis with a focus on novel surface biomarkers of cellular senescence and discuss their emergence as senotherapeutic targets.
      Citation: Cells
      PubDate: 2021-07-09
      DOI: 10.3390/cells10071740
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1741: Fostering “Education”: Do Extracellular
           Vesicles Exploit Their Own Delivery Code'

    • Authors: Mayra Paolillo, Sergio Comincini, Sergio Schinelli
      First page: 1741
      Abstract: Extracellular vesicles (EVs), comprising large microvesicles (MVs) and exosomes (EXs), play a key role in intercellular communication, both in physiological and in a wide variety of pathological conditions. However, the education of EV target cells has so far mainly been investigated as a function of EX cargo, while few studies have focused on the characterization of EV surface membrane molecules and the mechanisms that mediate the addressability of specific EVs to different cell types and tissues. Identifying these mechanisms will help fulfill the diagnostic, prognostic, and therapeutic promises fueled by our growing knowledge of EVs. In this review, we first discuss published studies on the presumed EV “delivery code” and on the combinations of the hypothesized EV surface membrane “sender” and “recipient” molecules that may mediate EV targeting in intercellular communication. Then we briefly review the main experimental approaches and techniques, and the bioinformatic tools that can be used to identify and characterize the structure and functional role of EV surface membrane molecules. In the final part, we present innovative techniques and directions for future research that would improve and deepen our understandings of EV-cell targeting.
      Citation: Cells
      PubDate: 2021-07-09
      DOI: 10.3390/cells10071741
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1742: Death-Associated Protein 6 (Daxx) Alleviates
           Liver Fibrosis by Modulating Smad2 Acetylation

    • Authors: Sung-Min Kim, Won-Hee Hur, Byung-Yoon Kang, Sung-Won Lee, Pu-Reun Roh, Dong-Jun Park, Pil-Soo Sung, Seung-Kew Yoon
      First page: 1742
      Abstract: Transforming growth factor-β (TGF-β) has been identified as an inducer of hepatocyte epithelial–mesenchymal transition (EMT), which triggers liver fibrosis. Death-associated protein 6 (Daxx) is known to be associated with the TGF-β-induced apoptotic pathway, but the function of Daxx in liver fibrosis remains unknown. This study aimed to elucidate the role of Daxx in liver fibrosis. We used liver fibrosis tissues from humans and mice to assess Daxx expression. EMT properties and TGF-β signaling pathway activation were investigated in the Daxx-overexpressing FL83B cell line. The therapeutic effect of Daxx was investigated in a mouse model of liver fibrosis by the hydrodynamic injection of plasmids. The expression of Daxx was markedly decreased in hepatocytes from fibrotic human and mouse livers, as well as in hepatocytes treated with TGF-β in vitro. The overexpression of Daxx inhibited the EMT process by interfering with the TGF-β-induced phosphorylation of Smad2. Coimmunoprecipitation analysis confirmed that Daxx reduced the transcriptional activity of Smad2 by binding to its MH1 domain and interfering with Smad2 acetylation. In addition, the therapeutic delivery of Daxx alleviated liver fibrosis in a thioacetamide-induced fibrosis mouse model. Overall, our results indicate that Daxx could be a potential therapeutic target to modulate fibrogenesis, as well as a useful biomarker for liver fibrosis.
      Citation: Cells
      PubDate: 2021-07-09
      DOI: 10.3390/cells10071742
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1743: Ancestral Sperm Ecotypes Reveal Multiple
           Invasions of a Non-Native Fish in Northern Europe

    • Authors: Leon Green, Apostolos Apostolou, Ellika Faust, Kajsa Palmqvist, Jane W. Behrens, Jonathan N. Havenhand, Erica H. Leder, Charlotta Kvarnemo
      First page: 1743
      Abstract: For externally fertilising organisms in the aquatic environment, the abiotic fertilisation medium can be a strong selecting force. Among bony fishes, sperm are adapted to function in a narrow salinity range. A notable exception is the family Gobiidae, where several species reproduce across a wide salinity range. The family also contains several wide-spread invasive species. To better understand how these fishes tolerate such varying conditions, we measured sperm performance in relation to salinity from a freshwater and a brackish population within their ancestral Ponto-Caspian region of the round goby, Neogobius melanostomus. These two ancestral populations were then compared to nine additional invaded sites across northern Europe, both in terms of their sperm traits and by using genomic SNP markers. Our results show clear patterns of ancestral adaptations to freshwater and brackish salinities in their sperm performance. Population genomic analyses show that the ancestral ecotypes have generally established themselves in environments that fit their sperm adaptations. Sites close to ports with intense shipping show that both outbreeding and admixture can affect the sperm performance of a population in a given salinity. Rapid adaptation to local conditions is also supported at some sites. Historical and contemporary evolution in the traits of the round goby sperm cells is tightly linked to the population and seascape genomics as well as biogeographic processes in these invasive fishes. Since the risk of a population establishing in an area is related to the genotype by environment match, port connectivity and the ancestry of the round goby population can likely be useful for predicting the species spread.
      Citation: Cells
      PubDate: 2021-07-09
      DOI: 10.3390/cells10071743
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1744: High Intakes of Bioavailable Phosphate May
           Promote Systemic Oxidative Stress and Vascular Calcification by Boosting
           Mitochondrial Membrane Potential—Is Good Magnesium Status an

    • Authors: Mark F. McCarty, Aaron Lerner, James J. DiNicolantonio, Simon B. Iloki-Assanga
      First page: 1744
      Abstract: Chronic kidney disease is characterized by markedly increased risk for cardiovascular mortality, vascular calcification, and ventricular hypertrophy, and is associated with increased systemic oxidative stress. Hyperphosphatemia, reflecting diminished glomerular phosphate (Pi) clearance, coupled with a compensatory increase in fibroblast growth factor 23 (FGF23) secretion are thought to be key mediators of this risk. Elevated serum and dietary Pi and elevated plasma FGF23 are associated with increased cardiovascular and total mortality in people with normal baseline renal function. FGF23 may mediate some of this risk by promoting cardiac hypertrophy via activation of fibroblast growth factor receptor 4 on cardiomyocytes. Elevated serum Pi can also cause a profound increase in systemic oxidative stress, and this may reflect the ability of Pi to act directly on mitochondria to boost membrane potential and thereby increase respiratory chain superoxide production. Moreover, elevated FGF23 likewise induces oxidative stress in vascular endothelium via activation of NADPH oxidase complexes. In vitro exposure of vascular smooth muscle cells to elevated Pi provokes an osteoblastic phenotypic transition that is mediated by increased mitochondrial oxidant production; this is offset dose-dependently by increased exposure to magnesium (Mg). In vivo, dietary Mg is protective in rodent models of vascular calcification. It is proposed that increased intracellular Mg opposes Pi’s ability to increase mitochondrial membrane potential; this model could explain its utility for prevention of vascular calcification and predicts that Mg may have a more global protective impact with regard to the direct pathogenic effects of hyperphosphatemia.
      Citation: Cells
      PubDate: 2021-07-09
      DOI: 10.3390/cells10071744
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1745: Piezo1 Mechanosensitive Ion Channel Mediates
           Stretch-Induced Nppb Expression in Adult Rat Cardiac Fibroblasts

    • Authors: Ploeg, Munts, Prinzen, Turner, van Bilsen, van Nieuwenhoven
      First page: 1745
      Abstract: In response to stretch, cardiac tissue produces natriuretic peptides, which have been suggested to have beneficial effects in heart failure patients. In the present study, we explored the mechanism of stretch-induced brain natriuretic peptide (Nppb) expression in cardiac fibroblasts. Primary adult rat cardiac fibroblasts subjected to 4 h or 24 h of cyclic stretch (10% 1 Hz) showed a 6.6-fold or 3.2-fold (p < 0.05) increased mRNA expression of Nppb, as well as induction of genes related to myofibroblast differentiation. Moreover, BNP protein secretion was upregulated 5.3-fold in stretched cardiac fibroblasts. Recombinant BNP inhibited TGFβ1-induced Acta2 expression. Nppb expression was >20-fold higher in cardiomyocytes than in cardiac fibroblasts, indicating that cardiac fibroblasts were not the main source of Nppb in the healthy heart. Yoda1, an agonist of the Piezo1 mechanosensitive ion channel, increased Nppb expression 2.1-fold (p < 0.05) and significantly induced other extracellular matrix (ECM) remodeling genes. Silencing of Piezo1 reduced the stretch-induced Nppb and Tgfb1 expression in cardiac fibroblasts. In conclusion, our study identifies Piezo1 as mediator of stretch-induced Nppb expression, as well as other remodeling genes, in cardiac fibroblasts.
      Citation: Cells
      PubDate: 2021-07-09
      DOI: 10.3390/cells10071745
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1746: A Switch from Cell-Associated to Soluble
           PDGF-B Protects against Atherosclerosis, despite Driving Extramedullary

    • Authors: Renée J. H. A. Tillie, Thomas L. Theelen, Kim van Kuijk, Lieve Temmerman, Jenny de Bruijn, Marion Gijbels, Christer Betsholtz, Erik A. L. Biessen, Judith C. Sluimer
      First page: 1746
      Abstract: Platelet-derived growth factor B (PDGF-B) is a mitogenic, migratory and survival factor. Cell-associated PDGF-B recruits stabilizing pericytes towards blood vessels through retention in extracellular matrix. We hypothesized that the genetic ablation of cell-associated PDGF-B by retention motif deletion would reduce the local availability of PDGF-B, resulting in microvascular pericyte loss, microvascular permeability and exacerbated atherosclerosis. Therefore, Ldlr-/-Pdgfbret/ret mice were fed a high cholesterol diet. Although plaque size was increased in the aortic root of Pdgfbret/ret mice, microvessel density and intraplaque hemorrhage were unexpectedly unaffected. Plaque macrophage content was reduced, which is likely attributable to increased apoptosis, as judged by increased TUNEL+ cells in Pdgfbret/ret plaques (2.1-fold) and increased Pdgfbret/ret macrophage apoptosis upon 7-ketocholesterol or oxidized LDL incubation in vitro. Moreover, Pdgfbret/ret plaque collagen content increased independent of mesenchymal cell density. The decreased macrophage matrix metalloproteinase activity could partly explain Pdgfbret/ret collagen content. In addition to the beneficial vascular effects, we observed reduced body weight gain related to smaller fat deposition in Pdgfbret/ret liver and adipose tissue. While dampening plaque inflammation, Pdgfbret/ret paradoxically induced systemic leukocytosis. The increased incorporation of 5-ethynyl-2′-deoxyuridine indicated increased extramedullary hematopoiesis and the increased proliferation of circulating leukocytes. We concluded that Pdgfbret/ret confers vascular and metabolic effects, which appeared to be protective against diet-induced cardiovascular burden. These effects were unrelated to arterial mesenchymal cell content or adventitial microvessel density and leakage. In contrast, the deletion drives splenic hematopoiesis and subsequent leukocytosis in hypercholesterolemia.
      Citation: Cells
      PubDate: 2021-07-10
      DOI: 10.3390/cells10071746
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1747: Influence of Subcellular Localization and
           Functional State on Protein Turnover

