Publisher: MDPI   (Total: 230 journals)

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Showing 1 - 200 of 230 Journals sorted alphabetically
Acoustics     Open Access   (Followers: 2)
Actuators     Open Access   (Followers: 4)
Administrative Sciences     Open Access   (Followers: 4)
Aerospace     Open Access   (Followers: 55, SJR: 0.305, CiteScore: 1)
Agriculture     Open Access   (Followers: 7, SJR: 0.33, CiteScore: 2)
AgriEngineering     Open Access   (Followers: 1)
Agronomy     Open Access   (Followers: 14, SJR: 0.695, CiteScore: 2)
Algorithms     Open Access   (Followers: 12, 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: 5, SJR: 0.303, CiteScore: 2)
Applied System Innovation     Open Access  
Arts     Open Access   (Followers: 8)
Atmosphere     Open Access   (Followers: 24)
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: 6)
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Biology     Open Access   (Followers: 4, SJR: 1.324, CiteScore: 3)
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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: 4)
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: 3)
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Chemistry     Open Access  
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Children     Open Access   (Followers: 2)
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Condensed Matter     Open Access   (Followers: 3)
Corrosion and Materials Degradation     Open Access   (Followers: 1)
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Crystals     Open Access   (Followers: 3, SJR: 0.566, CiteScore: 2)
Cyber     Open Access   (Followers: 2)
Dairy     Open Access   (Followers: 1)
Data     Open Access   (Followers: 3)
Dentistry J.     Open Access   (Followers: 6)
Designs     Open Access  
Diagnostics     Open Access   (Followers: 1, SJR: 0.669, CiteScore: 2)
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Electronics     Open Access   (Followers: 109, SJR: 0.548, CiteScore: 3)
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Entropy     Open Access   (Followers: 7, 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)
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Fluids     Open Access   (Followers: 1)
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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: 174, SJR: 0.219, CiteScore: 1)
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Information     Open Access   (Followers: 48, SJR: 0.222, CiteScore: 1)
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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: 25, SJR: 0.735, CiteScore: 2)
Intl. J. of Financial Studies     Open Access   (Followers: 5)
Intl. J. of Molecular Sciences     Open Access   (Followers: 2, SJR: 1.26, CiteScore: 4)
Intl. J. of Neonatal Screening     Open Access   (Followers: 3)
Intl. J. of Turbomachinery, Propulsion and Power     Open Access   (Followers: 10)
Inventions     Open Access  
IoT     Open Access   (Followers: 2)
ISPRS Intl. J. of Geo-Information     Open Access   (Followers: 6, 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 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)
Land     Open Access   (Followers: 4)
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Life     Open Access   (Followers: 2, SJR: 1.625, CiteScore: 3)
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Logistics     Open Access   (Followers: 3)
Lubricants     Open Access   (Followers: 2)
Machine Learning and Knowledge Extraction     Open Access   (Followers: 3)
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: 4, SJR: 0.645, CiteScore: 3)
Metabolites     Open Access   (Followers: 2, SJR: 1.026, CiteScore: 3)
Metals     Open Access   (Followers: 5, SJR: 0.55, CiteScore: 2)
Methods and Protocols     Open Access   (Followers: 1)
Microarrays     Open Access  
Micromachines     Open Access   (Followers: 3, SJR: 0.493, CiteScore: 2)
Microorganisms     Open Access   (Followers: 5)
Minerals     Open Access   (Followers: 1, 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: 5)
Neuroglia     Open Access   (Followers: 1)
Nitrogen     Open Access   (Followers: 2)
Non-Coding RNA     Open Access  
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)
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Photonics     Open Access   (Followers: 5, SJR: 0.709, CiteScore: 2)
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Plants     Open Access   (SJR: 1.39, CiteScore: 3)
Plasma     Open Access   (Followers: 3)
Polymers     Open Access   (Followers: 19, SJR: 0.852, CiteScore: 3)
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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: 54, SJR: 1.386, CiteScore: 4)
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Resources     Open Access   (SJR: 0.688, CiteScore: 3)
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Sci     Open Access  
Scientia Pharmaceutica     Open Access   (SJR: 0.268, CiteScore: 1)
Sensors     Open Access   (Followers: 23, SJR: 0.584, CiteScore: 3)
Separations     Open Access   (Followers: 6)

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Cells
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  [230 journals]
  • Cells, Vol. 9, Pages 1565: Mitochondrial Dysfunction and Inflammaging in
           Heart Failure: Novel Roles of CYP-Derived Epoxylipids

    • Authors: Hedieh Keshavarz-Bahaghighat, Ahmed M. Darwesh, Deanna K. Sosnowski, John M. Seubert
      First page: 1565
      Abstract: Age-associated changes leading to a decline in cardiac structure and function contribute to the increased susceptibility and incidence of cardiovascular diseases (CVD) in elderly individuals. Indeed, age is considered a risk factor for heart failure and serves as an important predictor for poor prognosis in elderly individuals. Effects stemming from chronic, low-grade inflammation, inflammaging, are considered important determinants in cardiac health; however, our understanding of the mechanisms involved remains unresolved. A steady decline in mitochondrial function is recognized as an important biological consequence found in the aging heart which contributes to the development of heart failure. Dysfunctional mitochondria contribute to increased cellular stress and an innate immune response by activating the NLRP-3 inflammasomes, which have a role in inflammaging and age-related CVD pathogenesis. Emerging evidence suggests a protective role for CYP450 epoxygenase metabolites of N-3 and N-6 polyunsaturated fatty acids (PUFA), epoxylipids, which modulate various aspects of the immune system and protect mitochondria. In this article, we provide insight into the potential roles N-3 and N-6 PUFA have modulating mitochondria, inflammaging and heart failure.
      Citation: Cells
      PubDate: 2020-06-27
      DOI: 10.3390/cells9071565
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1566: miR-615 Fine-Tunes Growth and Development and
           Has a Role in Cancer and in Neural Repair

    • Authors: Godínez-Rubí, Ortuño-Sahagún
      First page: 1566
      Abstract: MicroRNAs (miRNAs) are small noncoding RNAs that function as epigenetic modulators regulating almost any gene expression. Similarly, other noncoding RNAs, as well as epigenetic modifications, can regulate miRNAs. This reciprocal interaction forms a miRNA-epigenetic feedback loop, the deregulation of which affects physiological processes and contributes to a great diversity of diseases. In the present review, we focus on miR-615, a miRNA highly conserved across eutherian mammals. It is involved not only during embryogenesis in the regulation of growth and development, for instance during osteogenesis and angiogenesis, but also in the regulation of cell growth and the proliferation and migration of cells, acting as a tumor suppressor or tumor promoter. It therefore serves as a biomarker for several types of cancer, and recently has also been found to be involved in reparative processes and neural repair. In addition, we present the pleiad of functions in which miR-615 is involved, as well as their multiple target genes and the multiple regulatory molecules involved in its own expression. We do this by introducing in a comprehensible way the reported knowledge of their actions and interactions and proposing an integral view of its regulatory mechanisms.
      Citation: Cells
      PubDate: 2020-06-27
      DOI: 10.3390/cells9071566
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1567: mTORC2 Is Involved in the Induction of RSK
           Phosphorylation by Serum or Nutrient Starvation

    • Authors: Po-Chien Chou, Swati Rajput, Xiaoyun Zhao, Chadni Patel, Danielle Albaciete, Won Jun Oh, Heineken Queen Daguplo, Nikhil Patel, Bing Su, Guy Werlen, Estela Jacinto
      First page: 1567
      Abstract: Cells adjust to nutrient fluctuations to restore metabolic homeostasis. The mechanistic target of rapamycin (mTOR) complex 2 responds to nutrient levels and growth signals to phosphorylate protein kinases belonging to the AGC (Protein Kinases A,G,C) family such as Akt and PKC. Phosphorylation of these AGC kinases at their conserved hydrophobic motif (HM) site by mTORC2 enhances their activation and mediates the functions of mTORC2 in cell growth and metabolism. Another AGC kinase family member that is known to undergo increased phosphorylation at the homologous HM site (Ser380) is the p90 ribosomal S6 kinase (RSK). Phosphorylation at Ser380 is facilitated by the activation of the mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) in response to growth factor stimulation. Here, we demonstrate that optimal phosphorylation of RSK at this site requires an intact mTORC2. We also found that RSK is robustly phosphorylated at Ser380 upon nutrient withdrawal or inhibition of glycolysis, conditions that increase mTORC2 activation. However, pharmacological inhibition of mTOR did not abolish RSK phosphorylation at Ser380, indicating that mTOR catalytic activity is not required for this phosphorylation. Since RSK and SIN1β colocalize at the membrane during serum restimulation and acute glutamine withdrawal, mTORC2 could act as a scaffold to enhance RSK HM site phosphorylation. Among the known RSK substrates, the CCTβ subunit of the chaperonin containing TCP-1 (CCT) complex had defective phosphorylation in the absence of mTORC2. Our findings indicate that the mTORC2-mediated phosphorylation of the RSK HM site could confer RSK substrate specificity and reveal that RSK responds to nutrient fluctuations.
      Citation: Cells
      PubDate: 2020-06-27
      DOI: 10.3390/cells9071567
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1568: Role of Cyclin-Dependent Kinase 1 in
           Translational Regulation in the M-Phase

    • Authors: Jaroslav Kalous, Denisa Jansová, Andrej Šušor
      First page: 1568
      Abstract: Cyclin dependent kinase 1 (CDK1) has been primarily identified as a key cell cycle regulator in both mitosis and meiosis. Recently, an extramitotic function of CDK1 emerged when evidence was found that CDK1 is involved in many cellular events that are essential for cell proliferation and survival. In this review we summarize the involvement of CDK1 in the initiation and elongation steps of protein synthesis in the cell. During its activation, CDK1 influences the initiation of protein synthesis, promotes the activity of specific translational initiation factors and affects the functioning of a subset of elongation factors. Our review provides insights into gene expression regulation during the transcriptionally silent M-phase and describes quantitative and qualitative translational changes based on the extramitotic role of the cell cycle master regulator CDK1 to optimize temporal synthesis of proteins to sustain the division-related processes: mitosis and cytokinesis.
      Citation: Cells
      PubDate: 2020-06-27
      DOI: 10.3390/cells9071568
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1569: The RNA Replication Site of Tula
           Orthohantavirus Resides within a Remodelled Golgi Network

    • Authors: Katherine A. Davies, Benjamin Chadwick, Roger Hewson, Juan Fontana, Jamel Mankouri, John N. Barr
      First page: 1569
      Abstract: The family Hantaviridae within the Bunyavirales order comprises tri-segmented negative sense RNA viruses, many of which are rodent-borne emerging pathogens associated with fatal human disease. In contrast, hantavirus infection of corresponding rodent hosts results in inapparent or latent infections, which can be recapitulated in cultured cells that become persistently infected. In this study, we used Tula virus (TULV) to investigate the location of hantavirus replication during early, peak and persistent phases of infection, over a 30-day time course. Using immunofluorescent (IF) microscopy, we showed that the TULV nucleocapsid protein (NP) is distributed within both punctate and filamentous structures, with the latter increasing in size as the infection progresses. Transmission electron microscopy of TULV-infected cell sections revealed these filamentous structures comprised aligned clusters of filament bundles. The filamentous NP-associated structures increasingly co-localized with the Golgi and with the stress granule marker TIA-1 over the infection time course, suggesting a redistribution of these cellular organelles. The analysis of the intracellular distribution of TULV RNAs using fluorescent in-situ hybridization revealed that both genomic and mRNAs co-localized with Golgi-associated filamentous compartments that were positive for TIA. These results show that TULV induces a dramatic reorganization of the intracellular environment, including the establishment of TULV RNA synthesis factories in re-modelled Golgi compartments.
      Citation: Cells
      PubDate: 2020-06-27
      DOI: 10.3390/cells9071569
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1570: The Molecular Landscape of Hürthle Cell
           Thyroid Cancer Is Associated with Altered Mitochondrial Function—A
           Comprehensive Review

    • Authors: Sonam Kumari, Ruth Adewale, Joanna Klubo-Gwiezdzinska
      First page: 1570
      Abstract: Hürthle cell thyroid carcinoma (HTC) accounts for 3–5% of all thyroid malignancies. Widely invasive HTC is characterized by poor prognosis and limited responsiveness to standard therapy with radioiodine. The molecular landscape of HTC is significantly different from the genetic signature seen in other forms of thyroid cancer. We performed a comprehensive literature review on the association between the molecular features of HTC and cancer metabolism. We searched the Pubmed, Embase, and Medline databases for clinical and translational studies published between 1980 and 2020 in English, coupling “HTC” with the following keywords: “genomic analysis”, “mutations”, “exome sequencing”, “molecular”, “mitochondria”, “metabolism”, “oxidative phosphorylation”, “glycolysis”, “oxidative stress”, “reactive oxygen species”, and “oncogenes”. HTC is characterized by frequent complex I mitochondrial DNA mutations as early clonal events. This genetic signature is associated with the abundance of malfunctioning mitochondria in cancer cells. HTC relies predominantly on aerobic glycolysis as a source of energy production, as oxidative phosphorylation-related genes are downregulated. The enhanced glucose utilization by HTC is used for diagnostic purposes in the clinical setting for the detection of metastases by fluorodeoxyglucose positron emission tomography (FGD-PET/CT) imaging. A comprehensive metabolomic profiling of HTC in association with its molecular landscape might be necessary for the implementation of tumor-specific therapeutic approaches.
      Citation: Cells
      PubDate: 2020-06-27
      DOI: 10.3390/cells9071570
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1571: Boosting the Intra-Articular Efficacy of Low
           Dose Corticosteroid through a Biopolymeric Matrix: An In Vivo Model of
           Osteoarthritis

    • Authors: Tschon, Salamanna, Martini, Giavaresi, Lorenzini, Calzà, Fini
      First page: 1571
      Abstract: The purpose of this study was to verify the efficacy of a single intra-articular (i.a.) injection of a hyaluronic acid-chitlac (HY-CTL) enriched with two low dosages of triamcinolone acetonide (TA, 2.0 mg/mL and 4.5 mg/mL), in comparison with HY-CTL alone, with a clinical control (TA 40 mg/mL) and with saline solution (NaCl) in an in vivo osteoarthritis (OA) model. Seven days after chemical induction of OA, 80 Sprague Dawley male rats were grouped into five arms (n = 16) and received a single i.a. injection of: 40 mg/mL TA, HY-CTL alone, HY-CTL with 2.0 mg/mL TA (RV2), HY-CTL with 4.5 mg/mL TA (RV4.5) and 0.9% NaCl. Pain sensitivity and Catwalk were performed at baseline and at 7, 14 and 21 days after the i.a. treatments. The histopathology of the joint, meniscus and synovial reaction, type II collagen expression and aggrecan expression were assessed 21 days after treatments. RV4.5 improved the local pain sensitivity in comparison with TA and NaCl. RV4.5 and TA exerted similar beneficial effects in all gait parameters. Histopathological analyses, measured by Osteoarthritis Research Society International (OARSI) and Kumar scores and by immunohistochemistry, evidenced that RV4.5 and TA reduced OA features in the same manner and showed a stronger type II collagen and aggrecan expression; both treatments reduced synovitis, as measured by Krenn score and, at the meniscus level, RV4.5 improved degenerative signs as evaluated by Pauli score. TA or RV4.5 treatments limited the local articular cartilage deterioration in knee OA with an improvement of the physical structure of articular cartilage, gait parameters, the sensitivity to local pain and a reduction of the synovial inflammation.
      Citation: Cells
      PubDate: 2020-06-28
      DOI: 10.3390/cells9071571
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1572: Progressively De-Differentiated Pancreatic
           Cancer Cells Shift from Glycolysis to Oxidative Metabolism and Gain a
           Quiescent Stem State

    • Authors: Giulia Ambrosini, Elisa Dalla Pozza, Giuseppina Fanelli, Claudia Di Carlo, Andrea Vettori, Giuseppe Cannino, Chiara Cavallini, Cristian Andres Carmona-Carmona, Jessica Brandi, Sara Rinalducci, Maria Teresa Scupoli, Andrea Rasola, Daniela Cecconi, Marta Palmieri, Ilaria Dando
      First page: 1572
      Abstract: Pancreatic ductal adenocarcinoma (PDAC) is typically characterized by high chemoresistance and metastatic spread, features mainly attributable to cancer stem cells (CSCs). It is of central interest the characterization of CSCs and, in particular, the study of their metabolic features in order to selectively identify their peculiarities for an efficient therapeutic approach. In this study, CSCs have been obtained by culturing different PDAC cell lines with a specific growth medium. Cells were characterized for the typical stem/mesenchymal properties at short-, medium-, and long-term culture. Metabolomics, proteomics, analysis of oxygen consumption rate in live cells, and the effect of the inhibition of lactate transporter on cell proliferation have been performed to delineate the metabolism of CSCs. We show that gradually de-differentiated pancreatic cancer cells progressively increase the expression of both stem and epithelial-to-mesenchymal transition markers, shift their metabolism from a glycolytic to an oxidative one, and lastly gain a quiescent state. These quiescent stem cells are characterized by high chemo-resistance, clonogenic ability, and metastatic potential. Re-differentiation reverts these features, re-activating their proliferative capacity and glycolytic metabolism, which generally correlates with high aggressiveness. These observations add an important piece of knowledge to the comprehension of the biology of CSCs, whose metabolic plasticity could be exploited for the generation of promising and selective therapeutic approaches for PDAC patients.
      Citation: Cells
      PubDate: 2020-06-28
      DOI: 10.3390/cells9071572
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1573: Cetuximab and IL-15 Promote NK and Dendritic
           Cell Activation In Vitro in Triple Negative Breast Cancer

    • Authors: Juliá, Mordoh, Levy
      First page: 1573
      Abstract: Triple Negative Breast Cancer (TNBC) treatment is still challenging, and immunotherapy is a potential approach in this tumor subtype. Cetuximab is an IgG1 monoclonal antibody (mAb) directed against Epidermic Growth Factor Receptor (EGFR), a protein overexpressed in a subgroup of TNBC patients and associated with poor prognosis. Previously, we demonstrated in vitro that Cetuximab triggers Ab-dependent cell cytotoxicity against TNBC cells. In this study, using co-cultures including TNBC cells, and NK and Dendritic Cells (DCs) from healthy donors, we studied the effect of Cetuximab-activated NK cells on DC function. Given that we already demonstrated that TNBC has an immunosuppressive effect on NK cells, we also tested Cetuximab combination with IL-15. We determined that Cetuximab opsonization of TNBC cells increased IFN-γ and TNF-α production by NK cells co-cultured with DCs. Moreover, we showed that NK cells activated by TNBC cells opsonized with Cetuximab promoted tumor material uptake and maturation of DCs, as well as their ability to produce IL-12. Furthermore, the stimulation with IL-15 increased the activation of NK cells and the maturation of DCs. These results suggest that IL-15 may enhance the efficacy of Cetuximab in the treatment of TNBC by promoting activation of both NK cells and DCs.
      Citation: Cells
      PubDate: 2020-06-28
      DOI: 10.3390/cells9071573
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1574: Competing Endogenous RNAs, Non-Coding RNAs and
           Diseases: An Intertwined Story

    • Authors: Ugo Ala
      First page: 1574
      Abstract: MicroRNAs (miRNAs), a class of small non-coding RNA molecules, are responsible for RNA silencing and post-transcriptional regulation of gene expression. They can mediate a fine-tuned crosstalk among coding and non-coding RNA molecules sharing miRNA response elements (MREs). In a suitable environment, both coding and non-coding RNA molecules can be targeted by the same miRNAs and can indirectly regulate each other by competing for them. These RNAs, otherwise known as competing endogenous RNAs (ceRNAs), lead to an additional post-transcriptional regulatory layer, where non-coding RNAs can find new significance. The miRNA-mediated interplay among different types of RNA molecules has been observed in many different contexts. The analyses of ceRNA networks in cancer and other pathologies, as well as in other physiological conditions, provide new opportunities for interpreting omics data for the field of personalized medicine. The development of novel computational tools, providing putative predictions of ceRNA interactions, is a rapidly growing field of interest. In this review, I discuss and present the current knowledge of the ceRNA mechanism and its implications in a broad spectrum of different pathologies, such as cardiovascular or autoimmune diseases, cancers and neurodegenerative disorders.
      Citation: Cells
      PubDate: 2020-06-28
      DOI: 10.3390/cells9071574
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1575: NeuroHeal Reduces Muscle Atrophy and Modulates
           Associated Autophagy

