Publisher: MDPI   (Total: 233 journals)

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Showing 1 - 200 of 233 Journals sorted alphabetically
Acoustics     Open Access   (Followers: 4)
Actuators     Open Access   (Followers: 4)
Administrative Sciences     Open Access   (Followers: 6)
Aerospace     Open Access   (Followers: 60, SJR: 0.305, CiteScore: 1)
Agriculture     Open Access   (Followers: 9, SJR: 0.33, CiteScore: 2)
AgriEngineering     Open Access   (Followers: 1)
Agronomy     Open Access   (Followers: 14, SJR: 0.695, CiteScore: 2)
Algorithms     Open Access   (Followers: 13, SJR: 0.217, CiteScore: 1)
Allergies     Open Access   (Followers: 2)
Animals     Open Access   (Followers: 15, SJR: 0.744, CiteScore: 2)
Antibiotics     Open Access   (Followers: 9, 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: 26)
Atoms     Open Access   (Followers: 1)
Axioms     Open Access   (Followers: 1)
Batteries     Open Access   (Followers: 9)
Behavioral Sciences     Open Access   (Followers: 4)
Beverages     Open Access   (Followers: 1)
Big Data and Cognitive Computing     Open Access   (Followers: 7)
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: 3, SJR: 0.829, CiteScore: 4)
Brain Sciences     Open Access   (Followers: 5, SJR: 1.047, CiteScore: 3)
Buildings     Open Access   (Followers: 8)
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  
Climate     Open Access   (Followers: 6)
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   (Followers: 1)
Cosmetics     Open Access   (Followers: 5)
Cryptography     Open Access  
Crystals     Open Access   (Followers: 4, SJR: 0.566, CiteScore: 2)
Dairy     Open Access   (Followers: 2)
Data     Open Access   (Followers: 4)
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: 5)
Econometrics     Open Access   (Followers: 12)
Economies     Open Access   (Followers: 1)
Education     Open Access   (Followers: 13)
Electronics     Open Access   (Followers: 111, SJR: 0.548, CiteScore: 3)
Energies     Open Access   (Followers: 6, 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: 5)
Fermentation     Open Access   (Followers: 3)
Fibers     Open Access   (Followers: 7)
Fire     Open Access  
Fishes     Open Access  
Fluids     Open Access   (Followers: 1)
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: 178, SJR: 0.219, CiteScore: 1)
Galaxies     Open Access   (Followers: 6)
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: 3, SJR: 0.451, CiteScore: 2)
Geriatrics     Open Access   (Followers: 4)
Healthcare     Open Access   (Followers: 3)
Hearts     Open Access   (Followers: 3)
Heritage     Open Access  
High-Throughput     Open Access  
Histories     Open Access   (Followers: 1)
Horticulturae     Open Access   (Followers: 2)
Humanities     Open Access   (Followers: 15)
Hydrology     Open Access   (Followers: 5)
Informatics     Open Access   (Followers: 4)
Information     Open Access   (Followers: 49, 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: 11)
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: 2)
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: 10, SJR: 0.222, CiteScore: 1)
J. of Manufacturing and Materials Processing     Open Access  
J. of Marine Science and Engineering     Open Access   (Followers: 2)
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  
Land     Open Access   (Followers: 4)
Languages     Open Access   (Followers: 4)
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: 7)
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: 2)
Mathematics     Open Access   (Followers: 2)
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: 6)
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)
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: 4, SJR: 1.421, CiteScore: 4)
Pharmaceuticals     Open Access   (Followers: 6, 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  
Plants     Open Access   (SJR: 1.39, CiteScore: 3)
Plasma     Open Access   (Followers: 5)
Polymers     Open Access   (Followers: 21, 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: 1)
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: 55, SJR: 1.386, CiteScore: 4)
Reports     Open Access  
Resources     Open Access   (SJR: 0.688, CiteScore: 3)
Risks     Open Access  
Robotics     Open Access   (Followers: 9)
Safety     Open Access   (Followers: 2)
Sci     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  [233 journals]
  • Cells, Vol. 10, Pages 538: Gamma-Chain Receptor Cytokines & PD-1
           Manipulation to Restore HCV-Specific CD8+ T Cell Response during Chronic
           Hepatitis C

    • Authors: Julia Peña-Asensio, Henar Calvo, Miguel Torralba, Joaquín Miquel, Eduardo Sanz-de-Villalobos, Juan-Ramón Larrubia
      First page: 538
      Abstract: Hepatitis C virus (HCV)-specific CD8+ T cell response is essential in natural HCV infection control, but it becomes exhausted during persistent infection. Nowadays, chronic HCV infection can be resolved by direct acting anti-viral treatment, but there are still some non-responders that could benefit from CD8+ T cell response restoration. To become fully reactive, T cell needs the complete release of T cell receptor (TCR) signalling but, during exhaustion this is blocked by the PD-1 effect on CD28 triggering. The T cell pool sensitive to PD-1 modulation is the progenitor subset but not the terminally differentiated effector population. Nevertheless, the blockade of PD-1/PD-L1 checkpoint cannot be always enough to restore this pool. This is due to the HCV ability to impair other co-stimulatory mechanisms and metabolic pathways and to induce a pro-apoptotic state besides the TCR signalling impairment. In this sense, gamma-chain receptor cytokines involved in memory generation and maintenance, such as low-level IL-2, IL-7, IL-15, and IL-21, might carry out a positive effect on metabolic reprogramming, apoptosis blockade and restoration of co-stimulatory signalling. This review sheds light on the role of combinatory immunotherapeutic strategies to restore a reactive anti-HCV T cell response based on the mixture of PD-1 blocking plus IL-2/IL-7/IL-15/IL-21 treatment.
      Citation: Cells
      PubDate: 2021-03-03
      DOI: 10.3390/cells10030538
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 539: KLF4, Slug and EMT in Head and Neck Squamous
           Cell Carcinoma

    • Authors: Julia Ingruber, Dragana Savic, Teresa Bernadette Steinbichler, Susanne Sprung, Felix Fleischer, Rudolf Glueckert, Gabriele Schweigl, Ira-Ida Skvortsova, Herbert Riechelmann, József Dudás
      First page: 539
      Abstract: Epithelial to mesenchymal transition (EMT) is clinically relevant in head and neck squamous cell carcinoma (HNSCC). We hypothesized that EMT-transcription factors (EMT-TFs) and an anti-EMT factor, Krüppel-like-factor-4 (KLF4) regulate EMT in HNSCC. Ten control mucosa and 37 HNSCC tissue samples and three HNSCC cell lines were included for investigation of EMT-TFs, KLF4 and vimentin at mRNA and protein levels. Slug gene expression was significantly higher, whereas, KLF4 gene expression was significantly lower in HNSCC than in normal mucosa. In the majority of HNSCC samples, there was a significant negative correlation between KLF4 and Slug gene expression. Slug gene expression was significantly higher in human papilloma virus (HPV) negative HNSCC, and in tumor samples with irregular p53 gene sequence. Transforming-growth-factor-beta-1 (TGF- β1) contributed to downregulation of KLF4 and upregulation of Slug. Two possible regulatory pathways could be suggested: (1) EMT-factors induced pathway, where TGF-β1 induced Slug together with vimentin, and KLF4 was down regulated at the same time; (2) p53 mutations contributed to upregulation and stabilization of Slug, where also KLF4 could co-exist with EMT-TFs.
      Citation: Cells
      PubDate: 2021-03-03
      DOI: 10.3390/cells10030539
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 540: Astrocytes in Alzheimer’s Disease:
           Pathological Significance and Molecular Pathways

    • Authors: Pranav Preman, Maria Alfonso-Triguero, Elena Alberdi, Alexei Verkhratsky, Amaia M. Arranz
      First page: 540
      Abstract: Astrocytes perform a wide variety of essential functions defining normal operation of the nervous system and are active contributors to the pathogenesis of neurodegenerative disorders such as Alzheimer’s among others. Recent data provide compelling evidence that distinct astrocyte states are associated with specific stages of Alzheimer´s disease. The advent of transcriptomics technologies enables rapid progress in the characterisation of such pathological astrocyte states. In this review, we provide an overview of the origin, main functions, molecular and morphological features of astrocytes in physiological as well as pathological conditions related to Alzheimer´s disease. We will also explore the main roles of astrocytes in the pathogenesis of Alzheimer´s disease and summarize main transcriptional changes and altered molecular pathways observed in astrocytes during the course of the disease.
      Citation: Cells
      PubDate: 2021-03-04
      DOI: 10.3390/cells10030540
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 541: Targeting the Hypoxic and Acidic Tumor
           Microenvironment with pH-Sensitive Peptides

    • Authors: Nayanthara U. Dharmaratne, Alanna R. Kaplan, Peter M. Glazer
      First page: 541
      Abstract: The delivery of cancer therapeutics can be limited by pharmacological issues such as poor bioavailability and high toxicity to healthy tissue. pH-low insertion peptides (pHLIPs) represent a promising tool to overcome these limitations. pHLIPs allow for the selective delivery of agents to tumors on the basis of pH, taking advantage of the acidity of the hypoxic tumor microenvironment. This review article highlights the various applications in which pHLIPs have been utilized for targeting and treating diseases in hypoxic environments, including delivery of small molecule inhibitors, toxins, nucleic acid analogs, fluorescent dyes, and nanoparticles.
      Citation: Cells
      PubDate: 2021-03-04
      DOI: 10.3390/cells10030541
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 542: Modulation of Endosome Function, Vesicle
           Trafficking and Autophagy by Human Herpesviruses

    • Authors: Eduardo I. Tognarelli, Antonia Reyes, Nicolás Corrales, Leandro J. Carreño, Susan M. Bueno, Alexis M. Kalergis, Pablo A. González
      First page: 542
      Abstract: Human herpesviruses are a ubiquitous family of viruses that infect individuals of all ages and are present at a high prevalence worldwide. Herpesviruses are responsible for a broad spectrum of diseases, ranging from skin and mucosal lesions to blindness and life-threatening encephalitis, and some of them, such as Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein–Barr virus (EBV), are known to be oncogenic. Furthermore, recent studies suggest that some herpesviruses may be associated with developing neurodegenerative diseases. These viruses can establish lifelong infections in the host and remain in a latent state with periodic reactivations. To achieve infection and yield new infectious viral particles, these viruses require and interact with molecular host determinants for supporting their replication and spread. Important sets of cellular factors involved in the lifecycle of herpesviruses are those participating in intracellular membrane trafficking pathways, as well as autophagic-based organelle recycling processes. These cellular processes are required by these viruses for cell entry and exit steps. Here, we review and discuss recent findings related to how herpesviruses exploit vesicular trafficking and autophagy components by using both host and viral gene products to promote the import and export of infectious viral particles from and to the extracellular environment. Understanding how herpesviruses modulate autophagy, endolysosomal and secretory pathways, as well as other prominent trafficking vesicles within the cell, could enable the engineering of novel antiviral therapies to treat these viruses and counteract their negative health effects.
      Citation: Cells
      PubDate: 2021-03-04
      DOI: 10.3390/cells10030542
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 543: Cellular Immunotherapy Targeting Cancer Stem
           Cells: Preclinical Evidence and Clinical Perspective

    • Authors: Chiara Donini, Ramona Rotolo, Alessia Proment, Massimo Aglietta, Dario Sangiolo, Valeria Leuci
      First page: 543
      Abstract: The term “cancer stem cells” (CSCs) commonly refers to a subset of tumor cells endowed with stemness features, potentially involved in chemo-resistance and disease relapses. CSCs may present peculiar immunogenic features influencing their homeostasis within the tumor microenvironment. The susceptibility of CSCs to recognition and targeting by the immune system is a relevant issue and matter of investigation, especially considering the multiple emerging immunotherapy strategies. Adoptive cellular immunotherapies, especially those strategies encompassing the genetic redirection with chimeric antigen receptors (CAR), hold relevant promise in several tumor settings and might in theory provide opportunities for selective elimination of CSC subsets. Initial dedicated preclinical studies are supporting the potential targeting of CSCs by cellular immunotherapies, indirect evidence from clinical studies may be derived and new studies are ongoing. Here we review the main issues related to the putative immunogenicity of CSCs, focusing on and highlighting the existing evidence and opportunities for cellular immunotherapy approaches with T and non-T antitumor lymphocytes.
      Citation: Cells
      PubDate: 2021-03-04
      DOI: 10.3390/cells10030543
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 544: Extracellular Vesicles Analysis in the COVID-19
           Era: Insights on Serum Inactivation Protocols towards Downstream Isolation
           and Analysis

    • Authors: Roberto Frigerio, Angelo Musicò, Marco Brucale, Andrea Ridolfi, Silvia Galbiati, Riccardo Vago, Greta Bergamaschi, Anna Maria Ferretti, Marcella Chiari, Francesco Valle, Alessandro Gori, Marina Cretich
      First page: 544
      Abstract: Since the outbreak of the COVID-19 crisis, the handling of biological samples from confirmed or suspected SARS-CoV-2-positive individuals demanded the use of inactivation protocols to ensure laboratory operators’ safety. While not standardized, these practices can be roughly divided into two categories, namely heat inactivation and solvent-detergent treatments. These routine procedures should also apply to samples intended for Extracellular Vesicles (EVs) analysis. Assessing the impact of virus-inactivating pre-treatments is therefore of pivotal importance, given the well-known variability introduced by different pre-analytical steps on downstream EVs isolation and analysis. Arguably, shared guidelines on inactivation protocols tailored to best address EVs-specific requirements will be needed among the analytical community, yet deep investigations in this direction have not yet been reported. We here provide insights into SARS-CoV-2 inactivation practices to be adopted prior to serum EVs analysis by comparing solvent/detergent treatment vs. heat inactivation. Our analysis entails the evaluation of EVs recovery and purity along with biochemical, biophysical and biomolecular profiling by means of a set of complementary analytical techniques: Nanoparticle Tracking Analysis, Western Blotting, Atomic Force Microscopy, miRNA content (digital droplet PCR) and tetraspanin assessment by microarrays. Our data suggest an increase in ultracentrifugation (UC) recovery following heat treatment; however, it is accompanied by a marked enrichment in EVs-associated contaminants. On the other hand, solvent/detergent treatment is promising for small EVs (<150 nm range), yet a depletion of larger vesicular entities was detected. This work represents a first step towards the identification of optimal serum inactivation protocols targeted to EVs analysis.
      Citation: Cells
      PubDate: 2021-03-04
      DOI: 10.3390/cells10030544
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 545: Daratumumab in the Treatment of Light-Chain
           (AL) Amyloidosis

    • Authors: Giovanni Palladini, Paolo Milani, Fabio Malavasi, Giampaolo Merlini
      First page: 545
      Abstract: Systemic light-chain (AL) amyloidosis is caused by a small B cell, most commonly a plasma cell (PC), clone that produces toxic light chains (LC) that cause organ dysfunction and deposits in tissues. Due to the production of amyloidogenic, misfolded LC, AL PCs display peculiar biologic features. The small, indolent plasma cell clone is an ideal target for anti-CD38 immunotherapy. A recent phase III randomized study showed that in newly diagnosed patients, the addition of daratumumab to the standard of care increased the rate and depth of the hematologic response and granted more frequent organ responses. In the relapsed/refractory setting, daratumumab alone or as part of combination regimens gave very promising results. It is likely that daratumumab-based regimens will become new standards of care in AL amyloidosis. Another anti-CD38 monoclonal antibody, isatuximab, is at an earlier stage of development as a treatment for AL amyloidosis. The ability to target CD38 on the amyloid PC offers new powerful tools to treat AL amyloidosis. Future studies should define the preferable agents to combine with daratumumab upfront and in the rescue setting and assess the role of maintenance. In this review, we summarize the rationale for using anti-CD38 antibodies in the treatment of AL amyloidosis.
      Citation: Cells
      PubDate: 2021-03-04
      DOI: 10.3390/cells10030545
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 546: An Analysis of the Neurological and Molecular
           Alterations Underlying the Pathogenesis of Alzheimer’s Disease

    • Authors: Chantal Vidal, Li Zhang
      First page: 546
      Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by amyloid beta (Aβ) plaques, neurofibrillary tangles, and neuronal loss. Unfortunately, despite decades of studies being performed on these histological alterations, there is no effective treatment or cure for AD. Identifying the molecular characteristics of the disease is imperative to understanding the pathogenesis of AD. Furthermore, uncovering the key causative alterations of AD can be valuable in developing models for AD treatment. Several alterations have been implicated in driving this disease, including blood–brain barrier dysfunction, hypoxia, mitochondrial dysfunction, oxidative stress, glucose hypometabolism, and altered heme homeostasis. Although these alterations have all been associated with the progression of AD, the root cause of AD has not been identified. Intriguingly, recent studies have pinpointed dysfunctional heme metabolism as a culprit of the development of AD. Heme has been shown to be central in neuronal function, mitochondrial respiration, and oxidative stress. Therefore, dysregulation of heme homeostasis may play a pivotal role in the manifestation of AD and its various alterations. This review will discuss the most common neurological and molecular alterations associated with AD and point out the critical role heme plays in the development of this disease.
      Citation: Cells
      PubDate: 2021-03-04
      DOI: 10.3390/cells10030546
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 547: Decursin Alleviates Mechanical Allodynia in a
           Paclitaxel-Induced Neuropathic Pain Mouse Model

    • Authors: Dang Bao Son, Woosik Choi, Mingu Kim, Eun Jin Go, Dabeen Jeong, Chul-Kyu Park, Yong Ho Kim, Hanki Lee, Joo-Won Suh
      First page: 547
      Abstract: Chemotherapy-induced neuropathic pain (CINP) is a severe adverse effect of platinum- and taxane-derived anticancer drugs. The pathophysiology of CINP includes damage to neuronal networks and dysregulation of signal transduction due to abnormal Ca2+ levels. Therefore, methods that aid the recovery of neuronal networks could represent a potential treatment for CINP. We developed a mouse model of paclitaxel-induced peripheral neuropathy, representing CINP, to examine whether intrathecal injection of decursin could be effective in treating CINP. We found that decursin reduced capsaicin-induced intracellular Ca2+ levels in F11 cells and stimulated neurite outgrowth in a concentration-dependent manner. Decursin directly reduced mechanical allodynia, and this improvement was even greater with a higher frequency of injections. Subsequently, we investigated whether decursin interacts with the transient receptor potential vanilloid 1 (TRPV1). The web server SwissTargetPrediction predicted that TRPV1 is one of the target proteins that may enable the effective treatment of CINP. Furthermore, we discovered that decursin acts as a TRPV1 antagonist. Therefore, we demonstrated that decursin may be an important compound for the treatment of paclitaxel-induced neuropathic pain that functions via TRPV1 inhibition and recovery of damaged neuronal networks.
      Citation: Cells
      PubDate: 2021-03-04
      DOI: 10.3390/cells10030547
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 548: Emerging Role of Pericytes and Their Secretome
           in the Heart

    • Authors: Han Su, Aubrey C. Cantrell, Heng Zeng, Shai-Hong Zhu, Jian-Xiong Chen
      First page: 548
      Abstract: Pericytes, as mural cells covering microvascular capillaries, play an essential role in vascular remodeling and maintaining vascular functions and blood flow. Pericytes are crucial participants in the physiological and pathological processes of cardiovascular disease. They actively interact with endothelial cells, vascular smooth muscle cells (VSMCs), fibroblasts, and other cells via the mechanisms involved in the secretome. The secretome of pericytes, along with diverse molecules including proinflammatory cytokines, angiogenic growth factors, and the extracellular matrix (ECM), has great impacts on the formation, stabilization, and remodeling of vasculature, as well as on regenerative processes. Emerging evidence also indicates that pericytes work as mesenchymal cells or progenitor cells in cardiovascular regeneration. Their capacity for differentiation also contributes to vascular remodeling in different ways. Previous studies primarily focused on the roles of pericytes in organs such as the brain, retina, lung, and kidney; very few studies have focused on pericytes in the heart. In this review, following a brief introduction of the origin and fundamental characteristics of pericytes, we focus on pericyte functions and mechanisms with respect to heart disease, ending with the promising use of cardiac pericytes in the treatment of ischemic heart failure.
      Citation: Cells
      PubDate: 2021-03-04
      DOI: 10.3390/cells10030548
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 549: Involvement of the Catecholamine Pathway in
           Glioblastoma Development