    • Authors: Roya Yousefi, Kristina Jevdokimenko, Verena Kluever, David Pacheu-Grau, Eugenio F. Fornasiero
      First page: 1747
      Abstract: Protein homeostasis is an equilibrium of paramount importance that maintains cellular performance by preserving an efficient proteome. This equilibrium avoids the accumulation of potentially toxic proteins, which could lead to cellular stress and death. While the regulators of proteostasis are the machineries controlling protein production, folding and degradation, several other factors can influence this process. Here, we have considered two factors influencing protein turnover: the subcellular localization of a protein and its functional state. For this purpose, we used an imaging approach based on the pulse-labeling of 17 representative SNAP-tag constructs for measuring protein lifetimes. With this approach, we obtained precise measurements of protein turnover rates in several subcellular compartments. We also tested a selection of mutants modulating the function of three extensively studied proteins, the Ca2+ sensor calmodulin, the small GTPase Rab5a and the brain creatine kinase (CKB). Finally, we followed up on the increased lifetime observed for the constitutively active Rab5a (Q79L), and we found that its stabilization correlates with enlarged endosomes and increased interaction with membranes. Overall, our data reveal that both changes in protein localization and functional state are key modulators of protein turnover, and protein lifetime fluctuations can be considered to infer changes in cellular behavior.
      Citation: Cells
      PubDate: 2021-07-10
      DOI: 10.3390/cells10071747
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1748: RGS5 Attenuates Baseline Activity of ERK1/2
           and Promotes Growth Arrest of Vascular Smooth Muscle Cells

    • Authors: Eda Demirel, Caroline Arnold, Jaspal Garg, Marius Andreas Jäger, Carsten Sticht, Rui Li, Hanna Kuk, Nina Wettschureck, Markus Hecker, Thomas Korff
      First page: 1748
      Abstract: The regulator of G-protein signaling 5 (RGS5) acts as an inhibitor of Gαq/11 and Gαi/o activity in vascular smooth muscle cells (VSMCs), which regulate arterial tone and blood pressure. While RGS5 has been described as a crucial determinant regulating the VSMC responses during various vascular remodeling processes, its regulatory features in resting VSMCs and its impact on their phenotype are still under debate and were subject of this study. While Rgs5 shows a variable expression in mouse arteries, neither global nor SMC-specific genetic ablation of Rgs5 affected the baseline blood pressure yet elevated the phosphorylation level of the MAP kinase ERK1/2. Comparable results were obtained with 3D cultured resting VSMCs. In contrast, overexpression of RGS5 in 2D-cultured proliferating VSMCs promoted their resting state as evidenced by microarray-based expression profiling and attenuated the activity of Akt- and MAP kinase-related signaling cascades. Moreover, RGS5 overexpression attenuated ERK1/2 phosphorylation, VSMC proliferation, and migration, which was mimicked by selectively inhibiting Gαi/o but not Gαq/11 activity. Collectively, the heterogeneous expression of Rgs5 suggests arterial blood vessel type-specific functions in mouse VSMCs. This comprises inhibition of acute agonist-induced Gαq/11/calcium release as well as the support of a resting VSMC phenotype with low ERK1/2 activity by suppressing the activity of Gαi/o.
      Citation: Cells
      PubDate: 2021-07-11
      DOI: 10.3390/cells10071748
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1749: Vascularization Strategies in Bone Tissue

    • Authors: Filip Simunovic, Günter Finkenzeller
      First page: 1749
      Abstract: Bone is a highly vascularized tissue, and its development, maturation, remodeling, and regeneration are dependent on a tight regulation of blood vessel supply. This condition also has to be taken into consideration in the context of the development of artificial tissue substitutes. In classic tissue engineering, bone-forming cells such as primary osteoblasts or mesenchymal stem cells are introduced into suitable scaffolds and implanted in order to treat critical-size bone defects. However, such tissue substitutes are initially avascular. Because of the occurrence of hypoxic conditions, especially in larger tissue substitutes, this leads to the death of the implanted cells. Therefore, it is necessary to devise vascularization strategies aiming at fast and efficient vascularization of implanted artificial tissues. In this review article, we present and discuss the current vascularization strategies in bone tissue engineering. These are based on the use of angiogenic growth factors, the co-implantation of blood vessel forming cells, the ex vivo microfabrication of blood vessels by means of bioprinting, and surgical methods for creating surgically transferable composite tissues.
      Citation: Cells
      PubDate: 2021-07-11
      DOI: 10.3390/cells10071749
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1750: TMEM135 is a Novel Regulator of Mitochondrial
           Dynamics and Physiology with Implications for Human Health Conditions

    • Authors: Heather K. Beasley, Taylor A. Rodman, Greg V. Collins, Antentor Hinton, Vernat Exil
      First page: 1750
      Abstract: Transmembrane proteins (TMEMs) are integral proteins that span biological membranes. TMEMs function as cellular membrane gates by modifying their conformation to control the influx and efflux of signals and molecules. TMEMs also reside in and interact with the membranes of various intracellular organelles. Despite much knowledge about the biological importance of TMEMs, their role in metabolic regulation is poorly understood. This review highlights the role of a single TMEM, transmembrane protein 135 (TMEM135). TMEM135 is thought to regulate the balance between mitochondrial fusion and fission and plays a role in regulating lipid droplet formation/tethering, fatty acid metabolism, and peroxisomal function. This review highlights our current understanding of the various roles of TMEM135 in cellular processes, organelle function, calcium dynamics, and metabolism.
      Citation: Cells
      PubDate: 2021-07-11
      DOI: 10.3390/cells10071750
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1751: Effects of Micronutrient Supplementation on
           Glucose and Hepatic Lipid Metabolism in a Rat Model of Diet Induced

    • Authors: Saroj Khatiwada, Virginie Lecomte, Michael F. Fenech, Margaret J. Morris, Christopher A. Maloney
      First page: 1751
      Abstract: Obesity increases the risk of metabolic disorders, partly through increased oxidative stress. Here, we examined the effects of a dietary micronutrient supplement (consisting of folate, vitamin B6, choline, betaine, and zinc) with antioxidant and methyl donor activities. Male Sprague Dawley rats (3 weeks old, 17/group) were weaned onto control (C) or high-fat diet (HFD) or same diets with added micronutrient supplement (CS; HS). At 14.5 weeks of age, body composition was measured by magnetic resonance imaging. At 21 weeks of age, respiratory quotient and energy expenditure was measured using Comprehensive Lab Animal Monitoring System. At 22 weeks of age, an oral glucose tolerance test (OGTT) was performed, and using fasting glucose and insulin values, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was calculated as a surrogate measure of insulin resistance. At 30.5 weeks of age, blood and liver tissues were harvested. Liver antioxidant capacity, lipids and expression of genes involved in lipid metabolism (Cd36, Fabp1, Acaca, Fasn, Cpt1a, Srebf1) were measured. HFD increased adiposity (p < 0.001) and body weight (p < 0.001), both of which did not occur in the HS group. The animals fed HFD developed impaired fasting glucose, impaired glucose tolerance, and fasting hyperinsulinemia compared to control fed animals. Interestingly, HS animals demonstrated an improvement in fasting glucose and fasting insulin. Based on insulin release during OGTT and HOMA-IR, the supplement appeared to reduce the insulin resistance developed by HFD feeding. Supplementation increased hepatic glutathione content (p < 0.05) and reduced hepatic triglyceride accumulation (p < 0.001) regardless of diet; this was accompanied by altered gene expression (particularly of CPT-1). Our findings show that dietary micronutrient supplementation can reduce weight gain and adiposity, improve glucose metabolism, and improve hepatic antioxidant capacity and lipid metabolism in response to HFD intake.
      Citation: Cells
      PubDate: 2021-07-11
      DOI: 10.3390/cells10071751
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1752: Lock, Stock and Barrel: Role of
           Renin-Angiotensin-Aldosterone System in Coronavirus Disease 2019

    • Authors: Christian Zanza, Michele Fidel Tassi, Tatsiana Romenskaya, Fabio Piccolella, Ludovico Abenavoli, Francesco Franceschi, Andrea Piccioni, Veronica Ojetti, Angela Saviano, Barbara Canonico, Mariele Montanari, Loris Zamai, Marco Artico, Chiara Robba, Fabrizio Racca, Yaroslava Longhitano
      First page: 1752
      Abstract: Since the end of 2019, the medical-scientific community has been facing a terrible pandemic caused by a new airborne viral agent known as SARS-CoV2. Already in the early stages of the pandemic, following the discovery that the virus uses the ACE2 cell receptor as a molecular target to infect the cells of our body, it was hypothesized that the renin-angiotensin-aldosterone system was involved in the pathogenesis of the disease. Since then, numerous studies have been published on the subject, but the exact role of the renin-angiotensin-aldosterone system in the pathogenesis of COVID-19 is still a matter of debate. RAAS represents an important protagonist in the pathogenesis of COVID-19, providing the virus with the receptor of entry into host cells and determining its organotropism. Furthermore, following infection, the virus is able to cause an increase in plasma ACE2 activity, compromising the normal function of the RAAS. This dysfunction could contribute to the establishment of the thrombo-inflammatory state characteristic of severe forms of COVID-19. Drugs targeting RAAS represent promising therapeutic options for COVID-19 sufferers.
      Citation: Cells
      PubDate: 2021-07-11
      DOI: 10.3390/cells10071752
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1753: Multifunctionality of the Telomere-Capping
           Shelterin Complex Explained by Variations in Its Protein Composition

    • Authors: Claire Ghilain, Eric Gilson, Marie-Josèphe Giraud-Panis
      First page: 1753
      Abstract: Protecting telomere from the DNA damage response is essential to avoid the entry into cellular senescence and organismal aging. The progressive telomere DNA shortening in dividing somatic cells, programmed during development, leads to critically short telomeres that trigger replicative senescence and thereby contribute to aging. In several organisms, including mammals, telomeres are protected by a protein complex named Shelterin that counteract at various levels the DNA damage response at chromosome ends through the specific function of each of its subunits. The changes in Shelterin structure and function during development and aging is thus an intense area of research. Here, we review our knowledge on the existence of several Shelterin subcomplexes and the functional independence between them. This leads us to discuss the possibility that the multifunctionality of the Shelterin complex is determined by the formation of different subcomplexes whose composition may change during aging.
      Citation: Cells
      PubDate: 2021-07-11
      DOI: 10.3390/cells10071753
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1754: Adipose-Derived Stem Cells Features and MCF-7

    • Authors: Giuseppe Garroni, Francesca Balzano, Sara Cruciani, Renzo Pala, Donatella Coradduzza, Emanuela Azara, Emanuela Bellu, Maria Laura Cossu, Giorgio C. Ginesu, Ciriaco Carru, Carlo Ventura, Margherita Maioli
      First page: 1754
      Abstract: Human adipose tissue-derived stem cells (hADSCs) are highly suitable for regeneration therapies being easily collected and propagated in vitro. The effects of different external factors and culturing conditions are able to affect hADSC proliferation, senescence, differentiation, and migration, even at the molecular level. In the present paper, we exposed hADSCs to an exhausted medium from the breast cancer cell line (MCF-7) to evaluate whether the soluble factors released by these cells may be able to induce changes in stem cell behavior. In particular, we investigated the expression of stemness-related genes (OCT4; Sox 2; Nanog), the cell-cycle regulators p21 (WAF1/CIP1) p53, epigenetic markers (DNMT1 and Sirt1), and autophagy-related proteins. From our results, we can infer that the exhausted medium from MCF-7 is able to influence the hADSCs behavior increasing the expression of stemness-related genes, cell proliferation, and autophagy. Polyamines detectable in MCF-7 exhausted medium could be related to the higher proliferation capability observed in hADSCs, suggesting direct crosstalk between these molecules and the observed changes in stem cell potency.
      Citation: Cells
      PubDate: 2021-07-11
      DOI: 10.3390/cells10071754
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1755: Changes in Chromatin Organization Eradicate
           Cellular Stress Resilience to UVA/B Light and Induce Premature Aging