    • Authors: Sara Marmolejo-Martínez-Artesero, David Romeo-Guitart, Laura Mañas-García, Esther Barreiro, Caty Casas
      First page: 1575
      Abstract: Muscle wasting is an unmet medical need which leads to a reduction of myofiber diameter and a negative impact on the functional performance of daily activities. We previously found that a new neuroprotective drug called NeuroHeal reduced muscle atrophy produced by transient denervation. Aiming to decipher whether NeuroHeal has a direct role in muscle biology, we used herein different models of muscle atrophy: one caused by chronic denervation, another caused by hindlimb immobilization, and lastly, an in vitro model of myotube atrophy with Tumor Necrosis Factor-α (TNFα). In all these models, we observed that NeuroHeal reduced muscle atrophy and that SIRT1 activation seems to be required for that. The treatment downregulated some critical markers of protein degradation: Muscle Ring Finger 1 (MuRF1), K48 poly-Ub chains, and p62/SQSTM1. Moreover, it seems to restore the autophagy flux associated with denervation. Hence, we envisage a prospective use of NeuroHeal at clinics for different myopathies.
      Citation: Cells
      PubDate: 2020-06-28
      DOI: 10.3390/cells9071575
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1576: Notch-Inflammation Networks in Regulation of
           Breast Cancer Progression

    • Authors: Liubomirski, Ben-Baruch
      First page: 1576
      Abstract: Members of the Notch family and chronic inflammation were each separately demonstrated to have prominent malignancy-supporting roles in breast cancer. Recent investigations indicate that bi-directional interactions that exist between these two pathways promote the malignancy phenotype of breast tumor cells and of their tumor microenvironment. In this review article, we demonstrate the importance of Notch-inflammation interplays in malignancy by describing three key networks that act in breast cancer and their impacts on functions that contribute to disease progression: (1) Cross-talks of the Notch pathway with myeloid cells that are important players in cancer-related inflammation, focusing mainly on macrophages; (2) Cross-talks of the Notch pathway with pro-inflammatory factors, exemplified mainly by Notch interactions with interleukin 6 and its downstream pathways (STAT3); (3) Cross-talks of the Notch pathway with typical inflammatory transcription factors, primarily NF-κB. These three networks enhance tumor-promoting functions in different breast tumor subtypes and act in reciprocal manners, whereby Notch family members activate inflammatory elements and vice versa. These characteristics illustrate the fundamental roles played by Notch-inflammation interactions in elevating breast cancer progression and propose that joint targeting of both pathways together may provide more effective and less toxic treatment approaches in this disease.
      Citation: Cells
      PubDate: 2020-06-28
      DOI: 10.3390/cells9071576
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1577: K+ and Ca2+ Channels Regulate Ca2+ Signaling in
           Chondrocytes: An Illustrated Review

    • Authors: Suzuki, Yamamura, Imaizumi, Clark, Giles
      First page: 1577
      Abstract: An improved understanding of fundamental physiological principles and progressive pathophysiological processes in human articular joints (e.g., shoulders, knees, elbows) requires detailed investigations of two principal cell types: synovial fibroblasts and chondrocytes. Our studies, done in the past 8–10 years, have used electrophysiological, Ca2+ imaging, single molecule monitoring, immunocytochemical, and molecular methods to investigate regulation of the resting membrane potential (ER) and intracellular Ca2+ levels in human chondrocytes maintained in 2-D culture. Insights from these published papers are as follows: (1) Chondrocyte preparations express a number of different ion channels that can regulate their ER. (2) Understanding the basis for ER requires knowledge of a) the presence or absence of ligand (ATP/histamine) stimulation and b) the extraordinary ionic composition and ionic strength of synovial fluid. (3) In our chondrocyte preparations, at least two types of Ca2+-activated K+ channels are expressed and can significantly hyperpolarize ER. (4) Accounting for changes in ER can provide insights into the functional roles of the ligand-dependent Ca2+ influx through store-operated Ca2+ channels. Some of the findings are illustrated in this review. Our summary diagram suggests that, in chondrocytes, the K+ and Ca2+ channels are linked in a positive feedback loop that can augment Ca2+ influx and therefore regulate lubricant and cytokine secretion and gene transcription.
      Citation: Cells
      PubDate: 2020-06-29
      DOI: 10.3390/cells9071577
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1578: Checkpoint Inhibitors and Engineered Cells: New
           Weapons for Natural Killer Cell Arsenal Against Hematological Malignancies
           

    • Authors: Massimo Giuliani, Alessandro Poggi
      First page: 1578
      Abstract: Natural killer (NK) cells represent one of the first lines of defense against malignant cells. NK cell activation and recognition are regulated by a balance between activating and inhibitory receptors, whose specific ligands can be upregulated on tumor cells surface and tumor microenvironment (TME). Hematological malignancies set up an extensive network of suppressive factors with the purpose to induce NK cell dysfunction and impaired immune-surveillance ability. Over the years, several strategies have been developed to enhance NK cells-mediated anti-tumor killing, while other approaches have arisen to restore the NK cell recognition impaired by tumor cells and other cellular components of the TME. In this review, we summarize and discuss the strategies applied in hematological malignanciesto block the immune check-points and trigger NK cells anti-tumor effects through engineered chimeric antigen receptors.
      Citation: Cells
      PubDate: 2020-06-29
      DOI: 10.3390/cells9071578
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1579: Mechanistic Models of Signaling Pathways Reveal
           the Drug Action Mechanisms behind Gender-Specific Gene Expression for
           Cancer Treatments

    • Authors: Cankut Çubuk, Fatma E. Can, María Peña-Chilet, Joaquín Dopazo
      First page: 1579
      Abstract: Despite the existence of differences in gene expression across numerous genes between males and females having been known for a long time, these have been mostly ignored in many studies, including drug development and its therapeutic use. In fact, the consequences of such differences over the disease mechanisms or the drug action mechanisms are completely unknown. Here we applied mechanistic mathematical models of signaling activity to reveal the ultimate functional consequences that gender-specific gene expression activities have over cell functionality and fate. Moreover, we also used the mechanistic modeling framework to simulate the drug interventions and unravel how drug action mechanisms are affected by gender-specific differential gene expression. Interestingly, some cancers have many biological processes significantly affected by these gender-specific differences (e.g., bladder or head and neck carcinomas), while others (e.g., glioblastoma or rectum cancer) are almost insensitive to them. We found that many of these gender-specific differences affect cancer-specific pathways or in physiological signaling pathways, also involved in cancer origin and development. Finally, mechanistic models have the potential to be used for finding alternative therapeutic interventions on the pathways targeted by the drug, which lead to similar results compensating the downstream consequences of gender-specific differences in gene expression.
      Citation: Cells
      PubDate: 2020-06-29
      DOI: 10.3390/cells9071579
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1580: Heparin Anticoagulant for Human Bone Marrow
           Does Not Influence In Vitro Performance of Human Mesenchymal Stromal Cells
           

    • Authors: Yvonne Roger, Laura Burmeister, Anika Hamm, Kirsten Elger, Oliver Dittrich-Breiholz, Thilo Flörkemeier, Andrea Hoffmann
      First page: 1580
      Abstract: Mesenchymal stromal cells (MSCs) are a promising cell source for tissue engineering and regenerative medicine. In our lab, we found that MSC preparations from bone marrow of many different donors had a limited capacity of in vitro differentiation into osteogenic and chondrogenic lineages—a capacity claimed to be inherent to MSCs. The current study was designed to test the hypothesis that the amount of heparin used as anticoagulant during bone marrow harvest had an inhibitory influence on the in vitro differentiation capacity of isolated MSCs. Bone marrow was obtained from the femoral cavity of twelve donors during total hip arthroplasty in the absence or presence of heparin. No coagulation was observed in the absence of heparin. The number of mononuclear cells was independent of heparin addition. Isolated MSCs were characterized by morphology, population doubling times, expression of cell surface antigens and in vitro differentiation. Results of these analyses were independent of the amount of heparin. Transcriptome analyses of cells from three randomly chosen donors and quantitative realtime PCR (qRT-PCR) analysis from cells of all donors demonstrated no clear effect of heparin on the transcriptome of the cells. This excludes heparin as a potential source of disparate results.
      Citation: Cells
      PubDate: 2020-06-29
      DOI: 10.3390/cells9071580
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1581: MHC Class I-Restricted TCR-Transgenic CD4+ T
           

    • Authors: Sebastian J. Schober, Melanie Thiede, Hendrik Gassmann, Carolin Prexler, Busheng Xue, David Schirmer, Dirk Wohlleber, Stefanie Stein, Thomas G. P. Grünewald, Dirk H. Busch, Guenther H. S. Richter, Stefan E. G. Burdach, Uwe Thiel
      First page: 1581
      Abstract: In this study we report the functional comparison of T cell receptor (TCR)-engineered major histocompatibility complex (MHC) class I-restricted CD4+ versus CD8+ T cells targeting a peptide from six transmembrane epithelial antigen of the prostate 1 (STEAP1) in the context of HLA-A*02:01. STEAP1 is a tumor-associated antigen, which is overexpressed in many cancers, including Ewing sarcoma (EwS). Based on previous observations, we postulated strong antitumor potential of tumor-redirected CD4+ T cells transduced with an HLA class I-restricted TCR against a STEAP1-derived peptide. We compared CD4+ T cell populations to their CD8+ counterparts in vitro using impedance-based xCELLigence and cytokine/granzyme release assays. We further compared antitumor activity of STEAP130-TCR transgenic (tg) CD4+ versus CD8+ T cells in tumor-bearing xenografted Rag2−/−γc−/− mice. TCR tgCD4+ T cells showed increased cytotoxic features over time with similar functional avidity compared to tgCD8+ cells after 5–6 weeks of culture. In vivo, local tumor control was equal. Assessing metastatic organotropism of intraveniously (i.v.) injected tumors, only tgCD8+ cells were associated with reduced metastases. In this analysis, EwS-redirected tgCD4+ T cells contribute to local tumor control, but fail to control metastatic outgrowth in a model of xenografted EwS.
      Citation: Cells
      PubDate: 2020-06-29
      DOI: 10.3390/cells9071581
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1582: Expression of Annexin A2 Promotes Cancer
           Progression in Estrogen Receptor Negative Breast Cancers

    • Authors: Amira F. Mahdi, Beatrice Malacrida, Joanne Nolan, Mary E. McCumiskey, Anne B. Merrigan, Ashish Lal, Shona Tormey, Aoife J. Lowery, Kieran McGourty, Patrick A. Kiely
      First page: 1582
      Abstract: When breast cancer progresses to a metastatic stage, survival rates decline rapidly and it is considered incurable. Thus, deciphering the critical mechanisms of metastasis is of vital importance to develop new treatment options. We hypothesize that studying the proteins that are newly synthesized during the metastatic processes of migration and invasion will greatly enhance our understanding of breast cancer progression. We conducted a mass spectrometry screen following bioorthogonal noncanonical amino acid tagging to elucidate changes in the nascent proteome that occur during epidermal growth factor stimulation in migrating and invading cells. Annexin A2 was identified in this screen and subsequent examination of breast cancer cell lines revealed that Annexin A2 is specifically upregulated in estrogen receptor negative (ER-) cell lines. Furthermore, siRNA knockdown showed that Annexin A2 expression promotes the proliferation, wound healing and directional migration of breast cancer cells. In patients, Annexin A2 expression is increased in ER- breast cancer subtypes. Additionally, high Annexin A2 expression confers a higher probability of distant metastasis specifically for ER- patients. This work establishes a pivotal role of Annexin A2 in breast cancer progression and identifies Annexin A2 as a potential therapeutic target for the more aggressive and harder to treat ER- subtype.
      Citation: Cells
      PubDate: 2020-06-30
      DOI: 10.3390/cells9071582
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1583: Vasculopathy and Coagulopathy Associated with
           SARS-CoV-2 Infection

    • Authors: Nazzarena Labò, Hidetaka Ohnuki, Giovanna Tosato
      First page: 1583
      Abstract: The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has resulted in >500,000 deaths worldwide, including >125,000 deaths in the U.S. since its emergence in late December 2019 and June 2020. Neither curative anti-viral drugs nor a protective vaccine is currently available for the treatment and prevention of COVID-19. Recently, new clinical syndromes associated with coagulopathy and vasculopathy have emerged as a cause of sudden death and other serious clinical manifestations in younger patients infected with SARS-CoV-2 infection. Angiotensin converting enzyme 2 (ACE2), the receptor for SARS-CoV-2 and other coronaviruses, is a transmembrane protein expressed by lung alveolar epithelial cells, enterocytes, and vascular endothelial cells, whose physiologic role is to induce the maturation of angiotensin I to generate angiotensin 1-7, a peptide hormone that controls vasoconstriction and blood pressure. In this review, we provide the general context of the molecular and cellular mechanisms of SARS-CoV-2 infection with a focus on endothelial cells, describe the vasculopathy and coagulopathy syndromes in patients with SARS-CoV-2, and outline current understanding of the underlying mechanistic aspects.
      Citation: Cells
      PubDate: 2020-06-30
      DOI: 10.3390/cells9071583
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1584: Pro-Inflammatory Signaling Upregulates a
           Neurotoxic Conotoxin-Like Protein Encrypted Within Human Endogenous
           Retrovirus-K

    • Authors: Domenico Di Curzio, Mamneet Gurm, Matthew Turnbull, Marie-Josée Nadeau, Breanna Meek, Julia D. Rempel, Samuel Fineblit, Michael Jonasson, Sherry Hebert, Jennifer Ferguson-Parry, Renée N. Douville
      First page: 1584
      Abstract: Motor neuron degeneration and spinal cord demyelination are hallmark pathological events in Amyotrophic Lateral Sclerosis (ALS). Endogenous retrovirus-K (ERVK) expression has an established association with ALS neuropathology, with murine modeling pointing to a role for the ERVK envelope (env) gene in disease processes. Here, we describe a novel viral protein cryptically encoded within the ERVK env transcript, which resembles two distinct cysteine-rich neurotoxic proteins: conotoxin proteins found in marine snails and the Human Immunodeficiency Virus (HIV) Tat protein. Consistent with Nuclear factor-kappa B (NF-κB)-induced retrotransposon expression, the ERVK conotoxin-like protein (CTXLP) is induced by inflammatory signaling. CTXLP is found in the nucleus, impacting innate immune gene expression and NF-κB p65 activity. Using human autopsy specimens from patients with ALS, we further showcase CTXLP expression in degenerating motor cortex and spinal cord tissues, concomitant with inflammation linked pathways, including enhancement of necroptosis marker mixed lineage kinase domain-like (MLKL) protein and oligodendrocyte maturation/myelination inhibitor Nogo-A. These findings identify CTXLP as a novel ERVK protein product, which may act as an effector in ALS neuropathology.
      Citation: Cells
      PubDate: 2020-06-30
      DOI: 10.3390/cells9071584
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1585: Glypican-1 Level Is Elevated in Extracellular
           Vesicles Released from MC38 Colon Adenocarcinoma Cells Overexpressing
           Snail

    • Authors: Izabela Papiewska-Pająk, Damian Krzyżanowski, Maria Katela, Romain Rivet, Sylwia Michlewska, Patrycja Przygodzka, M. Anna Kowalska, Stéphane Brézillon
      First page: 1585
      Abstract: The transcription factor Snail triggers epithelial-to-mesenchymal transition (EMT), endowing cancer cells with invasive properties during tumor progression. Extracellular vesicles (EVs) released from cancer cells at various stages of cancer progression are known to influence the tumor pre-metastatic niche and metastatic potential. The aim of this study was to analyze the effect of Snail on murine colon adenocarcinoma cells (MC38 line) and on the characteristics of their EVs. Stable clones of Snail-overexpressing MC38 cells were investigated in vitro versus Mock cells. Increased expression of matrix metalloproteinase MMP-14 and augmented activity of MMP-9 and -14 were observed in Snail-MC38 cells. There was no change in the transcriptomic profile of proteoglycans in Snail-MC38 cells; however, the protein level of Glypican-1 (GPC1) was enhanced in EVs released from those cells. Our finding that GPC1 protein level was enhanced in EVs released from MC38 cells that overexpressed Snail and were in an early EMT stage might explain the specificity of the GPC1 biomarker in colon cancer diagnosis. Further, our data suggest that Snail, by changing the level of GPC1 on EVs released by colon cancer cells, may affect the generation of a distant premetastatic niche and metastatic organotropism in colon adenocarcinoma.
      Citation: Cells
      PubDate: 2020-06-30
      DOI: 10.3390/cells9071585
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1586: Role of FOXO Transcription Factors in Cancer
           Metabolism and Angiogenesis

    • Authors: Mohd Farhan, Marta Silva, Xing Xingan, Yu Huang, Wenhua Zheng
      First page: 1586
      Abstract: Forkhead box O transcription factors (FOXOs) regulate several signaling pathways and play crucial roles in health and disease. FOXOs are key regulators of the expression of genes involved in multiple cellular processes and their deregulation has been implicated in cancer. FOXOs are generally considered tumor suppressors and evidence also suggests that they may have a role in the regulation of cancer metabolism and angiogenesis. In order to continue growing and proliferating, tumor cells have to reprogram their metabolism and induce angiogenesis. Angiogenesis refers to the process of new blood capillary formation from pre-existing vessels, which is an essential driving force in cancer progression and metastasis through supplying tumor cells with oxygen and nutrients. This review summarizes the roles of FOXOs in the regulation of cancer metabolism and angiogenesis. A deeper knowledge of the involvement of FOXOs in these two key processes involved in cancer dissemination may help to develop novel therapeutic approaches for cancer treatment.
      Citation: Cells
      PubDate: 2020-06-30
      DOI: 10.3390/cells9071586
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1587: Effect of cAMP Signaling Regulation in
           Osteogenic Differentiation of Adipose-Derived Mesenchymal Stem Cells

    • Authors: Sławomir Rumiński, Ilona Kalaszczyńska, Małgorzata Lewandowska-Szumieł
      First page: 1587
      Abstract: The successful implementation of adipose-derived mesenchymal stem cells (ADSCs) in bone regeneration depends on efficient osteogenic differentiation. However, a literature survey and our own experience demonstrated that current differentiation methods are not effective enough. Since the differentiation of mesenchymal stem cells (MSCs) into osteoblasts and adipocytes can be regulated by cyclic adenosine monophosphate (cAMP) signaling, we investigated the effects of cAMP activator, forskolin, and inhibitor, SQ 22,536, on the early and late osteogenic differentiation of ADSCs cultured in spheroids or in a monolayer. Intracellular cAMP concentration, protein kinase A (PKA) activity, and inhibitor of DNA binding 2 (ID2) expression examination confirmed cAMP up- and downregulation. cAMP upregulation inhibited the cell cycle and protected ADSCs from osteogenic medium (OM)-induced apoptosis. Surprisingly, the upregulation of cAMP level at the early stages of osteogenic differentiation downregulated the expression of osteogenic markers RUNX2, Osterix, and IBSP, which was more significant in spheroids, and it is used for the more efficient commitment of ADSCs into preosteoblasts, according to the previously reported protocol. However, cAMP upregulation in a culture of ADSCs in spheroids resulted in significantly increased osteocalcin production and mineralization. Thus, undifferentiated and predifferentiated ADSCs respond differently to cAMP pathway stimulation in terms of osteogenesis, which might explain the ambiguous results from the literature.
      Citation: Cells
      PubDate: 2020-06-30
      DOI: 10.3390/cells9071587
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1588: T-Cell Gene Therapy in Cancer Immunotherapy:
           Why It Is No Longer Just CARs on The Road

    • Authors: Michael D. Crowther, Inge Marie Svane, Özcan Met
      First page: 1588
      Abstract: T-cells have a natural ability to fight cancer cells in the tumour microenvironment. Due to thymic selection and tissue-driven immunomodulation, these cancer-fighting T-cells are generally low in number and exhausted. One way to overcome these issues is to genetically alter T-cells to improve their effectiveness. This process can involve introducing a receptor that has high affinity for a tumour antigen, with two promising candidates known as chimeric-antigen receptors (CARs), or T-cell receptors (TCRs) with high tumour specificity. This review focuses on the editing of immune cells to introduce such novel receptors to improve immune responses to cancer. These new receptors redirect T-cells innate killing abilities to the appropriate target on cancer cells. CARs are modified receptors that recognise whole proteins on the surface of cancer cells. They have been shown to be very effective in haematological malignancies but have limited documented efficacy in solid cancers. TCRs recognise internal antigens and therefore enable targeting of a much wider range of antigens. TCRs require major histocompatibility complex (MHC) restriction but novel TCRs may have broader antigen recognition. Moreover, there are multiple cell types which can be used as targets to improve the “off-the-shelf” capabilities of these genetic engineering methods.
      Citation: Cells
      PubDate: 2020-06-30
      DOI: 10.3390/cells9071588
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1589: Oxidative Inactivation of the Proteasome
           Augments Alveolar Macrophage Secretion of Vesicular SOCS3