    • Authors: Zoltán Kraboth, Bela Kajtár, Bence Gálik, Attila Gyenesei, Attila Miseta, Bernadette Kalman
      First page: 549
      Abstract: Glioblastoma (GBM) is the most aggressive tumor of the central nervous system (CNS). The standard of care improves the overall survival of patients only by a few months. Explorations of new therapeutic targets related to molecular properties of the tumor are under way. Even though neurotransmitters and their receptors normally function as mediators of interneuronal communication, growing data suggest that these molecules are also involved in modulating the development and growth of GBM by acting on neuronal and glioblastoma stem cells. In our previous DNA CpG methylation studies, gene ontology analyses revealed the involvement of the monoamine pathway in sequential GBM. In this follow-up study, we quantitated the expression levels of four selected catecholamine pathway markers (alpha 1D adrenergic receptor—ADRA1D; adrenergic beta receptor kinase 1 or G protein-coupled receptor kinase 2—ADRBK1/GRK2; dopamine receptor D2—DRD2; and synaptic vesicle monoamine transporter—SLC18A2) by immunohistochemistry, and compared the histological scores with the methylation levels within the promoters + genes of these markers in 21 pairs of sequential GBM and in controls. Subsequently, we also determined the promoter and gene methylation levels of the same markers in an independent database cohort of sequential GBM pairs. These analyses revealed partial inverse correlations between the catecholamine protein expression and promoter + gene methylation levels, when the tumor and control samples were compared. However, we found no differences in the promoter + gene methylation levels of these markers in either our own or in the database primary–recurrent GBM pairs, despite the higher protein expression of all markers in the primary samples. This observation suggests that regulation of catecholamine expression is only partially related to CpG methylation within the promoter + gene regions, and additional mechanisms may also influence the expression of these markers in progressive GBM. These analyses underscore the involvement of certain catecholamine pathway markers in GBM development and suggest that these molecules mediating or modulating tumor growth merit further exploration.
      Citation: Cells
      PubDate: 2021-03-04
      DOI: 10.3390/cells10030549
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 550: Combined Inactivation of Pocket Proteins and
           APC/CCdh1 by Cdk4/6 Controls Recovery from DNA Damage in G1 Phase

    • Authors: Indra A. Shaltiel, Alba Llopis, Melinda Aprelia, Rob Klompmaker, Apostolos Menegakis, Lenno Krenning, René H. Medema
      First page: 550
      Abstract: Most Cyclin-dependent kinases (Cdks) are redundant for normal cell division. Here we tested whether these redundancies are maintained during cell cycle recovery after a DNA damage-induced arrest in G1. Using non-transformed RPE-1 cells, we find that while Cdk4 and Cdk6 act redundantly during normal S-phase entry, they both become essential for S-phase entry after DNA damage in G1. We show that this is due to a greater overall dependency for Cdk4/6 activity, rather than to independent functions of either kinase. In addition, we show that inactivation of pocket proteins is sufficient to overcome the inhibitory effects of complete Cdk4/6 inhibition in otherwise unperturbed cells, but that this cannot revert the effects of Cdk4/6 inhibition in DNA damaged cultures. Indeed, we could confirm that, in addition to inactivation of pocket proteins, Cdh1-dependent anaphase-promoting complex/cyclosome (APC/CCdh1) activity needs to be inhibited to promote S-phase entry in damaged cultures. Collectively, our data indicate that DNA damage in G1 creates a unique situation where high levels of Cdk4/6 activity are required to inactivate pocket proteins and APC/CCdh1 to promote the transition from G1 to S phase.
      Citation: Cells
      PubDate: 2021-03-04
      DOI: 10.3390/cells10030550
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 551: Quantitative Optical Coherence Tomography
           Angiography (OCTA) Parameters in a Black Diabetic Population and
           Correlations with Systemic Diseases

    • Authors: Lincoln T. Shaw, Saira Khanna, Lindsay Y. Chun, Rose C. Dimitroyannis, Sarah H. Rodriguez, Nathalie Massamba, Seenu M. Hariprasad, Dimitra Skondra
      First page: 551
      Abstract: This is a cross-sectional, prospective study of a population of black diabetic participants without diabetic retinopathy aimed to investigate optical coherence tomography angiography (OCTA) characteristics and correlations with systemic diseases in this population. These parameters could serve as novel biomarkers for microvascular complications; especially in black populations which are more vulnerable to diabetic microvascular complications. Linear mixed models were used to obtain OCTA mean values ± standard deviation and analyze statistical correlations to systemic diseases. Variables showing significance on univariate mixed model analysis were further analyzed with multivariate mixed models. 92 eyes of 52 black adult subjects were included. After multivariate analysis; signal strength intensity (SSI) and heart disease had statistical correlations to superficial capillary plexus vessel density in our population. SSI and smoking status had statistical correlations to deep capillary plexus vessel density in a univariate analysis that persisted in part of the imaging subset in a multivariate analysis. Hyperlipidemia; hypertension; smoking status and pack-years; diabetes duration; creatinine; glomerular filtration rate; total cholesterol; hemoglobin A1C; and albumin-to-creatinine ratio were not significantly associated with any OCTA measurement in multivariate analysis. Our findings suggest that OCTA measures may serve as valuable biomarkers to track systemic vascular functioning in diabetes mellitus in black patients.
      Citation: Cells
      PubDate: 2021-03-04
      DOI: 10.3390/cells10030551
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 552: Biomechanics of Ex Vivo-Generated Red Blood

    • Authors: Claudia Bernecker, Maria Augusta R. B. F. Lima, Catalin D. Ciubotaru, Peter Schlenke, Isabel Dorn, Dan Cojoc
      First page: 552
      Abstract: Ex vivo-generated red blood cells are a promising resource for future safe blood products, manufactured independently of voluntary blood donations. The physiological process of terminal maturation from spheroid reticulocytes to biconcave erythrocytes has not been accomplished yet. A better biomechanical characterization of cultured red blood cells (cRBCs) will be of utmost interest for manufacturer approval and therapeutic application. Here, we introduce a novel optical tweezer (OT) approach to measure the deformation and elasticity of single cells trapped away from the coverslip. To investigate membrane properties dependent on membrane lipid content, two culture conditions of cRBCs were investigated, cRBCPlasma with plasma and cRBCHPL supplemented with human platelet lysate. Biomechanical characterization of cells under optical forces proves the similar features of native RBCs and cRBCHPL, and different characteristics for cRBCPlasma. To confirm these results, we also applied a second technique, digital holographic microscopy (DHM), for cells laid on the surface. OT and DHM provided related results in terms of cell deformation and membrane fluctuations, allowing a reliable discrimination between cultured and native red blood cells. The two techniques are compared and discussed in terms of application and complementarity.
      Citation: Cells
      PubDate: 2021-03-04
      DOI: 10.3390/cells10030552
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 553: Radiologic Assessment of Osteosarcoma Lung
           Metastases: State of the Art and Recent Advances

    • Authors: Anna Maria Chiesa, Paolo Spinnato, Marco Miceli, Giancarlo Facchini
      First page: 553
      Abstract: The lung is the most frequent site of osteosarcoma (OS) metastases, which are a critical point in defining a patient’s prognosis. Chest computed tomography (CT) represents the gold standard for the detection of lung metastases even if its sensitivity widely ranges in the literature since lung localizations are often atypical. ESMO guidelines represent one of the major references for the follow-up program of OS patients. The development of new reconstruction techniques, such as the iterative method and the deep learning-based image reconstruction (DLIR), has led to a significant reduction of the radiation dose with the low-dose CT. The improvement of these techniques has great importance considering the young-onset of the disease and the strict chest surveillance during follow-up programs. The use of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT is still controversial, while volume doubling time (VDT) and computer-aided diagnosis (CAD) systems are recent diagnostic tools that could support radiologists for lung nodules evaluation. Their use, well-established for other malignancies, needs to be further evaluated, focusing on OS patients.
      Citation: Cells
      PubDate: 2021-03-04
      DOI: 10.3390/cells10030553
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 554: Downregulation of Mcl-1 by Panobinostat
           Potentiates Proton Beam Therapy in Hepatocellular Carcinoma Cells

    • Authors: Changhoon Choi, Ga Haeng Lee, Arang Son, Gyu Sang Yoo, Jeong Il Yu, Hee Chul Park
      First page: 554
      Abstract: Epigenetic modulation by histone deacetylase (HDAC) inhibitors is an attractive anti-cancer strategy for diverse hematological and solid cancers. Herein, we explored the relative effectiveness of the pan-HDAC inhibitor panobinostat in combination with proton over X-ray irradiation in HCC cells. Clonogenic survival assays revealed that radiosensitization of Huh7 and Hep3B cells by panobinostat was more evident when combined with protons than X-rays. Panobinostat increased G2/M arrest and production of intracellular reactive oxygen species, which was further enhanced by proton irradiation. Immunofluorescence staining of γH2AX showed that panobinostat enhanced proton-induced DNA damage. Panobinostat dose-dependently decreased expression of an anti-apoptotic protein, Mcl-1, concomitant with increasing acetylation of histone H4. The combination of panobinostat with proton irradiation enhanced apoptotic cell death to a greater extent than that with X-ray irradiation. Depletion of Mcl-1 by RNA interference enhanced proton-induced apoptosis and proton radiosensitization, suggesting a potential role of Mcl-1 in determining proton sensitivity. Together, our findings suggest that panobinostat may be a promising combination agent for proton beam therapy in HCC treatment.
      Citation: Cells
      PubDate: 2021-03-04
      DOI: 10.3390/cells10030554
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 555: Historical Perspective of the G Protein-Coupled
           Receptor Kinase Family

    • Authors: Jeffrey L. Benovic
      First page: 555
      Abstract: Agonist activation of G protein-coupled receptors promotes sequential interaction of the receptor with heterotrimeric G proteins, G protein-coupled receptor kinases (GRKs), and arrestins. GRKs play a central role in mediating the switch from G protein to arrestin interaction and thereby control processes such as receptor desensitization and trafficking and arrestin-mediated signaling. In this review, I provide a historical perspective on some of the early studies that identified the family of GRKs with a primary focus on the non-visual GRKs. These studies included identification, purification, and cloning of the β-adrenergic receptor kinase in the mid- to late-1980s and subsequent cloning and characterization of additional members of the GRK family. This helped to lay the groundwork for ensuing work focused on understanding the structure and function of these important enzymes.
      Citation: Cells
      PubDate: 2021-03-04
      DOI: 10.3390/cells10030555
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 556: Treatment with Cyclic AMP Activators Reduces
           Glioblastoma Growth and Invasion as Assessed by Two-Photon Microscopy

    • Authors: Krista Minéia Wartchow, Benjamin Schmid, Philipp Tripal, Andreas Stadlbauer, Michael Buchfelder, Carlos-Alberto Gonçalves, Andrea Kleindienst
      First page: 556
      Abstract: (1) Background: Despite progress in surgery and radio-chemotherapy of glioblastoma (GB), the prognosis remains very poor. GB cells exhibit a preference for hypoxia to maintain their tumor-forming capacity. Enhancing oxidative phosphorylation—known as the anti-Warburg effect—with cyclic AMP activators has been demonstrated to drive GB cells from proliferation to differentiation thereby reducing tumor growth in a cell culture approach. Here we re-evaluate this treatment in a more clinically relevant model. (2) Methods: The effect of treatment with dibutyryl cyclic AMP (dbcAMP, 1 mM) and the cAMP activator forskolin (50µM) was assessed in a GB cell line (U87GFP+, 104 cells) co-cultured with mouse organotypic brain slices providing architecture and biochemical properties of normal brain tissue. Cell viability was determined by propidium-iodide, and gross metabolic effects were excluded in the extracellular medium. Tumor growth was quantified in terms of area, volume, and invasion at the start of culture, 48 h, 7 days, and 14 days after treatment. (3) Results: The tumor area was significantly reduced following dbcAMP or forskolin treatment (F2,249 = 5.968, p = 0.0029). 3D volumetric quantification utilizing two-photon fluorescence microscopy revealed that the treated tumors maintained a spheric shape while the untreated controls exhibited the GB typical invasive growth pattern. (4) Conclusions: Our data demonstrate that treatment with a cAMP analog/activator reduces GB growth and invasion.
      Citation: Cells
      PubDate: 2021-03-04
      DOI: 10.3390/cells10030556
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 557: Rap1a Overlaps the AGE/RAGE Signaling Cascade
           to Alter Expression of α-SMA, p-NF-κB, and p-PKC-ζ in Cardiac
           Fibroblasts Isolated from Type 2 Diabetic Mice

    • Authors: Stephanie D. Burr, James A. Stewart
      First page: 557
      Abstract: Cardiovascular disease, specifically heart failure, is a common complication for individuals with type 2 diabetes mellitus. Heart failure can arise with stiffening of the left ventricle, which can be caused by “active” cardiac fibroblasts (i.e., myofibroblasts) remodeling the extracellular matrix (ECM). Differentiation of fibroblasts to myofibroblasts has been demonstrated to be an outcome of AGE/RAGE signaling. Hyperglycemia causes advanced glycated end products (AGEs) to accumulate within the body, and this process is greatly accelerated under chronic diabetic conditions. AGEs can bind and activate their receptor (RAGE) to trigger multiple downstream outcomes, such as altering ECM remodeling, inflammation, and oxidative stress. Previously, our lab has identified a small GTPase, Rap1a, that possibly overlaps the AGE/RAGE signaling cascade to affect the downstream outcomes. Rap1a acts as a molecular switch connecting extracellular signals to intracellular responses. Therefore, we hypothesized that Rap1a crosses the AGE/RAGE cascade to alter the expression of AGE/RAGE associated signaling proteins in cardiac fibroblasts in type 2 diabetic mice. To delineate this cascade, we used genetically different cardiac fibroblasts from non-diabetic, diabetic, non-diabetic RAGE knockout, diabetic RAGE knockout, and Rap1a knockout mice and treated them with pharmacological modifiers (exogenous AGEs, EPAC, Rap1a siRNA, and pseudosubstrate PKC-ζ). We examined changes in expression of proteins implicated as markers for myofibroblasts (α-SMA) and inflammation/oxidative stress (NF-κB and SOD-1). In addition, oxidative stress was also assessed by measuring hydrogen peroxide concentration. Our results indicated that Rap1a connects to the AGE/RAGE cascade to promote and maintain α-SMA expression in cardiac fibroblasts. Moreover, Rap1a, in conjunction with activation of the AGE/RAGE cascade, increased NF-κB expression as well as hydrogen peroxide concentration, indicating a possible oxidative stress response. Additionally, knocking down Rap1a expression resulted in an increase in SOD-1 expression suggesting that Rap1a can affect oxidative stress markers independently of the AGE/RAGE signaling cascade. These results demonstrated that Rap1a contributes to the myofibroblast population within the heart via AGE/RAGE signaling as well as promotes possible oxidative stress. This study offers a new potential therapeutic target that could possibly reduce the risk for developing diabetic cardiovascular complications attributed to AGE/RAGE signaling.
      Citation: Cells
      PubDate: 2021-03-04
      DOI: 10.3390/cells10030557
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 558: Oxidized Phospholipids in Tumor
           Microenvironment Stimulate Tumor Metastasis via Regulation of Autophagy

    • Authors: Jin Kyung Seok, Eun-Hee Hong, Gabsik Yang, Hye Eun Lee, Sin-Eun Kim, Kwang-Hyeon Liu, Han Chang Kang, Yong-Yeon Cho, Hye Suk Lee, Joo Young Lee
      First page: 558
      Abstract: Oxidized phospholipids are well known to play physiological and pathological roles in regulating cellular homeostasis and disease progression. However, their role in cancer metastasis has not been entirely understood. In this study, effects of oxidized phosphatidylcholines such as 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC) on epithelial-mesenchymal transition (EMT) and autophagy were determined in cancer cells by immunoblotting and confocal analysis. Metastasis was analyzed by a scratch wound assay and a transwell migration/invasion assay. The concentrations of POVPC and 1-palmitoyl-2-glutaroyl-sn-glycero-phosphocholine (PGPC) in tumor tissues obtained from patients were measured by LC-MS/MS analysis. POVPC induced EMT, resulting in increase of migration and invasion of human hepatocellular carcinoma cells (HepG2) and human breast cancer cells (MCF7). POVPC induced autophagic flux through AMPK-mTOR pathway. Pharmacological inhibition or siRNA knockdown of autophagy decreased migration and invasion of POVPC-treated HepG2 and MCF7 cells. POVPC and PGPC levels were greatly increased at stage II of patient-derived intrahepatic cholangiocarcinoma tissues. PGPC levels were higher in malignant breast tumor tissues than in adjacent nontumor tissues. The results show that oxidized phosphatidylcholines increase metastatic potential of cancer cells by promoting EMT, mediated through autophagy. These suggest the positive regulatory role of oxidized phospholipids accumulated in tumor microenvironment in the regulation of tumorigenesis and metastasis.
      Citation: Cells
      PubDate: 2021-03-04
      DOI: 10.3390/cells10030558
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 559: Stroma-Mediated Resistance to S63845 and
           Venetoclax through MCL-1 and BCL-2 Expression Changes Induced by
           miR-193b-3p and miR-21-5p Dysregulation in Multiple Myeloma

    • Authors: Esperanza M. Algarín, Dalia Quwaider, Francisco J. Campos-Laborie, Andrea Díaz-Tejedor, Pedro Mogollón, Elena Vuelta, Montserrat Martín-Sánchez, Laura San-Segundo, Lorena González-Méndez, Norma C. Gutiérrez, Ramón García-Sanz, Teresa Paíno, Javier De Las Rivas, Enrique M. Ocio, Mercedes Garayoa
      First page: 559
      Abstract: BH3-mimetics targeting anti-apoptotic proteins such as MCL-1 (S63845) or BCL-2 (venetoclax) are currently being evaluated as effective therapies for the treatment of multiple myeloma (MM). Interleukin 6, produced by mesenchymal stromal cells (MSCs), has been shown to modify the expression of anti-apoptotic proteins and their interaction with the pro-apoptotic BIM protein in MM cells. In this study, we assess the efficacy of S63845 and venetoclax in MM cells in direct co-culture with MSCs derived from MM patients (pMSCs) to identify additional mechanisms involved in the stroma-induced resistance to these agents. MicroRNAs miR-193b-3p and miR-21-5p emerged among the top deregulated miRNAs in myeloma cells when directly co-cultured with pMSCs, and we show their contribution to changes in MCL-1 and BCL-2 protein expression and in the activity of S63845 and venetoclax. Additionally, direct contact with pMSCs under S63845 and/or venetoclax treatment modifies myeloma cell dependence on different BCL-2 family anti-apoptotic proteins in relation to BIM, making myeloma cells more dependent on the non-targeted anti-apoptotic protein or BCL-XL. Finally, we show a potent effect of the combination of S63845 and venetoclax even in the presence of pMSCs, which supports this combinatorial approach for the treatment of MM.
      Citation: Cells
      PubDate: 2021-03-04
      DOI: 10.3390/cells10030559
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 560: Selective Proliferation of Highly Functional
           Adipose-Derived Stem Cells in Microgravity Culture with Stirred

    • Authors: Takanobu Mashiko, Koji Kanayama, Natsumi Saito, Takako Shirado, Rintaro Asahi, Masanori Mori, Kotaro Yoshimura
      First page: 560
      Abstract: Therapeutic effects of adult stem-cell transplantations are limited by poor cell-retention in target organs, and a reduced potential for optimal cell differentiation compared to embryonic stem cells. However, contemporary studies have indicated heterogeneity within adult stem-cell pools, and a novel culturing technique may address these limitations by selecting those for cell proliferation which are highly functional. Here, we report the preservation of stemness in human adipose-derived stem cells (hASCs) by using microgravity conditions combined with microspheres in a stirred suspension. The cells were bound to microspheres (100−300 μm) and cultured using a wave-stirring shaker. One-week cultures using polystyrene and collagen microspheres increased the proportions of SSEA-3(+) hASCs 4.4- and 4.3-fold (2.7- and 2.9-fold increases in their numbers), respectively, compared to normal culture conditions. These cultured hASCs expressed higher levels of pluripotent markers (OCT4, SOX2, NANOG, MYC, and KLF), and had improved abilities for proliferation, colony formation, network formation, and multiple-mesenchymal differentiation. We believe that this novel culturing method may further enhance regenerative therapies using hASCs.
      Citation: Cells
      PubDate: 2021-03-04
      DOI: 10.3390/cells10030560
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 561: Emerging Roles of TRIM8 in Health and Disease