    • Authors: Bela Vasileva, Dessislava Staneva, Natalia Krasteva, George Miloshev, Milena Georgieva
      First page: 1755
      Abstract: Complex interactions among DNA and nuclear proteins maintain genome organization and stability. The nuclear proteins, particularly the histones, organize, compact, and preserve the stability of DNA, but also allow its dynamic reorganization whenever the nuclear processes require access to it. Five histone classes exist and they are evolutionarily conserved among eukaryotes. The linker histones are the fifth class and over time, their role in chromatin has been neglected. Linker histones interact with DNA and the other histones and thus sustain genome stability and nuclear organization. Saccharomyces cerevisiae is a brilliant model for studying linker histones as the gene for it is a single-copy and is non-essential. We, therefore, created a linker histone-free yeast strain using a knockout of the relevant gene and traced the way cells age chronologically. Here we present our results demonstrating that the altered chromatin dynamics during the chronological lifespan of the yeast cells with a mutation in ARP4 (the actin-related protein 4) and without the gene HHO1 for the linker histone leads to strong alterations in the gene expression profiles of a subset of genes involved in DNA repair and autophagy. The obtained results further prove that the yeast mutants have reduced survival upon UVA/B irradiation possibly due to the accelerated decompaction of chromatin and impaired proliferation. Our hypothesis posits that the higher-order chromatin structure and the interactions among chromatin proteins are crucial for the maintenance of chromatin organization during chronological aging under optimal and UVA-B stress conditions.
      Citation: Cells
      PubDate: 2021-07-11
      DOI: 10.3390/cells10071755
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1756: Antiviral Activity of Influenza A Virus
           Defective Interfering Particles against SARS-CoV-2 Replication In Vitro
           through Stimulation of Innate Immunity

    • Authors: Ulfert Rand, Sascha Young Kupke, Hanna Shkarlet, Marc Dominique Hein, Tatjana Hirsch, Pavel Marichal-Gallardo, Luka Cicin-Sain, Udo Reichl, Dunja Bruder
      First page: 1756
      Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) emerged in late 2019 and resulted in a devastating pandemic. Although the first approved vaccines were already administered by the end of 2020, worldwide vaccine availability is still limited. Moreover, immune escape variants of the virus are emerging against which the current vaccines may confer only limited protection. Further, existing antivirals and treatment options against COVID-19 show only limited efficacy. Influenza A virus (IAV) defective interfering particles (DIPs) were previously proposed not only for antiviral treatment of the influenza disease but also for pan-specific treatment of interferon (IFN)-sensitive respiratory virus infections. To investigate the applicability of IAV DIPs as an antiviral for the treatment of COVID-19, we conducted in vitro co-infection experiments with cell culture-derived DIPs and the IFN-sensitive SARS-CoV-2 in human lung cells. We show that treatment with IAV DIPs leads to complete abrogation of SARS-CoV-2 replication. Moreover, this inhibitory effect was dependent on janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling. Further, our results suggest boosting of IFN-induced antiviral activity by IAV DIPs as a major contributor in suppressing SARS-CoV-2 replication. Thus, we propose IAV DIPs as an effective antiviral agent for treatment of COVID-19, and potentially also for suppressing the replication of new variants of SARS-CoV-2.
      Citation: Cells
      PubDate: 2021-07-11
      DOI: 10.3390/cells10071756
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1757: FOS Rescues Neuronal Differentiation of
           Sox2-Deleted Neural Stem Cells by Genome-Wide Regulation of Common SOX2
           and AP1(FOS-JUN) Target Genes

    • Authors: Miriam Pagin, Mattias Pernebrink, Mattia Pitasi, Federica Malighetti, Chew-Yee Ngan, Sergio Ottolenghi, Giulio Pavesi, Claudio Cantù, Silvia K. Nicolis
      First page: 1757
      Abstract: The transcription factor SOX2 is important for brain development and for neural stem cells (NSC) maintenance. Sox2-deleted (Sox2-del) NSC from neonatal mouse brain are lost after few passages in culture. Two highly expressed genes, Fos and Socs3, are strongly downregulated in Sox2-del NSC; we previously showed that Fos or Socs3 overexpression by lentiviral transduction fully rescues NSC’s long-term maintenance in culture. Sox2-del NSC are severely defective in neuronal production when induced to differentiate. NSC rescued by Sox2 reintroduction correctly differentiate into neurons. Similarly, Fos transduction rescues normal or even increased numbers of immature neurons expressing beta-tubulinIII, but not more differentiated markers (MAP2). Additionally, many cells with both beta-tubulinIII and GFAP expression appear, indicating that FOS stimulates the initial differentiation of a “mixed” neuronal/glial progenitor. The unexpected rescue by FOS suggested that FOS, a SOX2 transcriptional target, might act on neuronal genes, together with SOX2. CUT&RUN analysis to detect genome-wide binding of SOX2, FOS, and JUN (the AP1 complex) revealed that a high proportion of genes expressed in NSC are bound by both SOX2 and AP1. Downregulated genes in Sox2-del NSC are highly enriched in genes that are also expressed in neurons, and a high proportion of the “neuronal” genes are bound by both SOX2 and AP1.
      Citation: Cells
      PubDate: 2021-07-12
      DOI: 10.3390/cells10071757
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1758: Vasculogenic Mimicry in Breast Cancer:
           Clinical Relevance and Drivers

    • Authors: Gabriela Morales-Guadarrama, Rocío García-Becerra, Edgar Armando Méndez-Pérez, Janice García-Quiroz, Euclides Avila, Lorenza Díaz
      First page: 1758
      Abstract: In solid tumors, vasculogenic mimicry (VM) is the formation of vascular structures by cancer cells, allowing to generate a channel-network able to transport blood and tumor cells. While angiogenesis is undertaken by endothelial cells, VM is assumed by cancer cells. Besides the participation of VM in tumor neovascularization, the clinical relevance of this process resides in its ability to favor metastasis and to drive resistance to antiangiogenic therapy. VM occurs in many tumor types, including breast cancer, where it has been associated with a more malignant phenotype, such as triple-negative and HER2-positive tumors. The latter may be explained by known drivers of VM, like hypoxia, TGFB, TWIST1, EPHA2, VEGF, matrix metalloproteinases, and other tumor microenvironment-derived factors, which altogether induce the transformation of tumor cells to a mesenchymal phenotype with a high expression rate of stemness markers. This review analyzes the current literature in the field, including the participation of some microRNAs and long noncoding RNAs in VM-regulation and tumorigenesis of breast cancer. Considering the clinical relevance of VM and its association with the tumor phenotype and clinicopathological parameters, further studies are granted to target VM in the clinic.
      Citation: Cells
      PubDate: 2021-07-12
      DOI: 10.3390/cells10071758
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1759: The Role of Coagulation and Complement Factors
           for Mast Cell Activation in the Pathogenesis of Chronic Spontaneous

    • Authors: Yuhki Yanase, Shunsuke Takahagi, Koichiro Ozawa, Michihiro Hide
      First page: 1759
      Abstract: Chronic spontaneous urticaria (CSU) is a common skin disorder characterized by an almost daily recurrence of wheal and flare with itch for more than 6 weeks, in association with the release of stored inflammatory mediators, such as histamine, from skin mast cells and/or peripheral basophils. The involvement of the extrinsic coagulation cascade triggered by tissue factor (TF) and complement factors, such as C3a and C5a, has been implied in the pathogenesis of CSU. However, it has been unclear how the TF-triggered coagulation pathway and complement factors induce the activation of skin mast cells and peripheral basophils in patients with CSU. In this review, we focus on the role of vascular endothelial cells, leukocytes, extrinsic coagulation factors and complement components on TF-induced activation of skin mast cells and peripheral basophils followed by the edema formation clinically recognized as urticaria. These findings suggest that medications targeting activated coagulation factors and/or complement components may represent new and effective treatments for patients with severe and refractory CSU.
      Citation: Cells
      PubDate: 2021-07-12
      DOI: 10.3390/cells10071759
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1760: Optical Microscopy and the Extracellular
           Matrix Structure: A Review

    • Authors: Poole, Mostaço-Guidolin
      First page: 1760
      Abstract: Biological tissues are not uniquely composed of cells. A substantial part of their volume is extracellular space, which is primarily filled by an intricate network of macromolecules constituting the extracellular matrix (ECM). The ECM serves as the scaffolding for tissues and organs throughout the body, playing an essential role in their structural and functional integrity. Understanding the intimate interaction between the cells and their structural microenvironment is central to our understanding of the factors driving the formation of normal versus remodelled tissue, including the processes involved in chronic fibrotic diseases. The visualization of the ECM is a key factor to track such changes successfully. This review is focused on presenting several optical imaging microscopy modalities used to characterize different ECM components. In this review, we describe and provide examples of applications of a vast gamut of microscopy techniques, such as widefield fluorescence, total internal reflection fluorescence, laser scanning confocal microscopy, multipoint/slit confocal microscopy, two-photon excited fluorescence (TPEF), second and third harmonic generation (SHG, THG), coherent anti-Stokes Raman scattering (CARS), fluorescence lifetime imaging microscopy (FLIM), structured illumination microscopy (SIM), stimulated emission depletion microscopy (STED), ground-state depletion microscopy (GSD), and photoactivated localization microscopy (PALM/fPALM), as well as their main advantages, limitations.
      Citation: Cells
      PubDate: 2021-07-12
      DOI: 10.3390/cells10071760
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1761: Cytokine Storm Syndrome in SARS-CoV-2
           Infections: A Functional Role of Mast Cells

    • Authors: Hafezi, Chan, Knapp, Karimi, Alizadeh, Mehrani, Bridle, Karimi
      First page: 1761
      Abstract: Cytokine storm syndrome is a cascade of escalated immune responses disposing the immune system to exhaustion, which might ultimately result in organ failure and fatal respiratory distress. Infection with severe acute respiratory syndrome-coronavirus-2 can result in uncontrolled production of cytokines and eventually the development of cytokine storm syndrome. Mast cells may react to viruses in collaboration with other cells and lung autopsy findings from patients that died from the coronavirus disease that emerged in 2019 (COVID-19) showed accumulation of mast cells in the lungs that was thought to be the cause of pulmonary edema, inflammation, and thrombosis. In this review, we present evidence that a cytokine response by mast cells may initiate inappropriate antiviral immune responses and cause the development of cytokine storm syndrome. We also explore the potential of mast cell activators as adjuvants for COVID-19 vaccines and discuss the medications that target the functions of mast cells and could be of value in the treatment of COVID-19. Recognition of the cytokine storm is crucial for proper treatment of patients and preventing the release of mast cell mediators, as impeding the impacts imposed by these mediators could reduce the severity of COVID-19.
      Citation: Cells
      PubDate: 2021-07-12
      DOI: 10.3390/cells10071761
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1762: Viral MicroRNAs Encoded by Nucleocapsid Gene
           of SARS-CoV-2 Are Detected during Infection, and Targeting Metabolic
           Pathways in Host Cells

