Publisher: MDPI   (Total: 233 journals)

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Showing 1 - 200 of 233 Journals sorted alphabetically
Acoustics     Open Access   (Followers: 3)
Actuators     Open Access   (Followers: 4)
Administrative Sciences     Open Access   (Followers: 4)
Aerospace     Open Access   (Followers: 58, SJR: 0.305, CiteScore: 1)
Agriculture     Open Access   (Followers: 8, SJR: 0.33, CiteScore: 2)
AgriEngineering     Open Access   (Followers: 1)
Agronomy     Open Access   (Followers: 14, SJR: 0.695, CiteScore: 2)
Algorithms     Open Access   (Followers: 13, SJR: 0.217, CiteScore: 1)
Allergies     Open Access   (Followers: 2)
Animals     Open Access   (Followers: 15, SJR: 0.744, CiteScore: 2)
Antibiotics     Open Access   (Followers: 9, SJR: 1.063, CiteScore: 3)
Antibodies     Open Access   (Followers: 2, SJR: 0.931, CiteScore: 3)
Antioxidants     Open Access   (Followers: 5, SJR: 0.847, CiteScore: 3)
Applied Sciences     Open Access   (Followers: 6, SJR: 0.303, CiteScore: 2)
Applied System Innovation     Open Access  
Arts     Open Access   (Followers: 9)
Atmosphere     Open Access   (Followers: 25)
Atoms     Open Access   (Followers: 1)
Axioms     Open Access   (Followers: 1)
Batteries     Open Access   (Followers: 9)
Behavioral Sciences     Open Access   (Followers: 4)
Beverages     Open Access   (Followers: 1)
Big Data and Cognitive Computing     Open Access   (Followers: 7)
Bioengineering     Open Access   (Followers: 4)
Biology     Open Access   (Followers: 4, SJR: 1.324, CiteScore: 3)
Biomedicines     Open Access   (Followers: 1)
Biomimetics     Open Access  
Biomolecules     Open Access   (Followers: 1, SJR: 2.552, CiteScore: 6)
Biosensors     Open Access   (Followers: 3, SJR: 0.829, CiteScore: 4)
Brain Sciences     Open Access   (Followers: 5, SJR: 1.047, CiteScore: 3)
Buildings     Open Access   (Followers: 8)
C - J. of Carbon Research     Open Access   (Followers: 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)
ChemEngineering     Open Access  
Chemistry     Open Access  
Chemosensors     Open Access   (Followers: 1)
Children     Open Access   (Followers: 2)
Chromatography     Open Access   (Followers: 3)
Clean Technologies     Open Access  
Climate     Open Access   (Followers: 5)
Clocks & Sleep     Open Access   (Followers: 2)
Coatings     Open Access   (Followers: 4)
Colloids and Interfaces     Open Access  
Computation     Open Access   (Followers: 1)
Computers     Open Access   (Followers: 2)
Condensed Matter     Open Access   (Followers: 3)
Corrosion and Materials Degradation     Open Access   (Followers: 1)
Cosmetics     Open Access   (Followers: 5)
Cryptography     Open Access  
Crystals     Open Access   (Followers: 4, SJR: 0.566, CiteScore: 2)
Cyber     Open Access   (Followers: 2)
Dairy     Open Access   (Followers: 2)
Data     Open Access   (Followers: 4)
Dentistry J.     Open Access   (Followers: 6)
Designs     Open Access  
Diagnostics     Open Access   (Followers: 1, SJR: 0.669, CiteScore: 2)
Diseases     Open Access  
Diversity     Open Access   (Followers: 4)
Drones     Open Access   (Followers: 5)
Econometrics     Open Access   (Followers: 12)
Economies     Open Access   (Followers: 1)
Education     Open Access   (Followers: 13)
Electronics     Open Access   (Followers: 111, SJR: 0.548, CiteScore: 3)
Energies     Open Access   (Followers: 6, SJR: 0.67, CiteScore: 3)
Entropy     Open Access   (Followers: 8, SJR: 0.592, CiteScore: 2)
Environments     Open Access  
Epigenomes     Open Access  
European J. of Burn Care     Open Access  
European J. of Investigation in Health, Psychology and Education     Open Access   (Followers: 5)
Fermentation     Open Access   (Followers: 3)
Fibers     Open Access   (Followers: 7)
Fire     Open Access  
Fishes     Open Access  
Fluids     Open Access   (Followers: 1)
Foods     Open Access  
Forecasting     Open Access   (Followers: 1)
Forests     Open Access   (Followers: 2, SJR: 0.812, CiteScore: 2)
Fractal and Fractional     Open Access  
Future Internet     Open Access   (Followers: 178, SJR: 0.219, CiteScore: 1)
Galaxies     Open Access   (Followers: 6)
Games     Open Access   (Followers: 3, SJR: 0.242, CiteScore: 1)
Gastrointestinal Disorders     Open Access  
Gels     Open Access  
Genealogy     Open Access  
Genes     Open Access   (Followers: 2, SJR: 1.82, CiteScore: 3)
GeoHazards     Open Access   (Followers: 1)
Geosciences     Open Access   (Followers: 3, SJR: 0.451, CiteScore: 2)
Geriatrics     Open Access   (Followers: 4)
Healthcare     Open Access   (Followers: 3)
Hearts     Open Access   (Followers: 2)
Heritage     Open Access  
High-Throughput     Open Access  
Histories     Open Access   (Followers: 1)
Horticulturae     Open Access   (Followers: 2)
Humanities     Open Access   (Followers: 15)
Hydrology     Open Access   (Followers: 5)
Informatics     Open Access   (Followers: 4)
Information     Open Access   (Followers: 48, SJR: 0.222, CiteScore: 1)
Infrastructures     Open Access  
Inorganics     Open Access   (Followers: 3)
Insects     Open Access   (Followers: 2, SJR: 0.897, CiteScore: 2)
Instruments     Open Access  
Intl. J. of Environmental Research and Public Health     Open Access   (Followers: 26, SJR: 0.735, CiteScore: 2)
Intl. J. of Financial Studies     Open Access   (Followers: 5)
Intl. J. of Molecular Sciences     Open Access   (Followers: 3, SJR: 1.26, CiteScore: 4)
Intl. J. of Neonatal Screening     Open Access   (Followers: 4)
Intl. J. of Turbomachinery, Propulsion and Power     Open Access   (Followers: 11)
Inventions     Open Access  
IoT     Open Access   (Followers: 2)
ISPRS Intl. J. of Geo-Information     Open Access   (Followers: 5, SJR: 0.493, CiteScore: 2)
J : Multidisciplinary Scientific J.     Open Access  
J. of Cardiovascular Development and Disease     Open Access   (Followers: 1)
J. of Clinical Medicine     Open Access   (Followers: 3)
J. of Composites Science     Open Access   (Followers: 3)
J. of Developmental Biology     Open Access   (Followers: 2)
J. of Functional Biomaterials     Open Access   (Followers: 3, SJR: 0.685, CiteScore: 3)
J. of Functional Morphology and Kinesiology     Open Access  
J. of Fungi     Open Access   (Followers: 3)
J. of Imaging     Open Access   (Followers: 3)
J. of Intelligence     Open Access   (Followers: 2)
J. of Low Power Electronics and Applications     Open Access   (Followers: 10, SJR: 0.222, CiteScore: 1)
J. of Manufacturing and Materials Processing     Open Access  
J. of Marine Science and Engineering     Open Access   (Followers: 2)
J. of Nanotheranostics     Open Access   (Followers: 1)
J. of Open Innovation : Technology, Market, and Complexity     Open Access   (Followers: 1)
J. of Otorhinolaryngology, Hearing and Balance Medicine     Open Access   (Followers: 1)
J. of Personalized Medicine     Open Access   (Followers: 3, SJR: 1.269, CiteScore: 3)
J. of Risk and Financial Management     Open Access   (Followers: 9)
J. of Sensor and Actuator Networks     Open Access   (Followers: 13)
J. of Xenobiotics     Open Access  
Land     Open Access   (Followers: 4)
Languages     Open Access   (Followers: 4)
Laws     Open Access   (Followers: 2)
Life     Open Access   (Followers: 2, SJR: 1.625, CiteScore: 3)
Literature     Open Access  
Logistics     Open Access   (Followers: 3)
Lubricants     Open Access   (Followers: 2)
Machine Learning and Knowledge Extraction     Open Access   (Followers: 5)
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: 6)
Minerals     Open Access   (Followers: 2, SJR: 0.462, CiteScore: 2)
Molbank     Open Access   (Followers: 1, SJR: 0.12, CiteScore: 0)
Molecules     Open Access   (Followers: 7, SJR: 0.855, CiteScore: 3)
Multimodal Technologies and Interaction     Open Access  
Nanomaterials     Open Access   (Followers: 5)
Neuroglia     Open Access   (Followers: 1)
Nitrogen     Open Access   (Followers: 2)
Non-Coding RNA     Open Access  
Nursing Reports     Open Access   (Followers: 3)
Nutrients     Open Access   (Followers: 11, SJR: 1.557, CiteScore: 4)
Oceans     Open Access  
Particles     Open Access  
Pathogens     Open Access   (Followers: 4, SJR: 1.421, CiteScore: 4)
Pharmaceuticals     Open Access   (Followers: 6, SJR: 1.293, CiteScore: 4)
Pharmaceutics     Open Access   (Followers: 4, SJR: 0.949, CiteScore: 4)
Pharmacy     Open Access   (Followers: 7)
Philosophies     Open Access  
Photonics     Open Access   (Followers: 6, SJR: 0.709, CiteScore: 2)
Physics     Open Access  
Plants     Open Access   (SJR: 1.39, CiteScore: 3)
Plasma     Open Access   (Followers: 5)
Polymers     Open Access   (Followers: 21, SJR: 0.852, CiteScore: 3)
Proceedings     Open Access   (Followers: 1)
Processes     Open Access  
Projects     Open Access   (Followers: 2)
Prosthesis     Open Access  
Proteomes     Open Access  
Psych     Open Access   (Followers: 1)
Publications     Open Access   (Followers: 7)
Quantum Beam Science     Open Access   (Followers: 1)
Quantum Reports     Open Access  
Quaternary     Open Access  
Reactions     Open Access   (Followers: 1)
Recycling     Open Access  
Religions     Open Access   (Followers: 4, SJR: 0.232, CiteScore: 1)
Remote Sensing     Open Access   (Followers: 54, SJR: 1.386, CiteScore: 4)
Reports     Open Access  
Resources     Open Access   (SJR: 0.688, CiteScore: 3)
Risks     Open Access  
Robotics     Open Access   (Followers: 9)
Safety     Open Access   (Followers: 2)
Sci     Open Access  