    • Authors: Flaviana Marzano, Luisa Guerrini, Graziano Pesole, Elisabetta Sbisà, Apollonia Tullo
      First page: 561
      Abstract: The superfamily of TRIM (TRIpartite Motif-containing) proteins is one of the largest groups of E3 ubiquitin ligases. Among them, interest in TRIM8 has greatly increased in recent years. In this review, we analyze the regulation of TRIM8 gene expression and how it is involved in many cell reactions in response to different stimuli such as genotoxic stress and attacks by viruses or bacteria, playing a central role in the immune response and orchestrating various fundamental biological processes such as cell survival, carcinogenesis, autophagy, apoptosis, differentiation and inflammation. Moreover, we show how TRIM8 functions are not limited to ubiquitination, and contrasting data highlight its role either as an oncogene or as a tumor suppressor gene, acting as a “double-edged weapon”. This is linked to its involvement in the selective regulation of three pivotal cellular signaling pathways: the p53 tumor suppressor, NF-κB and JAK-STAT pathways. Lastly, we describe how TRIM8 dysfunctions are linked to inflammatory processes, autoimmune disorders, rare developmental and cardiovascular diseases, ischemia, intellectual disability and cancer.
      Citation: Cells
      PubDate: 2021-03-05
      DOI: 10.3390/cells10030561
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 562: Towards a Framework for Better Understanding of
           Quiescent Cancer Cells

    • Authors: Wan Najbah Nik Nabil, Zhichao Xi, Zejia Song, Lei Jin, Xu Dong Zhang, Hua Zhou, Paul De Souza, Qihan Dong, Hongxi Xu
      First page: 562
      Abstract: Quiescent cancer cells (QCCs) are cancer cells that are reversibly suspended in G0 phase with the ability to re-enter the cell cycle and initiate tumor growth, and, ultimately, cancer recurrence and metastasis. QCCs are also therapeutically challenging due to their resistance to most conventional cancer treatments that selectively act on proliferating cells. Considering the significant impact of QCCs on cancer progression and treatment, better understanding of appropriate experimental models, and the evaluation of QCCs are key questions in the field that have direct influence on potential pharmacological interventions. Here, this review focuses on existing and emerging preclinical models and detection methods for QCCs and discusses their respective features and scope for application. By providing a framework for selecting appropriate experimental models and investigative methods, the identification of the key players that regulate the survival and activation of QCCs and the development of more effective QCC-targeting therapeutic agents may mitigate the consequences of QCCs.
      Citation: Cells
      PubDate: 2021-03-05
      DOI: 10.3390/cells10030562
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 563: Neutrophil Adhesion and the Release of the Free
           Amino Acid Hydroxylysine

    • Authors: Svetlana I. Galkina, Natalia V. Fedorova, Alexander L. Ksenofontov, Marina V. Serebryakova, Ekaterina A. Golenkina, Vladimir I. Stadnichuk, Ludmila A. Baratova, Galina F. Sud’ina
      First page: 563
      Abstract: During infection or certain metabolic disorders, neutrophils can escape from blood vessels, invade and attach to other tissues. The invasion and adhesion of neutrophils is accompanied and maintained by their own secretion. We have previously found that adhesion of neutrophils to fibronectin dramatically and selectively stimulates the release of the free amino acid hydroxylysine. The role of hydroxylysine and lysyl hydroxylase in neutrophil adhesion has not been studied, nor have the processes that control them. Using amino acid analysis, mass spectrometry and electron microscopy, we found that the lysyl hydroxylase inhibitor minoxidil, the matrix metalloproteinase inhibitor doxycycline, the PI3K/Akt pathway inhibitors wortmannin and the Akt1/2 inhibitor and drugs that affect the actin cytoskeleton significantly and selectively block the release of hydroxylysine and partially or completely suppress spreading of neutrophils. The actin cytoskeleton effectors and the Akt 1/2 inhibitor also increase the phenylalanine release. We hypothesize that hydroxylysine release upon adhesion is the result of the activation of lysyl hydroxylase in interaction with matrix metalloproteinase, the PI3K/Akt pathway and intact actin cytoskeleton, which play important roles in the recruitment of neutrophils into tissue through extracellular matrix remodeling.
      Citation: Cells
      PubDate: 2021-03-05
      DOI: 10.3390/cells10030563
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 564: The Immune Tolerance Role of the HMGB1-RAGE

    • Authors: Haruki Watanabe, Myoungsun Son
      First page: 564
      Abstract: The disruption of the immune tolerance induces autoimmunity such as systemic lupus erythematosus and vasculitis. A chromatin-binding non-histone protein, high mobility group box 1 (HMGB1), is released from the nucleus to the extracellular milieu in particular environments such as autoimmunity, sepsis and hypoxia. Extracellular HMGB1 engages pattern recognition receptors, including Toll-like receptors (TLRs) and the receptor for advanced glycation endproducts (RAGE). While the HMGB1-RAGE axis drives inflammation in various diseases, recent studies also focus on the anti-inflammatory effects of HMGB1 and RAGE. This review discusses current perspectives on HMGB1 and RAGE’s roles in controlling inflammation and immune tolerance. We also suggest how RAGE heterodimers responding microenvironments functions in immune responses.
      Citation: Cells
      PubDate: 2021-03-05
      DOI: 10.3390/cells10030564
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 565: Oligodendrocyte Dysfunction in Amyotrophic
           Lateral Sclerosis: Mechanisms and Therapeutic Perspectives

    • Authors: Stefano Raffaele, Marta Boccazzi, Marta Fumagalli
      First page: 565
      Abstract: Myelin is the lipid-rich structure formed by oligodendrocytes (OLs) that wraps the axons in multilayered sheaths, assuring protection, efficient saltatory signal conduction and metabolic support to neurons. In the last few years, the impact of OL dysfunction and myelin damage has progressively received more attention and is now considered to be a major contributing factor to neurodegeneration in several neurological diseases, including amyotrophic lateral sclerosis (ALS). Upon OL injury, oligodendrocyte precursor cells (OPCs) of adult nervous tissue sustain the generation of new OLs for myelin reconstitution, but this spontaneous regeneration process fails to successfully counteract myelin damage. Of note, the functions of OPCs exceed the formation and repair of myelin, and also involve the trophic support to axons and the capability to exert an immunomodulatory role, which are particularly relevant in the context of neurodegeneration. In this review, we deeply analyze the impact of dysfunctional OLs in ALS pathogenesis. The possible mechanisms underlying OL degeneration, defective OPC maturation, and impairment in energy supply to motor neurons (MNs) have also been examined to provide insights on future therapeutic interventions. On this basis, we discuss the potential therapeutic utility in ALS of several molecules, based on their remyelinating potential or capability to enhance energy metabolism.
      Citation: Cells
      PubDate: 2021-03-05
      DOI: 10.3390/cells10030565
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 566: Genetic Approaches Using Zebrafish to Study the
           Microbiota–Gut–Brain Axis in Neurological Disorders

    • Authors: Jae-Geun Lee, Hyun-Ju Cho, Yun-Mi Jeong, Jeong-Soo Lee
      First page: 566
      Abstract: The microbiota–gut–brain axis (MGBA) is a bidirectional signaling pathway mediating the interaction of the microbiota, the intestine, and the central nervous system. While the MGBA plays a pivotal role in normal development and physiology of the nervous and gastrointestinal system of the host, its dysfunction has been strongly implicated in neurological disorders, where intestinal dysbiosis and derived metabolites cause barrier permeability defects and elicit local inflammation of the gastrointestinal tract, concomitant with increased pro-inflammatory cytokines, mobilization and infiltration of immune cells into the brain, and the dysregulated activation of the vagus nerve, culminating in neuroinflammation and neuronal dysfunction of the brain and behavioral abnormalities. In this topical review, we summarize recent findings in human and animal models regarding the roles of the MGBA in physiological and neuropathological conditions, and discuss the molecular, genetic, and neurobehavioral characteristics of zebrafish as an animal model to study the MGBA. The exploitation of zebrafish as an amenable genetic model combined with in vivo imaging capabilities and gnotobiotic approaches at the whole organism level may reveal novel mechanistic insights into microbiota–gut–brain interactions, especially in the context of neurological disorders such as autism spectrum disorder and Alzheimer’s disease.
      Citation: Cells
      PubDate: 2021-03-05
      DOI: 10.3390/cells10030566
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 567: Annexin A2 Flop-Out Mediates the Non-Vesicular
           Release of DAMPs/Alarmins from C6 Glioma Cells Induced by Serum-Free

    • Authors: Hayato Matsunaga, Sebok Kumar Halder, Hiroshi Ueda
      First page: 567
      Abstract: Prothymosin alpha (ProTα) and S100A13 are released from C6 glioma cells under serum-free conditions via membrane tethering mediated by Ca2+-dependent interactions between S100A13 and p40 synaptotagmin-1 (Syt-1), which is further associated with plasma membrane syntaxin-1 (Stx-1). The present study revealed that S100A13 interacted with annexin A2 (ANXA2) and this interaction was enhanced by Ca2+ and p40 Syt-1. Amlexanox (Amx) inhibited the association between S100A13 and ANXA2 in C6 glioma cells cultured under serum-free conditions in the in situ proximity ligation assay. In the absence of Amx, however, the serum-free stress results in a flop-out of ANXA2 through the membrane, without the extracellular release. The intracellular delivery of anti-ANXA2 antibody blocked the serum-free stress-induced cellular loss of ProTα, S100A13, and Syt-1. The stress-induced externalization of ANXA2 was inhibited by pretreatment with siRNA for P4-ATPase, ATP8A2, under serum-free conditions, which ablates membrane lipid asymmetry. The stress-induced ProTα release via Stx-1A, ANXA2 and ATP8A2 was also evidenced by the knock-down strategy in the experiments using oxygen glucose deprivation-treated cultured neurons. These findings suggest that starvation stress-induced release of ProTα, S100A13, and p40 Syt-1 from C6 glioma cells is mediated by the ANXA2-flop-out via energy crisis-dependent recovery of membrane lipid asymmetry.
      Citation: Cells
      PubDate: 2021-03-05
      DOI: 10.3390/cells10030567
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 568: Generation and Evaluation of Isogenic iPSC as a
           Source of Cell Replacement Therapies in Patients with Kearns Sayre

    • Authors: Glen Lester Sequiera, Abhay Srivastava, Keshav Narayan Alagarsamy, Cheryl Rockman-Greenberg, Sanjiv Dhingra
      First page: 568
      Abstract: Kearns Sayre syndrome (KSS) is mitochondrial multisystem disorder with no proven effective treatment. The underlying cause for multisystem involvement is the energy deficit resulting from the load of mutant mitochondrial DNA (mtDNA), which manifests as loss of cells and tissue dysfunction. Therefore, functional organ or cellular replacement provides a promising avenue as a therapeutic option. Patient-specific induced pluripotent stem cells (iPSC) have become a handy tool to create personalized cell -based therapies. iPSC are capable of self-renewal, differentiation into all types of body cells including cardiomyocytes (CM) and neural progenitor cells (NPC). In KSS patients, mutations in mtDNA are largely found in the muscle tissue and are predominantly absent in the blood cells. Therefore, we conceptualized that peripheral blood mononuclear cells (PBMNC) from KSS patients can be reprogrammed to generate mutation free, patient specific iPSC lines that can be used as isogenic source of cell replacement therapies to treat affected organs. In the current study we generated iPSC lines from two female patients with clinical diagnosis of classic KSS. Our data demonstrate that iPSC from these KSS patients showed normal differentiation potential toward CM, NPC and fibroblasts without any mtDNA deletions over passages. Next, we also found that functional studies including ATP production, reactive oxygen species generation, lactate accumulation and mitochondrial membrane potential in iPSC, CM, NPC and fibroblasts of these KSS patients were not different from respective cells from healthy controls. PBMNCs from these KSS patients in the current study did not reproduce mtDNA mutations which were present in muscle biopsies. Furthermore, we demonstrate for the first time that this phenomenon provides opportunities to create isogenic mutation free iPSC with absent or very low level of expression of mtDNA deletion which can be banked for future cell replacement therapies in these patients as the disease progresses.
      Citation: Cells
      PubDate: 2021-03-05
      DOI: 10.3390/cells10030568
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 569: Mitochondrial Dysfunction and Permeability
           Transition in Neonatal Brain and Lung Injuries

    • Authors: Vadim S. Ten, Anna A. Stepanova, Veniamin Ratner, Maria Neginskaya, Zoya Niatsetskaya, Sergey Sosunov, Anatoly Starkov
      First page: 569
      Abstract: This review discusses the potential mechanistic role of abnormally elevated mitochondrial proton leak and mitochondrial bioenergetic dysfunction in the pathogenesis of neonatal brain and lung injuries associated with premature birth. Providing supporting evidence, we hypothesized that mitochondrial dysfunction contributes to postnatal alveolar developmental arrest in bronchopulmonary dysplasia (BPD) and cerebral myelination failure in diffuse white matter injury (WMI). This review also analyzes data on mitochondrial dysfunction triggered by activation of mitochondrial permeability transition pore(s) (mPTP) during the evolution of perinatal hypoxic-ischemic encephalopathy. While the still cryptic molecular identity of mPTP continues to be a subject for extensive basic science research efforts, the translational significance of mitochondrial proton leak received less scientific attention, especially in diseases of the developing organs. This review is focused on the potential mechanistic relevance of mPTP and mitochondrial dysfunction to neonatal diseases driven by developmental failure of organ maturation or by acute ischemia-reperfusion insult during development.
      Citation: Cells
      PubDate: 2021-03-05
      DOI: 10.3390/cells10030569
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 570: Genome-Wide Association Study Identifies Eight
           Novel Loci for Susceptibility of Scrub Typhus and Highlights
           Immune-Related Signaling Pathways in Its Pathogenesis

    • Authors: Yong-Chan Kim, Soriul Kim, Hee-Kwon Kim, Yi Lee, Chol Shin, Chang-Seop Lee, Byung-Hoon Jeong
      First page: 570
      Abstract: Scrub typhus is a fatal zoonotic disease caused by Orientia tsutsugamushi. This disease is accompanied by systemic vasculitis, lymphadenopathy, headache, myalgia, and eschar. In recent studies, a novel strain that is resistant to current medical treatment was identified in Thailand. Thus, the development of new specific drugs for scrub typhus is needed. However, the exact molecular mechanism governing the progression of scrub typhus has not been fully elucidated. To understand disease-related genetic factors and mechanisms associated with the progression of scrub typhus, we performed a genome-wide association study (GWAS) in scrub typhus-infected patients and found a scrub typhus-related signaling pathway by molecular interaction search tool (MIST) and PANTHER. We identified eight potent scrub typhus-related single nucleotide polymorphisms (SNPs) located on the PRMT6, PLGLB2, DTWD2, BATF, JDP2, ONECUT1, WDR72, KLK, MAP3K7, and TGFBR2 genes using a GWAS. We also identified 224 genes by analyzing protein-protein interactions among candidate genes of scrub typhus and identified 15 signaling pathways associated with over 10 genes by classifying these genes according to signaling pathways. The signaling pathway with the largest number of associated genes was the gonadotropin-releasing hormone receptor pathway, followed by the TGF-beta signaling pathway and the apoptosis signaling pathway. To the best of our knowledge, this report describes the first GWAS in scrub typhus.
      Citation: Cells
      PubDate: 2021-03-05
      DOI: 10.3390/cells10030570
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 571: Metal Ions Induce Liquid Condensate Formation
           by the F Domain of Aedes aegypti Ecdysteroid Receptor. New Perspectives of
           Nuclear Receptor Studies

    • Authors: Więch, Tarczewska, Ożyhar, Orłowski
      First page: 571
      Abstract: The superfamily of nuclear receptors (NRs), composed of ligand-activated transcription factors, is responsible for gene expression as a reaction to physiological and environmental changes. Transcriptional machinery may require phase separation to fulfil its role. Although NRs have a similar canonical structure, their C-terminal domains (F domains) are considered the least conserved and known regions. This article focuses on the peculiar molecular properties of the intrinsically disordered F domain of the ecdysteroid receptor from the Aedes aegypti mosquito (AaFEcR), the vector of the world’s most devastating human diseases such as dengue and Zika. The His-Pro-rich segment of AaFEcR was recently shown to form the unique poly-proline helix II (PPII) in the presence of Cu2+. Here, using widefield microscopy of fluorescently labeled AaFEcR, Zn2+- and Cu2+-induced liquid-liquid phase separation (LLPS) was observed for the first time for the members of NRs. The perspectives of this finding on future research on the F domain are discussed, especially in relation to other NR members.
      Citation: Cells
      PubDate: 2021-03-05
      DOI: 10.3390/cells10030571
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 572: Rapid Identification of New Biomarkers for the
           Classification of GM1 Type 2 Gangliosidosis Using an Unbiased 1H
           NMR-Linked Metabolomics Strategy

    • Authors: Benita C. Percival, Yvonne L. Latour, Cynthia J. Tifft, Martin Grootveld
      First page: 572
      Abstract: Biomarkers currently available for the diagnosis, prognosis, and therapeutic monitoring of GM1 gangliosidosis type 2 (GM1T2) disease are mainly limited to those discovered in targeted proteomic-based studies. In order to identify and establish new, predominantly low-molecular-mass biomarkers for this disorder, we employed an untargeted, multi-analyte approach involving high-resolution 1H NMR analysis coupled to a range of multivariate analysis and computational intelligence technique (CIT) strategies to explore biomolecular distinctions between blood plasma samples collected from GM1T2 and healthy control (HC) participants (n = 10 and 28, respectively). The relationship of these differences to metabolic mechanisms underlying the pathogenesis of GM1T2 disorder was also investigated. 1H NMR-linked metabolomics analyses revealed significant GM1T2-mediated dysregulations in ≥13 blood plasma metabolites (corrected p < 0.04), and these included significant upregulations in 7 amino acids, and downregulations in lipoprotein-associated triacylglycerols and alanine. Indeed, results acquired demonstrated a profound distinctiveness between the GM1T2 and HC profiles. Additionally, employment of a genome-scale network model of human metabolism provided evidence that perturbations to propanoate, ethanol, amino-sugar, aspartate, seleno-amino acid, glutathione and alanine metabolism, fatty acid biosynthesis, and most especially branched-chain amino acid degradation (p = 10−12−10−5) were the most important topologically-highlighted dysregulated pathways contributing towards GM1T2 disease pathology. Quantitative metabolite set enrichment analysis revealed that pathological locations associated with these dysfunctions were in the order fibroblasts > Golgi apparatus > mitochondria > spleen ≈ skeletal muscle ≈ muscle in general. In conclusion, results acquired demonstrated marked metabolic imbalances and alterations to energy demand, which are consistent with GM1T2 disease pathogenesis mechanisms.
      Citation: Cells
      PubDate: 2021-03-05
      DOI: 10.3390/cells10030572
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 573: The Legacy of Parker, Baker and Smith 1972:
           Gamete Competition, the Evolution of Anisogamy and Model Robustness

    • Authors: Jussi Lehtonen
      First page: 573
      Abstract: The evolution of anisogamy or gamete size dimorphism is a fundamental transition in evolutionary history, and it is the origin of the female and male sexes. Although mathematical models attempting to explain this transition have been published as early as 1932, the 1972 model of Parker, Baker, and Smith is considered to be the first explanation for the evolution of anisogamy that is consistent with modern evolutionary theory. The central idea of the model is ingenious in its simplicity: selection simultaneously favours large gametes for zygote provisioning, and small gametes for numerical competition, and under certain conditions the outcome is anisogamy. In this article, I derive novel analytical solutions to a 2002 game theoretical update of the 1972 anisogamy model, and use these solutions to examine its robustness to variation in its central assumptions. Combining new results with those from earlier papers, I find that the model is quite robust to variation in its central components. This kind of robustness is crucially important in a model for an early evolutionary transition where we may only have an approximate understanding of constraints that the different parts of the model must obey.
      Citation: Cells
      PubDate: 2021-03-05
      DOI: 10.3390/cells10030573
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 574: High Density Lipoprotein Cholesterol Efflux
           Capacity and Atherosclerosis in Cardiovascular Disease: Pathophysiological
           Aspects and Pharmacological Perspectives