    • Authors: Meng, Siu, Mok, Sun, Fung, Lam, Wong, Gedefaw, Luo, Lee, Yip, Huang
      First page: 1762
      Abstract: MicroRNAs (miRNAs) are critical regulators of gene expression that may be used to identify the pathological pathways influenced by disease and cellular interactions. Viral miRNAs (v-miRNAs) encoded by both DNA and RNA viruses induce immune dysregulation, virus production, and disease pathogenesis. Given the absence of effective treatment and the prevalence of highly infective SARS-CoV-2 strains, improved understanding of viral-associated miRNAs could provide novel mechanistic insights into the pathogenesis of COVID-19. In this study, SARS-CoV-2 v-miRNAs were identified by deep sequencing in infected Calu-3 and Vero E6 cell lines. Among the ~0.1% small RNA sequences mapped to the SARS-CoV-2 genome, the top ten SARS-CoV-2 v-miRNAs (including three encoded by the N gene; v-miRNA-N) were selected. After initial screening of conserved v-miRNA-N-28612, which was identified in both SARS-CoV and SARS-CoV-2, its expression was shown to be positively associated with viral load in COVID-19 patients. Further in silico analysis and synthetic-mimic transfection of validated SARS-CoV-2 v-miRNAs revealed novel functional targets and associations with mechanisms of cellular metabolism and biosynthesis. Our findings support the development of v-miRNA-based biomarkers and therapeutic strategies based on improved understanding of the pathophysiology of COVID-19.
      Citation: Cells
      PubDate: 2021-07-12
      DOI: 10.3390/cells10071762
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1763: Extracellular Vesicles under Oxidative Stress
           Conditions: Biological Properties and Physiological Roles

    • Authors: Chiaradia, Tancini, Emiliani, Delo, Pellegrino, Tognoloni, Urbanelli, Buratta
      First page: 1763
      Abstract: Under physio-pathological conditions, cells release membrane-surrounded structures named Extracellular Vesicles (EVs), which convey their molecular cargo to neighboring or distant cells influencing their metabolism. Besides their involvement in the intercellular communication, EVs might represent a tool used by cells to eliminate unnecessary/toxic material. Here, we revised the literature exploring the link between EVs and redox biology. The first proof of this link derives from evidence demonstrating that EVs from healthy cells protect target cells from oxidative insults through the transfer of antioxidants. Oxidative stress conditions influence the release and the molecular cargo of EVs that, in turn, modulate the redox status of target cells. Oxidative stress-related EVs exert both beneficial or harmful effects, as they can carry antioxidants or ROS-generating enzymes and oxidized molecules. As mediators of cell-to-cell communication, EVs are also implicated in the pathophysiology of oxidative stress-related diseases. The review found evidence that numerous studies speculated on the role of EVs in redox signaling and oxidative stress-related pathologies, but few of them unraveled molecular mechanisms behind this complex link. Thus, the purpose of this review is to report and discuss this evidence, highlighting that the analysis of the molecular content of oxidative stress-released EVs (reminiscent of the redox status of originating cells), is a starting point for the use of EVs as diagnostic and therapeutic tools in oxidative stress-related diseases.
      Citation: Cells
      PubDate: 2021-07-12
      DOI: 10.3390/cells10071763
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1764: Hypoxia, Hypoxia-Inducible Factors and Liver

    • Authors: Beatrice Foglia, Erica Novo, Francesca Protopapa, Marina Maggiora, Claudia Bocca, Stefania Cannito, Maurizio Parola
      First page: 1764
      Abstract: Liver fibrosis is a potentially reversible pathophysiological event, leading to excess deposition of extracellular matrix (ECM) components and taking place as the net result of liver fibrogenesis, a dynamic and highly integrated process occurring during chronic liver injury of any etiology. Liver fibrogenesis and fibrosis, together with chronic inflammatory response, are primarily involved in the progression of chronic liver diseases (CLD). As is well known, a major role in fibrogenesis and fibrosis is played by activated myofibroblasts (MFs), as well as by macrophages and other hepatic cell populations involved in CLD progression. In the present review, we will focus the attention on the emerging pathogenic role of hypoxia, hypoxia-inducible factors (HIFs) and related mediators in the fibrogenic progression of CLD.
      Citation: Cells
      PubDate: 2021-07-13
      DOI: 10.3390/cells10071764
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1765: Programmed Cell Death in Health and Disease

    • Authors: Lara Gibellini, Loredana Moro
      First page: 1765
      Abstract: Programmed cell death is a conserved evolutionary process of cell suicide that is central to the development and integrity of eukaryotic organisms [...]
      Citation: Cells
      PubDate: 2021-07-13
      DOI: 10.3390/cells10071765
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1766: Addendum: López-Vidal et al. Is Autophagy
           Involved in Pepper Fruit Ripening' Cells 2020, 9, 106

    • Authors: Omar López-Vidal, Adela Olmedilla, Luisa María Sandalio, Francisca Sevilla, Ana Jiménez
      First page: 1766
      Abstract: The authors would like to make an addendum to their published paper [...]
      Citation: Cells
      PubDate: 2021-07-13
      DOI: 10.3390/cells10071766
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1767: Renin–Angiotensin–Aldosterone System and
           Immunomodulation: A State-of-the-Art Review

    • Authors: Driss Laghlam, Mathieu Jozwiak, Lee S. Nguyen
      First page: 1767
      Abstract: The renin–angiotensin system (RAS) has long been described in the field of cardiovascular physiology as the main player in blood pressure homeostasis. However, other effects have since been described, and include proliferation, fibrosis, and inflammation. To illustrate the immunomodulatory properties of the RAS, we chose three distinct fields in which RAS may play a critical role and be the subject of specific treatments. In oncology, RAS hyperactivation has been associated with tumor migration, survival, cell proliferation, and angiogenesis; preliminary data showed promise of the benefit of RAS blockers in patients treated for certain types of cancer. In intensive care medicine, vasoplegic shock has been associated with severe macro- and microcirculatory imbalance. A relative insufficiency in angiotensin II (AngII) was associated to lethal outcomes and synthetic AngII has been suggested as a specific treatment in these cases. Finally, in solid organ transplantation, both AngI and AngII have been associated with increased rejection events, with a regional specificity in the RAS activity. These elements emphasize the complexity of the direct and indirect interactions of RAS with immunomodulatory pathways and warrant further research in the field.
      Citation: Cells
      PubDate: 2021-07-13
      DOI: 10.3390/cells10071767
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1768: Transthyretin: From Structural Stability to
           Osteoarticular and Cardiovascular Diseases

    • Authors: Elżbieta Wieczorek, Andrzej Ożyhar
      First page: 1768
      Abstract: Transthyretin (TTR) is a tetrameric protein transporting hormones in the plasma and brain, which has many other activities that have not been fully acknowledged. TTR is a positive indicator of nutrition status and is negatively correlated with inflammation. TTR is a neuroprotective and oxidative-stress-suppressing factor. The TTR structure is destabilized by mutations, oxidative modifications, aging, proteolysis, and metal cations, including Ca2+. Destabilized TTR molecules form amyloid deposits, resulting in senile and familial amyloidopathies. This review links structural stability of TTR with the environmental factors, particularly oxidative stress and Ca2+, and the processes involved in the pathogenesis of TTR-related diseases. The roles of TTR in biomineralization, calcification, and osteoarticular and cardiovascular diseases are broadly discussed. The association of TTR-related diseases and vascular and ligament tissue calcification with TTR levels and TTR structure is presented. It is indicated that unaggregated TTR and TTR amyloid are bound by vicious cycles, and that TTR may have an as yet undetermined role(s) at the crossroads of calcification, blood coagulation, and immune response.
      Citation: Cells
      PubDate: 2021-07-13
      DOI: 10.3390/cells10071768
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1769: The Vascular Circadian Clock in Chronic Kidney

    • Authors: Søren Egstrand, Maria L. Mace, Klaus Olgaard, Ewa Lewin
      First page: 1769
      Abstract: Chronic kidney disease is associated with extremely high cardiovascular mortality. The circadian rhythms (CR) have an impact on vascular function. The disruption of CR causes serious health problems and contributes to the development of cardiovascular diseases. Uremia may affect the master pacemaker of CR in the hypothalamus. A molecular circadian clock is also expressed in peripheral tissues, including the vasculature, where it regulates the different aspects of both vascular physiology and pathophysiology. Here, we address the impact of CKD on the intrinsic circadian clock in the vasculature. The expression of the core circadian clock genes in the aorta is disrupted in CKD. We propose a novel concept of the disruption of the circadian clock system in the vasculature of importance for the pathology of the uremic vasculopathy.
      Citation: Cells
      PubDate: 2021-07-13
      DOI: 10.3390/cells10071769
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1770: CK2α/CSNK2A1 Induces Resistance to
           Doxorubicin through SIRT6-Mediated Activation of the DNA Damage Repair

    • Authors: Usama Khamis Hussein, Asmaa Gamal Ahmed, Yiping Song, Kyoung Min Kim, Young Jae Moon, Ae-Ri Ahn, Ho Sung Park, Su Jin Ahn, See-Hyoung Park, Jung Ryul Kim, Kyu Yun Jang
      First page: 1770
      Abstract: CK2α/CSNK2A1 is involved in cancer progression by phosphorylating various signaling molecules. Considering the role of CSNK2A1 in cancer progression and the phosphorylation of SIRT6 and the role of SIRT6 in chemoresistance through the DNA damage repair pathway, CSNK2A1 and SIRT6 might be involved in resistance to conventional anti-cancer therapies. We evaluated the expression of CSNK2A1 and phosphorylated SIRT6 in the 37 osteosarcoma patients and investigated the effects of CSNK2A1 and the phosphorylation of SIRT6 on Ser338 on resistance to the anti-cancer effects of doxorubicin. Higher expression of CSNK2A1 and phosphorylated SIRT6 was associated with shorter survival in osteosarcoma patients. U2OS and KHOS/NP osteosarcoma cells with induced overexpression of CSNK2A1 were resistant to the cytotoxic effects of doxorubicin, and the knock-down of CSNK2A1 potentiated the cytotoxic effects of doxorubicin. CSNK2A1 overexpression-mediated resistance to doxorubicin was associated with SIRT6 phosphorylation and the induction of the DNA damage repair pathway molecules. CSNK2A1- and SIRT6-mediated resistance to doxorubicin in vivo was attenuated via mutation of SIRT6 at the Ser338 phosphorylation site. Emodin, a CSNK2A1 inhibitor, potentiated the cytotoxic effects of doxorubicin in osteosarcoma cells. This study suggests that blocking the CSNK2A1-SIRT6-DNA damage repair pathway might be a new therapeutic stratagem for osteosarcomas.
      Citation: Cells
      PubDate: 2021-07-13
      DOI: 10.3390/cells10071770
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1771: sRNA Profiler: A User-Focused Interface for
           Small RNA Mapping and Profiling

    • Authors: Charith Raj Adkar-Purushothama, Pavithran Sridharan Iyer, Teruo Sano, Jean-Pierre Perreault
      First page: 1771
      Abstract: Viroids are circular, highly structured, single-stranded, non-coding RNA pathogens known to infect and cause disease in several plant species. They are known to trigger the host plant’s RNA silencing machinery. The detection of viroid-derived small RNAs (vd-sRNA) in viroid-infected host plants opened a new avenue of study in host–viroid pathogenicity. Since then, several viroid research groups have studied the vd-sRNA retrieved from different host–viroid combinations. Such studies require the segregation of 21- to 24-nucleotide long small RNAs (sRNA) from a deep-sequencing databank, followed by separating the vd-sRNA from any sRNA within this group that showed sequence similarity with either the genomic or the antigenomic strands of the viroid. Such mapped vd-sRNAs are then profiled on both the viroid’s genomic and antigenomic strands for visualization. Although several commercial interfaces are currently available for this purpose, they are all programmed for linear RNA molecules. Hence, viroid researchers must develop a computer program that accommodates the sRNAs derived from the circular viroid genome. This is a laborious process, and consequently, it often creates a bottleneck for biologists. In order to overcome this constraint, and to help the research community in general, in this study, a python-based pattern matching interface was developed so as to be able to both profile and map sRNAs on a circular genome. A “matching tolerance” feature has been included in the program, thus permitting the mapping of the sRNAs derived from the quasi-species. Additionally, the “topology” feature allows the researcher to profile sRNA derived from both linear and circular RNA molecules. The efficiency of the program was tested using previously reported deep-sequencing data obtained from two independent studies. Clearly, this novel software should be a key tool with which to both evaluate the production of sRNA and to profile them on their target RNA species, irrespective of the topology of the target RNA molecule.
      Citation: Cells
      PubDate: 2021-07-13
      DOI: 10.3390/cells10071771
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1772: Potential Therapies Targeting Metabolic
           Pathways in Cancer Stem Cells