    • Authors: Mikel D. Haggadone, Peter Mancuso, Marc Peters-Golden
      First page: 1589
      Abstract: Extracellular vesicles (EVs) contain a diverse array of molecular cargoes that alter cellular phenotype and function following internalization by recipient cells. In the lung, alveolar macrophages (AMs) secrete EVs containing suppressor of cytokine signaling 3 (SOCS3), a cytosolic protein that promotes homeostasis via vesicular transfer to neighboring alveolar epithelial cells. Although changes in the secretion of EV molecules—including but not limited to SOCS3—have been described in response to microenvironmental stimuli, the cellular and molecular machinery that control alterations in vesicular cargo packaging remain poorly understood. Furthermore, the use of quantitative methods to assess the sorting of cytosolic cargo molecules into EVs is lacking. Here, we utilized cigarette smoke extract (CSE) exposure of AMs as an in vitro model of oxidative stress to address these gaps in knowledge. We demonstrate that the accumulation of reactive oxygen species (ROS) in AMs was sufficient to augment vesicular SOCS3 release in this model. Using nanoparticle tracking analysis (NTA) in tandem with a new carboxyfluorescein succinimidyl ester (CFSE)-based intracellular protein packaging assay, we show that the stimulatory effects of CSE were at least in part attributable to elevated amounts of SOCS3 packaged per EV secreted by AMs. Furthermore, the use of a 20S proteasome activity assay alongside treatment of AMs with conventional proteasome inhibitors strongly suggest that ROS stimulated SOCS3 release via inactivation of the proteasome. These data demonstrate that tuning of AM proteasome function by microenvironmental oxidants is a critical determinant of the packaging and secretion of cytosolic SOCS3 protein within EVs.
      Citation: Cells
      PubDate: 2020-06-30
      DOI: 10.3390/cells9071589
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1590: Non-Muscle Myosin 2A (NM2A): Structure,
           Regulation and Function

    • Authors: Cláudia Brito, Sandra Sousa
      First page: 1590
      Abstract: Non-muscle myosin 2A (NM2A) is a motor cytoskeletal enzyme with crucial importance from the early stages of development until adulthood. Due to its capacity to convert chemical energy into force, NM2A powers the contraction of the actomyosin cytoskeleton, required for proper cell division, adhesion and migration, among other cellular functions. Although NM2A has been extensively studied, new findings revealed that a lot remains to be discovered concerning its spatiotemporal regulation in the intracellular environment. In recent years, new functions were attributed to NM2A and its activity was associated to a plethora of illnesses, including neurological disorders and infectious diseases. Here, we provide a concise overview on the current knowledge regarding the structure, the function and the regulation of NM2A. In addition, we recapitulate NM2A-associated diseases and discuss its potential as a therapeutic target.
      Citation: Cells
      PubDate: 2020-07-01
      DOI: 10.3390/cells9071590
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1591: All-Trans Retinoic Acid Enhances both the
           Signaling for Priming and the Glycolysis for Activation of NLRP3
           Inflammasome in Human Macrophage

    • Authors: Ahmad Alatshan, Gergő E. Kovács, Azzam Aladdin, Zsolt Czimmerer, Krisztina Tar, Szilvia Benkő
      First page: 1591
      Abstract: All-trans retinoic acid (ATRA) is a derivative of vitamin A that has many important biological functions, including the modulation of immune responses. ATRA actions are mediated through the retinoic acid receptor that functions as a nuclear receptor, either regulating gene transcription in the nucleus or modulating signal transduction in the cytoplasm. NLRP3 inflammasome is a multiprotein complex that is activated by a huge variety of stimuli, including pathogen- or danger-related molecules. Activation of the inflammasome is required for the production of IL-1β, which drives the inflammatory responses of infectious or non-infectious sterile inflammation. Here, we showed that ATRA prolongs the expression of IL-6 and IL-1β following a 2-, 6-, 12-, and 24-h LPS (100ng/mL) activation in human monocyte-derived macrophages. We describe for the first time that ATRA modulates both priming and activation signals required for NLRP3 inflammasome function. ATRA alone induces NLRP3 expression, and enhances LPS-induced expression of NLRP3 and pro-IL-1β via the regulation of signal transduction pathways, like NF-κB, p38, and ERK. We show that ATRA alleviates the negative feedback loop effect of IL-10 anti-inflammatory cytokine on NLRP3 inflammasome function by inhibiting the Akt-mTOR-STAT3 signaling axis. We also provide evidence that ATRA enhances hexokinase 2 expression, and shifts the metabolism of LPS-activated macrophages toward glycolysis, leading to the activation of NLRP3 inflammasome.
      Citation: Cells
      PubDate: 2020-07-01
      DOI: 10.3390/cells9071591
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1592: Targeted Brain Tumor Therapy by Inhibiting the
           MDM2 Oncogene: In Vitro and In Vivo Antitumor Activity and Mechanism of
           Action

    • Authors: Surendra R. Punganuru, Viswanath Artula, Wei Zhao, Mehrdad Rajaei, Hemantkumar Deokar, Ruiwen Zhang, John K. Buolamwini, Kalkunte S. Srivenugopal, Wei Wang
      First page: 1592
      Abstract: There is a desperate need for novel and efficacious chemotherapeutic strategies for human brain cancers. There are abundant molecular alterations along the p53 and MDM2 pathways in human glioma, which play critical roles in drug resistance. The present study was designed to evaluate the in vitro and in vivo antitumor activity of a novel brain-penetrating small molecule MDM2 degrader, termed SP-141. In a panel of nine human glioblastoma and medulloblastoma cell lines, SP-141, as a single agent, potently killed the brain tumor-derived cell lines with IC50 values ranging from 35.8 to 688.8 nM. Treatment with SP-141 resulted in diminished MDM2 and increased p53 and p21cip1 levels, G2/M cell cycle arrest, and marked apoptosis. In intracranial xenograft models of U87MG glioblastoma (wt p53) and DAOY medulloblastoma (mutant p53) expressing luciferase, treatment with SP-141 caused a significant 4- to 9-fold decrease in tumor growth in the absence of discernible toxicity. Further, combination treatment with a low dose of SP-141 (IC20) and temozolomide, a standard anti-glioma drug, led to synergistic cell killing (1.3- to 31-fold) in glioma cell lines, suggesting a novel means for overcoming temozolomide resistance. Considering that SP-141 can be taken up by the brain without the need for any special delivery, our results suggest that SP-141 should be further explored for the treatment of tumors of the central nervous system, regardless of the p53 status of the tumor.
      Citation: Cells
      PubDate: 2020-07-01
      DOI: 10.3390/cells9071592
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1593: DNA Damage- But Not Enzalutamide-Induced
           Senescence in Prostate Cancer Promotes Senolytic Bcl-xL Inhibitor
           Sensitivity

    • Authors: Nicolas Malaquin, Arthur Vancayseele, Sophie Gilbert, Laureen Antenor-Habazac, Marc-Alexandre Olivier, Zakia Ait Ali Brahem, Fred Saad, Guila Delouya, Francis Rodier
      First page: 1593
      Abstract: Cellular senescence is a natural tumor suppression mechanism defined by a stable proliferation arrest. In the context of cancer treatment, cancer cell therapy-induced senescence (TIS) is emerging as an omnipresent cell fate decision that can be pharmacologically targeted at the molecular level to enhance the beneficial aspects of senescence. In prostate cancer (PCa), TIS has been reported using multiple different model systems, and a more systematic analysis would be useful to identify relevant senescence manipulation molecular targets. Here we show that a spectrum of PCa senescence phenotypes can be induced by clinically relevant therapies. We found that DNA damage inducers like irradiation and poly (ADP-ribose) polymerase1 (PARP) inhibitors triggered a stable PCa-TIS independent of the p53 status. On the other hand, enzalutamide triggered a reversible senescence-like state that lacked evidence of cell death or DNA damage. Using a small senolytic drug panel, we found that senescence inducers dictated senolytic sensitivity. While Bcl-2 family anti-apoptotic inhibitor were lethal for PCa-TIS cells harboring evidence of DNA damage, they were ineffective against enzalutamide-TIS cells. Interestingly, piperlongumine, which was described as a senolytic, acted as a senomorphic to enhance enzalutamide-TIS proliferation arrest without promoting cell death. Overall, our results suggest that TIS phenotypic hallmarks need to be evaluated in a context-dependent manner because they can vary with senescence inducers, even within identical cancer cell populations. Defining this context-dependent spectrum of senescence phenotypes is key to determining subsequent molecular strategies that target senescent cancer cells.
      Citation: Cells
      PubDate: 2020-07-01
      DOI: 10.3390/cells9071593
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1594: Circulating Tumor Cell Migration Requires
           Fibronectin Acting through Integrin B1 or SLUG

    • Authors: Jeannette Huaman, Olorunseun O. Ogunwobi
      First page: 1594
      Abstract: Fibronectin (FN1) is an extracellular matrix protein gaining increasing attention for its multifaceted roles in cancer progression. Using our recently established circulating tumor cell (CTC) lines, we had demonstrated increased FN1 expression and enhanced migration in CTC lines, in comparison to primary tumor cell lines. Whether increased FN1 expression is directly required for CTC migration, and the specific role of FN1’s regulation of integrin B1 (ITGB1) and SLUG (SNAI2) in CTC migration remains unclear. Here, for the first time, we report that the knockdown of FN1, ITGB1, or SLUG expression in CTCs leads to a significant decrease in CTC migration. Knocking down two or all three of these proteins simultaneously did not further inhibit migration. We observed a corresponding increase in CTC migration when recombinant FN1 was added to CTCs. This effect was significantly impeded by prior knockdown of ITGB1 or SLUG. Using knock down experiments and western blotting analysis, we confirmed FN1’s regulation of ITGB1 and SLUG to occur via two separate, independent pathways. Consequently, we can conclude that FN1-dependent enhanced migration of CTCs requires downstream signaling through either ITGB1 or SLUG and that FN1 regulation of ITGB1 and SLUG may have important implications for cancer progression and metastasis.
      Citation: Cells
      PubDate: 2020-07-01
      DOI: 10.3390/cells9071594
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1595: Microglia Purinoceptor P2Y6: An Emerging
           Therapeutic Target in CNS Diseases

    • Authors: Shehata Anwar, Vincent Pons, Serge Rivest
      First page: 1595
      Abstract: The purinergic receptor P2Y6 is expressed in immune cells, including the microglia that are implicated in neurological disorders. Its ligand, UDP, is a signaling molecule that can serve as an “find-me” signal when released in significant quantities by damaged/dying cells. The binding of UDP by P2Y6R leads to the activation of different biochemical pathways, depending on the disease context and the pathological environment. Generally, P2Y6R stimulates phagocytosis. However, whether or not phagocytosis coincides with cell activation or the secretion of pro-inflammatory cytokines needs further investigation. The current review aims to discuss the various functions of P2Y6R in some CNS disorders. We present evidence that P2Y6R may have a detrimental or beneficial role in the nervous system, in the context of neurological pathologies, such as ischemic stroke, Alzheimer’s disease, Parkinson’s disease, radiation-induced brain injury, and neuropathic pain.
      Citation: Cells
      PubDate: 2020-07-01
      DOI: 10.3390/cells9071595
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1596: Exploring Therapeutic Targets to Reverse or
           Prevent the Transition from Metabolically Healthy to Unhealthy Obesity

    • Authors: Tenzin D. Dagpo, Christopher J. Nolan, Viviane Delghingaro-Augusto
      First page: 1596
      Abstract: The prevalence of obesity and obesity-related metabolic comorbidities are rapidly increasing worldwide, placing a huge economic burden on health systems. Excessive nutrient supply combined with reduced physical exercise results in positive energy balance that promotes adipose tissue expansion. However, the metabolic response and pattern of fat accumulation is variable, depending on the individual’s genetic and acquired susceptibility factors. Some develop metabolically healthy obesity (MHO) and are resistant to obesity-associated metabolic diseases for some time, whereas others readily develop metabolically unhealthy obesity (MUO). An unhealthy response to excess fat accumulation could be due to susceptibility intrinsic factors (e.g., increased likelihood of dedifferentiation and/or inflammation), or by pathogenic drivers extrinsic to the adipose tissue (e.g., hyperinsulinemia), or a combination of both. This review outlines the major transcriptional factors and genes associated with adipogenesis and regulation of adipose tissue homeostasis and describes which of these are disrupted in MUO compared to MHO individuals. It also examines the potential role of pathogenic insulin hypersecretion as an extrinsic factor capable of driving the changes in adipose tissue which cause transition from MHO to MUO. On this basis, therapeutic approaches currently available and emerging to prevent and reverse the transition from MHO to MUO transition are reviewed.
      Citation: Cells
      PubDate: 2020-07-01
      DOI: 10.3390/cells9071596
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1597: Chemically Functionalized Water-Soluble
           Single-Walled Carbon Nanotubes Obstruct Vesicular/Plasmalemmal Recycling
           in Astrocytes Down-Stream of Calcium Ions

    • Authors: Manoj K Gottipati, Elena Bekyarova, Robert C Haddon, Vladimir Parpura
      First page: 1597
      Abstract: We used single-walled carbon nanotubes chemically functionalized with polyethylene glycol (SWCNT-PEG) to assess the effects of this nanomaterial on astrocytic endocytosis and exocytosis. We observed that the SWCNT-PEG do not affect the adenosine triphosphate (ATP)-evoked Ca2+ elevations in astrocytes but significantly reduce the Ca2+-dependent glutamate release. There was a significant decrease in the endocytic load of the recycling dye during constitutive and ATP-evoked recycling. Furthermore, SWCNT-PEG hampered ATP-evoked exocytotic release of the loaded recycling dye. Thus, by functionally obstructing evoked vesicular recycling, SWCNT-PEG reduced glutamate release from astrocytes via regulated exocytosis. These effects implicate SWCNT-PEG as a modulator of Ca2+-dependent exocytosis in astrocytes downstream of Ca2+, likely at the level of vesicle fusion with/pinching off the plasma membrane.
      Citation: Cells
      PubDate: 2020-07-01
      DOI: 10.3390/cells9071597
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1598: ROS Mediate xCT-Dependent Cell Death in Human
           Breast Cancer Cells under Glucose Deprivation

    • Authors: Mei-Chun Chen, Li-Lin Hsu, Sheng-Fan Wang, Chih-Yi Hsu, Hsin-Chen Lee, Ling-Ming Tseng
      First page: 1598
      Abstract: xCT, also known as solute carrier family 7 member 11 (SLC7A11), the light chain of the cystine/glutamate antiporter, is positively correlated with cancer progression due to antioxidant function. During glucose deprivation, the overexpression of xCT does not protect cancer cells but instead promotes cell death. Further understanding the mechanism of glucose deprivation-induced cell death is important for developing anticancer treatments targeting the glucose metabolism. In this study, we found that breast cancer cells with a high expression of xCT demonstrated increased levels of reactive oxygen species (ROS) and were more sensitive to glucose deprivation than the cells with a low expression of xCT. However, AMP-activated protein kinase (AMPK) did not significantly affect glucose-deprivation-induced cell death. The antioxidant N-acetyl-cysteine prevented glucose-deprivation-induced cell death, and the glutathione biosynthesis inhibitor L-buthionine-S, R-sulfoximine enhanced glucose-deprivation-induced cell death. The inhibition of xCT by sulfasalazine or a knockdown of xCT reduced the glucose-deprivation-increased ROS levels and glucose-deprivation-induced cell death. Glucose deprivation reduced the intracellular glutamate, and supplementation with α-ketoglutarate prevented the glucose-deprivation-increased ROS levels and rescued cell death. The knockdown of sirtuin-3 (SIRT3) further enhanced the ROS levels, and promoted xCT-related cell death after glucose deprivation. In conclusion, our results suggested that ROS play a critical role in xCT-dependent cell death in breast cancer cells under glucose deprivation.
      Citation: Cells
      PubDate: 2020-07-01
      DOI: 10.3390/cells9071598
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1599: Chemerin Impairs In Vitro Testosterone
           Production, Sperm Motility, and Fertility in Chicken: Possible Involvement
           of Its Receptor CMKLR1

    • Authors: Anthony Estienne, Maxime Reverchon, Agnieszka Partyka, Guillaume Bourdon, Jérémy Grandhaye, Alix Barbe, Erika Caldas-Silveira, Christelle Rame, Wojciech Niżański, Pascal Froment, Joelle Dupont
      First page: 1599
      Abstract: The chemokine chemerin is a novel adipokine involved in the regulation of energy metabolism but also female reproductive functions in mammals. Its effects on male fertility are less studied. Here, we investigated the involvement of chemerin in chicken male reproduction. Indeed, the improvement of the sperm of roosters is a challenge for the breeders since the sperm quantity and quality have largely decreased for several years. By using specific chicken antibodies, here we show that chemerin and its main receptor CMKLR1 (chemokine-like receptor 1) are expressed within the chicken testis with the lowest expression in adults as compared to the embryo or postnatal stages. Chemerin and CMKLR1 are present in all testicular cells, including Leydig, Sertoli, and germinal cells. Using in vitro testis explants, we observed that recombinant chicken chemerin through CMKLR1 inhibits hCG (human chorionic gonadotropin) stimulated testosterone production and this was associated to lower 3βHSD (3beta-hydroxysteroid dehydrogenase) and StAR (steroidogenic acute regulatory protein) expression and MAPK ERK2 (Mitogen-Activated Protein Kinase Extracellular signal-regulated kinase 2) phosphorylation. Furthermore, we demonstrate that chemerin in seminal plasma is lower than in blood plasma, but it is negatively correlated with the percentage of motility and the spermatozoa concentration in vivo in roosters. In vitro, we show that recombinant chicken chemerin reduces sperm mass and individual motility in roosters, and this effect is abolished when sperm is pre-incubated with an anti-CMKLR1 antibody. Moreover, we demonstrate that fresh chicken sperm treated with chemerin and used for artificial insemination (AI) in hen presented a lower efficiency in terms of eggs fertility for the four first days after AI. Taken together, seminal chemerin levels are negatively associated with the rooster fertility, and chemerin produced locally by the testis or male tract could negatively affect in vivo sperm quality and testosterone production through CMKLR1.
      Citation: Cells
      PubDate: 2020-07-01
      DOI: 10.3390/cells9071599
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1600: Loss of ZC4H2 and RNF220 Inhibits Neural Stem
           Cell Proliferation and Promotes Neuronal Differentiation

    • Authors: Longlong Zhang, Maosen Ye, Liang Zhu, Jingmei Cha, Chaocui Li, Yong-Gang Yao, Bingyu Mao
      First page: 1600
      Abstract: The ubiquitin E3 ligase RNF220 and its co-factor ZC4H2 are required for multiple neural developmental processes through different targets, including spinal cord patterning and the development of the cerebellum and the locus coeruleus. Here, we explored the effects of loss of ZC4H2 and RNF220 on the proliferation and differentiation of neural stem cells (NSCs) derived from mouse embryonic cortex. We showed that loss of either ZC4H2 or RNF220 inhibits the proliferation and promotes the differentiation abilities of NSCs in vitro. RNA-Seq profiling revealed 132 and 433 differentially expressed genes in the ZCH2-/- and RNF220-/- NSCs, compared to wild type (WT) NSCs, respectively. Specifically, Cend1, a key regulator of cell cycle exit and differentiation of neuronal precursors, was found to be upregulated in both ZCH2-/- and RNF220-/- NSCs at the mRNA and protein levels. The targets of Cend1, such as CyclinD1, Notch1 and Hes1, were downregulated both in ZCH2-/- and RNF220-/- NSCs, whereas p53 and p21 were elevated. ZCH2-/- and RNF220-/- NSCs showed G0/G1 phase arrest compared to WT NSCs in cell cycle analysis. These results suggested that ZC4H2 and RNF220 are likely involved in the regulation of neural stem cell proliferation and differentiation through Cend1.
      Citation: Cells
      PubDate: 2020-07-01
      DOI: 10.3390/cells9071600
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1601: Extracellular Vesicles as Delivery Vehicles of
           Specific Cellular Cargo