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

  This is an Open Access Journal Open Access journal
ISSN (Online) 2073-4409
Published by MDPI Homepage  [233 journals]
  • Cells, Vol. 10, Pages 195: Computer Navigation and 3D Printing in the
           Surgical Management of Bone Sarcoma

    • Authors: Robert Allan McCulloch, Tommaso Frisoni, Vineet Kurunskal, Davide Maria Donati, Lee Jeys
      First page: 195
      Abstract: The long-term outcomes of osteosarcoma have improved; however, patients with metastases, recurrence or axial disease continue to have a poor prognosis. Computer navigation in surgery is becoming ever more commonplace, and the proposed advantages, including precision during surgery, is particularly applicable to the field of orthopaedic oncology and challenging areas such as the axial skeleton. Within this article, we provide an overview of the field of computer navigation and computer-assisted tumour surgery (CATS), in particular its relevance to the surgical management of osteosarcoma.
      Citation: Cells
      PubDate: 2021-01-20
      DOI: 10.3390/cells10020195
      Issue No: Vol. 10, No. 2 (2021)
  • Cells, Vol. 10, Pages 196: Variability of Human rDNA

    • Authors: Smirnov, Chmúrčiaková, Liška, Bažantová, Cmarko
      First page: 196
      Abstract: In human cells, ribosomal DNA (rDNA) is arranged in ten clusters of multiple tandem repeats. Each repeat is usually described as consisting of two parts: the 13 kb long ribosomal part, containing three genes coding for 18S, 5.8S and 28S RNAs of the ribosomal particles, and the 30 kb long intergenic spacer (IGS). However, this standard scheme is, amazingly, often altered as a result of the peculiar instability of the locus, so that the sequence of each repeat and the number of the repeats in each cluster are highly variable. In the present review, we discuss the causes and types of human rDNA instability, the methods of its detection, its distribution within the locus, the ways in which it is prevented or reversed, and its biological significance. The data of the literature suggest that the variability of the rDNA is not only a potential cause of pathology, but also an important, though still poorly understood, aspect of the normal cell physiology.
      Citation: Cells
      PubDate: 2021-01-20
      DOI: 10.3390/cells10020196
      Issue No: Vol. 10, No. 2 (2021)
  • Cells, Vol. 10, Pages 197: Regulation of COX Assembly and Function by Twin
           CX9C Proteins—Implications for Human Disease

    • Authors: Gladyck, Aras, Hüttemann, Grossman
      First page: 197
      Abstract: Oxidative phosphorylation is a tightly regulated process in mammals that takes place in and across the inner mitochondrial membrane and consists of the electron transport chain and ATP synthase. Complex IV, or cytochrome c oxidase (COX), is the terminal enzyme of the electron transport chain, responsible for accepting electrons from cytochrome c, pumping protons to contribute to the gradient utilized by ATP synthase to produce ATP, and reducing oxygen to water. As such, COX is tightly regulated through numerous mechanisms including protein–protein interactions. The twin CX9C family of proteins has recently been shown to be involved in COX regulation by assisting with complex assembly, biogenesis, and activity. The twin CX9C motif allows for the import of these proteins into the intermembrane space of the mitochondria using the redox import machinery of Mia40/CHCHD4. Studies have shown that knockdown of the proteins discussed in this review results in decreased or completely deficient aerobic respiration in experimental models ranging from yeast to human cells, as the proteins are conserved across species. This article highlights and discusses the importance of COX regulation by twin CX9C proteins in the mitochondria via COX assembly and control of its activity through protein–protein interactions, which is further modulated by cell signaling pathways. Interestingly, select members of the CX9C protein family, including MNRR1 and CHCHD10, show a novel feature in that they not only localize to the mitochondria but also to the nucleus, where they mediate oxygen- and stress-induced transcriptional regulation, opening a new view of mitochondrial-nuclear crosstalk and its involvement in human disease.
      Citation: Cells
      PubDate: 2021-01-20
      DOI: 10.3390/cells10020197
      Issue No: Vol. 10, No. 2 (2021)
  • Cells, Vol. 10, Pages 198: Lipoprotein Lipase Regulates Microglial Lipid
           Droplet Accumulation

    • Authors: Bailey A. Loving, Maoping Tang, Mikaela C. Neal, Sachi Gorkhali, Robert Murphy, Robert H. Eckel, Kimberley D. Bruce
      First page: 198
      Abstract: Microglia become increasingly dysfunctional with aging and contribute to the onset of neurodegenerative disease (NDs) through defective phagocytosis, attenuated cholesterol efflux, and excessive secretion of pro-inflammatory cytokines. Dysfunctional microglia also accumulate lipid droplets (LDs); however, the mechanism underlying increased LD load is unknown. We have previously shown that microglia lacking lipoprotein lipase (LPL KD) are polarized to a pro-inflammatory state and have impaired lipid uptake and reduced fatty acid oxidation (FAO). Here, we also show that LPL KD microglia show excessive accumulation of LD-like structures. Moreover, LPL KD microglia display a pro-inflammatory lipidomic profile, increased cholesterol ester (CE) content, and reduced cholesterol efflux at baseline. We also show reduced expression of genes within the canonical cholesterol efflux pathway. Importantly, PPAR agonists (rosiglitazone and bezafibrate) rescued the LD-associated phenotype in LPL KD microglia. These data suggest that microglial-LPL is associated with lipid uptake, which may drive PPAR signaling and cholesterol efflux to prevent inflammatory lipid distribution and LD accumulation. Moreover, PPAR agonists can reverse LD accumulation, and therefore may be beneficial in aging and in the treatment of NDs.
      Citation: Cells
      PubDate: 2021-01-20
      DOI: 10.3390/cells10020198
      Issue No: Vol. 10, No. 2 (2021)
  • Cells, Vol. 10, Pages 199: Genetic Approach to Elucidate the Role of
           Cyclophilin D in Traumatic Brain Injury Pathology

    • Authors: Readnower, Hubbard, Kalimon, Geddes, Sullivan
      First page: 199
      Abstract: Cyclophilin D (CypD) has been shown to play a critical role in mitochondrial permeability transition pore (mPTP) opening and the subsequent cell death cascade. Studies consistently demonstrate that mitochondrial dysfunction, including mitochondrial calcium overload and mPTP opening, is essential to the pathobiology of cell death after a traumatic brain injury (TBI). CypD inhibitors, such as cyclosporin A (CsA) or NIM811, administered following TBI, are neuroprotective and quell neurological deficits. However, some pharmacological inhibitors of CypD have multiple biological targets and, as such, do not directly implicate a role for CypD in arbitrating cell death after TBI. Here, we reviewed the current understanding of the role CypD plays in TBI pathobiology. Further, we directly assessed the role of CypD in mediating cell death following TBI by utilizing mice lacking the CypD encoding gene Ppif. Following controlled cortical impact (CCI), the genetic knockout of CypD protected acute mitochondrial bioenergetics at 6 h post-injury and reduced subacute cortical tissue and hippocampal cell loss at 18 d post-injury. The administration of CsA following experimental TBI in Ppif-/- mice improved cortical tissue sparing, highlighting the multiple cellular targets of CsA in the mitigation of TBI pathology. The loss of CypD appeared to desensitize the mitochondrial response to calcium burden induced by TBI; this maintenance of mitochondrial function underlies the observed neuroprotective effect of the CypD knockout. These studies highlight the importance of maintaining mitochondrial homeostasis after injury and validate CypD as a therapeutic target for TBI. Further, these results solidify the beneficial effects of CsA treatment following TBI.
      Citation: Cells
      PubDate: 2021-01-20
      DOI: 10.3390/cells10020199
      Issue No: Vol. 10, No. 2 (2021)
  • Cells, Vol. 10, Pages 200: Phototropin 1 and 2 Influence Photosynthesis,
           UV-C Induced Photooxidative Stress Responses, and Cell Death