    • Authors: Maria Pia Adorni, Nicoletta Ronda, Franco Bernini, Francesca Zimetti
      First page: 574
      Abstract: Over the years, the relationship between high-density lipoprotein (HDL) and atherosclerosis, initially highlighted by the Framingham study, has been revealed to be extremely complex, due to the multiple HDL functions involved in atheroprotection. Among them, HDL cholesterol efflux capacity (CEC), the ability of HDL to promote cell cholesterol efflux from cells, has emerged as a better predictor of cardiovascular (CV) risk compared to merely plasma HDL-cholesterol (HDL-C) levels. HDL CEC is impaired in many genetic and pathological conditions associated to high CV risk such as dyslipidemia, chronic kidney disease, diabetes, inflammatory and autoimmune diseases, endocrine disorders, etc. The present review describes the current knowledge on HDL CEC modifications in these conditions, focusing on the most recent human studies and on genetic and pathophysiologic aspects. In addition, the most relevant strategies possibly modulating HDL CEC, including lifestyle modifications, as well as nutraceutical and pharmacological interventions, will be discussed. The objective of this review is to help understanding whether, from the current evidence, HDL CEC may be considered as a valid biomarker of CV risk and a potential pharmacological target for novel therapeutic approaches.
      Citation: Cells
      PubDate: 2021-03-05
      DOI: 10.3390/cells10030574
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 575: The Angiotensin II Receptor Blocker Losartan
           Sensitizes Human Liver Cancer Cells to Lenvatinib-Mediated Cytostatic and
           Angiostatic Effects

    • Authors: Hirotetsu Takagi, Kosuke Kaji, Norihisa Nishimura, Koji Ishida, Hiroyuki Ogawa, Hiroaki Takaya, Hideto Kawaratani, Kei Moriya, Tadashi Namisaki, Takemi Akahane, Akira Mitoro, Hitoshi Yoshiji
      First page: 575
      Abstract: Molecular targeted therapy with lenvatinib is commonly offered to advanced hepatocellular carcinoma (HCC) patients, although it is often interrupted by adverse effects which require a reduction in the initial dose. Thus, an alternative lenvatinib-based therapy to compensate for dose reduction is anticipated. This study aimed to assess the effect of combination of low-dose of lenvatinib and the angiotensin-II (AT-II) receptor blocker losartan on human HCC cell growth. In vitro studies found that losartan suppressed the proliferation by inducing G1 arrest and caused apoptosis as indicated by the cleavage of caspase-3 in AT-II-stimulated HCC cell lines (Huh-7, HLE, and JHH-6). Losartan attenuated the AT-II-stimulated production of vascular endothelial growth factor-A (VEGF-A) and interleukin-8 and suppressed lenvatinib-mediated autocrine VEGF-A production in HCC cells. Moreover, it directly inhibited VEGF-mediated endothelial cell growth. Notably, the combination of lenvatinib and losartan augmented the cytostatic and angiostatic effects of the former at a low-dose, reaching those achieved with a conventional dose. Correspondingly, a HCC tumor xenograft assay showed that the oral administration of losartan combined with lenvatinib reduced the subcutaneous tumor burden and intratumor vascularization in BALB/c nude mice. These findings support that this regimen could be a viable option for patients intolerant to standard lenvatinib dosage.
      Citation: Cells
      PubDate: 2021-03-05
      DOI: 10.3390/cells10030575
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 576: A New Epigenetic Model to Stratify Glioma
           Patients According to Their Immunosuppressive State

    • Authors: Maurizio Polano, Emanuele Fabbiani, Eva Adreuzzi, Federica Di Cintio, Luca Bedon, Davide Gentilini, Maurizio Mongiat, Tamara Ius, Mauro Arcicasa, Miran Skrap, Michele Dal Dal Bo, Giuseppe Toffoli
      First page: 576
      Abstract: Gliomas are the most common primary neoplasm of the central nervous system. A promising frontier in the definition of glioma prognosis and treatment is represented by epigenetics. Furthermore, in this study, we developed a machine learning classification model based on epigenetic data (CpG probes) to separate patients according to their state of immunosuppression. We considered 573 cases of low-grade glioma (LGG) and glioblastoma (GBM) from The Cancer Genome Atlas (TCGA). First, from gene expression data, we derived a novel binary indicator to flag patients with a favorable immune state. Then, based on previous studies, we selected the genes related to the immune state of tumor microenvironment. After, we improved the selection with a data-driven procedure, based on Boruta. Finally, we tuned, trained, and evaluated both random forest and neural network classifiers on the resulting dataset. We found that a multi-layer perceptron network fed by the 338 probes selected by applying both expert choice and Boruta results in the best performance, achieving an out-of-sample accuracy of 82.8%, a Matthews correlation coefficient of 0.657, and an area under the ROC curve of 0.9. Based on the proposed model, we provided a method to stratify glioma patients according to their epigenomic state.
      Citation: Cells
      PubDate: 2021-03-05
      DOI: 10.3390/cells10030576
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 577: A Review of Single-Cell Adhesion Force Kinetics
           and Applications

    • Authors: Ashwini Shinde, Kavitha Illath, Pallavi Gupta, Pallavi Shinde, Ki-Taek Lim, Moeto Nagai, Tuhin Subhra Santra
      First page: 577
      Abstract: Cells exert, sense, and respond to the different physical forces through diverse mechanisms and translating them into biochemical signals. The adhesion of cells is crucial in various developmental functions, such as to maintain tissue morphogenesis and homeostasis and activate critical signaling pathways regulating survival, migration, gene expression, and differentiation. More importantly, any mutations of adhesion receptors can lead to developmental disorders and diseases. Thus, it is essential to understand the regulation of cell adhesion during development and its contribution to various conditions with the help of quantitative methods. The techniques involved in offering different functionalities such as surface imaging to detect forces present at the cell-matrix and deliver quantitative parameters will help characterize the changes for various diseases. Here, we have briefly reviewed single-cell mechanical properties for mechanotransduction studies using standard and recently developed techniques. This is used to functionalize from the measurement of cellular deformability to the quantification of the interaction forces generated by a cell and exerted on its surroundings at single-cell with attachment and detachment events. The adhesive force measurement for single-cell microorganisms and single-molecules is emphasized as well. This focused review should be useful in laying out experiments which would bring the method to a broader range of research in the future.
      Citation: Cells
      PubDate: 2021-03-05
      DOI: 10.3390/cells10030577
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 578: Computational Hypothesis: How Intra-Hepatic
           Functional Heterogeneity May Influence the Cascading Progression of Free
           Fatty Acid-Induced Non-Alcoholic Fatty Liver Disease (NAFLD)

    • Authors: Hermann-Georg Holzhütter, Nikolaus Berndt
      First page: 578
      Abstract: Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common type of chronic liver disease in developed nations, affecting around 25% of the population. Elucidating the factors causing NAFLD in individual patients to progress in different rates and to different degrees of severity, is a matter of active medical research. Here, we aim to provide evidence that the intra-hepatic heterogeneity of rheological, metabolic and tissue-regenerating capacities plays a central role in disease progression. We developed a generic mathematical model that constitutes the liver as ensemble of small liver units differing in their capacities to metabolize potentially cytotoxic free fatty acids (FFAs) and to repair FFA-induced cell damage. Transition from simple steatosis to more severe forms of NAFLD is described as self-amplifying process of cascading liver failure, which, to stop, depends essentially on the distribution of functional capacities across the liver. Model simulations provided the following insights: (1) A persistently high plasma level of FFAs is sufficient to drive the liver through different stages of NAFLD; (2) Presence of NAFLD amplifies the deleterious impact of additional tissue-damaging hits; and (3) Coexistence of non-steatotic and highly steatotic regions is indicative for the later occurrence of severe NAFLD stages.
      Citation: Cells
      PubDate: 2021-03-05
      DOI: 10.3390/cells10030578
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 579: The Importance of Drosophila melanogaster
           Research to UnCover Cellular Pathways Underlying Parkinson’s Disease

    • Authors: Vos, Klein
      First page: 579
      Abstract: Parkinson’s disease (PD) is a complex neurodegenerative disorder that is currently incurable. As a consequence of an incomplete understanding of the etiology of the disease, therapeutic strategies mainly focus on symptomatic treatment. Even though the majority of PD cases remain idiopathic (~90%), several genes have been identified to be causative for PD, facilitating the generation of animal models that are a good alternative to study disease pathways and to increase our understanding of the underlying mechanisms of PD. Drosophila melanogaster has proven to be an excellent model in these studies. In this review, we will discuss the different PD models in flies and key findings identified in flies in different affected pathways in PD. Several molecular changes have been identified, of which mitochondrial dysfunction and a defective endo-lysosomal pathway emerge to be the most relevant for PD pathogenesis. Studies in flies have significantly contributed to our knowledge of how disease genes affect and interact in these pathways enabling a better understanding of the disease etiology and providing possible therapeutic targets for the treatment of PD, some of which have already resulted in clinical trials.
      Citation: Cells
      PubDate: 2021-03-06
      DOI: 10.3390/cells10030579
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 580: Zebrafish as a Neuroblastoma Model: Progress
           Made, Promise for the Future

    • Authors: Shuai Li, Kok Siong Yeo, Taylor M. Levee, Cassie J. Howe, Zuag Paj Her, Shizhen Zhu
      First page: 580
      Abstract: For nearly a decade, researchers in the field of pediatric oncology have been using zebrafish as a model for understanding the contributions of genetic alternations to the pathogenesis of neuroblastoma (NB), and exploring the molecular and cellular mechanisms that underlie neuroblastoma initiation and metastasis. In this review, we will enumerate and illustrate the key advantages of using the zebrafish model in NB research, which allows researchers to: monitor tumor development in real-time; robustly manipulate gene expression (either transiently or stably); rapidly evaluate the cooperative interactions of multiple genetic alterations to disease pathogenesis; and provide a highly efficient and low-cost methodology to screen for effective pharmaceutical interventions (both alone and in combination with one another). This review will then list some of the common challenges of using the zebrafish model and provide strategies for overcoming these difficulties. We have also included visual diagram and figures to illustrate the workflow of cancer model development in zebrafish and provide a summary comparison of commonly used animal models in cancer research, as well as key findings of cooperative contributions between MYCN and diverse singling pathways in NB pathogenesis.
      Citation: Cells
      PubDate: 2021-03-06
      DOI: 10.3390/cells10030580
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 581: Cerebral Insulin Bolus Revokes the Changes in
           Hepatic Lipid Metabolism Induced by Chronic Central Leptin Infusion

    • Authors: Vicente Barrios, Elena López-Villar, Laura M. Frago, Sandra Canelles, Francisca Díaz-González, Emma Burgos-Ramos, Gema Frühbeck, Julie A. Chowen, Jesús Argente
      First page: 581
      Abstract: Central actions of leptin and insulin on hepatic lipid metabolism can be opposing and the mechanism underlying this phenomenon remains unclear. Both hormones can modulate the central somatostatinergic system that has an inhibitory effect on growth hormone (GH) expression, which plays an important role in hepatic metabolism. Using a model of chronic central leptin infusion, we evaluated whether an increase in central leptin bioavailability modifies the serum lipid pattern through changes in hepatic lipid metabolism in male rats in response to an increase in central insulin and the possible involvement of the GH axis in these effects. We found a rise in serum GH in leptin plus insulin-treated rats, due to an increase in pituitary GH mRNA levels associated with lower hypothalamic somatostatin and pituitary somatostatin receptor-2 mRNA levels. An augment in hepatic lipolysis and a reduction in serum levels of non-esterified fatty acids (NEFA) and triglycerides were found in leptin-treated rats. These rats experienced a rise in lipogenic-related factors and normalization of serum levels of NEFA and triglycerides after insulin treatment. These results suggest that an increase in insulin in leptin-treated rats can act on the hepatic lipid metabolism through activation of the GH axis.
      Citation: Cells
      PubDate: 2021-03-06
      DOI: 10.3390/cells10030581
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 582: Overexpression of an Agave Phosphoenolpyruvate
           Carboxylase Improves Plant Growth and Stress Tolerance

    • Authors: Degao Liu, Rongbin Hu, Jin Zhang, Hao-Bo Guo, Hua Cheng, Linling Li, Anne M. Borland, Hong Qin, Jin-Gui Chen, Wellington Muchero, Gerald A. Tuskan, Xiaohan Yang
      First page: 582
      Abstract: It has been challenging to simultaneously improve photosynthesis and stress tolerance in plants. Crassulacean acid metabolism (CAM) is a CO2-concentrating mechanism that facilitates plant adaptation to water-limited environments. We hypothesized that the ectopic expression of a CAM-specific phosphoenolpyruvate carboxylase (PEPC), an enzyme that catalyzes primary CO2 fixation in CAM plants, would enhance both photosynthesis and abiotic stress tolerance. To test this hypothesis, we engineered a CAM-specific PEPC gene (named AaPEPC1) from Agave americana into tobacco. In comparison with wild-type and empty vector controls, transgenic tobacco plants constitutively expressing AaPEPC1 showed a higher photosynthetic rate and biomass production under normal conditions, along with significant carbon metabolism changes in malate accumulation, the carbon isotope ratio δ13C, and the expression of multiple orthologs of CAM-related genes. Furthermore, AaPEPC1 overexpression enhanced proline biosynthesis, and improved salt and drought tolerance in the transgenic plants. Under salt and drought stress conditions, the dry weight of transgenic tobacco plants overexpressing AaPEPC1 was increased by up to 81.8% and 37.2%, respectively, in comparison with wild-type plants. Our findings open a new door to the simultaneous improvement of photosynthesis and stress tolerance in plants.
      Citation: Cells
      PubDate: 2021-03-06
      DOI: 10.3390/cells10030582
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 583: Functions of Dendritic Cells and Its
           Association with Intestinal Diseases

    • Authors: Yang, Wang, Wang, Wang, Guo, Hua, Shang, Lu, Xu
      First page: 583
      Abstract: Dendritic cells (DCs), including conventional DCs (cDCs) and plasmacytoid DCs (pDCs), serve as the sentinel cells of the immune system and are responsible for presenting antigen information. Moreover, the role of DCs derived from monocytes (moDCs) in the development of inflammation has been emphasized. Several studies have shown that the function of DCs can be influenced by gut microbes including gut bacteria and viruses. Abnormal changes/reactions in intestinal DCs are potentially associated with diseases such as inflammatory bowel disease (IBD) and intestinal tumors, allowing DCs to be a new target for the treatment of these diseases. In this review, we summarized the physiological functions of DCs in the intestinal micro-environment, their regulatory relationship with intestinal microorganisms and their regulatory mechanism in intestinal diseases.
      Citation: Cells
      PubDate: 2021-03-06
      DOI: 10.3390/cells10030583
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 584: Asymmetrical Forces Dictate the Distribution
           and Morphology of Platelets in Blood Clots

    • Authors: Kovalenko, Giraud, Eckly, Ribba, Proamer, Fraboulet, Podoplelova, Valentin, Panteleev, Gonelle-Gispert, Cook, Lafanechère, Sveshnikova, Sadoul
      First page: 584
      Abstract: Primary hemostasis consists in the activation of platelets, which spread on the exposed extracellular matrix at the injured vessel surface. Secondary hemostasis, the coagulation cascade, generates a fibrin clot in which activated platelets and other blood cells get trapped. Active platelet-dependent clot retraction reduces the clot volume by extruding the serum. Thus, the clot architecture changes with time of contraction, which may have an important impact on the healing process and the dissolution of the clot, but the precise physiological role of clot retraction is still not completely understood. Since platelets are the only actors to develop force for the retraction of the clot, their distribution within the clot should influence the final clot architecture. We analyzed platelet distributions in intracoronary thrombi and observed that platelets and fibrin co-accumulate in the periphery of retracting clots in vivo. A computational mechanical model suggests that asymmetric forces are responsible for a different contractile behavior of platelets in the periphery versus the clot center, which in turn leads to an uneven distribution of platelets and fibrin fibers within the clot. We developed an in vitro clot retraction assay that reproduces the in vivo observations and follows the prediction of the computational model. Our findings suggest a new active role of platelet contraction in forming a tight fibrin- and platelet-rich boundary layer on the free surface of fibrin clots.
      Citation: Cells
      PubDate: 2021-03-06
      DOI: 10.3390/cells10030584
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 585: Elevated Serum Amyloid a Levels Are not
           Specific for Sarcoidosis but Associate with a Fibrotic Pulmonary Phenotype

    • Authors: Els Beijer, Claudia Roodenburg-Benschop, Milou C. Schimmelpennink, Jan C. Grutters, Bob Meek, Marcel Veltkamp
      First page: 585
      Abstract: Elevated Serum Amyloid A (SAA) levels have been found in several inflammatory diseases, including sarcoidosis. SAA is suggested to be involved in sarcoidosis pathogenesis by involvement in granuloma formation and maintenance. We hypothesized that SAA serum levels would be higher in sarcoidosis compared to other non-infectious granulomatous and non-granulomatous diseases. SAA levels were measured in serum from sarcoidosis, Hypersensitivity pneumonitis (HP), and (eosinophilic) granulomatosis with polyangiitis ((E)GPA) patients. Idiopathic pulmonary fibrosis (IPF) patients were included as non-granulomatous disease group. SAA levels of patients with sarcoidosis (31.0 µg/mL), HP (23.4 µg/mL), (E)GPA (36.9 µg/mL), and IPF (22.1 µg/mL) were all higher than SAA levels of healthy controls (10.1 µg/mL). SAA levels did not differ between the diagnostic groups. When SAA serum levels were analyzed in sarcoidosis subgroups, fibrotic sarcoidosis patients showed higher SAA levels than sarcoidosis patients without fibrosis (47.8 µg/mL vs. 29.4 µg/mL, p = 0.005). To conclude, the observation that fibrotic sarcoidosis patients have higher SAA levels, together with our finding that SAA levels were also increased in IPF patients, suggests that SAA may next to granulomatous processes also reflect the process of fibrogenesis. Further studies should clarify the exact role of SAA in fibrosis and the underlying mechanisms involved.
      Citation: Cells
      PubDate: 2021-03-07
      DOI: 10.3390/cells10030585
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 586: The Endocannabinoid System and PPARs: Focus on
           Their Signalling Crosstalk, Action and Transcriptional Regulation

    • Authors: Fabio Arturo Iannotti, Rosa Maria Vitale
      First page: 586
      Abstract: Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors including PPARα, PPARγ, and PPARβ/δ, acting as transcription factors to regulate the expression of a plethora of target genes involved in metabolism, immune reaction, cell differentiation, and a variety of other cellular changes and adaptive responses. PPARs are activated by a large number of both endogenous and exogenous lipid molecules, including phyto- and endo-cannabinoids, as well as endocannabinoid-like compounds. In this view, they can be considered an extension of the endocannabinoid system. Besides being directly activated by cannabinoids, PPARs are also indirectly modulated by receptors and enzymes regulating the activity and metabolism of endocannabinoids, and, vice versa, the expression of these receptors and enzymes may be regulated by PPARs. In this review, we provide an overview of the crosstalk between cannabinoids and PPARs, and the importance of their reciprocal regulation and modulation by common ligands, including those belonging to the extended endocannabinoid system (or “endocannabinoidome”) in the control of major physiological and pathophysiological functions.
      Citation: Cells
      PubDate: 2021-03-07
      DOI: 10.3390/cells10030586
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 587: Mesenchymal Stem Cell-Derived Exosomes Exhibit
           Promising Potential for Treating SARS-CoV-2-Infected Patients