    • Authors: Bilal Mir, Claudia Goettsch
      First page: 1601
      Abstract: Extracellular vesicles (EVs) mediate cell-to-cell communication via the transfer of biomolecules locally and systemically between organs. It has been elucidated that the specific EV cargo load is fundamental for cellular response upon EV delivery. Therefore, revealing the specific molecular machinery that functionally regulates the precise EV cargo intracellularly is of importance in understanding the role of EVs in physiology and pathophysiology and conveying therapeutic use. The purpose of this review is to summarize recent findings on the general rules, as well as specific modulator motifs governing EV cargo loading. Finally, we address available information on potential therapeutic strategies to alter cargo loading.
      Citation: Cells
      PubDate: 2020-07-02
      DOI: 10.3390/cells9071601
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1602: Roles of miR-640 and Zinc Finger Protein 91
           (ZFP91) in Angiopoietin-1-Induced In Vitro Angiogenesis

    • Authors: Sharon Harel, Veronica Sanchez-Gonzalez, Raquel Echavarria, Dominique Mayaki, Sabah NA Hussain
      First page: 1602
      Abstract: Angiopoietin-1 (Ang-1) is a ligand of Tie-2 receptors that promotes angiogenesis. It has been established that regulatory loops exist between angiogenic growth factors and distinct pro or anti-angiogenic miRNAs, but the nature and the roles of Ang-1-regulated miRNAs remain unclear. In this study, we assessed the role of miR-640 in Ang-1-induced angiogenesis in human umbilical vein endothelial cells (HUVECs). Exposure to Ang-1 (300 ng/mL) from 6 to 72 h significantly decreased expression of mature miR-640, a response that was mediated by Tie-2 receptors and was also observed in response to Ang-2, the vascular endothelial growth factor, and transforming growth factor β. Increasing miR-640 levels using a mimic inhibited Ang-1-induced cell migration and capillary-like tube formation whereas inhibition of miR-640 enhanced these responses. Pull down assays of biotinylated miR-640 revealed that miR-640 directly targets Zinc Finger Protein 91 (ZFP91), an atypical E3-ubiquitin ligase. Ang-1 exposure induced ZFP91 expression through down-regulation of miR-640. Silencing of ZFP91 significantly inhibited Ang-1-induced cell migration and tube formation. We conclude that Ang-1 upregulates ZFP91 expression through transcriptional down-regulation of miR-640 and that ZFP91 plays important roles in the promotion of Ang-1-induced endothelial cell migration and differentiation.
      Citation: Cells
      PubDate: 2020-07-02
      DOI: 10.3390/cells9071602
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1603: Expression of miR-135b in Psoriatic Skin and
           Its Association with Disease Improvement

    • Authors: Pablo Chicharro, Pedro Rodríguez-Jiménez, Mar Llamas-Velasco, Nuria Montes, Ancor Sanz-García, Danay Cibrian, Alicia Vara, Manuel J Gómez, María Jiménez-Fernández, Pedro Martínez-Fleta, Inés Sánchez-García, Marta Lozano-Prieto, Juan C Triviño, Rebeca Miñambres, Francisco Sánchez-Madrid, Hortensia de la Fuente, Esteban Dauden
      First page: 1603
      Abstract: miRNAs have been associated with psoriasis since just over a decade. However, we are far from a complete understanding of their role during the development of this disease. Our objective was to characterize the cutaneous expression of miRNAs not previously described in psoriasis, the changes induced following the treatment with biologicals and their association with disease improvement. Next generation sequencing was performed from five skin samples from psoriasis patients (lesional and non-lesional skin) and five controls, and from this cohort, 12 microRNAs were selected to be analyzed in skin samples from 44 patients with plaque psoriasis. In 15 patients, an additional sample was obtained after three months of biological treatment. MiR-9-5p, miR-133a-3p and miR-375 were downregulated in the lesional skin of psoriasis patients. After treatment, expression of miR-133a-3p, miR-375, miR-378a and miR-135b in residual lesions returned towards the levels observed in non-lesional skin. The decrease in miR-135b levels after treatment with biologics was associated with both the improvement of patients evaluated through Psoriasis Area and Severity Index score and the decrease in local inflammatory response. Moreover, basal expression of miR-135b along with age was associated with the improvement of psoriasis, suggesting its possible usefulness as a prognostic biomarker.
      Citation: Cells
      PubDate: 2020-07-02
      DOI: 10.3390/cells9071603
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1604: The Diversity of Intermediate Filaments in
           Astrocytes

    • Authors: Maja Potokar, Mitsuhiro Morita, Gerhard Wiche, Jernej Jorgačevski
      First page: 1604
      Abstract: Despite the remarkable complexity of the individual neuron and of neuronal circuits, it has been clear for quite a while that, in order to understand the functioning of the brain, the contribution of other cell types in the brain have to be accounted for. Among glial cells, astrocytes have multiple roles in orchestrating neuronal functions. Their communication with neurons by exchanging signaling molecules and removing molecules from extracellular space takes place at several levels and is governed by different cellular processes, supported by multiple cellular structures, including the cytoskeleton. Intermediate filaments in astrocytes are emerging as important integrators of cellular processes. Astrocytes express five types of intermediate filaments: glial fibrillary acidic protein (GFAP); vimentin; nestin; synemin; lamins. Variability, interactions with different cellular structures and the particular roles of individual intermediate filaments in astrocytes have been studied extensively in the case of GFAP and vimentin, but far less attention has been given to nestin, synemin and lamins. Similarly, the interplay between different types of cytoskeleton and the interaction between the cytoskeleton and membranous structures, which is mediated by cytolinker proteins, are understudied in astrocytes. The present review summarizes the basic properties of astrocytic intermediate filaments and of other cytoskeletal macromolecules, such as cytolinker proteins, and describes the current knowledge of their roles in normal physiological and pathological conditions.
      Citation: Cells
      PubDate: 2020-07-02
      DOI: 10.3390/cells9071604
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1605: IL-6 Trans-Signaling in the Brain Influences
           the Metabolic Phenotype of the 3xTg-AD Mouse Model of Alzheimer’s
           Disease

    • Authors: Anna Escrig, Amalia Molinero, Brenda Méndez, Mercedes Giralt, Gemma Comes, Paula Sanchis, Olaya Fernández-Gayol, Lydia Giménez-Llort, Christoph Becker-Pauly, Stefan Rose-John, Juan Hidalgo
      First page: 1605
      Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder that causes the most prevalent dementia in the elderly people. Obesity and insulin resistance, which may cause major health problems per se, are risk factors for AD, and cytokines such as interleukin-6 (IL-6) have a role in these conditions. IL-6 can signal either through a membrane receptor or by trans-signaling, which can be inhibited by the soluble form of the co-receptor gp130 (sgp130). We have addressed the possibility that blocking IL-6 trans-signaling in the brain could have an effect in the triple transgenic 3xTg-AD mouse model of AD and/or in obesity progression, by crossing 3xTg-AD mice with GFAP-sgp130Fc mice. To serve as control groups, GFAP-sgp130Fc mice were also crossed with C57BL/6JOlaHsd mice. Seventeen-month-old mice were fed a control diet (18% kcal from fat) and a high-fat diet (HFD; 58.4% kcal from fat). In our experimental conditions, the 3xTg-AD model showed a mild amyloid phenotype, which nevertheless altered the control of body weight and related endocrine and metabolic factors, suggestive of a hypermetabolic state. The inhibition of IL-6 trans-signaling modulated some of these traits in both 3xTg-AD and control mice, particularly during HFD, and in a sex-dependent manner. These experiments provide evidence of IL-6 trans-signaling playing a role in the CNS of a mouse model of AD.
      Citation: Cells
      PubDate: 2020-07-02
      DOI: 10.3390/cells9071605
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1606: The Role of Hyaluronic Acid in Cartilage
           Boundary Lubrication

    • Authors: Weifeng Lin, Zhang Liu, Nir Kampf, Jacob Klein
      First page: 1606
      Abstract: Hydration lubrication has emerged as a new paradigm for lubrication in aqueous and biological media, accounting especially for the extremely low friction (friction coefficients down to 0.001) of articular cartilage lubrication in joints. Among the ensemble of molecules acting in the joint, phosphatidylcholine (PC) lipids have been proposed as the key molecules forming, in a complex with other molecules including hyaluronic acid (HA), a robust layer on the outer surface of the cartilage. HA, ubiquitous in synovial joints, is not in itself a good boundary lubricant, but binds the PC lipids at the cartilage surface; these, in turn, massively reduce the friction via hydration lubrication at their exposed, highly hydrated phosphocholine headgroups. An important unresolved issue in this scenario is why the free HA molecules in the synovial fluid do not suppress the lubricity by adsorbing simultaneously to the opposing lipid layers, i.e., forming an adhesive, dissipative bridge between them, as they slide past each other during joint articulation. To address this question, we directly examined the friction between two hydrogenated soy PC (HSPC) lipid layers (in the form of liposomes) immersed in HA solution or two palmitoyl–oleoyl PC (POPC) lipid layers across HA–POPC solution using a surface force balance (SFB). The results show, clearly and surprisingly, that HA addition does not affect the outstanding lubrication provided by the PC lipid layers. A possible mechanism indicated by our data that may account for this is that multiple lipid layers form on each cartilage surface, so that the slip plane may move from the midplane between the opposing surfaces, which is bridged by the HA, to an HA-free interface within a multilayer, where hydration lubrication is freely active. Another possibility suggested by our model experiments is that lipids in synovial fluid may complex with HA, thereby inhibiting the HA molecules from adhering to the lipids on the cartilage surfaces.
      Citation: Cells
      PubDate: 2020-07-02
      DOI: 10.3390/cells9071606
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1607: KLF4 Acts as a wt-CFTR Suppressor through an
           AKT-Mediated Pathway

    • Authors: Luis Sousa, Ines Pankonien, Luka A Clarke, Iris Silva, Karl Kunzelmann, Margarida D Amaral
      First page: 1607
      Abstract: Cystic Fibrosis (CF) is caused by >2000 mutations in the CF transmembrane conductance regulator (CFTR) gene, but one mutation—F508del—occurs in ~80% of patients worldwide. Besides its main function as an anion channel, the CFTR protein has been implicated in epithelial differentiation, tissue regeneration, and, when dysfunctional, cancer. However, the mechanisms that regulate such relationships are not fully elucidated. Krüppel-like factors (KLFs) are a family of transcription factors (TFs) playing central roles in development, stem cell differentiation, and proliferation. Herein, we hypothesized that these TFs might have an impact on CFTR expression and function, being its missing link to differentiation. Our results indicate that KLF4 (but not KLF2 nor KLF5) is upregulated in CF vs. non-CF cells and that it negatively regulates wt-CFTR expression and function. Of note, F508del–CFTR expressing cells are insensitive to KLF4 modulation. Next, we investigated which KLF4-related pathways have an effect on CFTR. Our data also show that KLF4 modulates wt-CFTR (but not F508del–CFTR) via both the serine/threonine kinase AKT1 (AKT) and glycogen synthase kinase 3 beta (GSK3β) signaling. While AKT acts positively, GSK3β is a negative regulator of CFTR. This crosstalk between wt-CFTR and KLF4 via AKT/ GSK3β signaling, which is disrupted in CF, constitutes a novel mechanism linking CFTR to the epithelial differentiation.
      Citation: Cells
      PubDate: 2020-07-02
      DOI: 10.3390/cells9071607
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1608: Latest Developed Strategies to Minimize the
           Off-Target Effects in CRISPR-Cas-Mediated Genome Editing

    • Authors: Muhammad Naeem, Saman Majeed, Mubasher Zahir Hoque, Irshad Ahmad
      First page: 1608
      Abstract: Gene editing that makes target gene modification in the genome by deletion or addition has revolutionized the era of biomedicine. Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 emerged as a substantial tool due to its simplicity in use, less cost and extraordinary efficiency than the conventional gene-editing tools, including zinc finger nucleases (ZFNs) and Transcription activator-like effector nucleases (TALENs). However, potential off-target activities are crucial shortcomings in the CRISPR system. Numerous types of approaches have been developed to reduce off-target effects. Here, we review several latest approaches to reduce the off-target effects, including biased or unbiased off-target detection, cytosine or adenine base editors, prime editing, dCas9, Cas9 paired nickase, ribonucleoprotein (RNP) delivery and truncated gRNAs. This review article provides extensive information to cautiously interpret off-target effects to assist the basic and clinical applications in biomedicine.
      Citation: Cells
      PubDate: 2020-07-02
      DOI: 10.3390/cells9071608
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1609: Show Me Your Friends and I Tell You Who You
           Are: The Many Facets of Prion Protein in Stroke

    • Authors: Berta Puig, Denise Yang, Santra Brenna, Hermann Clemens Altmeppen, Tim Magnus
      First page: 1609
      Abstract: Ischemic stroke belongs to the leading causes of mortality and disability worldwide. Although treatments for the acute phase of stroke are available, not all patients are eligible. There is a need to search for therapeutic options to promote neurological recovery after stroke. The cellular prion protein (PrPC) has been consistently linked to a neuroprotective role after ischemic damage: it is upregulated in the penumbra area following stroke in humans, and animal models of stroke have shown that lack of PrPC aggravates the ischemic damage and lessens the functional outcome. Mechanistically, these effects can be linked to numerous functions attributed to PrPC: (1) as a signaling partner of the PI3K/Akt and MAPK pathways, (2) as a regulator of glutamate receptors, and (3) promoting stem cell homing mechanisms, leading to angio- and neurogenesis. PrPC can be cleaved at different sites and the proteolytic fragments can account for the manifold functions. Moreover, PrPC is present on extracellular vesicles (EVs), released membrane particles originating from all types of cells that have drawn attention as potential therapeutic tools in stroke and many other diseases. Thus, identification of the many mechanisms underlying PrPC-induced neuroprotection will not only provide further understanding of the physiological functions of PrPC but also new ideas for possible treatment options after ischemic stroke.
      Citation: Cells
      PubDate: 2020-07-02
      DOI: 10.3390/cells9071609
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1610: Identification of miRNA Master Regulators in
           Breast Cancer

    • Authors: Antonio Daniel Martinez-Gutierrez, David Cantú de León, Oliver Millan-Catalan, Jossimar Coronel-Hernandez, Alma D. Campos-Parra, Fany Porras-Reyes, Angelica Exayana-Alderete, César López-Camarillo, Nadia J Jacobo-Herrera, Rosalio Ramos-Payan, Carlos Pérez-Plasencia
      First page: 1610
      Abstract: Breast cancer is the neoplasm with the highest number of deaths in women. Although the molecular mechanisms associated with the development of this tumor have been widely described, metastatic disease has a high mortality rate. In recent years, several studies show that microRNAs or miRNAs regulate complex processes in different biological systems including cancer. In the present work, we describe a group of 61 miRNAs consistently over-expressed in breast cancer (BC) samples that regulate the breast cancer transcriptome. By means of data mining from TCGA, miRNA and mRNA sequencing data corresponding to 1091 BC patients and 110 normal adjacent tissues were downloaded and a miRNA–mRNA network was inferred. Calculations of their oncogenic activity demonstrated that they were involved in the regulation of classical cancer pathways such as cell cycle, PI3K–AKT, DNA repair, and k-Ras signaling. Using univariate and multivariate analysis, we found that five of these miRNAs could be used as biomarkers for the prognosis of overall survival. Furthermore, we confirmed the over-expression of two of them in 56 locally advanced BC samples obtained from the histopathological archive of the National Cancer Institute of Mexico, showing concordance with our previous bioinformatic analysis.
      Citation: Cells
      PubDate: 2020-07-03
      DOI: 10.3390/cells9071610
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1611: Identification of Novel Molecular Markers of
           Human Th17 Cells

    • Authors: Anna Sałkowska, Kaja Karaś, Iwona Karwaciak, Aurelia Walczak-Drzewiecka, Mariusz Krawczyk, Marta Sobalska-Kwapis, Jarosław Dastych, Marcin Ratajewski
      First page: 1611
      Abstract: Th17 cells are important players in host defense against pathogens such as Staphylococcus aureus, Candida albicans, and Bacillus anthracis. Th17 cell-mediated inflammation, under certain conditions in which balance in the immune system is disrupted, is the underlying pathogenic mechanism of certain autoimmune disorders, e.g., rheumatoid arthritis, Graves’ disease, multiple sclerosis, and psoriasis. In the present study, using transcriptomic profiling, we selected genes and analyzed the expression of these genes to find potential novel markers of Th17 lymphocytes. We found that APOD (apolipoprotein D); C1QL1 (complement component 1, Q subcomponent-like protein 1); and CTSL (cathepsin L) are expressed at significantly higher mRNA and protein levels in Th17 cells than in the Th1, Th2, and Treg subtypes. Interestingly, these genes and the proteins they encode are well associated with the function of Th17 cells, as these cells produce inflammation, which is linked with atherosclerosis and angiogenesis. Furthermore, we found that high expression of these genes in Th17 cells is associated with the acetylation of H2BK12 within their promoters. Thus, our results provide new information regarding this cell type. Based on these results, we also hope to better identify pathological conditions of clinical significance caused by Th17 cells.
      Citation: Cells
      PubDate: 2020-07-03
      DOI: 10.3390/cells9071611
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1612: Purinergic Signaling in the Hallmarks of Cancer

    • Authors: Anaí del Rocío Campos-Contreras, Mauricio Díaz-Muñoz, Francisco G. Vázquez-Cuevas
      First page: 1612
      Abstract: Cancer is a complex expression of an altered state of cellular differentiation associated with severe clinical repercussions. The effort to characterize this pathological entity to understand its underlying mechanisms and visualize potential therapeutic strategies has been constant. In this context, some cellular (enhanced duplication, immunological evasion), metabolic (aerobic glycolysis, failure in DNA repair mechanisms) and physiological (circadian disruption) parameters have been considered as cancer hallmarks. The list of these hallmarks has been growing in recent years, since it has been demonstrated that various physiological systems misfunction in well-characterized ways upon the onset and establishment of the carcinogenic process. This is the case with the purinergic system, a signaling pathway formed by nucleotides/nucleosides (mainly adenosine triphosphate (ATP), adenosine (ADO) and uridine triphosphate (UTP)) with their corresponding membrane receptors and defined transduction mechanisms. The dynamic equilibrium between ATP and ADO, which is accomplished by the presence and regulation of a set of ectonucleotidases, defines the pro-carcinogenic or anti-cancerous final outline in tumors and cancer cell lines. So far, the purinergic system has been recognized as a potential therapeutic target in cancerous and tumoral ailments.
      Citation: Cells
      PubDate: 2020-07-03
      DOI: 10.3390/cells9071612
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1613: Methylation in HOX Clusters and Its
           Applications in Cancer Therapy

    • Authors: Ana Paço, Simone Aparecida de Bessa Garcia, Renata Freitas
      First page: 1613
      Abstract: HOX genes are commonly known for their role in embryonic development, defining the positional identity of most structures along the anterior–posterior axis. In postembryonic life, HOX gene aberrant expression can affect several processes involved in tumorigenesis such as proliferation, apoptosis, migration and invasion. Epigenetic modifications are implicated in gene expression deregulation, and it is accepted that methylation events affecting HOX gene expression play crucial roles in tumorigenesis. In fact, specific methylation profiles in the HOX gene sequence or in HOX-associated histones are recognized as potential biomarkers in several cancers, helping in the prediction of disease outcomes and adding information for decisions regarding the patient’s treatment. The methylation of some HOX genes can be associated with chemotherapy resistance, and its identification may suggest the use of other treatment options. The use of epigenetic drugs affecting generalized or specific DNA methylation profiles, an approach that now deserves much attention, seems likely to be a promising weapon in cancer therapy in the near future. In this review, we summarize these topics, focusing particularly on how the regulation of epigenetic processes may be used in cancer therapy.
      Citation: Cells
      PubDate: 2020-07-03
      DOI: 10.3390/cells9071613
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1614: Neurovascular Inflammaging in Health and
           Disease