    • Authors: Rusaczonek, Czarnocka, Willems, Sujkowska-Rybkowska, Van Breusegem, Karpiński
      First page: 200
      Abstract: Phototropins are plasma membrane-associated photoreceptors of blue light and UV-A/B radiation. The Arabidopsis thaliana genome encodes two phototropins, PHOT1 and PHOT2, that mediate phototropism, chloroplast positioning, and stomatal opening. They are well characterized in terms of photomorphogenetic processes, but so far, little was known about their involvement in photosynthesis, oxidative stress responses, and cell death. By analyzing phot1, phot2 single, and phot1phot2 double mutants, we demonstrated that both phototropins influence the photochemical and non-photochemical reactions, photosynthetic pigments composition, stomata conductance, and water-use efficiency. After oxidative stress caused by UV-C treatment, phot1 and phot2 single and double mutants showed a significantly reduced accumulation of H2O2 and more efficient photosynthetic electron transport compared to the wild type. However, all phot mutants exhibited higher levels of cell death four days after UV-C treatment, as well as deregulated gene expression. Taken together, our results reveal that on the one hand, both phot1 and phot2 contribute to the inhibition of UV-C-induced foliar cell death, but on the other hand, they also contribute to the maintenance of foliar H2O2 levels and optimal intensity of photochemical reactions and non-photochemical quenching after an exposure to UV-C stress. Our data indicate a novel role for phototropins in the condition-dependent optimization of photosynthesis, growth, and water-use efficiency as well as oxidative stress and cell death response after UV-C exposure.
      Citation: Cells
      PubDate: 2021-01-20
      DOI: 10.3390/cells10020200
      Issue No: Vol. 10, No. 2 (2021)
  • Cells, Vol. 10, Pages 201: Role of Chitinase 3-Like 1 Protein in the
           Pathogenesis of Hepatic Insulin Resistance in Nonalcoholic Fatty Liver

    • Authors: Songhua Zhang, Aryanna Sousa, Mengqui Lin, Ayako Iwano, Rishubh Jain, Bing Ma, Chang Min Lee, Jin Wook Park, Suchitra Kamle, Rolf Carlson, Ghun Geun Lee, Jack A. Elias, Jack R. Wands
      First page: 201
      Abstract: A recently discovered human glycoprotein, chitinase 3-like 1 (Chi3L1), may play a role in inflammation, tissue remodeling, and visceral fat accumulation. We hypothesize that Chi3L1 gene expression is important in the development of hepatic insulin resistance characterized by the generation of pAKT, pGSK, and pERK in wild type and Chi3L1 knockout (KO) murine liver following insulin stimulation. The Chi3L1 gene and protein expression was evaluated by Real Time PCR and ELISA; lipid accumulation in hepatocytes was also assessed. To alter Chi3L1 function, three different anti-Chi3L1 monoclonal antibodies (mAbs) were administered in vivo and effects on the insulin signaling cascade and hepatic lipid deposition were determined. Transmission of the hepatic insulin signal was substantially improved following KO of the CHi3L1 gene and there was reduced lipid deposition produced by a HFD. The HFD-fed mice exhibited increased Chi3L1 expression in the liver and there was impaired insulin signal transduction. All three anti-Chi3L1 mAbs partially restored hepatic insulin sensitivity which was associated with reduced lipid accumulation in hepatocytes as well. A KO of the Chi3L1 gene reduced lipid accumulation and improved insulin signaling. Therefore, Chi3L1 gene upregulation may be an important factor in the generation of NAFLD/NASH phenotype.
      Citation: Cells
      PubDate: 2021-01-20
      DOI: 10.3390/cells10020201
      Issue No: Vol. 10, No. 2 (2021)
  • Cells, Vol. 10, Pages 202: Beyond the Warburg Effect: Oxidative and
           Glycolytic Phenotypes Coexist within the Metabolic Heterogeneity of

    • Authors: Tomás Duraj, Noemí García-Romero, Josefa Carrión-Navarro, Rodrigo Madurga, Ana Mendivil, Ricardo Prat-Acin, Lina Garcia-Cañamaque, Angel Ayuso-Sacido
      First page: 202
      Abstract: Glioblastoma (GBM) is the most aggressive primary brain tumor, with a median survival at diagnosis of 16–20 months. Metabolism represents a new attractive therapeutic target; however, due to high intratumoral heterogeneity, the application of metabolic drugs in GBM is challenging. We characterized the basal bioenergetic metabolism and antiproliferative potential of metformin (MF), dichloroacetate (DCA), sodium oxamate (SOD) and diazo-5-oxo-L-norleucine (DON) in three distinct glioma stem cells (GSCs) (GBM18, GBM27, GBM38), as well as U87MG. GBM27, a highly oxidative cell line, was the most resistant to all treatments, except DON. GBM18 and GBM38, Warburg-like GSCs, were sensitive to MF and DCA, respectively. Resistance to DON was not correlated with basal metabolic phenotypes. In combinatory experiments, radiomimetic bleomycin exhibited therapeutically relevant synergistic effects with MF, DCA and DON in GBM27 and DON in all other cell lines. MF and DCA shifted the metabolism of treated cells towards glycolysis or oxidation, respectively. DON consistently decreased total ATP production. Our study highlights the need for a better characterization of GBM from a metabolic perspective. Metabolic therapy should focus on both glycolytic and oxidative subpopulations of GSCs.
      Citation: Cells
      PubDate: 2021-01-20
      DOI: 10.3390/cells10020202
      Issue No: Vol. 10, No. 2 (2021)
  • Cells, Vol. 10, Pages 203: LRRK2 Modulates the Exocyst Complex Assembly by
           Interacting with Sec8

    • Authors: Milena Fais, Giovanna Sanna, Manuela Galioto, Thi Thanh Duyen Nguyen, Mai Uyên Thi Trần, Paola Sini, Franco Carta, Franco Turrini, Yulan Xiong, Ted M. Dawson, Valina L. Dawson, Claudia Crosio, Ciro Iaccarino
      First page: 203
      Abstract: Mutations in LRRK2 play a critical role in both familial and sporadic Parkinson’s disease (PD). Up to date, the role of LRRK2 in PD onset and progression remains largely unknown. However, experimental evidence highlights a critical role of LRRK2 in the control of vesicle trafficking, likely by Rab phosphorylation, that in turn may regulate different aspects of neuronal physiology. Here we show that LRRK2 interacts with Sec8, one of eight subunits of the exocyst complex. The exocyst complex is an evolutionarily conserved multisubunit protein complex mainly involved in tethering secretory vesicles to the plasma membrane and implicated in the regulation of multiple biological processes modulated by vesicle trafficking. Interestingly, Rabs and exocyst complex belong to the same protein network. Our experimental evidence indicates that LRRK2 kinase activity or the presence of the LRRK2 kinase domain regulate the assembly of exocyst subunits and that the over-expression of Sec8 significantly rescues the LRRK2 G2019S mutant pathological effect. Our findings strongly suggest an interesting molecular mechanism by which LRRK2 could modulate vesicle trafficking and may have important implications to decode the complex role that LRRK2 plays in neuronal physiology.
      Citation: Cells
      PubDate: 2021-01-20
      DOI: 10.3390/cells10020203
      Issue No: Vol. 10, No. 2 (2021)
  • Cells, Vol. 10, Pages 204: Calcium Signaling and Mitochondrial Function in
           Presenilin 2 Knock-Out Mice: Looking for Any Loss-of-Function Phenotype
           Related to Alzheimer’s Disease

    • Authors: Alice Rossi, Luisa Galla, Chiara Gomiero, Lorena Zentilin, Mauro Giacca, Valentina Giorgio, Tito Calì, Tullio Pozzan, Elisa Greotti, Paola Pizzo
      First page: 204
      Abstract: Alzheimer′s disease (AD) is the most common age-related neurodegenerative disorder in which learning, memory and cognitive functions decline progressively. Familial forms of AD (FAD) are caused by mutations in amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes. Presenilin 1 (PS1) and its homologue, presenilin 2 (PS2), represent, alternatively, the catalytic core of the γ-secretase complex that, by cleaving APP, produces neurotoxic amyloid beta (Aβ) peptides responsible for one of the histopathological hallmarks in AD brains, the amyloid plaques. Recently, PSEN1 FAD mutations have been associated with a loss-of-function phenotype. To investigate whether this finding can also be extended to PSEN2 FAD mutations, we studied two processes known to be modulated by PS2 and altered by FAD mutations: Ca2+ signaling and mitochondrial function. By exploiting neurons derived from a PSEN2 knock-out (PS2–/–) mouse model, we found that, upon IP3-generating stimulation, cytosolic Ca2+ handling is not altered, compared to wild-type cells, while mitochondrial Ca2+ uptake is strongly compromised. Accordingly, PS2–/– neurons show a marked reduction in endoplasmic reticulum–mitochondria apposition and a slight alteration in mitochondrial respiration, whereas mitochondrial membrane potential, and organelle morphology and number appear unchanged. Thus, although some alterations in mitochondrial function appear to be shared between PS2–/– and FAD-PS2-expressing neurons, the mechanisms leading to these defects are quite distinct between the two models. Taken together, our data appear to be difficult to reconcile with the proposal that FAD-PS2 mutants are loss-of-function, whereas the concept that PS2 plays a key role in sustaining mitochondrial function is here confirmed.
      Citation: Cells
      PubDate: 2021-01-21
      DOI: 10.3390/cells10020204
      Issue No: Vol. 10, No. 2 (2021)
  • Cells, Vol. 10, Pages 205: Research Progress in the Molecular Functions of
           Plant mTERF Proteins