    • Authors: Alok Raghav, Zeeshan Ahmad Khan, Viabhav Kumar Upadhayay, Prashant Tripathi, Kirti Amresh Gautam, Brijesh Kumar Mishra, Jamal Ahmad, Goo-Bo Jeong
      First page: 587
      Abstract: The novel coronavirus severe acute respiratory syndrome-CoV-2 (SARS-CoV-2) is responsible for COVID-19 infection. The COVID-19 pandemic represents one of the worst global threats in the 21st century since World War II. This pandemic has led to a worldwide economic recession and crisis due to lockdown. Biomedical researchers, pharmaceutical companies, and premier institutes throughout the world are claiming that new clinical trials are in progress. During the severe phase of this disease, mechanical ventilators are used to assist in the management of outcomes; however, their use can lead to the development of pneumonia. In this context, mesenchymal stem cell (MSC)-derived exosomes can serve as an immunomodulation treatment for COVID-19 patients. Exosomes possess anti-inflammatory, pro-angiogenic, and immunomodulatory properties that can be explored in an effort to improve the outcomes of SARS-CoV-2-infected patients. Currently, only one ongoing clinical trial (NCT04276987) is specifically exploring the use of MSC-derived exosomes as a therapy to treat SARS-CoV-2-associated pneumonia. The purpose of this review is to provide insights of using exosomes derived from mesenchymal stem cells in management of the co-morbidities associated with SARS-CoV-2-infected persons in direction of improving their health outcome. There is limited knowledge of using exosomes in SARS-CoV-2; the clinicians and researchers should exploit exosomes as therapeutic regime.
      Citation: Cells
      PubDate: 2021-03-07
      DOI: 10.3390/cells10030587
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 588: Mesenchymal Stem Cell-Based Therapy for Retinal
           Degenerative Diseases: Experimental Models and Clinical Trials

    • Authors: Vladimir Holan, Katerina Palacka, Barbora Hermankova
      First page: 588
      Abstract: Retinal degenerative diseases, such as age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy or glaucoma, represent the main causes of a decreased quality of vision or even blindness worldwide. However, despite considerable efforts, the treatment possibilities for these disorders remain very limited. A perspective is offered by cell therapy using mesenchymal stem cells (MSCs). These cells can be obtained from the bone marrow or adipose tissue of a particular patient, expanded in vitro and used as the autologous cells. MSCs possess potent immunoregulatory properties and can inhibit a harmful inflammatory reaction in the diseased retina. By the production of numerous growth and neurotrophic factors, they support the survival and growth of retinal cells. In addition, MSCs can protect retinal cells by antiapoptotic properties and could contribute to the regeneration of the diseased retina by their ability to differentiate into various cell types, including the cells of the retina. All of these properties indicate the potential of MSCs for the therapy of diseased retinas. This view is supported by the recent results of numerous experimental studies in different preclinical models. Here we provide an overview of the therapeutic properties of MSCs, and their use in experimental models of retinal diseases and in clinical trials.
      Citation: Cells
      PubDate: 2021-03-07
      DOI: 10.3390/cells10030588
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 589: 3D-Printed Collagen Scaffolds Promote
           Maintenance of Cryopreserved Patients-Derived Melanoma Explants

    • Authors: Yun-Mi Jeong, ChulHwan Bang, MinJi Park, Sun Shin, Seokhwan Yun, Chul Min Kim, GaHee Jeong, Yeun-Jun Chung, Woo-Soo Yun, Ji Hyun Lee, Songwan Jin
      First page: 589
      Abstract: The development of an in vitro three-dimensional (3D) culture system with cryopreserved biospecimens could accelerate experimental research screening anticancer drugs, potentially reducing costs and time bench-to-beside. However, minimal research has explored the application of 3D bioprinting-based in vitro cancer models to cryopreserved biospecimens derived from patients with advanced melanoma. We investigated whether 3D-printed collagen scaffolds enable the propagation and maintenance of patient-derived melanoma explants (PDMEs). 3D-printed collagen scaffolds were fabricated with a 3DX bioprinter. After thawing, fragments from cryopreserved PDMEs (approximately 1–2 mm) were seeded onto the 3D-printed collagen scaffolds, and incubated for 7 to 21 days. The survival rate was determined with MTT and live and dead assays. Western blot analysis and immunohistochemistry staining was used to express the function of cryopreserved PDMEs. The results show that 3D-printed collagen scaffolds could improve the maintenance and survival rate of cryopreserved PDME more than 2D culture. MITF, Mel A, and S100 are well-known melanoma biomarkers. In agreement with these observations, 3D-printed collagen scaffolds retained the expression of melanoma biomarkers in cryopreserved PDME for 21 days. Our findings provide insight into the application of 3D-printed collagen scaffolds for closely mimicking the 3D architecture of melanoma and its microenvironment using cryopreserved biospecimens.
      Citation: Cells
      PubDate: 2021-03-07
      DOI: 10.3390/cells10030589
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 590: Ambiguity about Splicing Factor 3b Subunit 3
           (SF3B3) and Sin3A Associated Protein 130 (SAP130)

    • Authors: Paula I. Metselaar, Celine Hos, Olaf Welting, Jos A. Bosch, Aletta D. Kraneveld, Wouter J. de Jonge, Anje A. Te Velde
      First page: 590
      Abstract: In 2020, three articles were published on a protein that can activate the immune system by binding to macrophage-inducible C-type lectin receptor (Mincle). In the articles, the protein was referred to as ‘SAP130, a subunit of the histone deacetylase complex.’ However, the Mincle ligand the authors aimed to investigate is splicing factor 3b subunit 3 (SF3B3). This splicing factor is unrelated to SAP130 (Sin3A associated protein 130, a subunit of the histone deacetylase-dependent Sin3A corepressor complex). The conclusions in the three articles were formulated for SF3B3, while the researchers used qPCR primers and antibodies against SAP130. We retraced the origins of the ambiguity about the two proteins and found that Online Mendelian Inheritance in Man (OMIM) added a Nature publication on SF3B3 as a reference for Sin3A associated protein 130 in 2016. Subsequently, companies such as Abcam referred to OMIM and the Nature article in their products for both SF3B3 and SAP130. In turn, the mistake by OMIM followed in the persistent and confusing use of ‘SAP130′ (spliceosome-associated protein 130) as an alternative symbol for SF3B3. With this report, we aim to eliminate the persistent confusion and separate the literature regarding the two proteins.
      Citation: Cells
      PubDate: 2021-03-08
      DOI: 10.3390/cells10030590
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 591: Small Activating RNAs: Towards the Development
           of New Therapeutic Agents and Clinical Treatments

    • Authors: Hossein Ghanbarian, Shahin Aghamiri, Mohamad Eftekhary, Nicole Wagner, Kay-Dietrich Wagner
      First page: 591
      Abstract: Small double-strand RNA (dsRNA) molecules can activate endogenous genes via an RNA-based promoter targeting mechanism. RNA activation (RNAa) is an evolutionarily conserved mechanism present in diverse eukaryotic organisms ranging from nematodes to humans. Small activating RNAs (saRNAs) involved in RNAa have been successfully used to activate gene expression in cultured cells, and thereby this emergent technique might allow us to develop various biotechnological applications, without the need to synthesize hazardous construct systems harboring exogenous DNA sequences. Accordingly, this thematic issue aims to provide insights into how RNAa cellular machinery can be harnessed to activate gene expression leading to a more effective clinical treatment of various diseases.
      Citation: Cells
      PubDate: 2021-03-08
      DOI: 10.3390/cells10030591
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 592: Deciphering the Code: Stem Cell-Immune Function
           and Cardiac Regeneration

    • Authors: Gustav Steinhoff
      First page: 592
      Abstract: The development of stem-cell-based and regenerative therapies for cardiovascular and other diseases has faced an unexpected roadblock in clinical translation [...]
      Citation: Cells
      PubDate: 2021-03-08
      DOI: 10.3390/cells10030592
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 593: Mural Cells: Potential Therapeutic Targets to
           Bridge Cardiovascular Disease and Neurodegeneration

    • Authors: Alexander Lin, Niridu Jude Peiris, Harkirat Dhaliwal, Maria Hakim, Weizhen Li, Subramaniam Ganesh, Yogambha Ramaswamy, Sanjay Patel, Ashish Misra
      First page: 593
      Abstract: Mural cells collectively refer to the smooth muscle cells and pericytes of the vasculature. This heterogenous population of cells play a crucial role in the regulation of blood pressure, distribution, and the structural integrity of the vascular wall. As such, dysfunction of mural cells can lead to the pathogenesis and progression of a number of diseases pertaining to the vascular system. Cardiovascular diseases, particularly atherosclerosis, are perhaps the most well-described mural cell-centric case. For instance, atherosclerotic plaques are most often described as being composed of a proliferative smooth muscle cap accompanied by a necrotic core. More recently, the role of dysfunctional mural cells in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, is being recognized. In this review, we begin with an exploration of the mechanisms underlying atherosclerosis and neurodegenerative diseases, such as mural cell plasticity. Next, we highlight a selection of signaling pathways (PDGF, Notch and inflammatory signaling) that are conserved across both diseases. We propose that conserved mural cell signaling mechanisms can be exploited for the identification or development of dual-pronged therapeutics that impart both cardio- and neuroprotective qualities.
      Citation: Cells
      PubDate: 2021-03-08
      DOI: 10.3390/cells10030593
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 594: Facial Rejuvenation with Concentrated
           Lipograft—A 12 Month Follow-Up Study

    • Authors: Lukas Prantl, Eva Brix, Sally Kempa, Oliver Felthaus, Andreas Eigenberger, Vanessa Brébant, Alexandra Anker, Catharina Strauss
      First page: 594
      Abstract: Lipofilling is a popular technique to treat volume loss in aging patients. The isolated adipose tissue is composed of adipocytes and stromal vascular fraction cells, which include adipose-derived stem cells (ASC). We hypothesize that the patient’s wrinkle severity scale (WSS) and patient’s satisfaction on the global aesthetic improvement scale (GAIS) can be improved after using concentrated lipoaspirate. Fourteen patients (54 years ± 11.09 years) with volume loss in the midface area underwent waterjet-assisted liposuction (Human Med AG, Schwerin, Germany). Fat was centrifuged in an ACP Double Syringe (Arthrex GmbH, Munich, Germany) using Rotofix 32A centrifuge (Andreas Hettich, GmbH & Co.KG, Tuttlingen, Germany). Homogenization was performed using the double syringe and a 1.4 mm female–female luerlock connector. After a second centrifugation, patients received periorbital (PO) and nasolabial (NL) lipografting. ASC count was performed after enzymatical digestion. Vitality of cells was assessed using a resazurin assay. During long-term follow up (12 months, n = 10), we found a high patient’s satisfaction (GAIS 1+/−0.52) and a good improvement of the WSS during short- and long-term follow-up. The ASC count of processed lipoaspirate was 2.1-fold higher than of unprocessed lipoaspirate (p < 0.001). The difference of ASC in sedimented and simply centrifuged lipoaspirate was also significant (p < 0.05). Facial rejuvenation with concentrated fat graft offers good results concerning objective aesthetic outcome and patient’s satisfaction.
      Citation: Cells
      PubDate: 2021-03-08
      DOI: 10.3390/cells10030594
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 595: Stem Cells and the Endometrium: From the
           Discovery of Adult Stem Cells to Pre-Clinical Models

    • Authors: Lucía de de Miguel-Gómez, Sara López-Martínez, Emilio Francés-Herrero, Adolfo Rodríguez-Eguren, Antonio Pellicer, Irene Cervelló
      First page: 595
      Abstract: Adult stem cells (ASCs) were long suspected to exist in the endometrium. Indeed, several types of endometrial ASCs were identified in rodents and humans through diverse isolation and characterization techniques. Putative stromal and epithelial stem cell niches were identified in murine models using label-retention techniques. In humans, functional methods (clonogenicity, long-term culture, and multi-lineage differentiation assays) and stem cell markers (CD146, SUSD2/W5C5, LGR5, NTPDase2, SSEA-1, or N-cadherin) facilitated the identification of three main types of endogenous endometrial ASCs: stromal, epithelial progenitor, and endothelial stem cells. Further, exogenous populations of stem cells derived from bone marrow may act as key effectors of the endometrial ASC niche. These findings are promoting the development of stem cell therapies for endometrial pathologies, with an evolution towards paracrine approaches. At the same time, promising therapeutic alternatives based on bioengineering have been proposed.
      Citation: Cells
      PubDate: 2021-03-08
      DOI: 10.3390/cells10030595
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 596: In Vitro Human Joint Models Combining Advanced
           3D Cell Culture and Cutting-Edge 3D Bioprinting Technologies

    • Authors: Christian Jorgensen, Matthieu Simon
      First page: 596
      Abstract: Joint-on-a-chip is a new technology able to replicate the joint functions into microscale systems close to pathophysiological conditions. Recent advances in 3D printing techniques allow the precise control of the architecture of the cellular compartments (including chondrocytes, stromal cells, osteocytes and synoviocytes). These tools integrate fluid circulation, the delivery of growth factors, physical stimulation including oxygen level, external pressure, and mobility. All of these structures must be able to mimic the specific functions of the diarthrodial joint: mobility, biomechanical aspects and cellular interactions. All the elements must be grouped together in space and reorganized in a manner close to the joint organ. This will allow the study of rheumatic disease physiopathology, the development of biomarkers and the screening of new drugs.
      Citation: Cells
      PubDate: 2021-03-08
      DOI: 10.3390/cells10030596
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 597: Apolipoprotein Mimetic Peptides: Potential New
           Therapies for Cardiovascular Diseases

    • Authors: Anna Wolska, Mart Reimund, Denis O. Sviridov, Marcelo J. Amar, Alan T. Remaley
      First page: 597
      Abstract: Since the seminal breakthrough of treating diabetic patients with insulin in the 1920s, there has been great interest in developing other proteins and their peptide mimetics as therapies for a wide variety of other medical disorders. Currently, there are at least 60 different peptides that have been approved for human use and over 150 peptides that are in various stages of clinical development. Peptides mimetic of the major proteins on lipoproteins, namely apolipoproteins, have also been developed first as tools for understanding apolipoprotein structure and more recently as potential therapeutics. In this review, we discuss the biochemistry, peptide mimetics design and clinical trials for peptides based on apoA-I, apoE and apoC-II. We primarily focus on applications of peptide mimetics related to cardiovascular diseases. We conclude with a discussion on the limitations of peptides as therapeutic agents and the challenges that need to be overcome before apolipoprotein mimetic peptides can be developed into new drugs.
      Citation: Cells
      PubDate: 2021-03-08
      DOI: 10.3390/cells10030597
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 598: The Nigral Coup in Parkinson’s Disease by
           α-Synuclein and Its Associated Rebels

    • Authors: Jeswinder Sian-Hulsmann, Peter Riederer
      First page: 598
      Abstract: The risk of Parkinson’s disease increases with age. However, the etiology of the illness remains obscure. It appears highly likely that the neurodegenerative processes involve an array of elements that influence each other. In addition, genetic, endogenous, or exogenous toxins need to be considered as viable partners to the cellular degeneration. There is compelling evidence that indicate the key involvement of modified α-synuclein (Lewy bodies) at the very core of the pathogenesis of the disease. The accumulation of misfolded α-synuclein may be a consequence of some genetic defect or/and a failure of the protein clearance system. Importantly, α-synuclein pathology appears to be a common denominator for many cellular deleterious events such as oxidative stress, mitochondrial dysfunction, dopamine synaptic dysregulation, iron dyshomeostasis, and neuroinflammation. These factors probably employ a common apoptotic/or autophagic route in the final stages to execute cell death. The misfolded α-synuclein inclusions skillfully trigger or navigate these processes and thus amplify the dopamine neuron fatalities. Although the process of neuroinflammation may represent a secondary event, nevertheless, it executes a fundamental role in neurodegeneration. Some viral infections produce parkinsonism and exhibit similar characteristic neuropathological changes such as a modest brain dopamine deficit and α-synuclein pathology. Thus, viral infections may heighten the risk of developing PD. Alternatively, α-synuclein pathology may induce a dysfunctional immune system. Thus, sporadic Parkinson’s disease is caused by multifactorial trigger factors and metabolic disturbances, which need to be considered for the development of potential drugs in the disorder.
      Citation: Cells
      PubDate: 2021-03-09
      DOI: 10.3390/cells10030598
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 599: New Insights into the Significance of PARP-1
           Activation: Flow Cytometric Detection of Poly(ADP-Ribose) as a Marker of
           Bovine Intramammary Infection

    • Authors: Giovanna De Matteis, Francesco Grandoni, Michele Zampieri, Anna Reale, Maria Carmela Scatà
      First page: 599
      Abstract: Bovine intramammary infections are common diseases affecting dairy cattle worldwide and represent a major focus of veterinary research due to financial losses and food safety concerns. The identification of new biomarkers of intramammary infection, useful for monitoring the health of dairy cows and wellness verification, represents a key advancement having potential beneficial effects on public health. In vitro experiments using bovine peripheral blood mononuclear cells (PBMC), stimulated with the bacterial endotoxin lipopolysaccharide (LPS) enabled a flow cytometric assay in order to evaluate in vivo poly-ADP-ribose (PAR) levels. Results showed a significant increase of PAR after 1 h of treatment, which is consistent with the involvement of PARP activity in the inflammatory response. This study investigated PARP-1 activation in leukocyte subpopulations from bovine milk samples during udder infection. A flow cytometric assay was, therefore, performed to evaluate the PAR content in milk leukocyte subsets of cows with and without intramammary infection (IMI). Results showed that milk lymphocytes and macrophages isolated from cows with IMI had a significant increase of PAR content compared to uninfected samples. These results suggest mastitis as a new model for the study of the role of PARP in zoonotic inflammatory diseases, opening a new perspective to the “One Health” approach.
      Citation: Cells
      PubDate: 2021-03-09
      DOI: 10.3390/cells10030599
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 600: Stem Cells in Cardiovascular Diseases:
           30,000-Foot View

    • Authors: Thomas J. Povsic, Bernard J. Gersh
      First page: 600
      Abstract: Stem cell and regenerative approaches that might rejuvenate the heart have immense intuitive appeal for the public and scientific communities. Hopes were fueled by initial findings from preclinical models that suggested that easily obtained bone marrow cells might have significant reparative capabilities; however, after initial encouraging pre-clinical and early clinical findings, the realities of clinical development have placed a damper on the field. Clinical trials were often designed to detect exceptionally large treatment effects with modest patient numbers with subsequent disappointing results. First generation approaches were likely overly simplistic and relied on a relatively primitive understanding of regenerative mechanisms and capabilities. Nonetheless, the field continues to move forward and novel cell derivatives, platforms, and cell/device combinations, coupled with a better understanding of the mechanisms that lead to regenerative capabilities in more primitive models and modifications in clinical trial design suggest a brighter future.
      Citation: Cells
      PubDate: 2021-03-09
      DOI: 10.3390/cells10030600
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 601: The Role of IL-9 Polymorphisms and Serum IL-9
           Levels in Carcinogenesis and Survival Rate for Laryngeal Squamous Cell

    • Authors: Agne Pasvenskaite, Rasa Liutkeviciene, Greta Gedvilaite, Alvita Vilkeviciute, Vykintas Liutkevicius, Virgilijus Uloza
      First page: 601
      Abstract: Recent studies have described the dichotomous function of IL-9 in various cancer diseases. However, its function has still not been analysed in laryngeal squamous cell carcinoma (LSCC). In the present study, we evaluated five single nucleotide polymorphisms (SNPs) of IL-9 (rs1859430, rs2069870, rs11741137, rs2069885, and rs2069884) and determined their associations with the patients’ five-year survival rate. Additionally, we analysed serum IL-9 levels using an enzyme-linked immunosorbent assay. Three hundred LSCC patients and 533 control subjects were included in this study. A significant association between the patients’ survival rate and distribution of IL-9 rs1859430 variants was revealed: patients carrying AA genotype had a higher risk of dying (p = 0.005). Haplotypes A-G-C-G-G of IL-9 (rs1859430, rs2069870, rs11741137, rs2069885, and rs2069884) were associated with 47% lower odds of LSCC occurrence (p = 0.035). Serum IL-9 levels were found detectable in three control group subjects (8.99 ± 12.03 pg/mL). In summary, these findings indicate that the genotypic distribution of IL-9 rs1859430 negatively influences the five-year survival rate of LSCC patients. The haplotypes A-G-C-G-G of IL-9 (rs1859430, rs2069870, rs11741137, rs2069885, and rs2069884) are associated with the lower odds of LSCC development.
      Citation: Cells
      PubDate: 2021-03-09
      DOI: 10.3390/cells10030601
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 602: Growth Arrest-Specific Gene 6 Administration
           Ameliorates Sepsis-Induced Organ Damage in Mice and Reduces ROS Formation
           In Vitro