    • Authors: Yao-An Shen, Chang-Cyuan Chen, Bo-Jung Chen, Yu-Ting Wu, Jiun-Ru Juan, Liang-Yun Chen, Yueh-Chun Teng, Yau-Huei Wei
      First page: 1772
      Abstract: Cancer stem cells (CSCs) are heterogeneous cells with stem cell-like properties that are responsible for therapeutic resistance, recurrence, and metastasis, and are the major cause for cancer treatment failure. Since CSCs have distinct metabolic characteristics that plays an important role in cancer development and progression, targeting metabolic pathways of CSCs appears to be a promising therapeutic approach for cancer treatment. Here we classify and discuss the unique metabolisms that CSCs rely on for energy production and survival, including mitochondrial respiration, glycolysis, glutaminolysis, and fatty acid metabolism. Because of metabolic plasticity, CSCs can switch between these metabolisms to acquire energy for tumor progression in different microenvironments compare to the rest of tumor bulk. Thus, we highlight the specific conditions and factors that promote or suppress CSCs properties to portray distinct metabolic phenotypes that attribute to CSCs in common cancers. Identification and characterization of the features in these metabolisms can offer new anticancer opportunities and improve the prognosis of cancer. However, the therapeutic window of metabolic inhibitors used alone or in combination may be rather narrow due to cytotoxicity to normal cells. In this review, we present current findings of potential targets in these four metabolic pathways for the development of more effective and alternative strategies to eradicate CSCs and treat cancer more effectively in the future.
      Citation: Cells
      PubDate: 2021-07-13
      DOI: 10.3390/cells10071772
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1773: Immune Cells Profiling in ANCA-Associated
           Vasculitis Patients—Relation to Disease Activity

    • Authors: Marcelina Żabińska, Katarzyna Kościelska-Kasprzak, Joanna Krajewska, Dorota Bartoszek, Hanna Augustyniak-Bartosik, Magdalena Krajewska
      First page: 1773
      Abstract: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are a group of necrotizing multiorgan autoimmune vasculitides that predominantly affect small blood vessels and are associated with the presence of ANCAs. The aim was to assess regulatory and effector cell populations accompanied by the suPAR biomarker level and link the so-defined immune state to the AAV disease activity. The research involved a multicomponent description of an immune state encompassing a range of B and T cell subsets such as transitional/regulatory B cells (CD19+CD24++CD38++), naïve B cells (CD19+CD24INTCD38INT), Th17 cells, T regulatory cells (CD4+CD25+FoxP3+) and cytotoxic CD4+CD28− cells by flow cytometry. The suPAR plasma level was measured by ELISA. The results indicate that AAV is associated with an increased suPAR plasma level and immune fingerprint characterized by an expansion of Th17 cells and T cells lacking the costimulatory molecule CD28, accompanied by a decrease of regulatory populations (Tregs and transitional B cells) and NK cells. Decreased numbers of regulatory T cells and transitional B cells were shown to be linked to activation of the AAV disease while the increased suPAR plasma level—to AAV-related deterioration of kidney function. The observed immune fingerprint might be a reflection of peripheral tolerance failure responsible for development and progression of ANCA-associated vasculitides.
      Citation: Cells
      PubDate: 2021-07-13
      DOI: 10.3390/cells10071773
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1774: β-(1→4)-Mannobiose Acts as an
           Immunostimulatory Molecule in Murine Dendritic Cells by Binding the
           TLR4/MD-2 Complex

    • Authors: Ting-Yu Cheng, Yen-Ju Lin, Wataru Saburi, Stefan Vieths, Stephan Scheurer, Stefan Schülke, Masako Toda
      First page: 1774
      Abstract: Some β-mannans, including those in coffee bean and soy, contain a mannose backbone with β-(1→4) bonds. Such mannooligosaccharides could have immunological functions involving direct interaction with immune cells, in addition to acting as prebiotics. This study aimed at assessing the immunological function of mannooligosaccharides with β-(1→4) bond, and elucidating their mechanism of action using bone marrow-derived murine dendritic cells (BMDCs). When BMDCs were stimulated with the mannooligosaccharides, only β-Man-(1→4)-Man significantly induced production of cytokines that included IL-6, IL-10, TNF-α, and IFN-β, and enhanced CD4+ T-cell stimulatory capacity. Use of putative receptor inhibitors revealed the binding of β-Man-(1→4)-Man to TLR4/MD2 complex and involvement with the complement C3a receptor (C3aR) for BMDC activation. Interestingly, β-Man-(1→4)-Man prolonged the production of pro-inflammatory cytokines (IL-6 and TNF-α), but not of the IL-10 anti-inflammatory cytokine during extended culture of BMDCs, associated with high glucose consumption. The results suggest that β-Man-(1→4)-Man is an immunostimulatory molecule, and that the promotion of glycolysis could be involved in the production of pro-inflammatory cytokine in β-Man-(1→4)-Man-stimulated BMDCs. This study could contribute to development of immune-boosting functional foods and a novel vaccine adjuvant.
      Citation: Cells
      PubDate: 2021-07-14
      DOI: 10.3390/cells10071774
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1775: Butyrate and the Intestinal Epithelium:
           Modulation of Proliferation and Inflammation in Homeostasis and Disease

    • Authors: Pooja S. Salvi, Robert A. Cowles
      First page: 1775
      Abstract: The microbial metabolite butyrate serves as a link between the intestinal microbiome and epithelium. The monocarboxylate transporters MCT1 and SMCT1 are the predominant means of butyrate transport from the intestinal lumen to epithelial cytoplasm, where the molecule undergoes rapid β-oxidation to generate cellular fuel. However, not all epithelial cells metabolize butyrate equally. Undifferentiated colonocytes, including neoplastic cells and intestinal stem cells at the epithelial crypt base preferentially utilize glucose over butyrate for cellular fuel. This divergent metabolic conditioning is central to the phenomenon known as “butyrate paradox”, in which butyrate induces contradictory effects on epithelial proliferation in undifferentiated and differentiated colonocytes. There is evidence that accumulation of butyrate in epithelial cells results in histone modification and altered transcriptional activation that halts cell cycle progression. This manifests in the apparent protective effect of butyrate against colonic neoplasia. A corollary to this process is butyrate-induced inhibition of intestinal stem cells. Yet, emerging research has illustrated that the evolution of the crypt, along with butyrate-producing bacteria in the intestine, serve to protect crypt base stem cells from butyrate’s anti-proliferative effects. Butyrate also regulates epithelial inflammation and tolerance to antigens, through production of anti-inflammatory cytokines and induction of tolerogenic dendritic cells. The role of butyrate in the pathogenesis and treatment of intestinal neoplasia, inflammatory bowel disease and malabsorptive states is evolving, and holds promise for the potential translation of butyrate’s cellular function into clinical therapies.
      Citation: Cells
      PubDate: 2021-07-14
      DOI: 10.3390/cells10071775
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1776: Short-Term Evaluation of Cellular Fate in an
           Ovine Bone Formation Model

    • Authors: Hareklea Markides, Nicola C. Foster, Jane S. McLaren, Timothy Hopkins, Cameron Black, Richard O. C. Oreffo, Brigitte E. Scammell, Iria Echevarria, Lisa J. White, Alicia J. El Haj
      First page: 1776
      Abstract: The ovine critical-sized defect model provides a robust preclinical model for testing tissue-engineered constructs for use in the treatment of non-union bone fractures and severe trauma. A critical question in cell-based therapies is understanding the optimal therapeutic cell dose. Key to defining the dose and ensuring successful outcomes is understanding the fate of implanted cells, e.g., viability, bio-distribution and exogenous infiltration post-implantation. This study evaluates such parameters in an ovine critical-sized defect model 2 and 7 days post-implantation. The fate of cell dose and behaviour post-implantation when combined with nanomedicine approaches for multi-model tracking and remote control using external magnetic fields is also addressed. Autologous STRO-4 selected mesenchymal stromal cells (MSCs) were labelled with a fluorescent lipophilic dye (CM-Dil), functionalised magnetic nanoparticles (MNPs) and delivered to the site within a naturally derived bone extracellular matrix (ECM) gel. Encapsulated cells were implanted within a critical-sized defect in an ovine medial femoral condyle and exposed to dynamic gradients of external magnetic fields for 1 h per day. Sheep were sacrificed at 2 and 7 days post-initial surgery where ECM was harvested. STRO-4-positive (STRO-4+) stromal cells expressed osteocalcin and survived within the harvested gels at day 2 and day 7 with a 50% loss at day 2 and a further 45% loss at 7 days. CD45-positive leucocytes were also observed in addition to endogenous stromal cells. No elevation in serum C-reactive protein (CRP) or non-haem iron levels was observed following implantation in groups containing MNPs with or without magnetic field gradients. The current study demonstrates how numbers of therapeutic cells reduce substantially after implantation in the repair site. Cell death is accompanied by enhanced leucocyte invasion, but not by inflammatory blood marker levels. Crucially, a proportion of implanted STRO-4+ stromal cells expressed osteocalcin, which is indicative of osteogenic differentiation. Furthermore, MNP labelling did not alter cell number or result in a further deleterious impact on stromal cells following implantation.
      Citation: Cells
      PubDate: 2021-07-14
      DOI: 10.3390/cells10071776
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1777: KIR Receptors as Key Regulators of NK Cells
           Activity in Health and Disease

    • Authors: Joanna Dębska-Zielkowska, Grażyna Moszkowska, Maciej Zieliński, Hanna Zielińska, Anna Dukat-Mazurek, Piotr Trzonkowski, Katarzyna Stefańska
      First page: 1777
      Abstract: Natural killer (NK) cells are part of the cellular immune response. They target mainly cancer and virally infected cells. To a high extent cytotoxic activity of NK cells is regulated inter alia by signals from killer immunoglobulin-like receptors (KIR). The major histocompatibility complex (MHC) class I molecules are important ligands for KIR receptors. Binding of ligands (such as MHC I) to the KIR receptors has the important role in solid organ or hematopoietic cell transplantation. Of note, the understanding of the relationship between KIR and MHC receptors may contribute to the improvement of transplant results. Donor-recipient matching, which also includes the KIR typing, may improve monitoring, individualize the treatment and allow for predicting possible effects after transplantation, such as the graft-versus-leukemia effect (GvL) or viral re-infection. There are also less evident implications of KIR/MHC matching, such as with pregnancy and cancer. In this review, we present the most relevant literature reports on the importance of the KIR/MHC relationship on NK cell activity and hematopoietic stem cell transplantation (HSCT)/solid organ transplantation (SOT) effects, the risk of allograft rejection, protection against post-transplant cytomegalovirus (CMV) infection, pregnancy complications, cancer and adoptive therapy with NK cells.
      Citation: Cells
      PubDate: 2021-07-14
      DOI: 10.3390/cells10071777
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1778: Effects of Combined Anti-Hypertensive and
           Statin Treatment on Memory, Fear Extinction, Adult Neurogenesis, and
           Angiogenesis in Adult and Middle-Aged Mice