    • Authors: Pedro Robles, Víctor Quesada
      First page: 205
      Abstract: Present-day chloroplast and mitochondrial genomes contain only a few dozen genes involved in ATP synthesis, photosynthesis, and gene expression. The proteins encoded by these genes are only a small fraction of the many hundreds of proteins that act in chloroplasts and mitochondria. Hence, the vast majority, including components of organellar gene expression (OGE) machineries, are encoded by nuclear genes, translated into the cytosol and imported to these organelles. Consequently, the expression of nuclear and organellar genomes has to be very precisely coordinated. Furthermore, OGE regulation is crucial to chloroplast and mitochondria biogenesis, and hence, to plant growth and development. Notwithstanding, the molecular mechanisms governing OGE are still poorly understood. Recent results have revealed the increasing importance of nuclear-encoded modular proteins capable of binding nucleic acids and regulating OGE. Mitochondrial transcription termination factor (mTERF) proteins are a good example of this category of OGE regulators. Plant mTERFs are located in chloroplasts and/or mitochondria, and have been characterized mainly from the isolation and analyses of Arabidopsis and maize mutants. These studies have revealed their fundamental roles in different plant development aspects and responses to abiotic stress. Fourteen mTERFs have been hitherto characterized in land plants, albeit to a different extent. These numbers are limited if we consider that 31 and 35 mTERFs have been, respectively, identified in maize and Arabidopsis. Notwithstanding, remarkable progress has been made in recent years to elucidate the molecular mechanisms by which mTERFs regulate OGE. Consequently, it has been experimentally demonstrated that plant mTERFs are required for the transcription termination of chloroplast genes (mTERF6 and mTERF8), transcriptional pausing and the stabilization of chloroplast transcripts (MDA1/mTERF5), intron splicing in chloroplasts (BSM/RUG2/mTERF4 and Zm-mTERF4) and mitochondria (mTERF15 and ZmSMK3) and very recently, also in the assembly of chloroplast ribosomes and translation (mTERF9). This review aims to provide a detailed update of current knowledge about the molecular functions of plant mTERF proteins. It principally focuses on new research that has made an outstanding contribution to unravel the molecular mechanisms by which plant mTERFs regulate the expression of chloroplast and mitochondrial genomes.
      Citation: Cells
      PubDate: 2021-01-21
      DOI: 10.3390/cells10020205
      Issue No: Vol. 10, No. 2 (2021)
  • Cells, Vol. 10, Pages 206: COVID-19: Characteristics and Therapeutics

    • Authors: Rameswari Chilamakuri, Saurabh Agarwal
      First page: 206
      Abstract: Novel coronavirus (COVID-19 or 2019-nCoV or SARS-CoV-2), which suddenly emerged in December 2019 is still haunting the entire human race and has affected not only the healthcare system but also the global socioeconomic balances. COVID-19 was quickly designated as a global pandemic by the World Health Organization as there have been about 98.0 million confirmed cases and about 2.0 million confirmed deaths, as of January 2021. Although, our understanding of COVID-19 has significantly increased since its outbreak, and multiple treatment approaches and pharmacological interventions have been tested or are currently under development to mitigate its risk-factors. Recently, some vaccine candidates showed around 95% clinical efficacy, and now receiving emergency use approvals in different countries. US FDA recently approved BNT162 and mRNA-1273 vaccines developed by Pfizer/BioNTech and Moderna Inc. for emergency use and vaccination in the USA. In this review, we present a succinct overview of the SARS-CoV-2 virus structure, molecular mechanisms of infection, COVID-19 epidemiology, diagnosis, and clinical manifestations. We also systematize different treatment strategies and clinical trials initiated after the pandemic outbreak, based on viral infection and replication mechanisms. Additionally, we reviewed the novel pharmacological intervention approaches and vaccine development strategies against COVID-19. We speculate that the current pandemic emergency will trigger detailed studies of coronaviruses, their mechanism of infection, development of systematic drug repurposing approaches, and novel drug discoveries for current and future pandemic outbreaks.
      Citation: Cells
      PubDate: 2021-01-21
      DOI: 10.3390/cells10020206
      Issue No: Vol. 10, No. 2 (2021)
  • Cells, Vol. 10, Pages 207: Effect of Interventions in WNT Signaling on
           Healing of Cardiac Injury: A Systematic Review

    • Authors: Evangelos P. Daskalopoulos, W. Matthijs Blankesteijn
      First page: 207
      Abstract: The wound healing that follows myocardial infarction is a complex process involving multiple mechanisms, such as inflammation, angiogenesis and fibrosis. In the last two decades, the involvement of WNT signaling has been extensively studied and effects on virtually all aspects of this wound healing have been reported. However, as often is the case in a newly emerging field, inconsistent and sometimes even contradictory findings have been reported. The aim of this systematic review is to provide a comprehensive overview of studies in which the effect of interventions in WNT signaling were investigated in in vivo models of cardiac injury. To this end, we used different search engines to perform a systematic search of the literature using the key words “WNT and myocardial and infarction”. We categorized the interventions according to their place in the WNT signaling pathway (ligand, receptor, destruction complex or nuclear level). The most consistent improvements of the wound healing response were observed in studies in which the acylation of WNT proteins was inhibited by administering porcupine inhibitors, by inhibiting of the downstream glycogen synthase kinase-3β (GSK3β) and by intervening in the β-catenin-mediated gene transcription. Interestingly, in several of these studies, evidence was presented for activation of cardiomyocyte proliferation around the infarct area. These findings indicate that inhibition of WNT signaling can play a valuable role in the repair of cardiac injury, thereby improving cardiac function and preventing the development of heart failure.
      Citation: Cells
      PubDate: 2021-01-21
      DOI: 10.3390/cells10020207
      Issue No: Vol. 10, No. 2 (2021)
  • Cells, Vol. 10, Pages 208: The Jekyll and Hyde of Cellular Senescence in

    • Authors: Dilara Demirci, Bengisu Dayanc, Fatma Aybuke Mazi, Serif Senturk
      First page: 208
      Abstract: Cellular senescence is a state of stable cell cycle arrest that can be triggered in response to various insults and is characterized by distinct morphological hallmarks, gene expression profiles, and the senescence-associated secretory phenotype (SASP). Importantly, cellular senescence is a key component of normal physiology with tumor suppressive functions. In the last few decades, novel cancer treatment strategies exploiting pro-senescence therapies have attracted considerable interest. Recent insight, however, suggests that therapy-induced senescence (TIS) elicits cell-autonomous and non-cell-autonomous implications that potentially entail detrimental consequences, reflecting the Jekyll and Hyde nature of cancer cell senescence. In essence, the undesirable manifestations that generally culminate in inflammation, cancer stemness, senescence reversal, therapy resistance, and disease recurrence are dictated by the persistent accumulation of senescent cells and the SASP. Thus, mitigating these pro-tumorigenic effects by eliminating these cells or inhibiting their SASP production holds great promise for developing innovative therapeutic strategies. In this review, we describe the fundamental aspects and dynamics of cancer cell senescence and summarize the comprehensive research on the adverse outcomes of TIS. Furthermore, we underline the rationale and motivation of emerging senotherapeutic modalities surrounding the removal of senescent cells and the SASP to help maximize the overall efficacy of cancer therapies.
      Citation: Cells
      PubDate: 2021-01-21
      DOI: 10.3390/cells10020208
      Issue No: Vol. 10, No. 2 (2021)
  • Cells, Vol. 10, Pages 209: Using iPSC Models to Understand the Role of
           Estrogen in Neuron–Glia Interactions in Schizophrenia and Bipolar