    • Authors: Ádám Mészáros, Kinga Molnár, Bernát Nógrádi, Zsófia Hernádi, Ádám Nyúl-Tóth, Imola Wilhelm, István A. Krizbai
      First page: 1614
      Abstract: Aging is characterized by a chronic low-grade sterile inflammation dubbed as inflammaging, which in part originates from accumulating cellular debris. These, acting as danger signals with many intrinsic factors such as cytokines, are sensed by a network of pattern recognition receptors and other cognate receptors, leading to the activation of inflammasomes. Due to the inflammasome activity-dependent increase in the levels of pro-inflammatory interleukins (IL-1β, IL-18), inflammation is initiated, resulting in tissue injury in various organs, the brain and the spinal cord included. Similarly, in age-related diseases of the central nervous system (CNS), inflammasome activation is a prominent moment, in which cells of the neurovascular unit occupy a significant position. In this review, we discuss the inflammatory changes in normal aging and summarize the current knowledge on the role of inflammasomes and contributing mechanisms in common CNS diseases, namely Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and stroke, all of which occur more frequently with aging.
      Citation: Cells
      PubDate: 2020-07-04
      DOI: 10.3390/cells9071614
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1615: Water-Soluble closo-Docecaborate-Containing
           Pteroyl Derivatives Targeting Folate Receptor-Positive Tumors for Boron
           Neutron Capture Therapy

    • Authors: Fumiko Nakagawa, Hidehisa Kawashima, Taiki Morita, Hiroyuki Nakamura
      First page: 1615
      Abstract: Water-soluble pteroyl-closo-dodecaborate conjugates (PBCs 1–4), were developed as folate receptor (FRα) targeting boron carriers for boron neutron capture therapy (BNCT). PBCs 1–4 had adequately low cytotoxicity with IC50 values in the range of 1~3 mM toward selected human cancer cells, low enough to use as BNCT boron agents. PBCs 1–3 showed significant cell uptake by FRα positive cells, especially U87MG glioblastoma cells, although the accumulation of PBC 4 was low compared with PBCs 1–3 and L-4-boronophenylalanine (L-BPA). The cellular uptake of PBC 1 and PBC 3 by HeLa cells was arrested by increasing the concentration of folate in the medium, indicating that the major uptake mechanisms of PBC 1–3 are primarily through FRα receptor-mediated endocytosis.
      Citation: Cells
      PubDate: 2020-07-03
      DOI: 10.3390/cells9071615
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1616: Deep Characterization of Circular RNAs from
           Human Cardiovascular Cell Models and Cardiac Tissue

    • Authors: Tobias Jakobi, Dominik Siede, Jessica Eschenbach, Andreas W. Heumüller, Martin Busch, Rouven Nietsch, Benjamin Meder, Patrick Most, Stefanie Dimmeler, Johannes Backs, Hugo A. Katus, Christoph Dieterich
      First page: 1616
      Abstract: For decades, cardiovascular disease (CVD) has been the leading cause of death throughout most developed countries. Several studies relate RNA splicing, and more recently also circular RNAs (circRNAs), to CVD. CircRNAs originate from linear transcripts and have been shown to exhibit tissue-specific expression profiles. Here, we present an in-depth analysis of sequence, structure, modification, and cardiac circRNA interactions. We used human induced pluripotent stem cell-derived cardiac myocytes (hiPSC-CMs), human healthy and diseased (ischemic cardiomyopathy, dilated cardiomyopathy) cardiac tissue, and human umbilical vein endothelial cells (HUVECs) to profile circRNAs. We identified shared circRNAs across all samples, as well as model-specific circRNA signatures. Based on these circRNAs, we identified 63 positionally conserved and expressed circRNAs in human, pig, and mouse hearts. Furthermore, we found that the sequence of circRNAs can deviate from the sequence derived from the genome sequence, an important factor in assessing potential functions. Integration of additional data yielded evidence for m6A-methylation of circRNAs, potentially linked to translation, as well as, circRNAs overlapping with potential Argonaute 2 binding sites, indicating potential association with the RISC complex. Moreover, we describe, for the first time in cardiac model systems, a sub class of circRNAs containing the start codon of their primary transcript (AUG circRNAs) and observe an enrichment for m6A-methylation for AUG circRNAs.
      Citation: Cells
      PubDate: 2020-07-04
      DOI: 10.3390/cells9071616
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1617: Nanoceria Particles Are an Eligible Candidate
           to Prevent Age-Related Macular Degeneration by Inhibiting Retinal Pigment
           Epithelium Cell Death and Autophagy Alterations

    • Authors: Annamaria Tisi, Vincenzo Flati, Simona Delle Monache, Luca Lozzi, Maurizio Passacantando, Rita Maccarone
      First page: 1617
      Abstract: Retinal pigment epithelium (RPE) dysfunction and degeneration underlie the development of age-related macular degeneration (AMD), which is the leading cause of blindness worldwide. In this study, we investigated whether cerium oxide nanoparticles (CeO2-NPs or nanoceria), which are anti-oxidant agents with auto-regenerative properties, are able to preserve the RPE. On ARPE-19 cells, we found that CeO2-NPs promoted cell viability against H2O2–induced cellular damage. For the in vivo studies, we used a rat model of acute light damage (LD), which mimics many features of AMD. CeO2-NPs intravitreally injected three days before LD prevented RPE cell death and degeneration and nanoceria labelled with fluorescein were found localized in the cytoplasm of RPE cells. CeO2-NPs inhibited epithelial-mesenchymal transition of RPE cells and modulated autophagy by the down-regulation of LC3B-II and p62. Moreover, the treatment inhibited nuclear localization of LC3B. Taken together, our study demonstrates that CeO2-NPs represent an eligible candidate to counteract RPE degeneration and, therefore, a powerful therapy for AMD.
      Citation: Cells
      PubDate: 2020-07-04
      DOI: 10.3390/cells9071617
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1618: Astrocyte- and Neuron-Derived Extracellular
           Vesicles from Alzheimer’s Disease Patients Effect Complement-Mediated
           Neurotoxicity

    • Authors: Carlos J. Nogueras-Ortiz, Vasiliki Mahairaki, Francheska Delgado-Peraza, Debamitra Das, Konstantinos Avgerinos, Erden Eren, Matthew Hentschel, Edward J. Goetzl, Mark P. Mattson, Dimitrios Kapogiannis
      First page: 1618
      Abstract: We have previously shown that blood astrocytic-origin extracellular vesicles (AEVs) from Alzheimer’s disease (AD) patients contain high complement levels. To test the hypothesis that circulating EVs from AD patients can induce complement-mediated neurotoxicity involving Membrane Attack Complex (MAC) formation, we assessed the effects of immunocaptured AEVs (using anti-GLAST antibody), in comparison with neuronal-origin (N)EVs (using anti-L1CAM antibody), and nonspecific CD81+ EVs (using anti-CD81 antibody), from the plasma of AD, frontotemporal lobar degeneration (FTLD), and control participants. AEVs (and, less effectively, NEVs) of AD participants induced Membrane Attack Complex (MAC) expression on recipient neurons (by immunohistochemistry), membrane disruption (by EthD-1 assay), reduced neurite density (by Tuj-1 immunohistochemistry), and decreased cell viability (by MTT assay) in rat cortical neurons and human iPSC-derived neurons. Demonstration of decreased cell viability was replicated in a separate cohort of autopsy-confirmed AD patients. These effects were not produced by CD81+ EVs from AD participants or AEVs/NEVs from FTLD or control participants, and were suppressed by the MAC inhibitor CD59 and other complement inhibitors. Our results support the stated hypothesis and should motivate future studies on the roles of neuronal MAC deposition and AEV/NEV uptake, as effectors of neurodegeneration in AD.
      Citation: Cells
      PubDate: 2020-07-04
      DOI: 10.3390/cells9071618
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1619: Canonical and Noncanonical Autophagy as
           Potential Targets for COVID-19

    • Authors: Melissa Bello-Perez, Isabel Sola, Beatriz Novoa, Daniel J. Klionsky, Alberto Falco
      First page: 1619
      Abstract: The SARS-CoV-2 pandemic necessitates a review of the molecular mechanisms underlying cellular infection by coronaviruses, in order to identify potential therapeutic targets against the associated new disease (COVID-19). Previous studies on its counterparts prove a complex and concomitant interaction between coronaviruses and autophagy. The precise manipulation of this pathway allows these viruses to exploit the autophagy molecular machinery while avoiding its protective apoptotic drift and cellular innate immune responses. In turn, the maneuverability margins of such hijacking appear to be so narrow that the modulation of the autophagy, regardless of whether using inducers or inhibitors (many of which are FDA-approved for the treatment of other diseases), is usually detrimental to viral replication, including SARS-CoV-2. Recent discoveries indicate that these interactions stretch into the still poorly explored noncanonical autophagy pathway, which might play a substantial role in coronavirus replication. Still, some potential therapeutic targets within this pathway, such as RAB9 and its interacting proteins, look promising considering current knowledge. Thus, the combinatory treatment of COVID-19 with drugs affecting both canonical and noncanonical autophagy pathways may be a turning point in the fight against this and other viral infections, which may also imply beneficial prospects of long-term protection.
      Citation: Cells
      PubDate: 2020-07-05
      DOI: 10.3390/cells9071619
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1620: Molecular Basis of the Function of
           Transcriptional Enhancers

    • Authors: Airat N. Ibragimov, Oleg V. Bylino, Yulii V. Shidlovskii
      First page: 1620
      Abstract: Transcriptional enhancers are major genomic elements that control gene activity in eukaryotes. Recent studies provided deeper insight into the temporal and spatial organization of transcription in the nucleus, the role of non-coding RNAs in the process, and the epigenetic control of gene expression. Thus, multiple molecular details of enhancer functioning were revealed. Here, we describe the recent data and models of molecular organization of enhancer-driven transcription.
      Citation: Cells
      PubDate: 2020-07-05
      DOI: 10.3390/cells9071620
      Issue No: Vol. 9, No. 7 (2020)
       
  • Cells, Vol. 9, Pages 1521: Hepatogenic Potential and Liver Regeneration
           Effect of Human Liver-derived Mesenchymal-Like Stem Cells

    • Authors: Jooyoung Lee, Jiwan Choi, Seoon Kang, Jiye Kim, Ryunjin Lee, Seongjun So, Young-In Yoon, Varvara A. Kirchner, Gi-Won Song, Shin Hwang, Sung-Gyu Lee, Eunju Kang, Eunyoung Tak
      First page: 1521
      Abstract: Human liver-derived stem cells (hLD-SCs) have been proposed as a possible resource for stem cell therapy in patients with irreversible liver diseases. However, it is not known whether liver resident hLD-SCs can differentiate toward a hepatic fate better than mesenchymal stem cells (MSCs) obtained from other origins. In this study, we compared the differentiation ability and regeneration potency of hLD-SCs with those of human umbilical cord matrix-derived stem cells (hUC-MSCs) by inducing hepatic differentiation. Undifferentiated hLD-SCs expressed relatively high levels of endoderm-related markers (GATA4 and FOXA1). During directed hepatic differentiation supported by two small molecules (Fasudil and 5-azacytidine), hLD-SCs presented more advanced mitochondrial respiration compared to hUC-MSCs. Moreover, hLD-SCs featured higher numbers of hepatic progenitor cell markers on day 14 of differentiation (CPM and CD133) and matured into hepatocyte-like cells by day 7 through 21 with increased hepatocyte markers (ALB, HNF4A, and AFP). During in vivo cell transplantation, hLD-SCs migrated into the liver of ischemia-reperfusion injury-induced mice within 2 h and relieved liver injury. In the thioacetamide (TAA)-induced liver injury mouse model, transplanted hLD-SCs trafficked into the liver and spontaneously matured into hepatocyte-like cells within 14 days. These results collectively suggest that hLD-SCs hold greater hepatogenic potential, and hepatic differentiation-induced hLD-SCs may be a promising source of stem cells for liver regeneration.
      Citation: Cells
      PubDate: 2020-06-22
      DOI: 10.3390/cells9061521
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1522: New Frontiers in Prostate Cancer Treatment: Are
           We Ready for Drug Combinations with Novel Agents'

    • Authors: Gaetano Aurilio, Alessia Cimadamore, Matteo Santoni, Franco Nolè, Marina Scarpelli, Francesco Massari, Antonio Lopez-Beltran, Liang Cheng, Rodolfo Montironi
      First page: 1522
      Abstract: Medical treatment for metastatic castration-resistant prostate cancer (mCRPC) patients has progressively been evolving from a nonspecific clinical approach to genomics-oriented therapies. The scientific community is in fact increasingly focusing on developing DNA damage repair (DDR) defect-driven novel molecules, both as single-agent therapy and in combined treatment strategies. Accordingly, research is under way into combined drug therapies targeting different pathways, e.g. androgen receptor signaling (ARS) and poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) enzymes, immune checkpoint (IC) and PARP, IC, and ARS, and prostate-specific membrane antigen (PSMA). In an attempt to formulate evolving treatment paradigms in mCRPC patients, here we selected clinical research into patients undergoing therapies with emerging molecules, with particular emphasis towards PARP-, IC-, and PSMA-inhibitors. In order to focus on those molecules and drug combinations most likely to be translated into routine clinical care in the near future, we selected only those clinical studies currently recruiting patients. A PubMed search focusing on the keywords “prostate cancer”, “metastatic castration-resistant prostate cancer”, “DDR pathways”, “ARS inhibitors”, “PARP inhibitors”, “IC inhibitors”, “PSMA-targeting agents”, and “drug combinations” was performed.
      Citation: Cells
      PubDate: 2020-06-22
      DOI: 10.3390/cells9061522
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1523: Potential Prognostic Role of SPARC Methylation
           in Non-Small-Cell Lung Cancer

    • Authors: Federico Pio Fabrizio, Angelo Sparaneo, Andrea Fontana, Tommaso Mazza, Paolo Graziano, Angela Pantalone, Paola Parente, Flavia Centra, Natalizia Orlando, Domenico Trombetta, Annamaria la Torre, Gian Maria Ferretti, Marco Taurchini, Concetta Martina Di Micco, Evaristo Maiello, Vito Michele Fazio, Antonio Rossi, Lucia Anna Muscarella
      First page: 1523
      Abstract: The silencing of SPARC (secreted protein acid and rich in cysteine) gene through methylation of its promoter region represents a common event in many solid tumors and it is frequently associated with tumor progression and an aggressive clinical outcome. Anyhow, the data concerning the epigenetic mechanism of SPARC deregulation and its prognostic value in lung cancer are still incomplete. We explored the aberrant methylation of SPARC and its effects in 4 non-small cell lung cancer (NSCLC) cell lines and 59 NSCLC tissues and correlated the methylation levels with clinical-pathological features and disease outcome of patients. In 3 out of 4 tumor cell lines high SPARC methylation levels were observed. An inverse correlation between the epigenetic silencing and SPARC expression was confirmed by 5-Aza-2′-deoxycytidine ((5-Aza-CdR) treatment that also significantly induced a reduction in cell viability, proliferation and tumor cell migration. In tissues, the DNA methylation levels of the SPARC gene were significantly lower in paired non-neoplastic lungs (NLs) and normal lungs distant from tumor (NLDTs) than in NSCLCs (p = 0.002 and p = 0.0034 respectively). A promoter hypermethylation was detected in 68% of squamous cell carcinoma (SqCCs, 17/25) and 56% of adenocarcinoma (ADCs, 19/34), with SqCC showing the highest levels of methylation. Higher SPARC methylation levels were significantly associated with higher mortality risk both in all NSCLCs early stage patients (Hazard Ratio, HR = 1.97; 95% Confidence Interval, CI: 1.32–2.93; p = 0.001) and in those with SqCC (HR = 2.96; 95% CI: 1.43–6.12; p = 0.003). Promoter methylation of SPARC gene should represent an interesting prognostic biomarker in NSCLC, with potential application in the squamous early-stage context. Further research in this setting on larger independent cohorts of lung patients with different histologies and stages of disease are warranted.
      Citation: Cells
      PubDate: 2020-06-22
      DOI: 10.3390/cells9061523
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1524: Flow Induced Symmetry Breaking in a Conceptual
           Polarity Model

    • Authors: Manon C. Wigbers, Fridtjof Brauns, Ching Yee Leung, Erwin Frey
      First page: 1524
      Abstract: Important cellular processes, such as cell motility and cell division, are coordinated by cell polarity, which is determined by the non-uniform distribution of certain proteins. Such protein patterns form via an interplay of protein reactions and protein transport. Since Turing’s seminal work, the formation of protein patterns resulting from the interplay between reactions and diffusive transport has been widely studied. Over the last few years, increasing evidence shows that also advective transport, resulting from cytosolic and cortical flows, is present in many cells. However, it remains unclear how and whether these flows contribute to protein-pattern formation. To address this question, we use a minimal model that conserves the total protein mass to characterize the effects of cytosolic flow on pattern formation. Combining a linear stability analysis with numerical simulations, we find that membrane-bound protein patterns propagate against the direction of cytoplasmic flow with a speed that is maximal for intermediate flow speed. We show that the mechanism underlying this pattern propagation relies on a higher protein influx on the upstream side of the pattern compared to the downstream side. Furthermore, we find that cytosolic flow can change the membrane pattern qualitatively from a peak pattern to a mesa pattern. Finally, our study shows that a non-uniform flow profile can induce pattern formation by triggering a regional lateral instability.
      Citation: Cells
      PubDate: 2020-06-23
      DOI: 10.3390/cells9061524
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1525: Intratumoral Versus Circulating Lymphoid Cells
           as Predictive Biomarkers in Lung Cancer Patients Treated with Immune
           Checkpoint Inhibitors: Is the Easiest Path the Best One'

    • Authors: Marta Gascón, Dolores Isla, Mara Cruellas, Eva M. Gálvez, Rodrigo Lastra, Maitane Ocáriz, José Ramón Paño, Ariel Ramírez, Andrea Sesma, Irene Torres-Ramón, Alfonso Yubero, Julián Pardo, Luis Martínez-Lostao
      First page: 1525
      Abstract: The molecular and cell determinants that modulate immune checkpoint (ICI) efficacy in lung cancer are still not well understood. However, there is a necessity to select those patients that will most benefit from these new treatments. Recent studies suggest the presence and/or the relative balance of specific lymphoid cells in the tumor microenvironment (TEM) including the T cell (activated, memory, and regulatory) and NK cell (CD56dim/bright) subsets, and correlate with a better response to ICI. The analyses of these cell subsets in peripheral blood, as a more accessible and homogeneous sample, might facilitate clinical decisions concerning fast prediction of ICI efficacy. Despite recent studies suggesting that lymphoid circulating cells might correlate with ICI efficacy and toxicity, more analyses and investigation are required to confirm if circulating lymphoid cells are a relevant picture of the lung TME and could be instrumental as ICI response biomarkers. This short review is aimed to discuss the recent advances in this fast-growing field.
      Citation: Cells
      PubDate: 2020-06-22
      DOI: 10.3390/cells9061525
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1526: Role of Elevated Intracellular
           S-Adenosylhomocysteine in the Pathogenesis of Alcohol-Related Liver
           Disease

    • Authors: Madan Kumar Arumugam, Sharanappa Talawar, Laura Listenberger, Terrence M. Donohue, Natalia A. Osna, Kusum K. Kharbanda
      First page: 1526
      Abstract: Background: The earliest manifestation of alcohol-related liver disease (ALD) is steatosis, characterized by the accumulation of lipid droplets (LDs) in hepatocytes. Findings from our laboratory have indicated that many pathological changes, including steatosis, correlate with the alcohol-induced hepatocellular increases in S-adenosylhomocysteine (SAH). Based on these considerations, we hypothesized that an experimental increase in intracellular SAH alone will result in similar steatotic changes to those seen after alcohol exposure. Methods: Freshly isolated rat hepatocytes grown on collagen-coated plates were exposed to serum-free medium containing 50 µmol/L oleic acid and varying concentrations of 3-deazaadenosine (DZA) to experimentally elevate intracellular SAH levels. Results: Overnight exposure to DZA treatment dose-dependently increased hepatocellular triglyceride accumulation, which was also evident by morphological visualization of larger-sized LDs. The rise in triglycerides and LDs accompanied increases in mRNA and protein levels of several LD-associated proteins known to regulate LD number and size. Furthermore, DZA treatment caused a decline in the levels of lipases that prevent fat accumulation as well as increased the expression of factors involved in lipogenesis and fatty acid mobilization. Collectively, our results indicate that the elevation of intracellular SAH is sufficient to promote fat accumulation in hepatocytes, which is similar to that seen after alcohol exposure.
      Citation: Cells
      PubDate: 2020-06-23
      DOI: 10.3390/cells9061526
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1527: Extracellular Vesicles from Skeletal Muscle
           Cells Efficiently Promote Myogenesis in Induced Pluripotent Stem Cells