    • Authors: Livia Salmi, Francesco Gavelli, Filippo Patrucco, Mattia Bellan, Pier Paolo Sainaghi, Gian Carlo Avanzi, Luigi Mario Castello
      First page: 602
      Abstract: Sepsis is a widespread life-threatening disease, with a high mortality rate due to inflammation-induced multiorgan failure (MOF). Thus, new effective modulators of the immune response are urgently needed to ameliorate the outcome of septic patients. As growth arrest-specific gene 6 (Gas6)/Tyro3, Axl, MerTK (TAM) receptors signaling has shown immunomodulatory activity in sepsis, here we sought to determine whether Gas6 protein injection could mitigate MOF in a cecal slurry mouse model of sepsis. Mice, divided into different groups according to treatment—i.e., placebo (B), ampicillin (BA), Gas6 alone (BG), and ampicillin plus Gas6 (BAG)—were assessed for vitality, histopathology and cytokine expression profile as well as inducible nitric oxide synthase (iNOS), ALT and LDH levels. BAG-treated mice displayed milder kidney and lung damage and reduced levels of cytokine expression and iNOS in the lungs compared to BA-treated mice. Notably, BAG-treated mice showed lower LDH levels compared to controls. Lastly, BAG-treated cells of dendritic, endothelial or monocytic origin displayed reduced ROS formation and increased cell viability, with a marked upregulation of mitochondrial activity. Altogether, our findings indicate that combined treatment with Gas6 and antibiotics ameliorates sepsis-induced organ damage and reduces systemic LDH levels in mice, suggesting that Gas6 intravenous injection may be a viable therapeutic option in sepsis.
      Citation: Cells
      PubDate: 2021-03-09
      DOI: 10.3390/cells10030602
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 603: Glomerular Macrophages in Human Auto- and
           Allo-Immune Nephritis

    • Authors: Solange Moll, Andrea Angeletti, Leonardo Scapozza, Andrea Cavalli, Gian Marco Ghiggeri, Marco Prunotto
      First page: 603
      Abstract: Macrophages are involved in tissue homeostasis. They participate in inflammatory episodes and are involved in tissue repair. Macrophages are characterized by a phenotypic heterogeneity and a profound cell plasticity. In the kidney, and more particularly within glomeruli, macrophages are thought to play a maintenance role that is potentially critical for preserving a normal glomerular structure. Literature on the glomerular macrophage role in human crescentic glomerulonephritis and renal transplantation rejection with glomerulitis, is sparse. Evidence from preclinical models indicates that macrophages profoundly modulate disease progression, both in terms of number—where depletion has resulted in a reduced glomerular lesion—and sub-phenotype—M1 being more profoundly detrimental than M2. This evidence is corroborated by better outcomes in patients with a lower number of glomerular macrophages. However, due to the very limited biopsy sample size, the type and role of macrophage subpopulations involved in human proliferative lesions is more difficult to precisely define and synthesize. Therefore, specific biomarkers of macrophage activation may enhance our ability to assess their role, potentially enabling improved monitoring of drug activity and ultimately allowing the development of novel therapeutic strategies to target these elusive cellular players.
      Citation: Cells
      PubDate: 2021-03-09
      DOI: 10.3390/cells10030603
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 604: Cytokine Profile in Plasma Extracellular
           Vesicles of Parkinson’s Disease and the Association with Cognitive

    • Authors: Lung Chan, Chen-Chih Chung, Jia-Hung Chen, Ruan-Ching Yu, Chien-Tai Hong
      First page: 604
      Abstract: Plasma extracellular vesicles (EVs) containing various molecules, including cytokines, can reflect the intracellular condition and participate in cell-to-cell signaling, thus emerging as biomarkers for Parkinson’s disease (PD). Inflammation may be a crucial risk factor for PD development and progression. The present study investigated the role of plasma EV cytokines as the biomarkers of PD. This cross-sectional study recruited 113 patients with PD, with mild to moderate stage disease, and 48 controls. Plasma EVs were isolated, and the levels of cytokines, including pro-interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β1, were evaluated. Patients with PD had significantly increased plasma EV pro-IL-1β and TNF-α levels compared with controls after adjustment for age and sex. Despite the lack of a significant association between plasma EV cytokines and motor symptom severity in patients with PD, cognitive dysfunction severity, assessed using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment, was significantly associated with plasma EV pro-IL-1β, IL-6, IL-10, and TNF-α levels. This association was PD specific and not found in controls. Furthermore, patients with PD cognitive deficit (MMSE < 26) exhibited a distinguished EV cytokine profile compared to those without cognitive deficit. The findings support the concept of inflammatory pathogenesis in the development and progression of PD and indicate that plasma EV cytokines may serve as PD biomarkers in future.
      Citation: Cells
      PubDate: 2021-03-09
      DOI: 10.3390/cells10030604
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 605: Direct Conversion of Human Fibroblasts into
           Adipocytes using a Novel Small Molecular Compound: Implications for
           Regenerative Therapy for Adipose Tissue Defects

    • Authors: Yoshihiro Sowa, Tsunao Kishida, Fiona Louis, Seiji Sawai, Makoto Seki, Toshiaki Numajiri, Kenji Takahashi, Osam Mazda
      First page: 605
      Abstract: There is a need in plastic surgery to prepare autologous adipocytes that can be transplanted in patients to reconstruct soft tissue defects caused by tumor resection, including breast cancer, and by trauma and other diseases. Direct conversion of somatic cells into adipocytes may allow sufficient functional adipocytes to be obtained for use in regeneration therapy. Chemical libraries of 10,800 molecules were screened for the ability to induce lipid accumulation in human dermal fibroblasts (HDFs) in culture. Chemical compound-mediated directly converted adipocytes (CCCAs) were characterized by lipid staining, immunostaining, and qRT-PCR, and were also tested for adipokine secretion and glucose uptake. CCCAs were also implanted into mice to examine their distribution in vivo. STK287794 was identified as a small molecule that induced the accumulation of lipid droplets in HDFs. CCCAs expressed adipocyte-related genes, secreted adiponectin and leptin, and abundantly incorporated glucose. After implantation in mice, CCCAs resided in granulation tissue and remained adipose-like. HDFs were successfully converted into adipocytes by adding a single chemical compound, STK287794. C/EBPα and PPARγ were upregulated in STK287794-treated cells, which strongly suggests involvement of these adipocyte-related transcription factors in the chemical direct conversion. Our method may be useful for the preparation of autogenous adipocytes for transplantation therapy for soft tissue defects and fat tissue atrophy.
      Citation: Cells
      PubDate: 2021-03-09
      DOI: 10.3390/cells10030605
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 606: Oxidative Stress and the Intersection of
           Oncogenic Signaling and Metabolism in Squamous Cell Carcinomas

    • Authors: Choe, Mazambani, Kim, Kim
      First page: 606
      Abstract: Squamous cell carcinomas (SCCs) arise from both stratified squamous and non-squamous epithelium of diverse anatomical sites and collectively represent one of the most frequent solid tumors, accounting for more than one million cancer deaths annually. Despite this prevalence, SCC patients have not fully benefited from recent advances in molecularly targeted therapy or immunotherapy. Rather, decades old platinum-based or radiation regimens retaining limited specificity to the unique characteristics of SCC remain first-line treatment options. Historically, a lack of a consolidated perspective on genetic aberrations driving oncogenic transformation and other such factors essential for SCC pathogenesis and intrinsic confounding cellular heterogeneity in SCC have contributed to a critical dearth in effective and specific therapies. However, emerging evidence characterizing the distinct genomic, epigenetic, and metabolic landscapes of SCC may be elucidating unifying features in a seemingly heterogeneous disease. In this review, by describing distinct metabolic alterations and genetic drivers of SCC revealed by recent studies, we aim to establish a conceptual framework for a previously unappreciated network of oncogenic signaling, redox perturbation, and metabolic reprogramming that may reveal targetable vulnerabilities at their intersection.
      Citation: Cells
      PubDate: 2021-03-09
      DOI: 10.3390/cells10030606
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 607: The Role of Cytokines and Chemokines in Shaping
           the Immune Microenvironment of Glioblastoma: Implications for

    • Authors: Yeo, Brown, Gargett, Ebert
      First page: 607
      Abstract: Glioblastoma is the most common form of primary brain tumour in adults. For more than a decade, conventional treatment has produced a relatively modest improvement in the overall survival of glioblastoma patients. The immunosuppressive mechanisms employed by neoplastic and non-neoplastic cells within the tumour can limit treatment efficacy, and this can include the secretion of immunosuppressive cytokines and chemokines. These factors can play a significant role in immune modulation, thus disabling anti-tumour responses and contributing to tumour progression. Here, we review the complex interplay between populations of immune and tumour cells together with defined contributions by key cytokines and chemokines to these intercellular interactions. Understanding how these tumour-derived factors facilitate the crosstalk between cells may identify molecular candidates for potential immunotherapeutic targeting, which may enable better tumour control and improved patient survival.
      Citation: Cells
      PubDate: 2021-03-09
      DOI: 10.3390/cells10030607
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 608: Tumor Necrosis Factor (TNF) is Required for
           Spatial Learning and Memory in Male Mice under Physiological, but not
           Immune-Challenged Conditions

    • Authors: Leda Mygind, Marianne Skov-Skov Bergh, Vivien Tejsi, Ramanan Vaitheeswaran, Kate L. Lambertsen, Bente Finsen, Athanasios Metaxas
      First page: 608
      Abstract: Increasing evidence demonstrates that inflammatory cytokines—such as tumor necrosis factor (TNF)—are produced at low levels in the brain under physiological conditions and may be crucial for synaptic plasticity, neurogenesis, learning and memory. Here, we examined the effects of developmental TNF deletion on spatial learning and memory using 11–13-month-old TNF knockout (KO) and C57BL6/J wild-type (WT) mice. The animals were tested in the Barnes maze (BM) arena under baseline conditions and 48 h following an injection of the endotoxin lipopolysaccharide (LPS), which was administered at a dose of 0.5 mg/kg. Vehicle-treated KO mice were impaired compared to WT mice during the acquisition and memory-probing phases of the BM test. No behavioral differences were observed between WT and TNF-KO mice after LPS treatment. Moreover, there were no differences in the hippocampal content of glutamate and noradrenaline between groups. The effects of TNF deletion on spatial learning and memory were observed in male, but not female mice, which were not different compared to WT mice under baseline conditions. These results indicate that TNF is required for spatial learning and memory in male mice under physiological, non-inflammatory conditions, however not following the administration of LPS. Inflammatory signalling can thereby modulate spatial cognition in male subjects, highlighting the importance of sex- and probably age-stratified analysis when examining the role of TNF in the brain.
      Citation: Cells
      PubDate: 2021-03-09
      DOI: 10.3390/cells10030608
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 609: The Relationship between the Antioxidant System
           and Proline Metabolism in the Leaves of Cucumber Plants Acclimated to Salt

    • Authors: Marcin Naliwajski, Maria Skłodowska
      First page: 609
      Abstract: The study examines the effect of acclimation on the antioxidant system and proline metabolism in cucumber leaves subjected to 100 and 150 NaCl stress. The levels of protein carbonyl group, thiobarbituric acid reactive substances, α-tocopherol, and activity of ascorbate and glutathione peroxidases, catalase, glutathione S-transferase, pyrroline-5-carboxylate: synthetase and reductase as well as proline dehydrogenase were determined after 24 and 72 h periods of salt stress in the acclimated and non-acclimated plants. Although both groups of plants showed high α-tocopherol levels, in acclimated plants was observed higher constitutive concentration of these compounds as well as after salt treatment. Furthermore, the activity of enzymatic antioxidants grew in response to salt stress, mainly in the acclimated plants. In the acclimated plants, protein carbonyl group levels collapsed on a constitutive level and in response to salt stress. Although both groups of plants showed a decrease in proline dehydrogenase activity, they differed with regard to the range and time. Differences in response to salt stress between the acclimated and non-acclimated plants may suggest a relationship between increased tolerance in acclimated plants and raised activity of antioxidant enzymes, high-level of α-tocopherol as well, as decrease enzyme activity incorporates in proline catabolism.
      Citation: Cells
      PubDate: 2021-03-10
      DOI: 10.3390/cells10030609
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 610: Resistance of Hypoxic Cells to Ionizing
           Radiation Is Mediated in Part via Hypoxia-Induced Quiescence

    • Authors: Apostolos Menegakis, Rob Klompmaker, Claire Vennin, Aina Arbusà, Maartje Damen, Bram van den Broek, Daniel Zips, Jacco van Rheenen, Lenno Krenning, René H. Medema
      First page: 610
      Abstract: Double strand breaks (DSBs) are highly toxic to a cell, a property that is exploited in radiation therapy. A critical component for the damage induction is cellular oxygen, making hypoxic tumor areas refractory to the efficacy of radiation treatment. During a fractionated radiation regimen, these hypoxic areas can be re-oxygenated. Nonetheless, hypoxia still constitutes a negative prognostic factor for the patient’s outcome. We hypothesized that this might be attributed to specific hypoxia-induced cellular traits that are maintained upon reoxygenation. Here, we show that reoxygenation of hypoxic non-transformed RPE-1 cells fully restored induction of DSBs but the cells remain radioresistant as a consequence of hypoxia-induced quiescence. With the use of the cell cycle indicators (FUCCI), cell cycle-specific radiation sensitivity, the cell cycle phase duration with live cell imaging, and single cell tracing were assessed. We observed that RPE-1 cells experience a longer G1 phase under hypoxia and retain a large fraction of cells that are non-cycling. Expression of HPV oncoprotein E7 prevents hypoxia-induced quiescence and abolishes the radioprotective effect. In line with this, HPV-negative cancer cell lines retain radioresistance, while HPV-positive cancer cell lines are radiosensitized upon reoxygenation. Quiescence induction in hypoxia and its HPV-driven prevention was observed in 3D multicellular spheroids. Collectively, we identify a new hypoxia-dependent radioprotective phenotype due to hypoxia-induced quiescence that accounts for a global decrease in radiosensitivity that can be retained upon reoxygenation and is absent in cells expressing oncoprotein E7.
      Citation: Cells
      PubDate: 2021-03-10
      DOI: 10.3390/cells10030610
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 611: Emergency Lung Transplantation after COVID-19:
           Immunopathological Insights on Two Affected Patients

    • Authors: Giorgio A. Croci, Valentina Vaira, Daria Trabattoni, Mara Biasin, Luca Valenti, Guido Baselli, Massimo Barberis, Elena Guerini Rocco, Giuliana Gregato, Mara Scandroglio, Evgeny Fominskiy, Alessandro Palleschi, Lorenzo Rosso, Mario Nosotti, Mario Clerici, Stefano Ferrero
      First page: 611
      Abstract: We herein characterize the immunopathological features of two Italian COVID-19 patients who underwent bilateral lung transplantation (bLTx). Removed lungs underwent histopathological evaluation. Gene expression profiling (GEP) for immune-related signatures was performed on lung specimens and SARS-CoV-2-stimulated peripheral blood mononuclear cells (PBMCs). Cytokine levels were measured on lungs, bronchoalveolar lavage fluids and in culture supernatants. Pathological assessment showed extensive lung damage with the pattern of proliferative to fibrotic phases, with diffuse alveolar damage mimicking usual interstitial pneumonia (UIP). Lungs’ GEP revealed overexpression of pathogen recognition receptors, effector cytokines and chemokines, immune activation receptors and of the inflammasome components. Multiplex cytokine analysis confirmed a proinflammatory state, with high levels of monocyte/macrophage chemotactic and activating factors and of IL-6 and TNF-α. A similar profile was observed in SARS-CoV-2-stimulated PBMCs collected 7 days after transplant. The pattern of tissue damage observed in the lungs suggests that this may represent the output of protracted disease, resembling a diffuse UIP-like picture. The molecular immune profiling supports the paradigm of a persistent proinflammatory state and sustained humoral immunity, conditions that are maintained despite the iatrogenic immunosuppression.
      Citation: Cells
      PubDate: 2021-03-10
      DOI: 10.3390/cells10030611
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 612: Nicotinamide Treatment Facilitates
           Mitochondrial Fission through Drp1 Activation Mediated by SIRT1-Induced
           Changes in Cellular Levels of cAMP and Ca2+

    • Authors: Seon Beom Song, Jin Sung Park, So Young Jang, Eun Seong Hwang
      First page: 612
      Abstract: Mitochondrial autophagy (or mitophagy) is essential for mitochondrial quality control, which is critical for cellular and organismal health by attenuating reactive oxygen species generation and maintaining bioenergy homeostasis. Previously, we showed that mitophagy is activated in human cells through SIRT1 activation upon treatment of nicotinamide (NAM). Further, mitochondria are maintained as short fragments in the treated cells. In the current study, molecular pathways for NAM-induced mitochondrial fragmentation were sought. NAM treatment induced mitochondrial fission, at least in part by activating dynamin-1-like protein (Drp1), and this was through attenuation of the inhibitory phosphorylation at serine 637 (S637) of Drp1. This Drp1 hypo-phosphorylation was attributed to SIRT1-mediated activation of AMP-activated protein kinase (AMPK), which in turn induced a decrease in cellular levels of cyclic AMP (cAMP) and protein kinase A (PKA) activity, a kinase targeting S637 of Drp1. Furthermore, in NAM-treated cells, cytosolic Ca2+ was highly maintained; and, as a consequence, activity of calcineurin, a Drp1-dephosphorylating phosphatase, is expected to be elevated. These results suggest that NAD+-mediated SIRT1 activation facilitates mitochondrial fission through activation of Drp1 by suppressing its phosphorylation and accelerating its dephosphorylation. Additionally, it is suggested that there is a cycle of mitochondrial fragmentation and cytosolic Ca2+-mediated Drp1 dephosphorylation that may drive sustained mitochondrial fragmentation.
      Citation: Cells
      PubDate: 2021-03-10
      DOI: 10.3390/cells10030612
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 613: Hypoxia-Induced Reactivity of Tumor-Associated
           Astrocytes Affects Glioma Cell Properties

    • Authors: Vasiliki Pantazopoulou, Pauline Jeannot, Rebecca Rosberg, Tracy J. Berg, Alexander Pietras
      First page: 613
      Abstract: Glioblastoma is characterized by extensive necrotic areas with surrounding hypoxia. The cancer cell response to hypoxia in these areas is well-described; it involves a metabolic shift and an increase in stem cell-like characteristics. Less is known about the hypoxic response of tumor-associated astrocytes, a major component of the glioma tumor microenvironment. Here, we used primary human astrocytes and a genetically engineered glioma mouse model to investigate the response of this stromal cell type to hypoxia. We found that astrocytes became reactive in response to intermediate and severe hypoxia, similarly to irradiated and temozolomide-treated astrocytes. Hypoxic astrocytes displayed a potent hypoxia response that appeared to be driven primarily by hypoxia-inducible factor 2-alpha (HIF-2α). This response involved the activation of classical HIF target genes and the increased production of hypoxia-associated cytokines such as TGF-β1, IL-3, angiogenin, VEGF-A, and IL-1 alpha. In vivo, astrocytes were present in proximity to perinecrotic areas surrounding HIF-2α expressing cells, suggesting that hypoxic astrocytes contribute to the glioma microenvironment. Extracellular matrix derived from hypoxic astrocytes increased the proliferation and drug efflux capability of glioma cells. Together, our findings suggest that hypoxic astrocytes are implicated in tumor growth and potentially stemness maintenance by remodeling the tumor microenvironment.
      Citation: Cells
      PubDate: 2021-03-10
      DOI: 10.3390/cells10030613
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 614: Intratumor Regulatory Noncytotoxic NK Cells in
           Patients with Hepatocellular Carcinoma