    • Authors: Denis Reis de Assis, Attila Szabo, Jordi Requena Osete, Francesca Puppo, Kevin S. O’Connell, Ibrahim A. Akkouh, Timothy Hughes, Evgeniia Frei, Ole A. Andreassen, Srdjan Djurovic
      First page: 209
      Abstract: Schizophrenia (SCZ) and bipolar disorder (BIP) are severe mental disorders with a considerable disease burden worldwide due to early age of onset, chronicity, and lack of efficient treatments or prevention strategies. Whilst our current knowledge is that SCZ and BIP are highly heritable and share common pathophysiological mechanisms associated with cellular signaling, neurotransmission, energy metabolism, and neuroinflammation, the development of novel therapies has been hampered by the unavailability of appropriate models to identify novel targetable pathomechanisms. Recent data suggest that neuron–glia interactions are disturbed in SCZ and BIP, and are modulated by estrogen (E2). However, most of the knowledge we have so far on the neuromodulatory effects of E2 came from studies on animal models and human cell lines, and may not accurately reflect many processes occurring exclusively in the human brain. Thus, here we highlight the advantages of using induced pluripotent stem cell (iPSC) models to revisit studies of mechanisms underlying beneficial effects of E2 in human brain cells. A better understanding of these mechanisms opens the opportunity to identify putative targets of novel therapeutic agents for SCZ and BIP. In this review, we first summarize the literature on the molecular mechanisms involved in SCZ and BIP pathology and the beneficial effects of E2 on neuron–glia interactions. Then, we briefly present the most recent developments in the iPSC field, emphasizing the potential of using patient-derived iPSCs as more relevant models to study the effects of E2 on neuron–glia interactions.
      Citation: Cells
      PubDate: 2021-01-21
      DOI: 10.3390/cells10020209
      Issue No: Vol. 10, No. 2 (2021)
  • Cells, Vol. 10, Pages 210: Berberine Prevents Disease Progression of
           Nonalcoholic Steatohepatitis through Modulating Multiple Pathways

    • Authors: Yanyan Wang, Yun-Ling Tai, Derrick Zhao, Yuan Zhang, Junkai Yan, Genta Kakiyama, Xuan Wang, Emily C. Gurley, Jinze Liu, Jinpeng Liu, Jimin Liu, Guanhua Lai, Phillip B. Hylemon, William M. Pandak, Weidong Chen, Huiping Zhou
      First page: 210
      Abstract: The disease progression of nonalcoholic fatty liver disease (NAFLD) from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH) is driven by multiple factors. Berberine (BBR) is an ancient Chinese medicine and has various beneficial effects on metabolic diseases, including NAFLD/NASH. However, the underlying mechanisms remain incompletely understood due to the limitation of the NASH animal models used. Methods: A high-fat and high-fructose diet-induced mouse model of NAFLD, the best available preclinical NASH mouse model, was used. RNAseq, histological, and metabolic pathway analyses were used to identify the potential signaling pathways modulated by BBR. LC–MS was used to measure bile acid levels in the serum and liver. The real-time RT-PCR and Western blot analysis were used to validate the RNAseq data. Results: BBR not only significantly reduced hepatic lipid accumulation by modulating fatty acid synthesis and metabolism but also restored the bile acid homeostasis by targeting multiple pathways. In addition, BBR markedly inhibited inflammation by reducing immune cell infiltration and inhibition of neutrophil activation and inflammatory gene expression. Furthermore, BBR was able to inhibit hepatic fibrosis by modulating the expression of multiple genes involved in hepatic stellate cell activation and cholangiocyte proliferation. Consistent with our previous findings, BBR’s beneficial effects are linked with the downregulation of microRNA34a and long noncoding RNA H19, which are two important players in promoting NASH progression and liver fibrosis. Conclusion: BBR is a promising therapeutic agent for NASH by targeting multiple pathways. These results provide a strong foundation for a future clinical investigation.
      Citation: Cells
      PubDate: 2021-01-21
      DOI: 10.3390/cells10020210
      Issue No: Vol. 10, No. 2 (2021)
  • Cells, Vol. 10, Pages 211: Pin1 Regulates IL-5 Induced Eosinophil
           Polarization and Migration

    • Authors: Zhong-Jian Shen, Jie Hu, Melissa A. O’Neal, James S. Malter
      First page: 211
      Abstract: Eosinophils become polarized in response to cytokines such IL-5 or eotaxin prior to directional migration. Polarization is preceded by F-actin assembly, but the mechanisms that regulate these events and how the shape change influences cell migration from the peripheral blood into the lung remain unclear. In this study, we show that the prolyl isomerase, Pin1, is required for IL-5-induced Eos polarization and migration. Co-immunoprecipitation and immunofluorescence analysis revealed that Pin1 directly interacts with members of Rho GTPase family. Mouse eosinophils lacking Pin1 or human cells treated with Pin1 inhibitors showed significantly reduced IL-5-induced GTPase activity and cofilin phosphorylation, resulting in reduced F-actin polymerization, cell polarization, and directional migration to chemokines. Our result suggests that Pin1 regulates cytoskeletal re-organization, eosinophil morphology, and cell migration through the modulation of Rho GTPase activity. Targeting Pin1 along with GTPases could provide a new approach to reduce pulmonary Eos accumulation during asthmatic exacerbations.
      Citation: Cells
      PubDate: 2021-01-21
      DOI: 10.3390/cells10020211
      Issue No: Vol. 10, No. 2 (2021)
  • Cells, Vol. 10, Pages 212: Longitudinal Multi-Parametric Liquid Biopsy
           Approach Identifies Unique Features of Circulating Tumor Cell,
           Extracellular Vesicle, and Cell-Free DNA Characterization for Disease
           Monitoring in Metastatic Breast Cancer Patients

    • Authors: Corinna Keup, Vinay Suryaprakash, Markus Storbeck, Oliver Hoffmann, Rainer Kimmig, Sabine Kasimir-Bauer
      First page: 212
      Abstract: Dynamics of mRNA from circulating tumor cells (CTCs), mRNA from extracellular vesicles (EVs), and cell-free DNA (cfDNA) were assessed to examine the relevance of a longitudinal multi-parametric liquid biopsy strategy. Eighteen milliliters of blood was drawn from 27 hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) patients at disease progression and at two subsequent radiologic staging time points. CTC mRNA and EV mRNA were analyzed using multi-marker qPCR, and cfDNA was analyzed using targeted next-generation sequencing (NGS). The presence of ERBB2 or ERBB3 overexpression signals in CTCs significantly correlated with disease progression (87% specificity, 36% sensitivity, p-value = 0.023), and the presence of either ERBB3 signals in CTCs or EVs or cfDNA variants in ERBB3 also showed a significant association with progressive MBC. Fluctuations during treatment were detected in the EV fraction with the appearance of hitherto undetected ERCC1 signals correlating with progressive disease (97% specificity, 18% sensitivity, p-value = 0.030). Allele frequency development of ESR1 and PIK3CA variants detected at subsequent staging time points could be used as a predictor for therapy success and, importantly, might help guide therapy decisions. The three analytes, each with their own unique features for disease monitoring, were shown to be complementary, underlining the usefulness of the longitudinal multi-parametric liquid biopsy approach.
      Citation: Cells
      PubDate: 2021-01-21
      DOI: 10.3390/cells10020212
      Issue No: Vol. 10, No. 2 (2021)
  • Cells, Vol. 10, Pages 213: Overproduction of Human Zip (SLC39) Zinc

    • Authors: Eva Ramos Becares, Per Amstrup Pedersen, Pontus Gourdon, Kamil Gotfryd
      First page: 213
      Abstract: Zinc constitutes the second most abundant transition metal in the human body, and it is implicated in numerous cellular processes, including cell division, DNA and protein synthesis as well as for the catalytic activity of many enzymes. Two major membrane protein families facilitate zinc homeostasis in the animal kingdom, i.e., Zrt/Irt-like proteins (ZIPs aka solute carrier 39, SLC39, family) and Zn transporters (ZnTs), essentially conducting zinc flux in the opposite directions. Human ZIPs (hZIPs) regulate import of extracellular zinc to the cytosol, being critical in preventing overaccumulation of this potentially toxic metal, and crucial for diverse physiological and pathological processes, including development of neurodegenerative disorders and several cancers. To date, our understanding of structure–function relationships governing hZIP-mediated zinc transport mechanism is scarce, mainly due to the notorious difficulty in overproduction of these proteins for biophysical characterization. Here we describe employment of a Saccharomyces cerevisiae-based platform for heterologous expression of hZIPs. We demonstrate that yeast is able to produce four full-length hZIP members belonging to three different subfamilies. One target (hZIP1) is purified in the high quantity and homogeneity required for the downstream biochemical analysis. Our work demonstrates the potential of the described production system for future structural and functional studies of hZIP transporters.
      Citation: Cells
      PubDate: 2021-01-21
      DOI: 10.3390/cells10020213
      Issue No: Vol. 10, No. 2 (2021)
  • Cells, Vol. 10, Pages 214: Quiescence, Stemness and Adipogenic
           Differentiation Capacity in Human DLK1−/CD34+/CD24+ Adipose
           Stem/Progenitor Cells