    • Authors: Denisa Baci, Maila Chirivì, Valentina Pace, Fabio Maiullari, Marika Milan, Andrea Rampin, Paolo Somma, Dario Presutti, Silvia Garavelli, Antonino Bruno, Stefano Cannata, Chiara Lanzuolo, Cesare Gargioli, Roberto Rizzi, Claudia Bearzi
      First page: 1527
      Abstract: The recent advances, offered by cell therapy in the regenerative medicine field, offer a revolutionary potential for the development of innovative cures to restore compromised physiological functions or organs. Adult myogenic precursors, such as myoblasts or satellite cells, possess a marked regenerative capacity, but the exploitation of this potential still encounters significant challenges in clinical application, due to low rate of proliferation in vitro, as well as a reduced self-renewal capacity. In this scenario, induced pluripotent stem cells (iPSCs) can offer not only an inexhaustible source of cells for regenerative therapeutic approaches, but also a valuable alternative for in vitro modeling of patient-specific diseases. In this study we established a reliable protocol to induce the myogenic differentiation of iPSCs, generated from pericytes and fibroblasts, exploiting skeletal muscle-derived extracellular vesicles (EVs), in combination with chemically defined factors. This genetic integration-free approach generates functional skeletal myotubes maintaining the engraftment ability in vivo. Our results demonstrate evidence that EVs can act as biological “shuttles” to deliver specific bioactive molecules for a successful transgene-free differentiation offering new opportunities for disease modeling and regenerative approaches.
      Citation: Cells
      PubDate: 2020-06-23
      DOI: 10.3390/cells9061527
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1528: A Single-Neuron: Current Trends and Future
           Prospects

    • Authors: Pallavi Gupta, Nandhini Balasubramaniam, Hwan-You Chang, Fan-Gang Tseng, Tuhin Subhra Santra
      First page: 1528
      Abstract: The brain is an intricate network with complex organizational principles facilitating a concerted communication between single-neurons, distinct neuron populations, and remote brain areas. The communication, technically referred to as connectivity, between single-neurons, is the center of many investigations aimed at elucidating pathophysiology, anatomical differences, and structural and functional features. In comparison with bulk analysis, single-neuron analysis can provide precise information about neurons or even sub-neuron level electrophysiology, anatomical differences, pathophysiology, structural and functional features, in addition to their communications with other neurons, and can promote essential information to understand the brain and its activity. This review highlights various single-neuron models and their behaviors, followed by different analysis methods. Again, to elucidate cellular dynamics in terms of electrophysiology at the single-neuron level, we emphasize in detail the role of single-neuron mapping and electrophysiological recording. We also elaborate on the recent development of single-neuron isolation, manipulation, and therapeutic progress using advanced micro/nanofluidic devices, as well as microinjection, electroporation, microelectrode array, optical transfection, optogenetic techniques. Further, the development in the field of artificial intelligence in relation to single-neurons is highlighted. The review concludes with between limitations and future prospects of single-neuron analyses.
      Citation: Cells
      PubDate: 2020-06-23
      DOI: 10.3390/cells9061528
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1529: Deferiprone (DFP) Targets Cancer Stem Cell
           (CSC) Propagation by Inhibiting Mitochondrial Metabolism and Inducing ROS
           Production

    • Authors: Marco Fiorillo, Fanni Tóth, Matteo Brindisi, Federica Sotgia, Michael P. Lisanti
      First page: 1529
      Abstract: Deferiprone (DFP), also known as Ferriprox, is an FDA-approved, orally active, iron chelator that is currently used clinically for the treatment of iron-overload, especially in thalassaemia major. As iron is a critical factor in Fe-S cluster assembly that is absolutely required for the metabolic function of mitochondria, we hypothesized that DFP treatment could be used to selectively target mitochondria in cancer stem cells (CSCs). For this purpose, we used two ER(+) human breast cancer cell lines, namely MCF7 and T47D cells, as model systems. More specifically, a 3D tumorsphere assay was employed as a functional readout of CSC activity which measures anchorage-independent growth under low attachment conditions. Here, we show that DFP dose dependently inhibited the propagation of CSCs, with an IC-50 of ~100 nM for MCF7 and an IC-50 of ~0.5 to 1 μM for T47D cells, making DFP one the most potent FDA-approved drugs that we and others have thus far identified for targeting CSCs. Mechanistically, we show that high concentrations of DFP metabolically targeted both mitochondrial oxygen consumption (OCR) and glycolysis (extracellular acidification rates (ECAR)) in MCF7 and T47D cell monolayers. Most importantly, we demonstrate that DFP also induced a generalized increase in reactive oxygen species (ROS) and mitochondrial superoxide production, and its effects reverted in the presence of N-acetyl-cysteine (NAC). Therefore, we propose that DFP is a new candidate therapeutic for drug repurposing and for Phase II clinical trials aimed at eradicating CSCs.
      Citation: Cells
      PubDate: 2020-06-23
      DOI: 10.3390/cells9061529
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1530: The Barley S-Adenosylmethionine Synthetase 3
           Gene HvSAMS3 Positively Regulates the Tolerance to Combined Drought and
           Salinity Stress in Tibetan Wild Barley

    • Authors: Imrul Mosaddek Ahmed, Umme Aktari Nadira, Cheng-Wei Qiu, Fangbin Cao, Zhong-Hua Chen, Eva Vincze, Feibo Wu
      First page: 1530
      Abstract: Drought and salinity are two of the most frequently co-occurring abiotic stresses. Despite recent advances in the elucidation of the effects of these stresses individually during the vegetative stage of plants, significant gaps exist in our understanding of the combined effects of these two frequently co-occurring stresses. Here, Tibetan wild barley XZ5 (drought tolerant), XZ16 (salt tolerant), and cultivated barley cv. CM72 (salt tolerant) were subjected to drought (D), salinity (S), or a combination of both treatments (D+S). Protein synthesis is one of the primary activities of the green part of the plant. Therefore, leaf tissue is an important parameter to evaluate drought and salinity stress conditions. Sixty differentially expressed proteins were identified by mass spectrometry (MALDI-TOF/TOF) and classified into 9 biological processes based on Gene Ontology annotation. Among them, 21 proteins were found to be expressed under drought or salinity alone; however, under D+S, 7 proteins, including S-adenosylmethionine synthetase 3 (SAMS3), were exclusively upregulated in drought-tolerant XZ5 but not in CM72. HvSAMS3 carries both N-terminal and central domains compared with Arabidopsis and activates the expression of several ethylene (ET)-responsive transcription factors. HvSAMS3 is mainly expressed in the roots and stems, and HvSAMS3 is a secretory protein located in the cell membrane and cytoplasm. Barley stripe mosaic virus-based virus-induced gene silencing (BSMV-VIGS) of HvSAMS3 in XZ5 severely compromised its tolerance to D+S and significantly reduced plant growth and K+ uptake. The reduced tolerance to the combined stress was associated with the inhibition of polyamines such as spermidine and spermine, polyamine oxidase, ethylene, biotin, and antioxidant enzyme activities. Furthermore, the exogenous application of ethylene and biotin improved the tolerance to D+S in BSMV-VIGS:HvSAMS3-inoculated plants. Our findings highlight the significance of HvSAMS3 in the tolerance to D+S in XZ5.
      Citation: Cells
      PubDate: 2020-06-23
      DOI: 10.3390/cells9061530
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1531: Multilineage Differentiation for Formation of
           Innervated Skeletal Muscle Fibers from Healthy and Diseased Human
           Pluripotent Stem Cells

    • Authors: Kilian Mazaleyrat, Cherif Badja, Natacha Broucqsault, Raphaël Chevalier, Camille Laberthonnière, Camille Dion, Lyla Baldasseroni, Claire El-Yazidi, Morgane Thomas, Richard Bachelier, Alexandre Altié, Karine Nguyen, Nicolas Lévy, Jérôme D. Robin, Frédérique Magdinier
      First page: 1531
      Abstract: Induced pluripotent stem cells (iPSCs) obtained by reprogramming primary somatic cells have revolutionized the fields of cell biology and disease modeling. However, the number protocols for generating mature muscle fibers with sarcolemmal organization using iPSCs remain limited, and partly mimic the complexity of mature skeletal muscle. Methods: We used a novel combination of small molecules added in a precise sequence for the simultaneous codifferentiation of human iPSCs into skeletal muscle cells and motor neurons. Results: We show that the presence of both cell types reduces the production time for millimeter-long multinucleated muscle fibers with sarcolemmal organization. Muscle fiber contractions are visible in 19–21 days, and can be maintained over long period thanks to the production of innervated multinucleated mature skeletal muscle fibers with autonomous cell regeneration of PAX7-positive cells and extracellular matrix synthesis. The sequential addition of specific molecules recapitulates key steps of human peripheral neurogenesis and myogenesis. Furthermore, this organoid-like culture can be used for functional evaluation and drug screening. Conclusion: Our protocol, which is applicable to hiPSCs from healthy individuals, was validated in Duchenne Muscular Dystrophy, Myotonic Dystrophy, Facio-Scapulo-Humeral Dystrophy and type 2A Limb-Girdle Muscular Dystrophy, opening new paths for the exploration of muscle differentiation, disease modeling and drug discovery.
      Citation: Cells
      PubDate: 2020-06-23
      DOI: 10.3390/cells9061531
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1532: Cytokine Profile in Striated Muscle
           Laminopathies: New Promising Biomarkers for Disease Prediction

    • Authors: Cristina Cappelletti, Irene Tramacere, Paola Cavalcante, Elisa Schena, Luisa Politano, Nicola Carboni, Alessandra Gambineri, Adele D’Amico, Lucia Ruggiero, Giulia Ricci, Gabriele Siciliano, Giuseppe Boriani, Tiziana Enrica Mongini, Liliana Vercelli, Elena Biagini, Matteo Ziacchi, Maria Rosaria D’Apice, Giovanna Lattanzi, Renato Mantegazza, Lorenzo Maggi, Pia Bernasconi
      First page: 1532
      Abstract: Laminopathies are a wide and heterogeneous group of rare human diseases caused by mutations of the LMNA gene or related nuclear envelope genes. The variety of clinical phenotypes and the wide spectrum of histopathological changes among patients carrying an identical mutation in the LMNA gene make the prognostic process rather difficult, and classical genetic screens appear to have limited predictive value for disease development. The aim of this study was to evaluate whether a comprehensive profile of circulating cytokines may be a useful tool to differentiate and stratify disease subgroups, support clinical follow-ups and contribute to new therapeutic approaches. Serum levels of 51 pro- and anti-inflammatory molecules, including cytokines, chemokines and growth factors, were quantified by a Luminex multiple immune-assay in 53 patients with muscular laminopathy (Musc-LMNA), 10 with non-muscular laminopathy, 22 with other muscular disorders and in 35 healthy controls. Interleukin-17 (IL-17), granulocyte colony-stimulating factor (G-CSF) and transforming growth factor beta (TGF-β2) levels significantly discriminated Musc-LMNA from controls; interleukin-1β (IL-1β), interleukin-4 (IL-4) and interleukin-8 (IL-8) were differentially expressed in Musc-LMNA patients compared to those with non-muscular laminopathies, whereas IL-17 was significantly higher in Musc-LMNA patients with muscular and cardiac involvement. These findings support the hypothesis of a key role of the immune system in Musc-LMNA and emphasize the potential use of cytokines as biomarkers for these disorders.
      Citation: Cells
      PubDate: 2020-06-23
      DOI: 10.3390/cells9061532
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1533: Why a Large-Scale Mode Can Be Essential for
           Understanding Intracellular Actin Waves

    • Authors: Carsten Beta, Nir S. Gov, Arik Yochelis
      First page: 1533
      Abstract: During the last decade, intracellular actin waves have attracted much attention due to their essential role in various cellular functions, ranging from motility to cytokinesis. Experimental methods have advanced significantly and can capture the dynamics of actin waves over a large range of spatio-temporal scales. However, the corresponding coarse-grained theory mostly avoids the full complexity of this multi-scale phenomenon. In this perspective, we focus on a minimal continuum model of activator–inhibitor type and highlight the qualitative role of mass conservation, which is typically overlooked. Specifically, our interest is to connect between the mathematical mechanisms of pattern formation in the presence of a large-scale mode, due to mass conservation, and distinct behaviors of actin waves.
      Citation: Cells
      PubDate: 2020-06-23
      DOI: 10.3390/cells9061533
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1534: Transcriptomic microRNA Profiling of Dendritic
           Cells in Response to Gut Microbiota-Secreted Vesicles

    • Authors: Natalia Díaz-Garrido, Sarah Bonnin, Marta Riera, Rosa Gíménez, Josefa Badia, Laura Baldomà
      First page: 1534
      Abstract: The interconnection between nutrients, metabolites and microbes is a key factor governing the healthy/pathological status of an individual. Thus, microbiota-based research is essential in order to better understand human health and nutrition. Gut bacteria release membrane vesicles (MVs) as an intercellular communication mechanism that allows the direct delivery of factors that prime the host’s innate immune system. We have previously shown that MVs from intestinal E. coli activate dendritic cells (DCs) in a strain-specific manner. To gain insights into the regulatory mechanisms involved, here, we have used an RNA deep sequencing approach to identify differentially expressed miRNAs (microRNAs) in DCs which are challenged by the MVs of the probiotic Nissle 1917 (EcN) or the commensal ECOR12. MicroRNAs are post-transcriptional regulatory mediators that permit the fine tuning of signaling pathways. This approach allowed the identification of a common set of miRNAs which are modulated by MVs from both strains and miRNAs which are differentially expressed in response to EcN or ECOR12 MVs. Based on the differential expression of the target genes and subsequent validation experiments, we correlated some of the selected miRNAs with the reported cytokine profile and specific T cell responses. As far as we know, this is the first study to analyze the regulation of miRNAs in DCs by MVs released by gut microbiota.
      Citation: Cells
      PubDate: 2020-06-23
      DOI: 10.3390/cells9061534
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1535: Macrophage Modification Strategies for
           Efficient Cell Therapy

    • Authors: Anastasiya S. Poltavets, Polina A. Vishnyakova, Andrey V. Elchaninov, Gennady T. Sukhikh, Timur Kh. Fatkhudinov
      First page: 1535
      Abstract: Macrophages, important cells of innate immunity, are known for their phagocytic activity, capability for antigen presentation, and flexible phenotypes. Macrophages are found in all tissues and therefore represent an attractive therapeutic target for the treatment of diseases of various etiology. Genetic programming of macrophages is an important issue of modern molecular and cellular medicine. The controllable activation of macrophages towards desirable phenotypes in vivo and in vitro will provide effective treatments for a number of inflammatory and proliferative diseases. This review is focused on the methods for specific alteration of gene expression in macrophages, including the controllable promotion of the desired M1 (pro-inflammatory) or M2 (anti-inflammatory) phenotypes in certain pathologies or model systems. Here we review the strategies of target selection, the methods of vector delivery, and the gene editing approaches used for modification of macrophages.
      Citation: Cells
      PubDate: 2020-06-24
      DOI: 10.3390/cells9061535
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1536: Lessons from the Endoplasmic Reticulum Ca2+
           Transporters—A Cancer Connection

    • Authors: Xingjian Zhai, Andra Mihaela Sterea, Yassine El Hiani
      First page: 1536
      Abstract: Ca2+ is an integral mediator of intracellular signaling, impacting almost every aspect of cellular life. The Ca2+-conducting transporters located on the endoplasmic reticulum (ER) membrane shoulder the responsibility of constructing the global Ca2+ signaling landscape. These transporters gate the ER Ca2+ release and uptake, sculpt signaling duration and intensity, and compose the Ca2+ signaling rhythm to accommodate a plethora of biological activities. In this review, we explore the mechanisms of activation and functional regulation of ER Ca2+ transporters in the establishment of Ca2+ homeostasis. We also contextualize the aberrant alterations of these transporters in carcinogenesis, presenting Ca2+-based therapeutic interventions as a means to tackle malignancies.
      Citation: Cells
      PubDate: 2020-06-24
      DOI: 10.3390/cells9061536
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1537: Diversity of Tumor-Infiltrating, γδ T-Cell
           Abundance in Solid Cancers

    • Authors: Ghita Chabab, Florence Boissière-Michot, Caroline Mollevi, Jeanne Ramos, Evelyne Lopez-Crapez, Pierre-Emmanuel Colombo, William Jacot, Nathalie Bonnefoy, Virginie Lafont
      First page: 1537
      Abstract: γδ T-cells contribute to the immune response against many tumor types through their direct cytolytic functions and their capacity to recruit and regulate the biological functions of other immune cells. As potent effectors of the anti-tumor immune response, they are considered an attractive therapeutic target for immunotherapies, but their presence and abundance in the tumor microenvironment are not routinely assessed in patients with cancer. Here, we validated an antibody for immunohistochemistry analysis that specifically detects all γδ T-cell subpopulations in healthy tissues and in the microenvironment of different cancer types. Tissue microarray analysis of breast, colon, ovarian, and pancreatic tumors showed that γδ T-cell density varies among cancer types. Moreover, the abundance of γδ tumor-infiltrating lymphocytes was variably associated with the outcome depending on the cancer type, suggesting that γδ T-cell recruitment is influenced by the context. These findings also suggest that γδ T-cell detection and analysis might represent a new and interesting diagnostic or prognostic marker.
      Citation: Cells
      PubDate: 2020-06-24
      DOI: 10.3390/cells9061537
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1538: Chondroitin Sulphate Proteoglycan 4 (NG2/CSPG4)
           Localization in Low- and High-Grade Gliomas

    • Authors: Marta Mellai, Laura Annovazzi, Ilaria Bisogno, Cristiano Corona, Paola Crociara, Barbara Iulini, Paola Cassoni, Cristina Casalone, Renzo Boldorini, Davide Schiffer
      First page: 1538
      Abstract: Background: Neuron glial antigen 2 or chondroitin sulphate proteoglycan 4 (NG2/CSPG4) is expressed by immature precursors/progenitor cells and is possibly involved in malignant cell transformation. The aim of this study was to investigate its role on the progression and survival of sixty-one adult gliomas and nine glioblastoma (GB)-derived cell lines. Methods: NG2/CSPG4 protein expression was assessed by immunohistochemistry and immunofluorescence. Genetic and epigenetic alterations were detected by molecular genetic techniques. Results: NG2/CSPG4 was frequently expressed in IDH-mutant/1p19q-codel oligodendrogliomas (59.1%) and IDH-wild type GBs (40%) and rarely expressed in IDH-mutant or IDH-wild type astrocytomas (14.3%). Besides tumor cells, NG2/CSPG4 immunoreactivity was found in the cytoplasm and/or cell membranes of reactive astrocytes and vascular pericytes/endothelial cells. In GB-derived neurospheres, it was variably detected according to the number of passages of the in vitro culture. In GB-derived adherent cells, a diffuse positivity was found in most cells. NG2/CSPG4 expression was significantly associated with EGFR gene amplification (p = 0.0005) and poor prognosis (p = 0.016) in astrocytic tumors. Conclusion: The immunoreactivity of NG2/CSPG4 provides information on the timing of the neoplastic transformation and could have prognostic and therapeutic relevance as a promising tumor-associated antigen for antibody-based immunotherapy in patients with malignant gliomas.
      Citation: Cells
      PubDate: 2020-06-24
      DOI: 10.3390/cells9061538
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1539: Aneuploid Circulating Tumor-Derived Endothelial
           Cell (CTEC): A Novel Versatile Player in Tumor Neovascularization and
           Cancer Metastasis

    • Authors: Peter Ping Lin
      First page: 1539
      Abstract: Hematogenous and lymphogenous cancer metastases are significantly impacted by tumor neovascularization, which predominantly consists of blood vessel-relevant angiogenesis, vasculogenesis, vasculogenic mimicry, and lymphatic vessel-related lymphangiogenesis. Among the endothelial cells that make up the lining of tumor vasculature, a majority of them are tumor-derived endothelial cells (TECs), exhibiting cytogenetic abnormalities of aneuploid chromosomes. Aneuploid TECs are generated from “cancerization of stromal endothelial cells” and “endothelialization of carcinoma cells” in the hypoxic tumor microenvironment. Both processes crucially engage the hypoxia-triggered epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndoMT). Compared to the cancerization process, endothelialization of cancer cells, which comprises the fusion of tumor cells with endothelial cells and transdifferentiation of cancer cells into TECs, is the dominant pathway. Tumor-derived endothelial cells, possessing the dual properties of cancerous malignancy and endothelial vascularization ability, are thus the endothelialized cancer cells. Circulating tumor-derived endothelial cells (CTECs) are TECs shed into the peripheral circulation. Aneuploid CD31+ CTECs, together with their counterpart CD31- circulating tumor cells (CTCs), constitute a unique pair of cellular circulating tumor biomarkers. This review discusses a proposed cascaded framework that focuses on the origins of TECs and CTECs in the hypoxic tumor microenvironment and their clinical implications for tumorigenesis, neovascularization, disease progression, and cancer metastasis. Aneuploid CTECs, harboring hybridized properties of malignancy, vascularization and motility, may serve as a unique target for developing a novel metastasis blockade cancer therapy.
      Citation: Cells
      PubDate: 2020-06-24
      DOI: 10.3390/cells9061539
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1540: Methylation-Based Therapies for Colorectal
           Cancer