    • Authors: Seungwoo Yoo, Matthew Stremlau, Alejandro Pinto, Hyewon Woo, Olivia Curtis, Henriette van Praag
      First page: 1778
      Abstract: Hyperlipidemia and hypertension are modifiable risk factors for cognitive decline. About 25% of adults over age 65 use both antihypertensives (AHTs) and statins to treat these conditions. Recent research in humans suggests that their combined use may delay or prevent dementia onset. However, it is not clear whether and how combination treatment may benefit brain function. To begin to address this question, we examined effects of atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, and Captopril, an angiotensin-converting enzyme inhibitor (ACEI), administration on memory function, anxiety-like behavior, adult hippocampal neurogenesis and angiogenesis in adult and middle-aged male C57Bl/6J mice. In adult mice (3-months-old) combination (combo) treatment, as well as administration of each compound individually, for six weeks, accelerated memory extinction in contextual fear conditioning. However, pattern separation in the touchscreen-based location discrimination test, a behavior linked to adult hippocampal neurogenesis, was unchanged. In addition, dentate gyrus (DG) neurogenesis and vascularization were unaffected. In middle-aged mice (10-months-old) combo treatment had no effect on spatial memory in the Morris water maze, but did reduce anxiety in the open field test. A potential underlying mechanism may be the modest increase in new hippocampal neurons (~20%) in the combo as compared to the control group. DG vascularization was not altered. Overall, our findings suggest that statin and anti-hypertensive treatment may serve as a potential pharmacotherapeutic approach for anxiety, in particular for post-traumatic stress disorder (PTSD) patients who have impairments in extinction of aversive memories.
      Citation: Cells
      PubDate: 2021-07-14
      DOI: 10.3390/cells10071778
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1779: Cellular Therapy via Spermatogonial Stem Cells
           for Treating Impaired Spermatogenesis, Non-Obstructive Azoospermia

    • Authors: Nesma E. Abdelaal, Bereket Molla Tanga, Mai Abdelgawad, Sahar Allam, Mostafa Fathi, Islam M. Saadeldin, Seonggyu Bang, Jongki Cho
      First page: 1779
      Abstract: Male infertility is a major health problem affecting about 8–12% of couples worldwide. Spermatogenesis starts in the early fetus and completes after puberty, passing through different stages. Male infertility can result from primary or congenital, acquired, or idiopathic causes. The absence of sperm in semen, or azoospermia, results from non-obstructive causes (pretesticular and testicular), and post-testicular obstructive causes. Several medications such as antihypertensive drugs, antidepressants, chemotherapy, and radiotherapy could lead to impaired spermatogenesis and lead to a non-obstructive azoospermia. Spermatogonial stem cells (SSCs) are the basis for spermatogenesis and fertility in men. SSCs are characterized by their capacity to maintain the self-renewal process and differentiation into spermatozoa throughout the male reproductive life and transmit genetic information to the next generation. SSCs originate from gonocytes in the postnatal testis, which originate from long-lived primordial germ cells during embryonic development. The treatment of infertility in males has a poor prognosis. However, SSCs are viewed as a promising alternative for the regeneration of the impaired or damaged spermatogenesis. SSC transplantation is a promising technique for male infertility treatment and restoration of spermatogenesis in the case of degenerative diseases such as cancer, radiotherapy, and chemotherapy. The process involves isolation of SSCs and cryopreservation from a testicular biopsy before starting cancer treatment, followed by intra-testicular stem cell transplantation. In general, treatment for male infertility, even with SSC transplantation, still has several obstacles. The efficiency of cryopreservation, exclusion of malignant cells contamination in cancer patients, and socio-cultural attitudes remain major challenges to the wider application of SSCs as alternatives. Furthermore, there are limitations in experience and knowledge regarding cryopreservation of SSCs. However, the level of infrastructure or availability of regulatory approval to process and preserve testicular tissue makes them tangible and accurate therapy options for male infertility caused by non-obstructive azoospermia, though in their infancy, at least to date.
      Citation: Cells
      PubDate: 2021-07-14
      DOI: 10.3390/cells10071779
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1780: The Interactome of the VAP Family of Proteins:
           An Overview

    • Authors: Christina James, Ralph H. Kehlenbach
      First page: 1780
      Abstract: Membrane contact sites (MCS) are sites of close apposition of two organelles that help in lipid transport and synthesis, calcium homeostasis and several other biological processes. The VAMP-associated proteins (VAPs) VAPA, VAPB, MOSPD2 and the recently described MOSPD1 and MOSPD3 are tether proteins of MCSs that are mainly found at the endoplasmic reticulum (ER). VAPs interact with various proteins with a motif called FFAT (two phenylalanines in an acidic tract), recruiting the associated organelle to the ER. In addition to the conventional FFAT motif, the recently described FFNT (two phenylalanines in a neutral tract) and phospho-FFAT motifs contribute to the interaction with VAPs. In this review, we summarize and compare the recent interactome studies described for VAPs, including in silico and proximity labeling methods. Collectively, the interaction repertoire of VAPs is very diverse and highlights the complexity of interactions mediated by the different FFAT motifs to the VAPs.
      Citation: Cells
      PubDate: 2021-07-14
      DOI: 10.3390/cells10071780
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1781: WWOX and Its Binding Proteins in

    • Authors: Che-Yu Hsu, Kuan-Ting Lee, Tzu-Yu Sun, Chun-I Sze, Shenq-Shyang Huang, Li-Jin Hsu, Nan-Shan Chang
      First page: 1781
      Abstract: WW domain-containing oxidoreductase (WWOX) is known as one of the risk factors for Alzheimer’s disease (AD), a neurodegenerative disease. WWOX binds Tau via its C-terminal SDR domain and interacts with Tau phosphorylating enzymes ERK, JNK, and GSK-3β, and thereby limits AD progression. Loss of WWOX in newborns leads to severe neural diseases and early death. Gradual loss of WWOX protein in the hippocampus and cortex starting from middle age may slowly induce aggregation of a protein cascade that ultimately causes accumulation of extracellular amyloid beta plaques and intracellular tau tangles, along with reduction in inhibitory GABAergic interneurons, in AD patients over 70 years old. Age-related increases in pS14-WWOX accumulation in the brain promotes neuronal degeneration. Suppression of Ser14 phosphorylation by a small peptide Zfra leads to enhanced protein degradation, reduction in NF-κB-mediated inflammation, and restoration of memory loss in triple transgenic mice for AD. Intriguingly, tumor suppressors p53 and WWOX may counteract each other in vivo, which leads to upregulation of AD-related protein aggregation in the brain and lung. WWOX has numerous binding proteins. We reported that the stronger the binding between WWOX and its partners, the better the suppression of cancer growth and reduction in inflammation. In this regard, the stronger complex formation between WWOX and partners may provide a better blockade of AD progression. In this review, we describe whether and how WWOX and partner proteins control inflammatory response and protein aggregation and thereby limit AD progression.
      Citation: Cells
      PubDate: 2021-07-14
      DOI: 10.3390/cells10071781
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1782: Cancer Metabostemness and Metabolic
           Reprogramming via P2X7 Receptor

    • Authors: Izadora Lorrany Alves Rabelo, Vanessa Fernandes Arnaud-Sampaio, Elena Adinolfi, Henning Ulrich, Claudiana Lameu
      First page: 1782
      Abstract: The heterogeneity of tumor cell mass and the plasticity of cancer cell phenotypes in solid tumors allow for the insurgence of resistant and metastatic cells, responsible for cancer patients’ clinical management’s main challenges. Among several factors that are responsible for increased cancer aggression, metabolic reprogramming is recently emerging as an ultimate cancer hallmark, as it is central for cancer cell survival and self-renewal, metastasis and chemoresistance. The P2X7 receptor, whose expression is upregulated in many solid and hematological malignancies, is also emerging as a good candidate in cancer metabolic reprogramming and the regulation of stem cell proliferation and differentiation. Metabostemness refers to the metabolic reprogramming of cancer cells toward less differentiated (CSCs) cellular states, and we believe that there is a strong correlation between metabostemness and P2X7 receptor functions in oncogenic processes. Here, we summarize important aspects of P2X7 receptor functions in normal and tumor tissues as well as essential aspects of its structure, regulation, pharmacology and its clinical use. Finally, we review current knowledge implicating P2X7 receptor functions in cancer-related molecular pathways, in metabolic reprogramming and in metabostemness.
      Citation: Cells
      PubDate: 2021-07-14
      DOI: 10.3390/cells10071782
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1783: Sex-Specific Differences in Glioblastoma

    • Authors: Anna Carrano, Juan Jose Juarez, Diego Incontri, Antonio Ibarra, Hugo Guerrero Cazares
      First page: 1783
      Abstract: Sex differences have been well identified in many brain tumors. Even though glioblastoma (GBM) is the most common primary malignant brain tumor in adults and has the worst outcome, well-established differences between men and women are limited to incidence and outcome. Little is known about sex differences in GBM at the disease phenotype and genetical/molecular level. This review focuses on a deep understanding of the pathophysiology of GBM, including hormones, metabolic pathways, the immune system, and molecular changes, along with differences between men and women and how these dimorphisms affect disease outcome. The information analyzed in this review shows a greater incidence and worse outcome in male patients with GBM compared with female patients. We highlight the protective role of estrogen and the upregulation of androgen receptors and testosterone having detrimental effects on GBM. Moreover, hormones and the immune system work in synergy to directly affect the GBM microenvironment. Genetic and molecular differences have also recently been identified. Specific genes and molecular pathways, either upregulated or downregulated depending on sex, could potentially directly dictate GBM outcome differences. It appears that sexual dimorphism in GBM affects patient outcome and requires an individualized approach to management considering the sex of the patient, especially in relation to differences at the molecular level.
      Citation: Cells
      PubDate: 2021-07-14
      DOI: 10.3390/cells10071783
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1784: Transcryptomic Analysis of Human Brain
           -Microvascular Endothelial Cell Driven Changes in -Vascular Pericytes

    • Authors: Kurmann, Okoniewski, Dubey
      First page: 1784
      Abstract: Many pathological conditions of the brain are associated with structural abnormalities within the neurovascular system and linked to pericyte (PC) loss and/or dysfunction. Since crosstalk between endothelial cells (ECs) and PCs greatly impacts the function of the blood–brain barrier (BBB), effects of PCs on endothelial integrity and function have been investigated extensively. However, the impact of ECs on the function and activity of PCs remains largely unknown. Hence, using co-cultures of human brain vascular PCs with human cerebral microvascular ECs on opposite sides of porous Transwell inserts which facilitates direct EC–PC contact and improves EC barrier function, we analyzed EC-driven transcriptomic changes in PCs using microarrays and changes in cytokines/chemokines using proteome arrays. Gene expression analysis (GEA) in PCs co-cultured with ECs versus PCs cultured alone showed significant upregulation of 1′334 genes and downregulation of 964 genes. GEA in co-cultured PCs revealed increased expression of five prominent PC markers as well as soluble factors, such as transforming growth factor beta, fibroblast growth factor, angiopoietin 1, brain-derived neurotrophic factor, all of which are involved in EC–PC crosstalk and BBB induction. Pathway enrichment analysis of modulated genes showed a strong impact on many inflammatory and extracellular matrix (ECM) pathways including interferon and interleukin signaling, TGF-β and interleukin-1 regulation of ECM, as well as on the mRNA processing pathway. Interestingly, while co-culture induced the mRNA expression of many chemokines and cytokines, including several CCL- and CXC-motif ligands and interleukins, we observed a decreased expression of the same inflammatory mediators on the protein level. Importantly, in PCs, ECs significantly induced interferon associated proteins (IFIT1, IFI44L, IF127, IFIT3, IFI6, IFI44) with anti-viral actions; downregulated prostaglandin E receptor 2 (prevent COX-2 mediated BBB damage); upregulated fibulin-3 and connective tissue growth factor essential for BBB integrity; and multiple ECMs (collagens and integrins) that inhibit cell migration. Our findings suggest that via direct contact, ECs prime PCs to induce molecules to promote BBB integrity and cell survival during infection and inflammatory insult. Taken together, we provide first evidence that interaction with ECs though porous membranes induces major changes in the transcriptomic and proteomic profile of PCs. ECs influence genes involved in diverse aspects of PC function including PC maturation, cell survival, anti-viral defense, blood flow regulation, immuno-modulation and ECM deposition.
      Citation: Cells
      PubDate: 2021-07-14
      DOI: 10.3390/cells10071784
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1785: TNFR2 Signaling Regulates the Immunomodulatory
           Function of Oligodendrocyte Precursor Cells