    • Authors: Alessandra Zecca, Valeria Barili, Danila Rizzo, Andrea Olivani, Elisabetta Biasini, Diletta Laccabue, Raffaele Dalla Valle, Carlo Ferrari, Elisabetta Cariani, Gabriele Missale
      First page: 614
      Abstract: Previous studies support the role of natural killer (NK) cells in controlling hepatocellular carcinoma (HCC) progression. However, ambiguity remains about the multiplicity and the role of different NK cell subsets, as a pro-oncogenic function has been suggested. We performed phenotypic and functional characterization of NK cells infiltrating HCC, with the corresponding nontumorous tissue and liver from patients undergoing liver resection for colorectal liver metastasis used as controls. We identified a reduced number of NK cells in tumors with higher frequency of CD56BRIGHTCD16- NK cells associated with higher expression of NKG2A, NKp44, and NKp30 and downregulation of NKG2D. Liver-resident (CXCR6+) NK cells were reduced in the tumors where T-bethiEomeslo expression was predominant. HCCs showed higher expression of CD49a with particular enrichment in CD49a+Eomes+ NK cells, a subset typically represented in the decidua and playing a proangiogenic function. Functional analysis showed reduced TNF-α production along with impaired cytotoxic capacity that was inversely related to CXCR6-, T-bethiEomeslo, and CD49a+Eomes+ NK cells. In conclusion, we identified a subset of NK cells infiltrating HCC, including non-liver-resident cells that coexpressed CD49a and Eomes and showed reduced cytotoxic potential. This NK cell subset likely plays a regulatory role in proangiogenic function.
      Citation: Cells
      PubDate: 2021-03-10
      DOI: 10.3390/cells10030614
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 615: Muscle Enriched Lamin Interacting Protein
           (Mlip) Binds Chromatin and Is Required for Myoblast Differentiation

    • Authors: Elmira Ahmady, Alexandre Blais, Patrick G. Burgon
      First page: 615
      Abstract: Muscle-enriched A-type lamin-interacting protein (Mlip) is a recently discovered Amniota gene that encodes proteins of unknown biological function. Here we report Mlip’s direct interaction with chromatin, and it may function as a transcriptional co-factor. Chromatin immunoprecipitations with microarray analysis demonstrated a propensity for Mlip to associate with genomic regions in close proximity to genes that control tissue-specific differentiation. Gel mobility shift assays confirmed that Mlip protein complexes with genomic DNA. Blocking Mlip expression in C2C12 myoblasts down-regulates myogenic regulatory factors (MyoD and MyoG) and subsequently significantly inhibits myogenic differentiation and the formation of myotubes. Collectively our data demonstrate that Mlip is required for C2C12 myoblast differentiation into myotubes. Mlip may exert this role as a transcriptional regulator of a myogenic program that is unique to amniotes.
      Citation: Cells
      PubDate: 2021-03-10
      DOI: 10.3390/cells10030615
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 616: Kappa Free Light Chains in the Context of Blood
           Contamination, and Other IgA- and IgM-Related Cerebrospinal Fluid Disease

    • Authors: Malte Johannes Hannich, Alexander Dressel, Kathrin Budde, Astrid Petersmann, Matthias Nauck, Marie Süße
      First page: 616
      Abstract: In this retrospective, monocentric cohort study, we tested if an intrathecal free light chain kappa (FLC-k) synthesis reflects not only an IgG but also IgA and IgM synthesis. We also analysed if FLC-k can help to distinguish between an inflammatory process and a blood contamination of cerebrospinal fluid (CSF). A total of 296 patient samples were identified and acquired from patients of the department of Neurology, University Medicine Greifswald (Germany). FLC-k were analysed in paired CSF and serum samples using the Siemens FLC-k kit. To determine an intrathecal FLC-k and immunoglobulin (Ig) A/-M-synthesis we analysed CSF/serum quotients in quotient diagrams, according to Reiber et al. Patient samples were grouped into three cohorts: cohort I (n = 41), intrathecal IgA and/or IgM synthesis; cohort II (n = 16), artificial blood contamination; and the control group (n = 239), no intrathecal immunoglobulin synthesis. None of the samples had intrathecal IgG synthesis, as evaluated with quotient diagrams or oligoclonal band analysis. In cohort I, 98% of patient samples presented an intrathecal synthesis of FLC-k. In cohort II, all patients lacked intrathecal FLC-k synthesis. In the control group, 6.5% presented an intrathecal synthesis of FLC-k. The data support the concept that an intrathecal FLC-k synthesis is independent of the antibody class produced. In patients with an artificial intrathecal Ig synthesis due to blood contamination, FLC-k synthesis is lacking. Thus, additional determination of FLC-k in quotient diagrams helps to discriminate an inflammatory process from a blood contamination of CSF.
      Citation: Cells
      PubDate: 2021-03-11
      DOI: 10.3390/cells10030616
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 617: Genetic Deletion of Polo-Like Kinase 2 Induces
           a Pro-Fibrotic Pulmonary Phenotype

    • Authors: Theresa A. Kant, Manja Newe, Luise Winter, Maximilian Hoffmann, Susanne Kämmerer, Erik Klapproth, Karolina Künzel, Mark P. Kühnel, Lavinia Neubert, Ali El-Armouche, Stephan R. Künzel
      First page: 617
      Abstract: Pulmonary fibrosis is the chronic-progressive replacement of healthy lung tissue by extracellular matrix, leading to the destruction of the alveolar architecture and ultimately death. Due to limited pathophysiological knowledge, causal therapies are still missing and consequently the prognosis is poor. Thus, there is an urgent clinical need for models to derive effective therapies. Polo-like kinase 2 (PLK2) is an emerging regulator of fibroblast function and fibrosis. We found a significant downregulation of PLK2 in four different entities of human pulmonary fibrosis. Therefore, we characterized the pulmonary phenotype of PLK2 knockout (KO) mice. Isolated pulmonary PLK2 KO fibroblasts displayed a pronounced myofibroblast phenotype reflected by increased expression of αSMA, reduced proliferation rates and enhanced ERK1/2 and SMAD2/3 phosphorylation. In PLK2 KO, the expression of the fibrotic cytokines osteopontin and IL18 was elevated compared to controls. Histological analysis of PLK2 KO lungs revealed early stage remodeling in terms of alveolar wall thickening, increased alveolar collagen deposition and myofibroblast foci. Our results prompt further investigation of PLK2 function in pulmonary fibrosis and suggest that the PLK2 KO model displays a genetic predisposition towards pulmonary fibrosis, which could be leveraged in future research on this topic.
      Citation: Cells
      PubDate: 2021-03-11
      DOI: 10.3390/cells10030617
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 618: Differential Involvement of ACKR3 C-Tail in
           β-Arrestin Recruitment, Trafficking and Internalization

    • Authors: Aurélien Zarca, Claudia Perez, Jelle van den Bor, Jan Paul Bebelman, Joyce Heuninck, Rianna J. F. de Jonker, Thierry Durroux, Henry F. Vischer, Marco Siderius, Martine J. Smit
      First page: 618
      Abstract: Background: The atypical chemokine receptor 3 (ACKR3) belongs to the superfamily of G protein-coupled receptors (GPCRs). Unlike classical GPCRs, this receptor does not activate G proteins in most cell types but recruits β-arrestins upon activation. ACKR3 plays an important role in cancer and vascular diseases. As recruitment of β-arrestins is triggered by phosphorylation of the C-terminal tail of GPCRs, we studied the role of different potential phosphorylation sites within the ACKR3 C-tail to further delineate the molecular mechanism of internalization and trafficking of this GPCR. Methods: We used various bioluminescence and fluorescence resonance energy transfer-based sensors and techniques in Human Embryonic Kidney (HEK) 293T cells expressing WT or phosphorylation site mutants of ACKR3 to measure CXCL12-induced recruitment of β-arrestins and G-protein-coupled receptor kinases (GRKs), receptor internalization and trafficking. Results: Upon CXCL12 stimulation, ACKR3 recruits both β-arrestin 1 and 2 with equivalent kinetic profiles. We identified interactions with GRK2, 3 and 5, with GRK2 and 3 being important for β-arrestin recruitment. Upon activation, ACKR3 internalizes and recycles back to the cell membrane. We demonstrate that β-arrestin recruitment to the receptor is mainly determined by a single cluster of phosphorylated residues on the C-tail of ACKR3, and that residue T352 and in part S355 are important residues for β-arrestin1 recruitment. Phosphorylation of the C-tail appears essential for ligand-induced internalization and important for differential β-arrestin recruitment. GRK2 and 3 play a key role in receptor internalization. Moreover, ACKR3 can still internalize when β-arrestin recruitment is impaired or in the absence of β-arrestins, using alternative internalization pathways. Our data indicate that distinct residues within the C-tail of ACKR3 differentially regulate CXCL12-induced β-arrestin recruitment, ACKR3 trafficking and internalization.
      Citation: Cells
      PubDate: 2021-03-11
      DOI: 10.3390/cells10030618
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 619: The G-Protein-Coupled Estrogen Receptor (GPER)
           Regulates Trimethylation of Histone H3 at Lysine 4 and Represses Migration
           and Proliferation of Ovarian Cancer Cells In Vitro

    • Authors: Nan Han, Sabine Heublein, Udo Jeschke, Christina Kuhn, Anna Hester, Bastian Czogalla, Sven Mahner, Miriam Rottmann, Doris Mayr, Elisa Schmoeckel, Fabian Trillsch
      First page: 619
      Abstract: Histone H3 lysine 4 trimethylation (H3K4me3) is one of the most recognized epigenetic regulators of transcriptional activity representing, an epigenetic modification of Histone H3. Previous reports have suggested that the broad H3K4me3 domain can be considered as an epigenetic signature for tumor-suppressor genes in human cells. G-protein-coupled estrogen receptor (GPER), a new membrane-bound estrogen receptor, acts as an inhibitor on cell growth via epigenetic regulation in breast and ovarian cancer cells. This study was conducted to evaluate the relationship of GPER and H3K4me3 in ovarian cancer tissue samples as well as in two different cell lines (Caov3 and Caov4). Silencing of GPER by a specific siRNA and two selective regulators with agonistic (G1) and antagonistic (G15) activity were applied for consecutive in vitro studies to investigate their impacts on tumor cell growth and the changes in phosphorylated ERK1/2 (p-ERK1/2) and H3K4me3. We found a positive correlation between GPER and H3K4me3 expression in ovarian cancer patients. Patients overexpressing GPER as well as H3K4me3 had significantly improved overall survival. Increased H3K4me3 and p-ERK1/2 levels and attenuated cell proliferation and migration were observed in Caov3 and Caov4 cells via activation of GPER by G1. Conversely, antagonizing GPER activity by G15 resulted in opposite effects in the Caov4 cell line. In conclusion, interaction of GPER and H3K4me3 appears to be of prognostic significance for ovarian cancer patients. The results of the in vitro analyses confirm the biological rationale for their interplay and identify GPER agonists, such as G1, as a potential therapeutic approach for future investigations.
      Citation: Cells
      PubDate: 2021-03-11
      DOI: 10.3390/cells10030619
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 620: Measuring Pre- and Post-Copulatory Sexual
           Selection and Their Interaction in Socially Monogamous Species with
           Extra-Pair Paternity

    • Authors: Emily Rebecca Alison Cramer
      First page: 620
      Abstract: When females copulate with multiple males, pre- and post-copulatory sexual selection may interact synergistically or in opposition. Studying this interaction in wild populations is complex and potentially biased, because copulation and fertilization success are often inferred from offspring parentage rather than being directly measured. Here, I simulated 15 species of socially monogamous birds with varying levels of extra-pair paternity, where I could independently cause a male secondary sexual trait to improve copulation success, and a sperm trait to improve fertilization success. By varying the degree of correlation between the male and sperm traits, I show that several common statistical approaches, including univariate selection gradients and paired t-tests comparing extra-pair males to the within-pair males they cuckolded, can give highly biased results for sperm traits. These tests should therefore be avoided for sperm traits in socially monogamous species with extra-pair paternity, unless the sperm trait is known to be uncorrelated with male trait(s) impacting copulation success. In contrast, multivariate selection analysis and a regression of the proportion of extra-pair brood(s) sired on the sperm trait of the extra-pair male (including only broods where the male sired ≥1 extra-pair offspring) were unbiased, and appear likely to be unbiased under a broad range of conditions for this mating system. In addition, I investigated whether the occurrence of pre-copulatory selection impacted the strength of post-copulatory selection, and vice versa. I found no evidence of an interaction under the conditions simulated, where the male trait impacted only copulation success and the sperm trait impacted only fertilization success. Instead, direct selection on each trait was independent of whether the other trait was under selection. Although pre- and post-copulatory selection strength was independent, selection on the two traits was positively correlated across species because selection on both traits increased with the frequency of extra-pair copulations in these socially monogamous species.
      Citation: Cells
      PubDate: 2021-03-11
      DOI: 10.3390/cells10030620
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 621: Cancer Stem Cells: Significance in Origin,
           Pathogenesis and Treatment of Glioblastoma

    • Authors: Karina Biserova, Arvids Jakovlevs, Romans Uljanovs, Ilze Strumfa
      First page: 621
      Abstract: Cancer stem cells (CSCs), known also as tumor-initiating cells, are quiescent, pluripotent, self-renewing neoplastic cells that were first identified in hematologic tumors and soon after in solid malignancies. CSCs have attracted remarkable research interest due to their role in tumor resistance to chemotherapy and radiation treatment as well as recurrence. Extensive research has been devoted to the role of CSCs in glioblastoma multiforme (GBM), the most common primary brain tumor in adults, which is characterized by a dismal prognosis because of its aggressive course and poor response to treatment. The aim of the current paper is to provide an overview of current knowledge on the role of cancer stem cells in the pathogenesis and treatment resistance of glioblastoma. The six regulatory mechanisms of glioma stem cells (GSCs)—tumor microenvironment, niche concept, metabolism, immunity, genetics, and epigenetics—are reviewed. The molecular markers used to identify GSCs are described. The role of GSCs in the treatment resistance of glioblastoma is reviewed, along with future treatment options targeting GSCs. Stem cells of glioblastoma thus represent both a driving mechanism of major treatment difficulties and a possible target for more effective future approaches.
      Citation: Cells
      PubDate: 2021-03-11
      DOI: 10.3390/cells10030621
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 622: Rab27a-Dependent Paracrine Communication
           Controls Dendritic Spine Formation and Sensory Responses in the Barrel

    • Authors: Longbo Zhang, Xiaobing Zhang, Lawrence S. Hsieh, Tiffany V. Lin, Angélique Bordey
      First page: 622
      Abstract: Rab27a is an evolutionarily conserved small GTPase that regulates vesicle trafficking, and copy number variants of RAB27a are associated with increased risk of autism. However, the function of Rab27a on brain development is unknown. Here, we identified a form of paracrine communication that regulates spine development between distinct populations of developing cortical neurons. In the developing somatosensory cortex of mice, we show that decreasing Rab27a levels in late-born pyramidal neurons destined for layer (L) 2/3 had no cell-autonomous effect on their synaptic integration but increased excitatory synaptic transmission onto L4 neurons that receive somatosensory information. This effect resulted in an increased number of L4 neurons activated by whisker stimulation in juvenile mice. In addition, we found that Rab27a, the level of which decreases as neurons mature, regulates the release of small extracellular vesicles (sEVs) in developing neurons in vitro and decreasing Rab27a levels led to the accumulation of CD63-positive vesicular compartments in L2/3 neurons in vivo. Together, our study reveals that Rab27a-mediated paracrine communication regulates the development of synaptic connectivity, ultimately tuning responses to sensory stimulation, possibly via controlling the release of sEVs.
      Citation: Cells
      PubDate: 2021-03-11
      DOI: 10.3390/cells10030622
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 623: PARP7 and Mono-ADP-Ribosylation Negatively
           Regulate Estrogen Receptor α Signaling in Human Breast Cancer Cells

    • Authors: Marit Rasmussen, Susanna Tan, Venkata S. Somisetty, David Hutin, Ninni Elise Olafsen, Anders Moen, Jan H. Anonsen, Denis M. Grant, Jason Matthews
      First page: 623
      Abstract: ADP-ribosylation is a post-translational protein modification catalyzed by a family of proteins known as poly-ADP-ribose polymerases. PARP7 (TIPARP; ARTD14) is a mono-ADP-ribosyltransferase involved in several cellular processes, including responses to hypoxia, innate immunity and regulation of nuclear receptors. Since previous studies suggested that PARP7 was regulated by 17β-estradiol, we investigated whether PARP7 regulates estrogen receptor α signaling. We confirmed the 17β-estradiol-dependent increases of PARP7 mRNA and protein levels in MCF-7 cells, and observed recruitment of estrogen receptor α to the promoter of PARP7. Overexpression of PARP7 decreased ligand-dependent estrogen receptor α signaling, while treatment of PARP7 knockout MCF-7 cells with 17β-estradiol resulted in increased expression of and recruitment to estrogen receptor α target genes, in addition to increased proliferation. Co-immunoprecipitation assays revealed that PARP7 mono-ADP-ribosylated estrogen receptor α, and mass spectrometry mapped the modified peptides to the receptor’s ligand-independent transactivation domain. Co-immunoprecipitation with truncated estrogen receptor α variants identified that the hinge region of the receptor is required for PARP7-dependent mono-ADP-ribosylation. These results imply that PARP7-mediated mono-ADP-ribosylation may play an important role in estrogen receptor positive breast cancer.
      Citation: Cells
      PubDate: 2021-03-11
      DOI: 10.3390/cells10030623
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 624: Spermatogenic Activity and Sperm Traits in
           Post-Pubertal and Adult Tomcats (Felis catus): Implication of Intra-Male
           Variation in Sperm Size

    • Authors: Eliana Pintus, Martin Kadlec, Barbora Karlasová, Marek Popelka, José Luis Ros-Santaella
      First page: 624
      Abstract: Tomcats are considered to be adults at 1 year of age, although many reach sexual maturity at an earlier age. Nevertheless, we still know little about whether the spermatogenic activity and sperm quality of mature under one-year-old tomcats differ from those of tomcats that are over one-year-old. This study aims to evaluate the spermatogenic activity, sperm traits, and their relationships in mature tomcats at two different ages. Sixteen tomcats showing complete spermatogenesis and spermatozoa in their epididymal caudae were used and classified according to their age as post-pubertal (<1 year old) or adult (˃1 year old). Our results show that adult cats have higher epididymal sperm concentration and lower coefficient of variation in sperm head width and ellipticity than post-pubertal cats. However, they do not differ in their testicular and epididymal mass, spermatogenesis, and sperm traits such as motility, mitochondrial activity, morphology, morphometry, as well as plasma membrane, acrosome, and DNA integrity. Reduced intra-male variation of sperm head ellipticity is associated with higher testis mass, epididymis mass, and sperm concentration. Interestingly, low intra-male variation in sperm head size is associated with increased Sertoli cell function and reduced post-meiotic germ cell loss. These findings increase our knowledge about feline reproductive physiology and provide new insights into the functional significance of low intra-male variation in sperm size and shape in tomcats.
      Citation: Cells
      PubDate: 2021-03-11
      DOI: 10.3390/cells10030624
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 625: Beyond Self-Recycling: Cell-Specific Role of
           Autophagy in Atherosclerosis

    • Authors: James M. Henderson, Christian Weber, Donato Santovito
      First page: 625
      Abstract: Atherosclerosis is a chronic inflammatory disease of the arterial vessel wall and underlies the development of cardiovascular diseases, such as myocardial infarction and ischemic stroke. As such, atherosclerosis stands as the leading cause of death and disability worldwide and intensive scientific efforts are made to investigate its complex pathophysiology, which involves the deregulation of crucial intracellular pathways and intricate interactions between diverse cell types. A growing body of evidence, including in vitro and in vivo studies involving cell-specific deletion of autophagy-related genes (ATGs), has unveiled the mechanistic relevance of cell-specific (endothelial, smooth-muscle, and myeloid cells) defective autophagy in the processes of atherogenesis. In this review, we underscore the recent insights on autophagy’s cell-type-dependent role in atherosclerosis development and progression, featuring the relevance of canonical catabolic functions and emerging noncanonical mechanisms, and highlighting the potential therapeutic implications for prevention and treatment of atherosclerosis and its complications.
      Citation: Cells
      PubDate: 2021-03-11
      DOI: 10.3390/cells10030625
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 626: Hydrogen Nano-Bubble Water Suppresses ROS
           Generation, Adipogenesis, and Interleukin-6 Secretion in
           Hydrogen-Peroxide- or PMA-Stimulated Adipocytes and Three-Dimensional
           Subcutaneous Adipose Equivalents