    • Authors: Klara Cervena, Anna Siskova, Tomas Buchler, Pavel Vodicka, Veronika Vymetalkova
      First page: 1540
      Abstract: Colorectal carcinogenesis (CRC) is caused by the gradual long-term accumulation of both genetic and epigenetic changes. Recently, epigenetic alterations have been included in the classification of the CRC molecular subtype, and this points out their prognostic impact. As epigenetic modifications are reversible, they may represent relevant therapeutic targets. DNA methylation, catalyzed by DNA methyltransferases (DNMTs), regulates gene expression. For many years, the deregulation of DNA methylation has been considered to play a substantial part in CRC etiology and evolution. Despite considerable advances in CRC treatment, patient therapy response persists as limited, and their profit from systemic therapies are often hampered by the introduction of chemoresistance. In addition, inter-individual changes in therapy response in CRC patients can arise from their specific (epi)genetic compositions. In this review article, we summarize the options of CRC treatment based on DNA methylation status for their predictive value. This review also includes the therapy outcomes based on the patient’s methylation status in CRC patients. In addition, the current challenge of research is to develop therapeutic inhibitors of DNMT. Based on the essential role of DNA methylation in CRC development, the application of DNMT inhibitors was recently proposed for the treatment of CRC patients, especially in patients with DNA hypermethylation.
      Citation: Cells
      PubDate: 2020-06-24
      DOI: 10.3390/cells9061540
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1541: Early Onset of Sex-Dependent Mitochondrial
           Deficits in the Cortex of 3xTg Alzheimer’s Mice

    • Authors: Jelena Djordjevic, Subir Roy Chowdhury, Wanda M. Snow, Claudia Perez, Chris Cadonic, Paul Fernyhough, Benedict C. Albensi
      First page: 1541
      Abstract: Alzheimer’s disease (AD) is a major public health concern worldwide. Advanced age and female sex are two of the most prominent risk factors for AD. AD is characterized by progressive neuronal loss, especially in the cortex and hippocampus, and mitochondrial dysfunction has been proposed to be an early event in the onset and progression of the disease. Our results showed early perturbations in mitochondrial function in 3xTg mouse brain, with the cortex being more susceptible to mitochondrial changes than the hippocampus. In the cortex of 3xTg females, decreased coupled and uncoupled respiration were evident early (at 2 months of age), while in males it appeared later at 6 months of age. We observed increased coupled respiration in the hippocampus of 2-month-old 3xTg females, but no changes were detected later in life. Changes in mitochondrial dynamics were indicated by decreased mitofusin (Mfn2) and increased dynamin related protein 1 (Drp1) (only in females) in the hippocampus and cortex of 3xTg mice. Our findings highlight the importance of controlling and accounting for sex, brain region, and age in studies examining brain bioenergetics using this common AD model in order to more accurately evaluate potential therapies and improve the sex-specific translatability of preclinical findings.
      Citation: Cells
      PubDate: 2020-06-24
      DOI: 10.3390/cells9061541
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1542: Keratinocyte-Expressed Podoplanin is
           Dispensable for Multi-Step Skin Carcinogenesis

    • Authors: Marko Sesartić, Kristian Ikenberg, Sun-Young Yoon, Michael Detmar
      First page: 1542
      Abstract: Podoplanin is a small transmembrane mucin-like glycoprotein that plays a crucial role in the development of the lung, heart and lymphatic vascular system. Its expression is upregulated in several types of human carcinomas and podoplanin levels in squamous cell carcinomas (SCCs) of the oral cavity and the lung correlate with cancer invasiveness, lymph node metastasis and shorter survival time of patients, indicating that podoplanin promotes tumor progression. However, its role during the early stages of carcinogenesis remain unclear. We generated mice with a specific deletion of podoplanin in epidermal keratinocytes (K5-Cre;Pdpnflox/flox mice) and subjected them to a multistep chemical skin carcinogenesis regimen. The rate of tumor initiation; the number, size and differentiation of tumors; and the malignant transformation rate were comparable in K5-Cre;Pdpnflox/flox mice and Pdpnflox/flox control mice. However, tumor cell invasion was reduced in K5-Cre;Pdpnflox/flox mice, in particular single cell invasion. Quantitative immunofluorescence analyses revealed that peritumoral lymphangiogenesis was reduced in K5-Cre;Pdpnflox/flox mice, whereas there were no major changes of tumor-associated immune cell subpopulations. Thus, keratinocyte-expressed podoplanin is dispensable for the early steps of skin carcinogenesis but contributes to the progression of established tumors.
      Citation: Cells
      PubDate: 2020-06-24
      DOI: 10.3390/cells9061542
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1543: Genetic Control of Muscle Diversification and
           Homeostasis: Insights from Drosophila

    • Authors: Preethi Poovathumkadavil, Krzysztof Jagla
      First page: 1543
      Abstract: In the fruit fly, Drosophila melanogaster, the larval somatic muscles or the adult thoracic flight and leg muscles are the major voluntary locomotory organs. They share several developmental and structural similarities with vertebrate skeletal muscles. To ensure appropriate activity levels for their functions such as hatching in the embryo, crawling in the larva, and jumping and flying in adult flies all muscle components need to be maintained in a functionally stable or homeostatic state despite constant strain. This requires that the muscles develop in a coordinated manner with appropriate connections to other cell types they communicate with. Various signaling pathways as well as extrinsic and intrinsic factors are known to play a role during Drosophila muscle development, diversification, and homeostasis. In this review, we discuss genetic control mechanisms of muscle contraction, development, and homeostasis with particular emphasis on the contractile unit of the muscle, the sarcomere.
      Citation: Cells
      PubDate: 2020-06-25
      DOI: 10.3390/cells9061543
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1544: Circular RNAs in Sepsis: Biogenesis, Function,
           and Clinical Significance

    • Authors: Jesús Beltrán-García, Rebeca Osca-Verdegal, Elena Nacher-Sendra, Federico V. Pallardó, José Luis García-Giménez
      First page: 1544
      Abstract: Sepsis is a life-threatening condition that occurs when the body responds to an infection that damages it is own tissues. The major problem in sepsis is rapid, vital status deterioration in patients, which can progress to septic shock with multiple organ failure if not properly treated. As there are no specific treatments, early diagnosis is mandatory to reduce high mortality. Despite more than 170 different biomarkers being postulated, early sepsis diagnosis and prognosis remain a challenge for clinicians. Recent findings propose that circular RNAs (circRNAs) may play a prominent role in regulating the patients’ immune system against different pathogens, including bacteria and viruses. Mounting evidence also suggests that the misregulation of circRNAs is an early event in a wide range of diseases, including sepsis. Despite circRNA levels being altered in sepsis, the specific mechanisms controlling the dysregulation of these noncoding RNAs are not completely elucidated, although many factors are known to affect circRNA biogenesis. Therefore, there is a need to explore the molecular pathways that lead to this disorder. This review describes the role of this new class of regulatory RNAs in sepsis and the feasibility of using circRNAs as diagnostic biomarkers for sepsis, opening up new avenues for circRNA-based medicine.
      Citation: Cells
      PubDate: 2020-06-25
      DOI: 10.3390/cells9061544
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1545: A Systematic Review of WNT Signaling in
           Endothelial Cell Oligodendrocyte Interactions: Potential Relevance to
           Cerebral Small Vessel Disease

    • Authors: Narek Manukjan, Zubair Ahmed, Daniel Fulton, W. Matthijs Blankesteijn, Sébastien Foulquier
      First page: 1545
      Abstract: Key pathological features of cerebral small vessel disease (cSVD) include impairment of the blood brain barrier (BBB) and the progression of white matter lesions (WMLs) amongst other structural lesions, leading to the clinical manifestations of cSVD. The function of endothelial cells (ECs) is of major importance to maintain a proper BBB. ECs interact with several cell types to provide structural and functional support to the brain. Oligodendrocytes (OLs) myelinate axons in the central nervous system and are crucial in sustaining the integrity of white matter. The interplay between ECs and OLs and their precursor cells (OPCs) has received limited attention yet seems of relevance for the study of BBB dysfunction and white matter injury in cSVD. Emerging evidence shows a crosstalk between ECs and OPCs/OLs, mediated by signaling through the Wingless and Int-1 (WNT)/β-catenin pathway. As the latter is involved in EC function (e.g., angiogenesis) and oligodendrogenesis, we reviewed the role of WNT/β-catenin signaling for both cell types and performed a systematic search to identify studies describing a WNT-mediated interplay between ECs and OPCs/OLs. Dysregulation of this interaction may limit remyelination of WMLs and render the BBB leaky, thereby initiating a vicious neuroinflammatory cycle. A better understanding of the role of this signaling pathway in EC–OL crosstalk is essential in understanding cSVD development.
      Citation: Cells
      PubDate: 2020-06-25
      DOI: 10.3390/cells9061545
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1546: Protein Kinase CK2 Regulates Nerve/Glial
           Antigen (NG)2-Mediated Angiogenic Activity of Human Pericytes

    • Authors: Beate M. Schmitt, Anne S. Boewe, Vivien Becker, Lisa Nalbach, Yuan Gu, Claudia Götz, Michael D. Menger, Matthias W. Laschke, Emmanuel Ampofo
      First page: 1546
      Abstract: Protein kinase CK2 is a crucial regulator of endothelial cell proliferation, migration and sprouting during angiogenesis. However, it is still unknown whether this kinase additionally affects the angiogenic activity of other vessel-associated cells. In this study, we investigated the effect of CK2 inhibition on primary human pericytes. We found that CK2 inhibition reduces the expression of nerve/glial antigen (NG)2, a crucial factor which is involved in angiogenic processes. Reporter gene assays revealed a 114 bp transcriptional active region of the human NG2 promoter, whose activity was decreased after CK2 inhibition. Functional analyses demonstrated that the pharmacological inhibition of CK2 by CX-4945 suppresses pericyte proliferation, migration, spheroid sprouting and the stabilization of endothelial tubes. Moreover, aortic rings of NG2−/− mice showed a significantly reduced vascular sprouting when compared to rings of NG2+/+ mice, indicating that NG2 is an important regulator of the angiogenic activity of pericytes. In vivo, implanted Matrigel plugs containing CX-4945-treated pericytes exhibited a lower microvessel density when compared to controls. These findings demonstrate that CK2 regulates the angiogenic activity of pericytes through NG2 gene expression. Hence, the inhibition of CK2 represents a promising anti-angiogenic strategy, because it does not only target endothelial cells, but also vessel-associated pericytes.
      Citation: Cells
      PubDate: 2020-06-25
      DOI: 10.3390/cells9061546
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1547: Insight into Salivary Gland Aquaporins

    • Authors: Claudia D’Agostino, Osama A. Elkashty, Clara Chivasso, Jason Perret, Simon D. Tran, Christine Delporte
      First page: 1547
      Abstract: The main role of salivary glands (SG) is the production and secretion of saliva, in which aquaporins (AQPs) play a key role by ensuring water flow. The AQPs are transmembrane channel proteins permeable to water to allow water transport across cell membranes according to osmotic gradient. This review gives an insight into SG AQPs. Indeed, it gives a summary of the expression and localization of AQPs in adult human, rat and mouse SG, as well as of their physiological role in SG function. Furthermore, the review provides a comprehensive view of the involvement of AQPs in pathological conditions affecting SG, including Sjögren’s syndrome, diabetes, agedness, head and neck cancer radiotherapy and SG cancer. These conditions are characterized by salivary hypofunction resulting in xerostomia. A specific focus is given on current and future therapeutic strategies aiming at AQPs to treat xerostomia. A deeper understanding of the AQPs involvement in molecular mechanisms of saliva secretion and diseases offered new avenues for therapeutic approaches, including drugs, gene therapy and tissue engineering. As such, AQP5 represents a potential therapeutic target in different strategies for the treatment of xerostomia.
      Citation: Cells
      PubDate: 2020-06-25
      DOI: 10.3390/cells9061547
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1548: Molecular Basis for Ser/Thr Specificity in PKA
           Signaling

    • Authors: Matthias J. Knape, Maximilian Wallbott, Nicole C.G. Burghardt, Daniela Bertinetti, Jan Hornung, Sven H. Schmidt, Robin Lorenz, Friedrich W. Herberg
      First page: 1548
      Abstract: cAMP-dependent protein kinase (PKA) is the major receptor of the second messenger cAMP and a prototype for Ser/Thr-specific protein kinases. Although PKA strongly prefers serine over threonine substrates, little is known about the molecular basis of this substrate specificity. We employ classical enzyme kinetics and a surface plasmon resonance (SPR)-based method to analyze each step of the kinase reaction. In the absence of divalent metal ions and nucleotides, PKA binds serine (PKS) and threonine (PKT) substrates, derived from the heat-stable protein kinase inhibitor (PKI), with similar affinities. However, in the presence of metal ions and adenine nucleotides, the Michaelis complex for PKT is unstable. PKA phosphorylates PKT with a higher turnover due to a faster dissociation of the product complex. Thus, threonine substrates are not necessarily poor substrates of PKA. Mutation of the DFG+1 phenylalanine to β-branched amino acids increases the catalytic efficiency of PKA for a threonine peptide substrate up to 200-fold. The PKA Cα mutant F187V forms a stable Michaelis complex with PKT and shows no preference for serine versus threonine substrates. Disease-associated mutations of the DFG+1 position in other protein kinases underline the importance of substrate specificity for keeping signaling pathways segregated and precisely regulated.
      Citation: Cells
      PubDate: 2020-06-25
      DOI: 10.3390/cells9061548
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1549: A Review on Notch Signaling and Colorectal
           Cancer

    • Authors: Ashish Tyagi, Arun K. Sharma, Chendil Damodaran
      First page: 1549
      Abstract: Colorectal cancer (CRC) has one of the highest mortality rates despite the advancement of treatment options. Aggressive CRC remains difficult to treat owing to the activation of oncogenic signaling pathways such as the Notch signaling pathway. The role of Notch receptors varies according to the difference in their structures; in particular, aberrant activation of Notch1 has been attributed to the severity of CRC. Notch1 activation in CRC is inhibited by small molecule inhibitors that target γ-secretase, an enzyme responsible for the third and last cleavage step of Notch receptors. γ-Secretase also produces the intracellular domain that finally carries out cellular functions by activating downstream effectors. However, most inhibitors block γ-secretase non-selectively and cause severe toxicity. Plant-source-derived small molecules, monoclonal antibodies, biological molecules (such as SiRNAs), and compounds targeting the Notch1 receptor itself or the downstream molecules such as HES1 are some of the options that are in advanced stages of clinical trials. The Negative Regulatory Region (NRR), which plays a central role in the transduction of Notch1 signaling in the event of ligand-dependent and ligand-independent Notch1 processing is also being targeted specifically by monoclonal antibodies (mAbs) to prevent aberrant Notch1 activation. In this review, we discuss the role of Notch1 in CRC, particularly its metastatic phenotype, and how mutations in Notch1, specifically in its NRR region, contribute to the aberrant activation of Notch1 signaling, which, in turn, contributes to CRC pathogenesis. We also discuss prevailing and emerging therapies that target the Notch1 receptor and the NRR region, and we highlight the potential of these therapies in abrogating Notch signaling and, thus, CRC development and progression.
      Citation: Cells
      PubDate: 2020-06-25
      DOI: 10.3390/cells9061549
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1550: Nicotinamide Supplementation during the In
           Vitro Maturation of Oocytes Improves the Developmental Competence of
           Preimplantation Embryos: Potential Link to SIRT1/AKT Signaling

    • Authors: Marwa El Sheikh, Ahmed Atef Mesalam, Muhammad Idrees, Tabinda Sidrat, Ayman Mesalam, Kyeong-Lim Lee, Il-Keun Kong
      First page: 1550
      Abstract: Nicotinamide (NAM), the amide form of vitamin B3, plays pivotal roles in regulating various cellular processes including energy production and maintenance of genomic stability. The current study aimed at deciphering the effect of NAM, when administered during in vitro maturation (IVM), on the developmental competence of bovine preimplantation embryos. Our results showed that low NAM concentrations reduced the oxidative stress and improved mitochondrial profile, total cleavage and 8–16 cell stage embryo development whereas the opposite profile was observed upon exposure to high NAM concentrations (10 mM onward). Remarkably, the hatching rates of day-7 and day-8 blastocysts were significantly improved under 0.1 mM NAM treatment. Using RT-qPCR and immunofluorescence, the autophagy-related (Beclin-1 (BECN1), LC3B, and ATG5) and the apoptotic (Caspases; CASP3 and 9) markers were upregulated in oocytes exposed to high NAM concentration (40 mM), whereas only CASP3 was affected, downregulated, following 0.1 mM treatment. Additionally, the number of cells per blastocyst and the levels of SIRT1, PI3K, AKT, and mTOR were higher, while the inner cell mass-specific transcription factors GATA6, SOX2, and OCT4 were more abundant, in day-8 embryos of NAM-treated group. Taken together, to our knowledge, this is the first study reporting that administration of low NAM concentrations during IVM can ameliorate the developmental competence of embryos through the potential regulation of oxidative stress, apoptosis, and SIRT1/AKT signaling.
      Citation: Cells
      PubDate: 2020-06-25
      DOI: 10.3390/cells9061550
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1551: Synthesis and Evaluation of Dodecaboranethiol
           Containing Kojic Acid (KA-BSH) as a Novel Agent for Boron Neutron Capture
           Therapy

    • Authors: Koji Takeuchi, Yoshihide Hattori, Shinji Kawabata, Gen Futamura, Ryo Hiramatsu, Masahiko Wanibuchi, Hiroki Tanaka, Shin-ichiro Masunaga, Koji Ono, Shin-Ichi Miyatake, Mitsunori Kirihata
      First page: 1551
      Abstract: Boron neutron capture therapy (BNCT) is a form of tumor-cell selective particle irradiation using low-energy neutron irradiation of boron-10 (10B) to produce high-linear energy transfer (LET) alpha particles and recoiling 7Li nuclei (10B [n, alpha] 7Li) in tumor cells. Therefore, it is important to achieve the selective delivery of large amounts of 10B to tumor cells, with only small amounts of 10B to normal tissues. To develop practical materials utilizing 10B carriers, we designed and synthesized novel dodecaboranethiol (BSH)-containing kojic acid (KA-BSH). In the present study, we evaluated the effects of this novel 10B carrier on cytotoxicity, 10B concentrations in F98 rat glioma cells, and micro-distribution of KA-BSH in vitro. Furthermore, biodistribution studies were performed in a rat brain tumor model. The tumor boron concentrations showed the highest concentrations at 1 h after the termination of administration. Based on these results, neutron irradiation was evaluated at the Kyoto University Research Reactor Institute (KURRI) with KA-BSH. Median survival times (MSTs) of untreated and irradiated control rats were 29.5 and 30.5 days, respectively, while animals that received KA-BSH, followed by neutron irradiation, had an MST of 36.0 days (p = 0.0027, 0.0053). Based on these findings, further studies are warranted in using KA-BSH as a new B compound for malignant glioma.
      Citation: Cells
      PubDate: 2020-06-25
      DOI: 10.3390/cells9061551
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1552: The NLRP3 Inflammasome as a Critical Actor in
           the Inflammaging Process

    • Authors: Maria Sebastian-Valverde, Giulio M. Pasinetti
      First page: 1552
      Abstract: As a consequence of the considerable increase in the human lifespan over the last century, we are experiencing the appearance and impact of new age-related diseases. The causal relationships between aging and an enhanced susceptibility of suffering from a broad spectrum of diseases need to be better understood. However, one specific shared feature seems to be of capital relevance for most of these conditions: the low-grade chronic inflammatory state inherently associated with aging, i.e., inflammaging. Here, we review the molecular and cellular mechanisms that link aging and inflammaging, focusing on the role of the innate immunity and more concretely on the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, as well as how the chronic activation of this inflammasome has a detrimental effect on different age-related disorders.
      Citation: Cells
      PubDate: 2020-06-26
      DOI: 10.3390/cells9061552
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1553: Amyloid Proteins and Peripheral Neuropathy