    • Authors: Haritha L. Desu, Placido Illiano, James S. Choi, Maureen C. Ascona, Han Gao, Jae K. Lee, Roberta Brambilla
      First page: 1785
      Abstract: Multiple sclerosis (MS) is a neuroimmune disorder characterized by inflammation, CNS demyelination, and progressive neurodegeneration. Chronic MS patients exhibit impaired remyelination capacity, partly due to the changes that oligodendrocyte precursor cells (OPCs) undergo in response to the MS lesion environment. The cytokine tumor necrosis factor (TNF) is present in the MS-affected CNS and has been implicated in disease pathophysiology. Of the two active forms of TNF, transmembrane (tmTNF) and soluble (solTNF), tmTNF signals via TNFR2 mediating protective and reparative effects, including remyelination, whereas solTNF signals predominantly via TNFR1 promoting neurotoxicity. To better understand the mechanisms underlying repair failure in MS, we investigated the cellular responses of OPCs to inflammatory exposure and the specific role of TNFR2 signaling in their modulation. Following treatment of cultured OPCs with IFNγ, IL1β, and TNF, we observed, by RNA sequencing, marked inflammatory and immune activation of OPCs, accompanied by metabolic changes and dysregulation of their proliferation and differentiation programming. We also established the high likelihood of cell–cell interaction between OPCs and microglia in neuroinflammatory conditions, with OPCs able to produce chemokines that can recruit and activate microglia. Importantly, we showed that these functions are exacerbated when TNFR2 is ablated. Together, our data indicate that neuroinflammation leads OPCs to shift towards an immunomodulatory phenotype while diminishing their capacity to proliferate and differentiate, thus impairing their repair function. Furthermore, we demonstrated that TNFR2 plays a key role in this process, suggesting that boosting TNFR2 activation or its downstream signals could be an effective strategy to restore OPC reparative capacity in demyelinating disease.
      Citation: Cells
      PubDate: 2021-07-15
      DOI: 10.3390/cells10071785
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1786: GSI Treatment Preserves Protein Synthesis in
           C2C12 Myotubes

    • Authors: Joshua R. Huot, Brian Thompson, Charlotte McMullen, Joseph S. Marino, Susan T. Arthur
      First page: 1786
      Abstract: It has been demonstrated that inhibiting Notch signaling through γ-secretase inhibitor (GSI) treatment increases myogenesis, AKT/mTOR signaling, and muscle protein synthesis (MPS) in C2C12 myotubes. The purpose of this study was to determine if GSI-mediated effects on myogenesis and MPS are dependent on AKT/mTOR signaling. C2C12 cells were assessed for indices of myotube formation, anabolic signaling, and MPS following GSI treatment in combination with rapamycin and API-1, inhibitors of mTOR and AKT, respectively. GSI treatment increased several indices of myotube fusion and MPS in C2C12 myotubes. GSI-mediated effects on myotube formation and fusion were completely negated by treatment with rapamycin and API-1. Meanwhile, GSI treatment was able to rescue MPS in C2C12 myotubes exposed to rapamycin or rapamycin combined with API-1. Examination of protein expression revealed that GSI treatment was able to rescue pGSK3β Ser9 despite AKT inhibition by API-1. These findings demonstrate that GSI treatment is able to rescue MPS independent of AKT/mTOR signaling, possibly via GSK3β modulation.
      Citation: Cells
      PubDate: 2021-07-15
      DOI: 10.3390/cells10071786
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1787: Recellularization of Native Tissue Derived
           Acellular Scaffolds with Mesenchymal Stem Cells

    • Authors: Ebtehal Ahmed, Tarek Saleh, Meifeng Xu
      First page: 1787
      Abstract: The functionalization of decellularized scaffolds is still challenging because of the recellularization-related limitations, including the finding of the most optimal kind of cell(s) and the best way to control their distribution within the scaffolds to generate native mimicking tissues. That is why researchers have been encouraged to study stem cells, in particular, mesenchymal stem cells (MSCs), as alternative cells to repopulate and functionalize the scaffolds properly. MSCs could be obtained from various sources and have therapeutic effects on a wide range of inflammatory/degenerative diseases. Therefore, in this mini-review, we will discuss the benefits using of MSCs for recellularization, the factors affecting their efficiency, and the drawbacks that may need to be overcome to generate bioengineered transplantable organs.
      Citation: Cells
      PubDate: 2021-07-15
      DOI: 10.3390/cells10071787
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1788: MiRNA Profiling in Plasma and Placenta of
           SARS-CoV-2-Infected Pregnant Women

    • Authors: Irma Saulle, Micaela Garziano, Claudio Fenizia, Gioia Cappelletti, Francesca Parisi, Mario Clerici, Irene Cetin, Valeria Savasi, Mara Biasin
      First page: 1788
      Abstract: MicroRNAs are gene expression regulators associated with several human pathologies, including those generated by viral infections. Their role in SARS-CoV-2 infection and COVID-19 has been investigated and reviewed in many informative studies; however, a thorough miRNA outline in SARS-CoV-2-infected pregnant women (SIPW), at both systemic and placental levels, is missing. To fill this gap, blood and placenta biopsies collected at delivery from 15 asymptomatic SIPW were immediately analysed for: miRNA expression (n = 84) (QPCR array), antiviral/immune mRNA target expression (n = 74) (QGene) and cytokine/chemokines production (n = 27) (Multiplex ELISA). By comparing these results with those obtained from six uninfected pregnant women (UPW), we observed that, following SARS-CoV-2 infection, the transcriptomic profile of pregnant women is significantly altered in different anatomical districts, even in the absence of clinical symptoms and vertical transmission. This characteristic combination of miRNA and antiviral/immune factors seems to control both the infection and the dysfunctional immune reaction, thus representing a positive correlate of protection and a potential therapeutic target against SARS-CoV-2.
      Citation: Cells
      PubDate: 2021-07-15
      DOI: 10.3390/cells10071788
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1789: Amyotrophic Lateral Sclerosis (ALS): Stressed
           by Dysfunctional Mitochondria-Endoplasmic Reticulum Contacts (MERCs)

    • Authors: Junsheng Chen, Arthur Bassot, Fabrizio Giuliani, Thomas Simmen
      First page: 1789
      Abstract: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease for which there is currently no cure. Progress in the characterization of other neurodegenerative mechanisms has shifted the spotlight onto an intracellular structure called mitochondria-endoplasmic reticulum (ER) contacts (MERCs) whose ER portion can be biochemically isolated as mitochondria-associated membranes (MAMs). Within the central nervous system (CNS), these structures control the metabolic output of mitochondria and keep sources of oxidative stress in check via autophagy. The most relevant MERC controllers in the ALS pathogenesis are vesicle-associated membrane protein-associated protein B (VAPB), a mitochondria-ER tether, and the ubiquitin-specific chaperone valosin containing protein (VCP). These two systems cooperate to maintain mitochondrial energy output and prevent oxidative stress. In ALS, mutant VAPB and VCP take a central position in the pathology through MERC dysfunction that ultimately alters or compromises mitochondrial bioenergetics. Intriguingly, both proteins are targets themselves of other ALS mutant proteins, including C9orf72, FUS, or TDP-43. Thus, a new picture emerges, where different triggers cause MERC dysfunction in ALS, subsequently leading to well-known pathological changes including endoplasmic reticulum (ER) stress, inflammation, and motor neuron death.
      Citation: Cells
      PubDate: 2021-07-15
      DOI: 10.3390/cells10071789
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1790: Cerebral Organoids—Challenges to
           Establish a Brain Prototype

    • Authors: Artem V. Eremeev, Olga S. Lebedeva, Margarita E. Bogomiakova, Maria A. Lagarkova, Alexandra N. Bogomazova
      First page: 1790
      Abstract: The new cellular models based on neural cells differentiated from induced pluripotent stem cells have greatly enhanced our understanding of human nervous system development. Highly efficient protocols for the differentiation of iPSCs into different types of neural cells have allowed the creation of 2D models of many neurodegenerative diseases and nervous system development. However, the 2D culture of neurons is an imperfect model of the 3D brain tissue architecture represented by many functionally active cell types. The development of protocols for the differentiation of iPSCs into 3D cerebral organoids made it possible to establish a cellular model closest to native human brain tissue. Cerebral organoids are equally suitable for modeling various CNS pathologies, testing pharmacologically active substances, and utilization in regenerative medicine. Meanwhile, this technology is still at the initial stage of development.
      Citation: Cells
      PubDate: 2021-07-15
      DOI: 10.3390/cells10071790
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1791: Consequences of SUR2[A478V] Mutation in
           Skeletal Muscle of Murine Model of Cantu Syndrome

    • Authors: Rosa Scala, Fatima Maqoud, Nicola Zizzo, Giuseppe Passantino, Antonietta Mele, Giulia Maria Camerino, Conor McClenaghan, Theresa M. Harter, Colin G. Nichols, Domenico Tricarico
      First page: 1791
      Abstract: (1) Background: Cantu syndrome (CS) arises from gain-of-function (GOF) mutations in the ABCC9 and KCNJ8 genes, which encode ATP-sensitive K+ (KATP) channel subunits SUR2 and Kir6.1, respectively. Most CS patients have mutations in SUR2, the major component of skeletal muscle KATP, but the consequences of SUR2 GOF in skeletal muscle are unknown. (2) Methods: We performed in vivo and ex vivo characterization of skeletal muscle in heterozygous SUR2[A478V] (SUR2wt/AV) and homozygous SUR2[A478V] (SUR2AV/AV) CS mice. (3) Results: In SUR2wt/AV and SUR2AV/AV mice, forelimb strength and diaphragm amplitude movement were reduced; muscle echodensity was enhanced. KATP channel currents recorded in Flexor digitorum brevis fibers showed reduced MgATP-sensitivity in SUR2wt/AV, dramatically so in SUR2AV/AV mice; IC50 for MgATP inhibition of KATP currents were 1.9 ± 0.5 × 10−5 M in SUR2wt/AV and 8.6 ± 0.4 × 10−6 M in WT mice and was not measurable in SUR2AV/AV. A slight rightward shift of sensitivity to inhibition by glibenclamide was detected in SUR2AV/AV mice. Histopathological and qPCR analysis revealed atrophy of soleus and tibialis anterior muscles and up-regulation of atrogin-1 and MuRF1 mRNA in CS mice. (4) Conclusions: SUR2[A478V] “knock-in” mutation in mice impairs KATP channel modulation by MgATP, markedly so in SUR2AV/AV, with atrophy and non-inflammatory edema in different skeletal muscle phenotypes.
      Citation: Cells
      PubDate: 2021-07-15
      DOI: 10.3390/cells10071791
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1792: Unveiling the Roles of Low-Density Lipoprotein
           Receptor-Related Protein 6 in Intestinal Homeostasis, Regeneration and