    • Authors: Florian M. Hatzmann, Asim Ejaz, G. Jan Wiegers, Markus Mandl, Camille Brucker, Stefan Lechner, Tina Rauchenwald, Marit Zwierzina, Saphira Baumgarten, Sonja Wagner, Monika Mattesich, Petra Waldegger, Gerhard Pierer, Werner Zwerschke
      First page: 214
      Abstract: We explore the status of quiescence, stemness and adipogenic differentiation capacity in adipose stem/progenitor cells (ASCs) ex vivo, immediately after isolation from human subcutaneous white adipose tissue, by sorting the stromal vascular fraction into cell-surface DLK1+/CD34−, DLK1+/CD34dim and DLK1−/CD34+ cells. We demonstrate that DLK1−/CD34+ cells, the only population exhibiting proliferative and adipogenic capacity, express ex vivo the bonafide quiescence markers p21Cip1, p27Kip1 and p57Kip2 but neither proliferation markers nor the senescence marker p16Ink4a. The pluripotency markers NANOG, SOX2 and OCT4 are barely detectable in ex vivo ASCs while the somatic stemness factors, c-MYC and KLF4 and the early adipogenic factor C/EBPβ are highly expressed. Further sorting of ASCs into DLK1−/CD34+/CD24− and DLK1−/CD34+/CD24+ fractions shows that KLF4 and c-MYC are higher expressed in DLK1−/CD34+/CD24+ cells correlating with higher colony formation capacity and considerably lower adipogenic activity. Proliferation capacity is similar in both populations. Next, we show that ASCs routinely isolated by plastic-adherence are DLK1−/CD34+/CD24+. Intriguingly, CD24 knock-down in these cells reduces proliferation and adipogenesis. In conclusion, DLK1−/CD34+ ASCs in human sWAT exist in a quiescent state, express high levels of somatic stemness factors and the early adipogenic transcription factor C/EBPβ but senescence and pluripotency markers are barely detectable. Moreover, our data indicate that CD24 is necessary for adequate ASC proliferation and adipogenesis and that stemness is higher and adipogenic capacity lower in DLK1−/CD34+/CD24+ relative to DLK1−/CD34+/CD24− subpopulations.
      Citation: Cells
      PubDate: 2021-01-22
      DOI: 10.3390/cells10020214
      Issue No: Vol. 10, No. 2 (2021)
  • Cells, Vol. 10, Pages 215: Targeting Aquaporins in Novel Therapies for
           Male and Female Breast and Reproductive Cancers

    • Authors: Sidra Khan, Carmela Ricciardelli, Andrea J. Yool
      First page: 215
      Abstract: Aquaporins are membrane channels in the broad family of major intrinsic proteins (MIPs), with 13 classes showing tissue-specific distributions in humans. As key physiological modulators of water and solute homeostasis, mutations, and dysfunctions involving aquaporins have been associated with pathologies in all major organs. Increases in aquaporin expression are associated with greater severity of many cancers, particularly in augmenting motility and invasiveness for example in colon cancers and glioblastoma. However, potential roles of altered aquaporin (AQP) function in reproductive cancers have been understudied to date. Published work reviewed here shows distinct classes aquaporin have differential roles in mediating cancer metastasis, angiogenesis, and resistance to apoptosis. Known mechanisms of action of AQPs in other tissues are proving relevant to understanding reproductive cancers. Emerging patterns show AQPs 1, 3, and 5 in particular are highly expressed in breast, endometrial, and ovarian cancers, consistent with their gene regulation by estrogen response elements, and AQPs 3 and 9 in particular are linked with prostate cancer. Continuing work is defining avenues for pharmacological targeting of aquaporins as potential therapies to reduce female and male reproductive cancer cell growth and invasiveness.
      Citation: Cells
      PubDate: 2021-01-22
      DOI: 10.3390/cells10020215
      Issue No: Vol. 10, No. 2 (2021)
  • Cells, Vol. 10, Pages 216: Adipokines and Autoimmunity in Inflammatory

    • Authors: Elena Neumann, Rebecca Hasseli, Selina Ohl, Uwe Lange, Klaus W. Frommer, Ulf Müller-Ladner
      First page: 216
      Abstract: Adipokines are adipose tissue-derived factors not only playing an important role in metabolism but also influencing other central processes of the body, such as inflammation. In autoimmune diseases, adipokines are involved in inflammatory pathways affecting different cell types. Many rheumatic diseases belong to the group of autoimmune diseases, for example rheumatoid arthritis (RA) and psoriatic arthritis. Due to the autoimmune responses, a chronic inflammatory milieu develops, which affects the whole body, including adipose tissue. Metabolic alterations such as obesity influence inflammatory responses in autoimmune diseases. Adipokines are bioactive mediators mainly produced by adipose tissue. Due to alterations of systemic adipokine levels, their role as biomarkers with diagnostic potential has been suggested in the context of rheumatic diseases. In the affected joints of RA patients, different synoviocytes but also osteoclasts, osteoblasts, and chondrocytes produce several adipokines, contributing to the unique inflammatory microenvironment. Adipokines have been shown to be potent modulatory effectors on different cell types of the immune system but also local cells in synovial tissue, cartilage, and bone. This review highlights the most recent findings on the role of adipokines in the pathophysiology of inflammatory arthritis with a distinct focus on RA in the quickly developing research field.
      Citation: Cells
      PubDate: 2021-01-22
      DOI: 10.3390/cells10020216
      Issue No: Vol. 10, No. 2 (2021)
  • Cells, Vol. 10, Pages 217: Nurse-Like Cells and Chronic Lymphocytic

    • Authors: Stefania Fiorcari, Rossana Maffei, Claudio Giacinto Atene, Leonardo Potenza, Mario Luppi, Roberto Marasca
      First page: 217
      Abstract: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries and is an example of hematological disease where cooperation between genetic defects and tumor microenvironmental interaction is involved in pathogenesis. CLL is a disease that is considered as “addicted to the host”; indeed, the crosstalk between leukemic cells and the tumor microenvironment is essential for leukemic clone maintenance supporting CLL cells’ survival, proliferation, and protection from drug-induced apoptosis. CLL cells are not innocent bystanders but actively model and manipulate the surrounding microenvironment to their own advantage. Besides the different players involved in this crosstalk, nurse-like cells (NLC) resemble features related to leukemia-associated macrophages with an important function in preserving CLL cell survival and supporting an immunosuppressive microenvironment. This review provides a comprehensive overview of the role played by NLC in creating a nurturing and permissive milieu for CLL cells, illustrating the therapeutic possibilities in order to specifically target and re-educate them.
      Citation: Cells
      PubDate: 2021-01-22
      DOI: 10.3390/cells10020217
      Issue No: Vol. 10, No. 2 (2021)
  • Cells, Vol. 10, Pages 218: Multiplex Analysis of Adipose-Derived Stem Cell
           (ASC) Immunophenotype Adaption to In Vitro Expansion

    • Authors: Qiuyue Peng, Martyna Duda, Guoqiang Ren, Zongzhe Xuan, Cristian Pablo Pennisi, Simone Riis Porsborg, Trine Fink, Vladimir Zachar
      First page: 218
      Abstract: In order to enhance the therapeutic potential, it is important that sufficient knowledge regarding the dynamic changes of adipose-derived stem cell (ASC) immunophenotypical and biological properties during in vitro growth is available. Consequently, we embarked on a study to follow the evolution of highly defined cell subsets from three unrelated donors in the course of eight passages on tissue culture polystyrene. The co-expression patterns were defined by panels encompassing seven and five cell surface markers, including CD34, CD146, CD166, CD200, CD248, CD271, and CD274 and CD29, CD31, CD36, CD201, and Stro-1, respectively. The analysis was performed using multichromatic flow cytometry. We observed a major paradigm shift, where the CD166-CD34+ combination which was found across all cell subsets early in the culture was replaced by the CD166+ phenotype as the population homogeneity increased with time. At all analysis points, the cultures were dominated by a few major clones that were highly prevalent in most of the donors. The selection process resulted in two predominant clones in the larger panel (CD166+CD34−CD146−CD271− CD274−CD248−CD200− and CD166+CD34+ CD146−CD271−CD274−CD248−CD200−) and one clone in the smaller panel (CD29+CD201+CD36− Stro-1− CD31−). The minor subsets, including CD166+CD34−CD146−CD271+CD274−CD248−CD200− and CD166+CD34+CD146+CD271−CD274−CD248−CD200−, and CD29+CD201−CD36−Stro-1−CD31−, CD29+CD201+CD36−Stro-1+CD31−, and CD29+CD201+CD36+Stro-1−CD31−, in the seven and five marker panels, respectively, were, on the other, hand highly fluctuating and donor-dependent. The results demonstrate that only a limited number of phenotypical repertoires are possible in ASC cultures. Marked differences in their relative occurrence between distinct individuals underscore the need for potency standardization of different ASC preparation to improve the clinical outcome.
      Citation: Cells
      PubDate: 2021-01-22
      DOI: 10.3390/cells10020218
      Issue No: Vol. 10, No. 2 (2021)
  • Cells, Vol. 10, Pages 219: Methods for Studying Endometrial Pathology and
           the Potential of Atomic Force Microscopy in the Research of Endometrium

    • Authors: Agnieszka Kurek, Estera Kłosowicz, Kamila Sofińska, Robert Jach, Jakub Barbasz
      First page: 219
      Abstract: The endometrium lines the uterine cavity, enables implantation of the embryo, and provides an environment for its development and growth. Numerous methods, including microscopic and immunoenzymatic techniques, have been used to study the properties of the cells and tissue of the endometrium to understand changes during, e.g., the menstrual cycle or implantation. Taking into account the existing state of knowledge on the endometrium and the research carried out using other tissues, it can be concluded that the mechanical properties of the tissue and its cells are crucial for their proper functioning. This review intends to emphasize the potential of atomic force microscopy (AFM) in the research of endometrium properties. AFM enables imaging of tissues or single cells, roughness analysis, and determination of the mechanical properties (Young’s modulus) of single cells or tissues, or their adhesion. AFM has been previously shown to be useful to derive force maps. Combining the information regarding cell mechanics with the alternations of cell morphology or gene/protein expression provides deeper insight into the uterine pathology. The determination of the elastic modulus of cells in pathological states, such as cancer, has been proved to be useful in diagnostics.
      Citation: Cells
      PubDate: 2021-01-22
      DOI: 10.3390/cells10020219
      Issue No: Vol. 10, No. 2 (2021)
  • Cells, Vol. 10, Pages 220: Hydrogen Sulfide, an Endogenous Stimulator of
           Mitochondrial Function in Cancer Cells