    • Authors: Mohammed M. H. Asiri, Sjoukje Engelsman, Niels Eijkelkamp, Jo W. M. Höppener
      First page: 1553
      Abstract: Painful peripheral neuropathy affects millions of people worldwide. Peripheral neuropathy develops in patients with various diseases, including rare familial or acquired amyloid polyneuropathies, as well as some common diseases, including type 2 diabetes mellitus and several chronic inflammatory diseases. Intriguingly, these diseases share a histopathological feature—deposits of amyloid-forming proteins in tissues. Amyloid-forming proteins may cause tissue dysregulation and damage, including damage to nerves, and may be a common cause of neuropathy in these, and potentially other, diseases. Here, we will discuss how amyloid proteins contribute to peripheral neuropathy by reviewing the current understanding of pathogenic mechanisms in known inherited and acquired (usually rare) amyloid neuropathies. In addition, we will discuss the potential role of amyloid proteins in peripheral neuropathy in some common diseases, which are not (yet) considered as amyloid neuropathies. We conclude that there are many similarities in the molecular and cell biological defects caused by aggregation of the various amyloid proteins in these different diseases and propose a common pathogenic pathway for “peripheral amyloid neuropathies”.
      Citation: Cells
      PubDate: 2020-06-26
      DOI: 10.3390/cells9061553
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1554: Moonlighting in Mitosis: Analysis of the
           Mitotic Functions of Transcription and Splicing Factors

    • Authors: Maria Patrizia Somma, Evgeniya N. Andreyeva, Gera A. Pavlova, Claudia Pellacani, Elisabetta Bucciarelli, Julia V. Popova, Silvia Bonaccorsi, Alexey V. Pindyurin, Maurizio Gatti
      First page: 1554
      Abstract: Moonlighting proteins can perform one or more additional functions besides their primary role. It has been posited that a protein can acquire a moonlighting function through a gradual evolutionary process, which is favored when the primary and secondary functions are exerted in different cellular compartments. Transcription factors (TFs) and splicing factors (SFs) control processes that occur in interphase nuclei and are strongly reduced during cell division, and are therefore in a favorable situation to evolve moonlighting mitotic functions. However, recently published moonlighting protein databases, which comprise almost 400 proteins, do not include TFs and SFs with secondary mitotic functions. We searched the literature and found several TFs and SFs with bona fide moonlighting mitotic functions, namely they localize to specific mitotic structure(s), interact with proteins enriched in the same structure(s), and are required for proper morphology and functioning of the structure(s). In addition, we describe TFs and SFs that localize to mitotic structures but cannot be classified as moonlighting proteins due to insufficient data on their biochemical interactions and mitotic roles. Nevertheless, we hypothesize that most TFs and SFs with specific mitotic localizations have either minor or redundant moonlighting functions, or are evolving towards the acquisition of these functions.
      Citation: Cells
      PubDate: 2020-06-26
      DOI: 10.3390/cells9061554
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1555: Redox Regulation of NOX Isoforms on
           FAK(Y397)/SRC(Y416) Phosphorylation Driven Epithelial-to-Mesenchymal
           Transition in Malignant Cervical Epithelial Cells

    • Authors: Young Mee Kim, Karthika Muthuramalingam, Moonjae Cho
      First page: 1555
      Abstract: Epithelial-to-mesenchymal transition (EMT) promulgates epithelial cell associated disease-defining characteristics in tumorigenesis and organ fibrosis. Growth factors such as epidermal growth factor and fibroblast growth factor in addition to cytokines such as transforming growth factor-β1 (TGF-β1) is said to play a prominent role in remodeling related pathological events of cancer progression such as invasion, metastasis, apoptosis, EMT, etc. through redox related cellular secondary messengers, in particular the reactive oxygen species (ROS). However, the signaling cascade underlying the redox mechanism and thereby the progression of EMT remains largely unknown. In this study, upon TGF-β1 treatment, we observed an induction in NOX isoforms—NOX2 and NOX4—that have time (early and late) and cellular localization (nucleus and autophagosome co-localized) dependent effects in mediating EMT associated cell proliferation and migration through activation of the focal adhesion kinase (FAK)/SRC pathway in HeLa, human cervical cancer cells. Upon silencing NOX2/4 gene expression and using the SRC inhibitor (AZD0530), progression of TGF-β1 induced EMT related cellular remodeling, extra cellular matrix (ECM) production, cell migration and invasion, got significantly reverted. Together, these results indicate that NOX2 and NOX4 play important, albeit distinct, roles in the activation of cytokine mediated EMT and its associated processes via tyrosine phosphorylation of the FAK/SRC pathway.
      Citation: Cells
      PubDate: 2020-06-26
      DOI: 10.3390/cells9061555
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1556: Circulating microRNA Signature Associated to
           Interstitial Lung Abnormalities in Respiratory Asymptomatic Subjects

    • Authors: Blanca Ortiz-Quintero, Ivette Buendía-Roldán, Eric Gustavo Ramírez-Salazar, Yalbi I Balderas-Martínez, Sandra Lizbeth Ramírez-Rodríguez, Karen Martínez-Espinosa, Moisés Selman
      First page: 1556
      Abstract: Interstitial lung abnormalities (ILA) are observed in around 9% of older respiratory asymptomatic subjects, mainly smokers. Evidence suggests that ILA may precede the development of interstitial lung diseases and may evolve to progressive fibrosis. Identifying biomarkers of this subclinical status is relevant for early diagnosis and to predict outcome. We aimed to identify circulating microRNAs (miRNAs) associated to ILA in a cohort of respiratory asymptomatic subjects older than 60 years. We identified 81 subjects with ILA from our Lung-Aging Program in Mexico City (n = 826). We randomly selected 112 subjects without ILA (Ctrl) from the same cohort. Using polymerase chain reaction PCR-Array technology (24 ILA and 24 Ctrl, screening cohort) and reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) (57 ILA and 88 Ctr, independent validation cohort) we identified seven up-regulated miRNAs in serum of ILA compared to Ctrl (miR-193a-5p, p < 0.0001; miR-502-3p, p < 0.0001; miR-200c-3p, p = 0.003; miR-16-5p, p = 0.003; miR-21-5p, p = 0.002; miR-126-3p, p = 0.004 and miR-34a-5p, p < 0.005). Pathways regulated by these miRNAs include transforming growth factor beta (TGF-β), Wnt, mammalian target of rapamycin (mTOR), Insulin, mitogen-activated protein kinase (MAPK) signaling, and senescence. Receiver operator characteristic (ROC) curve analysis indicated that miR-193a-5p (area under the curve AUC: 0.75) and miR-502-3p (AUC 0.71) have acceptable diagnostic value. This is the first identification of circulating miRNAs associated to ILA in respiratory asymptomatic subjects, providing potential non-invasive biomarkers and molecular targets to better understand the pathogenic mechanisms associated to ILA.
      Citation: Cells
      PubDate: 2020-06-26
      DOI: 10.3390/cells9061556
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1557: Substantially Altered Expression Profile of
           Diabetes/Cardiovascular/Cerebrovascular Disease Associated microRNAs in
           Children Descending from Pregnancy Complicated by Gestational Diabetes
           Mellitus—One of Several Possible Reasons for an Increased Cardiovascular
           Risk

    • Authors: Ilona Hromadnikova, Katerina Kotlabova, Lenka Dvorakova, Ladislav Krofta, Jan Sirc
      First page: 1557
      Abstract: Gestational diabetes mellitus (GDM), one of the major pregnancy-related complications, characterized as a transitory form of diabetes induced by insulin resistance accompanied by a low/absent pancreatic beta-cell compensatory adaptation to the increased insulin demand, causes the acute, long-term, and transgenerational health complications. The aim of the study was to assess if alterations in gene expression of microRNAs associated with diabetes/cardiovascular/cerebrovascular diseases are present in whole peripheral blood of children aged 3–11 years descending from GDM complicated pregnancies. A substantially altered microRNA expression profile was found in children descending from GDM complicated pregnancies. Almost all microRNAs with the exception of miR-92a-3p, miR-155-5p, and miR-210-3p were upregulated. The microRNA expression profile also differed between children after normal and GDM complicated pregnancies in relation to the presence of overweight/obesity, prehypertension/hypertension, and/or valve problems and heart defects. Always, screening based on the combination of microRNAs was superior over using individual microRNAs, since at 10.0% false positive rate it was able to identify a large proportion of children with an aberrant microRNA expression profile (88.14% regardless of clinical findings, 75.41% with normal clinical findings, and 96.49% with abnormal clinical findings). In addition, the higher incidence of valve problems and heart defects was found in children with a prior exposure to GDM. The extensive file of predicted targets of all microRNAs aberrantly expressed in children descending from GDM complicated pregnancies indicates that a large group of these genes is involved in ontologies of diabetes/cardiovascular/cerebrovascular diseases. In general, children with a prior exposure to GDM are at higher risk of later development of diabetes mellitus and cardiovascular/cerebrovascular diseases, and would benefit from dispensarisation as well as implementation of primary prevention strategies.
      Citation: Cells
      PubDate: 2020-06-26
      DOI: 10.3390/cells9061557
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1558: Targeting Cardiac Stem Cell Senescence to Treat
           Cardiac Aging and Disease

    • Authors: Eleonora Cianflone, Michele Torella, Flavia Biamonte, Antonella De Angelis, Konrad Urbanek, Francesco S. Costanzo, Marcello Rota, Georgina M. Ellison-Hughes, Daniele Torella
      First page: 1558
      Abstract: Adult stem/progenitor are a small population of cells that reside in tissue-specific niches and possess the potential to differentiate in all cell types of the organ in which they operate. Adult stem cells are implicated with the homeostasis, regeneration, and aging of all tissues. Tissue-specific adult stem cell senescence has emerged as an attractive theory for the decline in mammalian tissue and organ function during aging. Cardiac aging, in particular, manifests as functional tissue degeneration that leads to heart failure. Adult cardiac stem/progenitor cell (CSC) senescence has been accordingly associated with physiological and pathological processes encompassing both non-age and age-related decline in cardiac tissue repair and organ dysfunction and disease. Senescence is a highly active and dynamic cell process with a first classical hallmark represented by its replicative limit, which is the establishment of a stable growth arrest over time that is mainly secondary to DNA damage and reactive oxygen species (ROS) accumulation elicited by different intrinsic stimuli (like metabolism), as well as external stimuli and age. Replicative senescence is mainly executed by telomere shortening, the activation of the p53/p16INK4/Rb molecular pathways, and chromatin remodeling. In addition, senescent cells produce and secrete a complex mixture of molecules, commonly known as the senescence-associated secretory phenotype (SASP), that regulate most of their non-cell-autonomous effects. In this review, we discuss the molecular and cellular mechanisms regulating different characteristics of the senescence phenotype and their consequences for adult CSCs in particular. Because senescent cells contribute to the outcome of a variety of cardiac diseases, including age-related and unrelated cardiac diseases like diabetic cardiomyopathy and anthracycline cardiotoxicity, therapies that target senescent cell clearance are actively being explored. Moreover, the further understanding of the reversibility of the senescence phenotype will help to develop novel rational therapeutic strategies.
      Citation: Cells
      PubDate: 2020-06-26
      DOI: 10.3390/cells9061558
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1559: Immunotherapy in Myeloproliferative Diseases

    • Authors: Lukas M. Braun, Robert Zeiser
      First page: 1559
      Abstract: Myeloproliferative diseases, including myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS), are driven by genetic abnormalities and increased inflammatory signaling and are at high risk to transform into acute myeloid leukemia (AML). Myeloid-derived suppressor cells were reported to enhance leukemia immune escape by suppressing an effective anti-tumor immune response. MPNs are a potentially immunogenic disease as shown by their response to interferon-α treatment and allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Novel immunotherapeutic approaches such as immune checkpoint inhibition, tumor vaccination, or cellular therapies using target-specific lymphocytes have so far not shown strong therapeutic efficacy. Potential reasons could be the pro-inflammatory and immunosuppressive microenvironment in the bone marrow of patients with MPN, driving tumor immune escape. In this review, we discuss the biology of MPNs with respect to the pro-inflammatory milieu in the bone marrow (BM) and potential immunotherapeutic approaches.
      Citation: Cells
      PubDate: 2020-06-26
      DOI: 10.3390/cells9061559
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1560: Mistletoe-Extract Drugs Stimulate Anti-Cancer
           Vγ9Vδ2 T Cells

    • Authors: Ling Ma, Swati Phalke, Caroline Stévigny, Florence Souard, David Vermijlen
      First page: 1560
      Abstract: Human phosphoantigen-reactive Vγ9Vδ2 T cells possess several characteristics, including MHC-independent recognition of tumor cells and potent killing potential, that make them attractive candidates for cancer immunotherapeutic approaches. Injectable preparations from the hemi-parasite plant Viscum album L. (European mistletoe) are commonly prescribed as complementary cancer therapy in European countries such as Germany, but their mechanism of action remains poorly understood. Here, we investigated in-depth the in vitro response of human T cells towards mistletoe-extract drugs by analyzing their functional and T-cell-receptor (TCR) response using flow cytometry and high-throughput sequencing respectively. Non-fermented mistletoe-extract drugs (AbnobaViscum), but not their fermented counterparts (Iscador), induced specific expansion of Vγ9Vδ2 T cells among T cells. Furthermore, AbnobaViscum rapidly induced the release of cytotoxic granules and the production of the cytokines IFNγ and TNFα in Vγ9Vδ2 T cells. This stimulation of anti-cancer Vγ9Vδ2 T cells was mediated by the butyrophilin BTN3A, did not depend on the accumulation of endogenous phosphoantigens and involved the same Vγ9Vδ2 TCR repertoire as those of phosphoantigen-reactive Vγ9Vδ2 T cells. These insights highlight Vγ9Vδ2 T cells as a potential target for mistletoe-extract drugs and their role in cancer patients receiving these herbal drugs needs to be investigated.
      Citation: Cells
      PubDate: 2020-06-26
      DOI: 10.3390/cells9061560
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1561: Cathelicidin-Related Antimicrobial Peptide
           Regulates CD73 Expression in Mouse Th17 Cells via p38

    • Authors: Jeonghyun Lee, Kyong-Oh Shin, Yesol Kim, Jaewon Cho, Hyung W. Lim, Sung-Il Yoon, Geun-Shik Lee, Hyun-Jeong Ko, Pyeung-Hyeun Kim, Yoshikazu Uchida, Kyungho Park, Seung Goo Kang
      First page: 1561
      Abstract: The effector function of tumor-infiltrated CD4+ T cells is readily suppressed by many types of immune regulators in the tumor microenvironment, which is one of the major mechanisms of immune tolerance against cancer. Cathelicidin-related antimicrobial peptide (CRAMP), the mouse analog of LL-37 peptide in humans, is a cationic antimicrobial peptide belonging to the cathelicidin family; however, its secretion by cancer cells and role in the tumor microenvironment (TME) remain unclear. In this study, we explored the possibility of an interaction between effector CD4+ T cells and CRAMP using in vitro-generated mouse Th17 cells. We found that CRAMP stimulates Th17 cells to express the ectonucleotidase CD73, while simultaneously inducing cell death. This finding suggested that CD73-expressing Th17 cells may function as immune suppressor cells instead of effector cells. In addition, treatment of pharmacological inhibitors of the transforming growth factor-beta (TGF-β) signaling pathway showed that induction of CD73 expression is mediated by the p38 signaling pathway. Overall, our findings suggest that tumor-derived LL-37 likely functions as an immune suppressor that induces immune tolerance against tumors through shaping effector Th17 cells into suppressor Th17 cells, suggesting a new intervention target to improve cancer immunotherapy.
      Citation: Cells
      PubDate: 2020-06-26
      DOI: 10.3390/cells9061561
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1562: Characterization of Hspb8 in Zebrafish

    • Authors: Magda Dubińska-Magiera, Joanna Niedbalska-Tarnowska, Marta Migocka-Patrzałek, Ewelina Posyniak, Małgorzata Daczewska
      First page: 1562
      Abstract: Hspb8 is a member of the small heat shock protein (sHSP) family. Its expression is known to be upregulated under heat shock. This protein interacts with different partners and can, therefore, be involved in various processes relevant to tissue integrity and functioning. In humans, mutations in the gene encoding Hspb8 can lead to the development of various diseases such as myopathies and neuropathies. In our study, we aimed to perform an in-depth characterization of zebrafish Hspb8 during zebrafish development. We applied techniques such as RT-qPCR, Western blot, immunofluorescence, co-immunoprecipitation, LC-MS, and morpholino-mediated knockdown. We broadened the knowledge regarding zebrafish hspb8 expression during development under normal and heat shock conditions as well as its tissue- and subcellular-specific localization. A co-IP analysis allowed us to conclude that zebrafish Hspb8 can interact with proteins such as Bag3 and Hsc70, which are crucial for formation of an autophagy-inducing complex. We also demonstrated that hspb8 morpholino-mediated knockdown has an impact on zebrafish embryos’ morphology, muscle ultrastructure, and motility behavior. Our research provides a valuable resource for the potential use of the zebrafish as a model for studying pathological conditions associated with hspb8 disorders.
      Citation: Cells
      PubDate: 2020-06-26
      DOI: 10.3390/cells9061562
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1563: Polysaccharide Multilayer Films in Sensors for
           Detecting Prostate Tumor Cells Based on Hyaluronan-CD44 Interactions

    • Authors: João Batista Maia Rocha Neto, Andrey Coatrini Soares, Rogério Aparecido Bataglioli, Olívia Carr, Carlos Alberto Rodrigues Costa, Osvaldo N. Oliveira, Marisa Masumi Beppu, Hernandes F. Carvalho
      First page: 1563
      Abstract: The increasing need for point-of-care diagnosis has sparked the development of label-free sensing platforms, some of which are based on impedance measurements with biological cells. Here, interdigitated electrodes were functionalized with layer-by-layer (LbL) films of hyaluronan (HA) and chitosan (CHI) to detect prostatic tumor cells (PC3 line). The deposition of LbL films was confirmed with atomic force microscopy and polarization-modulated infrared reflection absorption spectroscopy (PM-IRRAS), which featured the vibrational modes of the HA top layer capable of interacting specifically with glycoprotein CD44 receptors overexpressed in tumor cells. Though the CHI/HA LbL films cannot be considered as a traditional biosensor due to their limited selectivity, it was possible to distinguish prostate tumor cells in the range from 50 to 600 cells/µL in in vitro experiments with impedance spectroscopy. This was achieved by treating the impedance data with information visualization methods, which confirmed the distinguishing ability of the films by observing the absence of false positives in a series of control experiments. The CD44–HA interactions may, therefore, be exploited in clinical analyses and point-of-care diagnostics for cancer, particularly if computational methods are used to process the data.
      Citation: Cells
      PubDate: 2020-06-26
      DOI: 10.3390/cells9061563
      Issue No: Vol. 9, No. 6 (2020)
       
  • Cells, Vol. 9, Pages 1564: Kynurenines in the Pathogenesis of Multiple
           Sclerosis: Therapeutic Perspectives

    • Authors: Tamás Biernacki, Dániel Sandi, Krisztina Bencsik, László Vécsei
      First page: 1564
      Abstract: Over the past years, an increasing amount of evidence has emerged in support of the kynurenine pathway’s (KP) pivotal role in the pathogenesis of several neurodegenerative, psychiatric, vascular and autoimmune diseases. Different neuroactive metabolites of the KP are known to exert opposite effects on neurons, some being neuroprotective (e.g., picolinic acid, kynurenic acid, and the cofactor nicotinamide adenine dinucleotide), while others are toxic to neurons (e.g., 3-hydroxykynurenine, quinolinic acid). Not only the alterations in the levels of the metabolites but also disturbances in their ratio (quinolinic acid/kynurenic acid) have been reported in several diseases. In addition to the metabolites, the enzymes participating in the KP have been unearthed to be involved in modulation of the immune system, the energetic upkeep of neurons and have been shown to influence redox processes and inflammatory cascades, revealing a sophisticated, intertwined system. This review considers various methods through which enzymes and metabolites of the kynurenine pathway influence the immune system, the roles they play in the pathogenesis of neuroinflammatory diseases based on current evidence with a focus on their involvement in multiple sclerosis, as well as therapeutic approaches.
      Citation: Cells
      PubDate: 2020-06-26
      DOI: 10.3390/cells9061564
      Issue No: Vol. 9, No. 6 (2020)
       
 
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