    • Authors: Jennifer Raisch, Anthony Côté-Biron, Marie-Josée Langlois, Caroline Leblanc, Nathalie Rivard
      First page: 1792
      Abstract: Intestinal epithelial self-renewal is tightly regulated by signaling pathways controlling stem cell proliferation, determination and differentiation. In particular, Wnt/β-catenin signaling controls intestinal crypt cell division, survival and maintenance of the stem cell niche. Most colorectal cancers are initiated by mutations activating the Wnt/β-catenin pathway. Wnt signals are transduced through Frizzled receptors and LRP5/LRP6 coreceptors to downregulate GSK3β activity, resulting in increased nuclear β-catenin. Herein, we explored if LRP6 expression is required for maintenance of intestinal homeostasis, regeneration and oncogenesis. Mice with an intestinal epithelial cell-specific deletion of Lrp6 (Lrp6IEC-KO) were generated and their phenotype analyzed. No difference in intestinal architecture nor in proliferative and stem cell numbers was found in Lrp6IEC-KO mice in comparison to controls. Nevertheless, using ex vivo intestinal organoid cultures, we found that LRP6 expression was critical for crypt cell proliferation and stem cell maintenance. When exposed to dextran sodium sulfate, Lrp6IEC-KO mice developed more severe colitis than control mice. However, loss of LRP6 did not affect tumorigenesis in ApcMin/+ mice nor growth of human colorectal cancer cells. By contrast, Lrp6 silencing diminished anchorage-independent growth of BRafV600E-transformed intestinal epithelial cells (IEC). Thus, LRP6 controls intestinal stem cell functionality and is necessary for BRAF-induced IEC oncogenesis.
      Citation: Cells
      PubDate: 2021-07-15
      DOI: 10.3390/cells10071792
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1793: Fisher vs. The Worms: Extraordinary Sex Ratios
           in Nematodes and the Mechanisms That Produce Them

    • Authors: Van Goor, Shakes, Haag
      First page: 1793
      Abstract: Parker, Baker, and Smith provided the first robust theory explaining why anisogamy evolves in parallel in multicellular organisms. Anisogamy sets the stage for the emergence of separate sexes, and for another phenomenon with which Parker is associated: sperm competition. In outcrossing taxa with separate sexes, Fisher proposed that the sex ratio will tend towards unity in large, randomly mating populations due to a fitness advantage that accrues in individuals of the rarer sex. This creates a vast excess of sperm over that required to fertilize all available eggs, and intense competition as a result. However, small, inbred populations can experience selection for skewed sex ratios. This is widely appreciated in haplodiploid organisms, in which females can control the sex ratio behaviorally. In this review, we discuss recent research in nematodes that has characterized the mechanisms underlying highly skewed sex ratios in fully diploid systems. These include self-fertile hermaphroditism and the adaptive elimination of sperm competition factors, facultative parthenogenesis, non-Mendelian meiotic oddities involving the sex chromosomes, and environmental sex determination. By connecting sex ratio evolution and sperm biology in surprising ways, these phenomena link two “seminal” contributions of G. A. Parker. 
      Citation: Cells
      PubDate: 2021-07-15
      DOI: 10.3390/cells10071793
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1794: Implant Fibrosis and the Underappreciated Role
           of Myofibroblasts in the Foreign Body Reaction

    • Authors: Nina Noskovicova, Boris Hinz, Pardis Pakshir
      First page: 1794
      Abstract: Body implants and implantable medical devices have dramatically improved and prolonged the life of countless patients. However, our body repair mechanisms have evolved to isolate, reject, or destroy any object that is recognized as foreign to the organism and inevitably mounts a foreign body reaction (FBR). Depending on its severity and chronicity, the FBR can impair implant performance or create severe clinical complications that will require surgical removal and/or replacement of the faulty device. The number of review articles discussing the FBR seems to be proportional to the number of different implant materials and clinical applications and one wonders, what else is there to tell' We will here take the position of a fibrosis researcher (which, coincidentally, we are) to elaborate similarities and differences between the FBR, normal wound healing, and chronic healing conditions that result in the development of peri-implant fibrosis. After giving credit to macrophages in the inflammatory phase of the FBR, we will mainly focus on the activation of fibroblastic cells into matrix-producing and highly contractile myofibroblasts. While fibrosis has been discussed to be a consequence of the disturbed and chronic inflammatory milieu in the FBR, direct activation of myofibroblasts at the implant surface is less commonly considered. Thus, we will provide a perspective how physical properties of the implant surface control myofibroblast actions and accumulation of stiff scar tissue. Because formation of scar tissue at the surface and around implant materials is a major reason for device failure and extraction surgeries, providing implant surfaces with myofibroblast-suppressing features is a first step to enhance implant acceptance and functional lifetime. Alternative therapeutic targets are elements of the myofibroblast mechanotransduction and contractile machinery and we will end with a brief overview on such targets that are considered for the treatment of other organ fibroses.
      Citation: Cells
      PubDate: 2021-07-15
      DOI: 10.3390/cells10071794
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1795: Actin Cytoskeleton Role in the Maintenance of
           Neuronal Morphology and Long-Term Memory

    • Authors: Raphael Lamprecht
      First page: 1795
      Abstract: Evidence indicates that long-term memory formation creates long-lasting changes in neuronal morphology within a specific neuronal network that forms the memory trace. Dendritic spines, which include most of the excitatory synapses in excitatory neurons, are formed or eliminated by learning. These changes may be long-lasting and correlate with memory strength. Moreover, learning-induced changes in the morphology of existing spines can also contribute to the formation of the neuronal network that underlies memory. Altering spines morphology after memory consolidation can erase memory. These observations strongly suggest that learning-induced spines modifications can constitute the changes in synaptic connectivity within the neuronal network that form memory and that stabilization of this network maintains long-term memory. The formation and elimination of spines and other finer morphological changes in spines are mediated by the actin cytoskeleton. The actin cytoskeleton forms networks within the spine that support its structure. Therefore, it is believed that the actin cytoskeleton mediates spine morphogenesis induced by learning. Any long-lasting changes in the spine morphology induced by learning require the preservation of the spine actin cytoskeleton network to support and stabilize the spine new structure. However, the actin cytoskeleton is highly dynamic, and the turnover of actin and its regulatory proteins that determine and support the actin cytoskeleton network structure is relatively fast. Molecular models, suggested here, describe ways to overcome the dynamic nature of the actin cytoskeleton and the fast protein turnover and to support an enduring actin cytoskeleton network within the spines, spines stability and long-term memory. These models are based on long-lasting changes in actin regulatory proteins concentrations within the spine or the formation of a long-lasting scaffold and the ability for its recurring rebuilding within the spine. The persistence of the actin cytoskeleton network within the spine is suggested to support long-lasting spine structure and the maintenance of long-term memory.
      Citation: Cells
      PubDate: 2021-07-15
      DOI: 10.3390/cells10071795
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1796: Combination of GP88 Expression in Tumor Cells
           and Tumor-Infiltrating Immune Cells Is an Independent Prognostic Factor
           for Bladder Cancer Patients

    • Authors: Eckstein, Lieb, Jung, Sikic, Weigelt, Stöhr, Geppert, Weyerer, Bertz, Serrero, Yue, Hartmann, Wullich, Taubert, Wach
      First page: 1796
      Abstract: Urothelial bladder cancer (BCa) is the ninth most commonly diagnosed cancer worldwide and accounts for approximately 3% of global cancer diagnoses. We are interested in prognostic markers that may characterize tumor cells (TCs) and immune cells (ICs) and their relationship in BCa. A potential candidate marker that meets these criteria is progranulin (GP88), which is expressed separately in TCs and ICs. We analyzed GP88 expression by immunohistochemistry (IHC) in 196 muscle-invasive BCa samples using a tissue microarray. The immunoreactive score for GP88 staining in TCs and the percentage of GP88-positive ICs was determined. An easy cutoff for the staining status of TCs (positive vs. negative) and ICs (0% vs. > 0%) and, more generally, negative vs. positive GP88 staining could be applied. We detected 93 patients (47.4%) and 92 patients (46.9%) with GP88-positive TCs or ICs, respectively. The IHC results were correlated with clinicopathological and survival data. Positive GP88 staining in TCs appeared to be an independent poor prognostic factor for disease-specific survival (DSS) (RR (relative risk) = 1.74; p = 0.009) and recurrence-free survival (RFS) (RR = 1.92; p = 0.002). In contrast, negative GP88 staining in ICs was an independent negative predictor for overall survival (OS) (RR = 2.18; p < 0.001), DSS (RR = 2.84; p < 0.001) and RFS (RR = 2.91; p < 0.001) in multivariate Cox’s regression analysis. When combining GP88 staining in TCs and ICs, a specific combination of GP88-positive TCs and GP88-negative ICs was associated with a 2.54-fold increased risk of death, a 4.21-fold increased risk of disease-specific death and a 4.81-fold increased risk of recurrence compared to GP88-negative TCs and GP88-positive ICs. In summary, GP88 positivity in TCs is a negative prognostic factor for DSS and RFS. In addition, GP88 positivity can mark ICs that are associated with a good prognosis (OS, DSS and RFS). The combination of GP88 staining in TCs and ICs appears to be a significant independent prognostic biomarker in muscle-invasive BCa.
      Citation: Cells
      PubDate: 2021-07-15
      DOI: 10.3390/cells10071796
      Issue No: Vol. 10, No. 7 (2021)
  • Cells, Vol. 10, Pages 1797: Development and Validation of a Good
           Manufacturing Process for IL-4-Driven Expansion of Chimeric Cytokine
           Receptor-Expressing CAR T-Cells

    • Authors: van Schalkwyk, van der Stegen, Bosshard-Carter, Graves, Papa, Parente-Pereira, Farzaneh, Fisher, Hope, Adami, Maher
      First page: 1797
      Abstract: Adoptive cancer immunotherapy using chimeric antigen receptor (CAR) engineered T-cells holds great promise, although several obstacles hinder the efficient generation of cell products under good manufacturing practice (GMP). Patients are often immune compromised, rendering it challenging to produce sufficient numbers of gene-modified cells. Manufacturing protocols are labour intensive and frequently involve one or more open processing steps, leading to increased risk of contamination. We set out to develop a simplified process to generate autologous gamma retrovirus-transduced T-cells for clinical evaluation in patients with head and neck cancer. T-cells were engineered to co-express a panErbB-specific CAR (T1E28z) and a chimeric cytokine receptor (4) that permits their selective expansion in response to interleukin (IL)-4. Using peripheral blood as starting material, sterile culture procedures were conducted in gas-permeable bags under static conditions. Pre-aliquoted medium and cytokines, bespoke connector devices and sterile welding/ sealing were used to maximise the use of closed manufacturing steps. Reproducible IL-4-dependent expansion and enrichment of CAR-engineered T-cells under GMP was achieved, both from patients and healthy donors. We also describe the development and approach taken to validate a panel of monitoring and critical release assays, which provide objective data on cell product quality.
      Citation: Cells
      PubDate: 2021-07-15
      DOI: 10.3390/cells10071797
      Issue No: Vol. 10, No. 7 (2021)
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