    • Authors: Szabo
      First page: 220
      Abstract: Hydrogen sulfide (H2S) has a long history as toxic gas and environmental hazard; inhibition of cytochrome c oxidase (mitochondrial Complex IV) is viewed as a primary mode of its cytotoxic action. However, studies conducted over the last two decades unveiled multiple biological regulatory roles of H2S as an endogenously produced mammalian gaseous transmitter. Cystathionine -lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST) are currently viewed as the principal mammalian H2S-generating enzymes. In contrast to its inhibitory (toxicological) mitochondrial effects, at lower (physiological) concentrations, H2S serves as a stimulator of electron transport in mammalian mitochondria, by acting as an electron donor—with sulfide:quinone oxidoreductase (SQR) being the immediate electron acceptor. The mitochondrial roles of H2S are significant in various cancer cells, many of which exhibit high expression and partial mitochondrial localization of various H2S producing enzymes. In addition to the stimulation of mitochondrial ATP production, the roles of endogenous H2S in cancer cells include the maintenance of mitochondrial organization (protection against mitochondrial fission) and the maintenance of mitochondrial DNA repair (via the stimulation of the assembly of mitochondrial DNA repair complexes). The current article overviews the state-of-the-art knowledge regarding the mitochondrial functions of endogenously produced H2S in cancer cells.
      Citation: Cells
      PubDate: 2021-01-22
      DOI: 10.3390/cells10020220
      Issue No: Vol. 10, No. 2 (2021)
  • Cells, Vol. 10, Pages 221: TDP-43 Regulation of AChE Expression Can
           Mediate ALS-Like Phenotype in Zebrafish

    • Authors: Maria-Letizia Campanari, Anca Marian, Sorana Ciura, Edor Kabashi
      First page: 221
      Abstract: The “distal axonopathy” hypothesis in amyotrophic lateral sclerosis (ALS) proposes that pathological changes occur at the neuromuscular junction (NMJ) early in the disease. While acetylcholinesterase (AChE) plays an important role in the functionality of the NMJ, its potential role in ALS remains unexplored. Here, we identified AChE as a limiting factor regulating muscle/motor neuron connection in a vertebrate model of ALS. Knockdown of the TAR DNA-binding protein 43 (TDP-43) orthologue in zebrafish resulted in early defects of motor functions coupled with NMJ disassembly. We found that a partially depleted tdp-43 caused a decrease of ache expression. Importantly, human AChE overexpression reduced the phenotypic defects in the tdp-43 loss of function model, with amelioration of post- and pre-synaptic deficits at the NMJ. In conclusion, our results provide a better understanding of the role of TDP-43 in the NMJ organization and indicate AChE as a contributing factor in the pathology of ALS. In particular, it may be implicated in the early defects that characterize NMJs in this major neurodegenerative disorder.
      Citation: Cells
      PubDate: 2021-01-22
      DOI: 10.3390/cells10020221
      Issue No: Vol. 10, No. 2 (2021)
  • Cells, Vol. 10, Pages 222: Arylsulfatase a Remodeling during Human Sperm
           In Vitro Capacitation Using Field Emission Scanning Electron Microscopy

    • Authors: María José Gómez-Torres, Natalia Huerta-Retamal, Laura Robles-Gómez, Paula Sáez-Espinosa, Jon Aizpurua, Manuel Avilés, Alejandro Romero
      First page: 222
      Abstract: Capacitation drives sperm biophysical and biochemical changes for sperm-oocyte interactions. It is a well-known fact that the molecular complex arylsulfatase A (ARSA), hyaluronidase sperm adhesion molecule 1 (SPAM1), and heat shock protein 2 (HSPA2) plays a significant role in sperm–zona pellucida (ZP) binding. However, the time-dependent capacitation effects on the sperm surface ARSA presence and specific topographic distributions remain to be elucidated. Here, we quantified the ARSA density and specific membrane domain locations before (US) and after in vitro capacitation (one and four hours; CS1–CS4) in human sperm using high-resolution field emission scanning electron microscopy (FE-SEM) and immunogold labeling. Our results showed a significant and progressive capacitation-mediated increase of labeled spermatozoa from the US (37%) to CS4 (100%) physiological conditions. In addition, surface mapping revealed a close relationship between the ARSA residues and their acrosomal repositioning. Compared with the ARSA surface heterogeneous distribution found in US, the CS1–4 conditions exhibited clustering on the peri-acrosomal region, showing that time-dependent capacitation also induced a ARSA residue dramatic translocation on sperm surfaces. Our findings provide novel insights into the molecular remodeling events preceding sperm-oocyte interactions.
      Citation: Cells
      PubDate: 2021-01-23
      DOI: 10.3390/cells10020222
      Issue No: Vol. 10, No. 2 (2021)
  • Cells, Vol. 10, Pages 223: Immune Infiltrates in Breast Cancer: Recent
           Updates and Clinical Implications

    • Authors: Maria Vittoria Dieci, Federica Miglietta, Valentina Guarneri
      First page: 223
      Abstract: In recent decades, the increasing interest in the field of immunotherapy has fostered an intense investigation of the breast cancer (BC) immune microenvironment. In this context, tumor-infiltrating lymphocytes (TILs) have emerged as a clinically relevant and highly reproducible biomarker capable of affecting BC prognosis and response to treatment. Indeed, the evaluation of TILs on primary tumors proved to be strongly prognostic in triple-negative (TN) BC patients treated with either adjuvant or neoadjuvant chemotherapy, as well as in early TNBC patients not receiving any systemic treatment, thus gaining level-1b evidence in this setting. In addition, a strong relationship between TILs and pathologic complete response after neoadjuvant chemotherapy has been reported in all BC subtypes and the prognostic role of higher TILs in early HER2-positive breast cancer patients has also been demonstrated. The interest in BC immune infiltrates has been further fueled by the introduction of the first immune checkpoint inhibitors in the treatment armamentarium of advanced TNBC in patients with PD-L1-positive status by FDA-approved assays. However, despite these advances, a biomarker capable of reliably and exhaustively predicting immunotherapy benefit in BC is still lacking, highlighting the imperative need to further deepen this issue. Finally, more comprehensive evaluation of immune infiltrates integrating both the quantity and quality of tumor-infiltrating immune cells and incorporation of TILs in composite scores encompassing other clinically or biologically relevant biomarkers, as well as the adoption of software-based and/or machine learning platforms for a more comprehensive characterization of BC immune infiltrates, are emerging as promising strategies potentially capable of optimizing patient selection and stratification in the research field. In the present review, we summarize available evidence and recent updates on immune infiltrates in BC, focusing on current clinical applications, potential clinical implications and major unresolved issues.
      Citation: Cells
      PubDate: 2021-01-23
      DOI: 10.3390/cells10020223
      Issue No: Vol. 10, No. 2 (2021)
  • Cells, Vol. 10, Pages 224: JAK-STAT Pathway Inhibition Partially Restores
           Intestinal Homeostasis in Hdac1- and Hdac2-Intestinal Epithelial
           Cell-Deficient Mice

    • Authors: Alexis Gonneaud, Naomie Turgeon, Francois-Michel Boisvert, Francois Boudreau, Claude Asselin
      First page: 224
      Abstract: We have previously reported that histone deacetylase epigenetic regulator Hdac1 and Hdac2 deletion in intestinal epithelial cells (IEC) disrupts mucosal tissue architecture and barrier, causing chronic inflammation. In this study, proteome and transcriptome analysis revealed the importance of signaling pathways induced upon genetic IEC-Hdac1 and Hdac2 deletion. Indeed, Gene Ontology biological process analysis of enriched deficient IEC RNA and proteins identified common pathways, including lipid metabolic and oxidation–reduction process, cell adhesion, and antigen processing and presentation, related to immune responses, correlating with dysregulation of major histocompatibility complex (MHC) class II genes. Top upstream regulators included regulators associated with environmental sensing pathways to xenobiotics, microbial and diet-derived ligands, and endogenous metabolites. Proteome analysis revealed mTOR signaling IEC-specific defects. In addition to mTOR, the STAT and Notch pathways were dysregulated specifically in jejunal IEC. To determine the impact of pathway dysregulation on mutant jejunum alterations, we treated mutant mice with Tofacitinib, a JAK inhibitor. Treatment with the inhibitor partially corrected proliferation and tight junction defects, as well as niche stabilization by increasing Paneth cell numbers. Thus, IEC-specific histone deacetylases 1 (HDAC1) and 2 (HDAC2) support intestinal homeostasis by regulating survival and translation processes, as well as differentiation and metabolic pathways. HDAC1 and HDAC2 may play an important role in the regulation of IEC-specific inflammatory responses by controlling, directly or indirectly, the JAK/STAT pathway. IEC-specific JAK/STAT pathway deregulation may be, at least in part, responsible for intestinal homeostasis disruption in mutant mice.
      Citation: Cells
      PubDate: 2021-01-23
      DOI: 10.3390/cells10020224
      Issue No: Vol. 10, No. 2 (2021)
  • Cells, Vol. 10, Pages 125: Mitochondrial Cyclosporine A-Independent
           Palmitate/Ca2+-Induced Permeability Transition Pore (PA-mPT Pore) and Its
           Role in Mitochondrial Function and Protection against Calcium Overload and
           Glutamate Toxicity