    • Authors: Li Xiao, Nobuhiko Miwa
      First page: 626
      Abstract: Reactive oxygen species (ROS)-induced oxidative stress in adipose tissue is associated with inflammation and the development of obesity-related metabolic disorders. The aim of this study is to investigate the effects of hydrogen nano-bubble water (HW) on ROS generation, adipogenesis, and interleukin-6 (IL-6) secretion in hydrogen peroxide (H2O2) or phorbol 12-myristate 13-acetate (PMA)-stimulated OP9 adipocytes, and three-dimensional (3D) subcutaneous adipose equivalents. Nanoparticle tracking analysis showed that fresh HW contains 1.17 × 108/mL of nano-sized hydrogen bubbles. Even after 8 to 13 months of storage, approximately half of the bubbles still remained in the water. CellROX® staining showed that HW could diminish H2O2- or PMA-induced intracellular ROS generation in human keratinocytes HaCaT and OP9 cells. We discovered that PMA could markedly increase lipid accumulation to 180% and IL-6 secretion 2.7-fold in OP9 adipocytes. Similarly, H2O2 (5 µM) also significantly stimulated lipid accumulation in OP9 cells and the 3D adipose equivalents. HW treatment significantly repressed H2O2- or PMA-induced lipid accumulation and IL-6 secretion in OP9 adipocytes and the 3D adipose equivalents. In conclusion, HW showed a possibility of repressing oxidative stress, inflammatory response, and adipogenesis at cellular/tissue levels. It can be used for preventing the development of metabolic disorders amongst obese people.
      Citation: Cells
      PubDate: 2021-03-11
      DOI: 10.3390/cells10030626
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 627: Progression of Metastasis through Lymphatic

    • Authors: Hengbo Zhou, Pin-ji Lei, Timothy P. Padera
      First page: 627
      Abstract: Lymph nodes are the most common sites of metastasis in cancer patients. Nodal disease status provides great prognostic power, but how lymph node metastases should be treated is under debate. Thus, it is important to understand the mechanisms by which lymph node metastases progress and how they can be targeted to provide therapeutic benefits. In this review, we focus on delineating the process of cancer cell migration to and through lymphatic vessels, survival in draining lymph nodes and further spread to other distant organs. In addition, emerging molecular targets and potential strategies to inhibit lymph node metastasis are discussed.
      Citation: Cells
      PubDate: 2021-03-12
      DOI: 10.3390/cells10030627
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 628: Thymic Aging May Be Associated with COVID-19
           Pathophysiology in the Elderly

    • Authors: Weikan Wang, Rachel Thomas, Jiyoung Oh, Dong-Ming Su
      First page: 628
      Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the global pandemic of coronavirus disease 2019 (COVID-19) and particularly exhibits severe symptoms and mortality in elderly individuals. Mounting evidence shows that the characteristics of the age-related clinical severity of COVID-19 are attributed to insufficient antiviral immune function and excessive self-damaging immune reaction, involving T cell immunity and associated with pre-existing basal inflammation in the elderly. Age-related changes to T cell immunosenescence is characterized by not only restricted T cell receptor (TCR) repertoire diversity, accumulation of exhausted and/or senescent memory T cells, but also by increased self-reactive T cell- and innate immune cell-induced chronic inflammation, and accumulated and functionally enhanced polyclonal regulatory T (Treg) cells. Many of these changes can be traced back to age-related thymic involution/degeneration. How these changes contribute to differences in COVID-19 disease severity between young and aged patients is an urgent area of investigation. Therefore, we attempt to connect various clues in this field by reviewing and discussing recent research on the role of the thymus and T cells in COVID-19 immunity during aging (a synergistic effect of diminished responses to pathogens and enhanced responses to self) impacting age-related clinical severity of COVID-19. We also address potential combinational strategies to rejuvenate multiple aging-impacted immune system checkpoints by revival of aged thymic function, boosting peripheral T cell responses, and alleviating chronic, basal inflammation to improve the efficiency of anti-SARS-CoV-2 immunity and vaccination in the elderly.
      Citation: Cells
      PubDate: 2021-03-12
      DOI: 10.3390/cells10030628
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 629: Molecular Mechanisms of Obesity-Linked Cardiac
           Dysfunction: An Up-Date on Current Knowledge

    • Authors: Jorge Gutiérrez-Cuevas, Ana Sandoval-Rodriguez, Alejandra Meza-Rios, Hugo Christian Monroy-Ramírez, Marina Galicia-Moreno, Jesús García-Bañuelos, Arturo Santos, Juan Armendariz-Borunda
      First page: 629
      Abstract: Obesity is defined as excessive body fat accumulation, and worldwide obesity has nearly tripled since 1975. Excess of free fatty acids (FFAs) and triglycerides in obese individuals promote ectopic lipid accumulation in the liver, skeletal muscle tissue, and heart, among others, inducing insulin resistance, hypertension, metabolic syndrome, type 2 diabetes (T2D), atherosclerosis, and cardiovascular disease (CVD). These diseases are promoted by visceral white adipocyte tissue (WAT) dysfunction through an increase in pro-inflammatory adipokines, oxidative stress, activation of the renin-angiotensin-aldosterone system (RAAS), and adverse changes in the gut microbiome. In the heart, obesity and T2D induce changes in substrate utilization, tissue metabolism, oxidative stress, and inflammation, leading to myocardial fibrosis and ultimately cardiac dysfunction. Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of carbohydrate and lipid metabolism, also improve insulin sensitivity, triglyceride levels, inflammation, and oxidative stress. The purpose of this review is to provide an update on the molecular mechanisms involved in obesity-linked CVD pathophysiology, considering pro-inflammatory cytokines, adipokines, and hormones, as well as the role of oxidative stress, inflammation, and PPARs. In addition, cell lines and animal models, biomarkers, gut microbiota dysbiosis, epigenetic modifications, and current therapeutic treatments in CVD associated with obesity are outlined in this paper.
      Citation: Cells
      PubDate: 2021-03-12
      DOI: 10.3390/cells10030629
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 630: The Uncovered Function of the Drosophila
           GBA1a-Encoded Protein

    • Authors: Or Cabasso, Sumit Paul, Gali Maor, Metsada Pasmanik-Chor, Wouter Kallemeijn, Johannes Aerts, Mia Horowitz
      First page: 630
      Abstract: Human GBA1 encodes lysosomal acid β-glucocerebrosidase (GCase), which hydrolyzes cleavage of the beta-glucosidic linkage of glucosylceramide (GlcCer). Mutations in this gene lead to reduced GCase activity, accumulation of glucosylceramide and glucosylsphingosine, and development of Gaucher disease (GD). Drosophila melanogaster has two GBA1 orthologs. Thus far, GBA1b was documented as a bone fide GCase-encoding gene, while the role of GBA1a encoded protein remained unclear. In the present study, we characterized a mutant variant of the fly GBA1a, which underwent ERAD and mildly activated the UPR machinery. RNA-seq analyses of homozygous mutant flies revealed upregulation of inflammation-associated as well as of cell-cycle related genes and reduction in programmed cell death (PCD)-associated genes, which was confirmed by qRT-PCR. We also observed compromised cell death in the midgut of homozygous larvae and a reduction in pupation. Our results strongly indicated that GBA1a-encoded protein plays a role in midgut maturation during larvae development.
      Citation: Cells
      PubDate: 2021-03-12
      DOI: 10.3390/cells10030630
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 631: Clinical, Pathological and Molecular
           Characteristics of Chilean Patients with Early-, Intermediate- and
           Late-Onset Colorectal Cancer

    • Authors: Karin Alvarez, Alessandra Cassana, Marjorie De La Fuente, Tamara Canales, Mario Abedrapo, Francisco López-Köstner
      First page: 631
      Abstract: Colorectal cancer (CRC) is the second most frequent neoplasm in Chile and its mortality rate is rising in all ages. However, studies characterizing CRC according to the age of onset are still lacking. This study aimed to identify clinical, pathological, and molecular features of CRC in Chilean patients according to the age of diagnosis: early- (≤50 years; EOCRC), intermediate- (51–69 years; IOCRC), and late-onset (≥70 years; LOCRC). The study included 426 CRC patients from Clinica Las Condes, between 2007 and 2019. A chi-square test was applied to explore associations between age of onset and clinicopathological characteristics. Body Mass Index (BMI) differences according to age of diagnosis was evaluated through t-test. Overall (OS) and cancer-specific survival (CSS) were estimated by the Kaplan–Meier method. We found significant differences between the age of onset, and gender, BMI, family history of cancer, TNM Classification of Malignant Tumors stage, OS, and CSS. EOCRC category was characterized by a family history of cancer, left-sided tumors with a more advanced stage of the disease but better survival at 10 years, and lower microsatellite instability (MSI), with predominant germline mutations. IOCRC has shown clinical similarities with the EOCRC and molecular similarities to the LOCRC, which agrees with other reports.
      Citation: Cells
      PubDate: 2021-03-12
      DOI: 10.3390/cells10030631
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 632: RNA Localization and Local Translation in Glia
           in Neurological and Neurodegenerative Diseases: Lessons from Neurons

    • Authors: Maite Blanco-Urrejola, Adhara Gaminde-Blasco, María Gamarra, Aida de la Cruz, Elena Vecino, Elena Alberdi, Jimena Baleriola
      First page: 632
      Abstract: Cell polarity is crucial for almost every cell in our body to establish distinct structural and functional domains. Polarized cells have an asymmetrical morphology and therefore their proteins need to be asymmetrically distributed to support their function. Subcellular protein distribution is typically achieved by localization peptides within the protein sequence. However, protein delivery to distinct cellular compartments can rely, not only on the transport of the protein itself but also on the transport of the mRNA that is then translated at target sites. This phenomenon is known as local protein synthesis. Local protein synthesis relies on the transport of mRNAs to subcellular domains and their translation to proteins at target sites by the also localized translation machinery. Neurons and glia specially depend upon the accurate subcellular distribution of their proteome to fulfil their polarized functions. In this sense, local protein synthesis has revealed itself as a crucial mechanism that regulates proper protein homeostasis in subcellular compartments. Thus, deregulation of mRNA transport and/or of localized translation can lead to neurological and neurodegenerative diseases. Local translation has been more extensively studied in neurons than in glia. In this review article, we will summarize the state-of-the art research on local protein synthesis in neuronal function and dysfunction, and we will discuss the possibility that local translation in glia and deregulation thereof contributes to neurological and neurodegenerative diseases.
      Citation: Cells
      PubDate: 2021-03-12
      DOI: 10.3390/cells10030632
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 633: Neurodegeneration, Neuroprotection and
           Regeneration in the Zebrafish Retina

    • Authors: Salvatore L. Stella, Jasmine S. Geathers, Sarah R. Weber, Michael A. Grillo, Alistair J. Barber, Jeffrey M. Sundstrom, Stephanie L. Grillo
      First page: 633
      Abstract: Neurodegenerative retinal diseases, such as glaucoma and diabetic retinopathy, involve a gradual loss of neurons in the retina as the disease progresses. Central nervous system neurons are not able to regenerate in mammals, therefore, an often sought after course of treatment for neuronal loss follows a neuroprotective or regenerative strategy. Neuroprotection is the process of preserving the structure and function of the neurons that have survived a harmful insult; while regenerative approaches aim to replace or rewire the neurons and synaptic connections that were lost, or induce regrowth of damaged axons or dendrites. In order to test the neuroprotective effectiveness or the regenerative capacity of a particular agent, a robust experimental model of retinal neuronal damage is essential. Zebrafish are being used more often in this type of study because their eye structure and development is well-conserved between zebrafish and mammals. Zebrafish are robust genetic tools and are relatively inexpensive to maintain. The large array of functional and behavioral tests available in zebrafish makes them an attractive model for neuroprotection studies. Some common insults used to model retinal disease and study neuroprotection in zebrafish include intense light, chemical toxicity and mechanical damage. This review covers the existing retinal neuroprotection and regeneration literature in the zebrafish and highlights their potential for future studies.
      Citation: Cells
      PubDate: 2021-03-12
      DOI: 10.3390/cells10030633
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 634: A Novel Therapeutic Target, BACH1, Regulates
           Cancer Metabolism

    • Authors: Joselyn Padilla, Jiyoung Lee
      First page: 634
      Abstract: BTB domain and CNC homology 1 (BACH1) is a transcription factor that is highly expressed in tumors including breast and lung, relative to their non-tumor tissues. BACH1 is known to regulate multiple physiological processes including heme homeostasis, oxidative stress response, senescence, cell cycle, and mitosis. In a tumor, BACH1 promotes invasion and metastasis of cancer cells, and the expression of BACH1 presents a poor outcome for cancer patients including breast and lung cancer patients. Recent studies identified novel functional roles of BACH1 in the regulation of metabolic pathways in cancer cells. BACH1 inhibits mitochondrial metabolism through transcriptional suppression of mitochondrial membrane genes. In addition, BACH1 suppresses activity of pyruvate dehydrogenase (PDH), a key enzyme that converts pyruvate to acetyl-CoA for the citric acid (TCA) cycle through transcriptional activation of pyruvate dehydrogenase kinase (PDK). Moreover, BACH1 increases glucose uptake and lactate secretion through the expression of metabolic enzymes involved such as hexokinase 2 (HK2) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) for aerobic glycolysis. Pharmacological or genetic inhibition of BACH1 could reprogram by increasing mitochondrial metabolism, subsequently rendering metabolic vulnerability of cancer cells against mitochondrial respiratory inhibition. Furthermore, inhibition of BACH1 decreased antioxidant-induced glycolysis rates as well as reduced migration and invasion of cancer cells, suggesting BACH1 as a potentially useful cancer therapeutic target.
      Citation: Cells
      PubDate: 2021-03-12
      DOI: 10.3390/cells10030634
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 635: Genome-Wide Identification of U-to-C RNA
           Editing Events for Nuclear Genes in Arabidopsis thaliana

    • Authors: Ruchika, Chisato Okudaira, Matomo Sakari, Toshifumi Tsukahara
      First page: 635
      Abstract: Cytosine-to-Uridine (C-to-U) RNA editing involves the deamination phenomenon, which is observed in animal nucleus and plant organelles; however, it has been considered the U-to-C is confined to the organelles of limited non-angiosperm plant species. Although previous RNA-seq-based analysis implied U-to-C RNA editing events in plant nuclear genes, it has not been broadly accepted due to inadequate confirmatory analyses. Here we examined the U-to-C RNA editing in Arabidopsis tissues at different developmental stages of growth. In this study, the high-throughput RNA sequencing (RNA-seq) of 12-day-old and 20-day-old Arabidopsis seedlings was performed, which enabled transcriptome-wide identification of RNA editing sites to analyze differentially expressed genes (DEGs) and nucleotide base conversions. The results showed that DEGs were expressed to higher levels in 12-day-old seedlings than in 20-day-old seedlings. Additionally, pentatricopeptide repeat (PPR) genes were also expressed at higher levels, as indicated by the log2FC values. RNA-seq analysis of 12-day- and 20-day-old Arabidopsis seedlings revealed candidates of U-to-C RNA editing events. Sanger sequencing of both DNA and cDNA for all candidate nucleotide conversions confirmed the seven U-to-C RNA editing sites. This work clearly demonstrated presence of U-to-C RNA editing for nuclear genes in Arabidopsis, which provides the basis to study the mechanism as well as the functions of the unique post-transcriptional modification.
      Citation: Cells
      PubDate: 2021-03-12
      DOI: 10.3390/cells10030635
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 636: TRPM4 Participates in Aldosterone-Salt-Induced
           Electrical Atrial Remodeling in Mice

    • Authors: Christophe Simard, Virginie Ferchaud, Laurent Sallé, Paul Milliez, Alain Manrique, Joachim Alexandre, Romain Guinamard
      First page: 636
      Abstract: Aldosterone plays a major role in atrial structural and electrical remodeling, in particular through Ca2+-transient perturbations and shortening of the action potential. The Ca2+-activated non-selective cation channel Transient Receptor Potential Melastatin 4 (TRPM4) participates in atrial action potential. The aim of our study was to elucidate the interactions between aldosterone and TRPM4 in atrial remodeling and arrhythmias susceptibility. Hyperaldosteronemia, combined with a high salt diet, was induced in mice by subcutaneously implanted osmotic pumps during 4 weeks, delivering aldosterone or physiological serum for control animals. The experiments were conducted in wild type animals (Trpm4+/+) as well as Trpm4 knock-out animals (Trpm4-/-). The atrial diameter measured by echocardiography was higher in Trpm4-/- compared to Trpm4+/+ animals, and hyperaldosteronemia-salt produced a dilatation in both groups. Action potentials duration and triggered arrhythmias were measured using intracellular microelectrodes on the isolated left atrium. Hyperaldosteronemia-salt prolong action potential in Trpm4-/- mice but had no effect on Trpm4+/+ mice. In the control group (no aldosterone-salt treatment), no triggered arrythmias were recorded in Trpm4+/+ mice, but a high level was detected in Trpm4-/- mice. Hyperaldosteronemia-salt enhanced the occurrence of arrhythmias (early as well as delayed-afterdepolarization) in Trpm4+/+ mice but decreased it in Trpm4-/- animals. Atrial connexin43 immunolabelling indicated their disorganization at the intercalated disks and a redistribution at the lateral side induced by hyperaldosteronemia-salt but also by Trpm4 disruption. In addition, hyperaldosteronemia-salt produced pronounced atrial endothelial thickening in both groups. Altogether, our results indicated that hyperaldosteronemia-salt and TRPM4 participate in atrial electrical and structural remodeling. It appears that TRPM4 is involved in aldosterone-induced atrial action potential shortening. In addition, TRPM4 may promote aldosterone-induced atrial arrhythmias, however, the underlying mechanisms remain to be explored.
      Citation: Cells
      PubDate: 2021-03-12
      DOI: 10.3390/cells10030636
      Issue No: Vol. 10, No. 3 (2021)
  • Cells, Vol. 10, Pages 637: Critical Effects on Akt Signaling in Adult
           Zebrafish Brain Following Alterations in Light Exposure

    • Authors: Nicholas S. Moore, Robert A. Mans, Mackenzee K. McCauley, Colton S. Allgood, Keri A. Barksdale
      First page: 637
      Abstract: Evidence from human and animal studies indicate that disrupted light cycles leads to alterations of the sleep state, poor cognition, and the risk of developing neuroinflammatory and generalized health disorders. Zebrafish exhibit a diurnal circadian rhythm and are an increasingly popular model in studies of neurophysiology and neuropathophysiology. Here, we investigate the effect of alterations in light cycle on the adult zebrafish brain: we measured the effect of altered, unpredictable light exposure in adult zebrafish telencephalon, homologous to mammalian hippocampus, and the optic tectum, a significant visual processing center with extensive telencephalon connections. The expression of heat shock protein-70 (HSP70), an important cell stress mediator, was significantly decreased in optic tectum of adult zebrafish brain following four days of altered light exposure. Further, pSer473-Akt (protein kinase B) was significantly reduced in telencephalon following light cycle alteration, and pSer9-GSK3β (glycogen synthase kinase-3β) was significantly reduced in both the telencephalon and optic tectum of light-altered fish. Animals exposed to five minutes of environmental enrichment showed significant increase in pSer473Akt, which was significantly attenuated by four days of altered light exposure. These data show for the first time that unpredictable light exposure alters HSP70 expression and dysregulates Akt-GSK3β signaling in the adult zebrafish brain.
      Citation: Cells
      PubDate: 2021-03-12
      DOI: 10.3390/cells10030637
      Issue No: Vol. 10, No. 3 (2021)
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