    • Authors: Galina D. Mironova, Evgeny V. Pavlov
      First page: 125
      Abstract: A sharp increase in the permeability of the mitochondrial inner membrane known as mitochondrial permeability transition (or mPT) occurs in mitochondria under the conditions of Ca2+ and ROS stress. Permeability transition can proceed through several mechanisms. The most common mechanism of mPT is based on the opening of a cyclosporine A (CSA)-sensitive protein channel in the inner membrane. In addition to the CSA-sensitive pathway, mPT can occur through the transient opening of lipid pores, emerging in the process of formation of palmitate/Ca2+ complexes. This pathway is independent of CSA and likely plays a protective role against Ca2+ and ROS toxicity. The review considers molecular mechanisms of formation and regulation of the palmitate/Ca2+-induced pores, which we designate as PA-mPT to distinguish it from the classical CSA-sensitive mPT. In the paper, we discuss conditions of its opening in the biological membranes, as well as its role in the physiological and pathophysiological processes. Additionally, we summarize data that indicate the involvement of PA-mPT in the protection of mitochondria against calcium overload and glutamate-induced degradation in neurons.
      Citation: Cells
      PubDate: 2021-01-11
      DOI: 10.3390/cells10010125
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 126: Effect of Microbial Short-Chain Fatty Acids on
           CYP3A4-Mediated Metabolic Activation of Human Pluripotent Stem
           Cell-Derived Liver Organoids

    • Authors: Seon Ju Mun, Jaeseo Lee, Kyung-Sook Chung, Mi-Young Son, Myung Jin Son
      First page: 126
      Abstract: The early and accurate prediction of the hepatotoxicity of new drug targets during nonclinical drug development is important to avoid postmarketing drug withdrawals and late-stage failures. We previously established long-term expandable and functional human-induced pluripotent stem cell (iPSC)-derived liver organoids as an alternative source for primary human hepatocytes. However, PSC-derived organoids are known to present immature fetal characteristics. Here, we treated these liver organoids with microbial short-chain fatty acids (SCFAs) to improve metabolic maturation based on microenvironmental changes in the liver during postnatal development. The effects of the three main SCFA components (acetate, propionate, and butyrate) and their mixture on liver organoids were determined. Propionate (1 µM) significantly promoted the CYP3A4/CYP3A7 expression ratio, and acetate (1 µM), propionate (1 µM), and butyrate (1 µM) combination treatment, compared to no treatment (control), substantially increased CYP3A4 activity and albumin secretion, as well as gene expression. More importantly, mixed SCFA treatment accurately revealed troglitazone-induced hepatotoxicity, which was redeemed on a potent CYP3A4 inhibitor ketoconazole treatment. Overall, we determined, for the first time, that SCFA mixture treatment might contribute to the accurate evaluation of the CYP3A4-dependent drug toxicity by improving metabolic activation, including CYP3A4 expression, of liver organoids.
      Citation: Cells
      PubDate: 2021-01-11
      DOI: 10.3390/cells10010126
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 127: Interactions between Cellulose and
           (1,3;1,4)-β-glucans and Arabinoxylans in the Regenerating Wall of
           Suspension Culture Cells of the Ryegrass Lolium multiflorum

    • Authors: Allison van de Meene, Lauren McAloney, Sarah M. Wilson, JiZhi Zhou, Wei Zeng, Paul McMillan, Antony Bacic, Monika S. Doblin
      First page: 127
      Abstract: Plant cell walls (PCWs) form the outer barrier of cells that give the plant strength and directly interact with the environment and other cells in the plant. PCWs are composed of several polysaccharides, of which cellulose forms the main fibrillar network. Enmeshed between these fibrils of cellulose are non-cellulosic polysaccharides (NCPs), pectins, and proteins. This study investigates the sequence, timing, patterning, and architecture of cell wall polysaccharide regeneration in suspension culture cells (SCC) of the grass species Lolium multiflorum (Lolium). Confocal, superresolution, and electron microscopies were used in combination with cytochemical labeling to investigate polysaccharide deposition in SCC after protoplasting. Cellulose was the first polysaccharide observed, followed shortly thereafter by (1,3;1,4)-β-glucan, which is also known as mixed-linkage glucan (MLG), arabinoxylan (AX), and callose. Cellulose formed fibrils with AX and produced a filamentous-like network, whereas MLG formed punctate patches. Using colocalization analysis, cellulose and AX were shown to interact during early stages of wall generation, but this interaction reduced over time as the wall matured. AX and MLG interactions increased slightly over time, but cellulose and MLG were not seen to interact. Callose initially formed patches that were randomly positioned on the protoplast surface. There was no consistency in size or location over time. The architecture observed via superresolution microscopy showed similarities to the biophysical maps produced using atomic force microscopy and can give insight into the role of polysaccharides in PCWs.
      Citation: Cells
      PubDate: 2021-01-11
      DOI: 10.3390/cells10010127
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 128: Mono(ADP-ribosyl)ation Enzymes and NAD+
           Metabolism: A Focus on Diseases and Therapeutic Perspectives

    • Authors: Palmiro Poltronieri, Angela Celetti, Luca Palazzo
      First page: 128
      Abstract: Mono(ADP-ribose) transferases and mono(ADP-ribosyl)ating sirtuins use NAD+ to perform the mono(ADP-ribosyl)ation, a simple form of post-translational modification of proteins and, in some cases, of nucleic acids. The availability of NAD+ is a limiting step and an essential requisite for NAD+ consuming enzymes. The synthesis and degradation of NAD+, as well as the transport of its key intermediates among cell compartments, play a vital role in the maintenance of optimal NAD+ levels, which are essential for the regulation of NAD+-utilizing enzymes. In this review, we provide an overview of the current knowledge of NAD+ metabolism, highlighting the functional liaison with mono(ADP-ribosyl)ating enzymes, such as the well-known ARTD10 (also named PARP10), SIRT6, and SIRT7. To this aim, we discuss the link of these enzymes with NAD+ metabolism and chronic diseases, such as cancer, degenerative disorders and aging.
      Citation: Cells
      PubDate: 2021-01-11
      DOI: 10.3390/cells10010128
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 129: Central Regulation of Metabolism by Growth

    • Authors: Jose Donato, Frederick Wasinski, Isadora C. Furigo, Martin Metzger, Renata Frazão
      First page: 129
      Abstract: Growth hormone (GH) is secreted by the pituitary gland, and in addition to its classical functions of regulating height, protein synthesis, tissue growth, and cell proliferation, GH exerts profound effects on metabolism. In this regard, GH stimulates lipolysis in white adipose tissue and antagonizes insulin’s effects on glycemic control. During the last decade, a wide distribution of GH-responsive neurons were identified in numerous brain areas, especially in hypothalamic nuclei, that control metabolism. The specific role of GH action in different neuronal populations is now starting to be uncovered, and so far, it indicates that the brain is an important target of GH for the regulation of food intake, energy expenditure, and glycemia and neuroendocrine changes, particularly in response to different forms of metabolic stress such as glucoprivation, food restriction, and physical exercise. The objective of the present review is to summarize the current knowledge about the potential role of GH action in the brain for the regulation of different metabolic aspects. The findings gathered here allow us to suggest that GH represents a hormonal factor that conveys homeostatic information to the brain to produce metabolic adjustments in order to promote energy homeostasis.
      Citation: Cells
      PubDate: 2021-01-11
      DOI: 10.3390/cells10010129
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 130: Calreticulin—Multifunctional Chaperone in
           Immunogenic Cell Death: Potential Significance as a Prognostic Biomarker
           in Ovarian Cancer Patients

    • Authors: Michal Kielbik, Izabela Szulc-Kielbik, Magdalena Klink
      First page: 130
      Abstract: Immunogenic cell death (ICD) is a type of death, which has the hallmarks of necroptosis and apoptosis, and is best characterized in malignant diseases. Chemotherapeutics, radiotherapy and photodynamic therapy induce intracellular stress response pathways in tumor cells, leading to a secretion of various factors belonging to a family of damage-associated molecular patterns molecules, capable of inducing the adaptive immune response. One of them is calreticulin (CRT), an endoplasmic reticulum-associated chaperone. Its presence on the surface of dying tumor cells serves as an “eat me” signal for antigen presenting cells (APC). Engulfment of tumor cells by APCs results in the presentation of tumor’s antigens to cytotoxic T-cells and production of cytokines/chemokines, which activate immune cells responsible for tumor cells killing. Thus, the development of ICD and the expression of CRT can help standard therapy to eradicate tumor cells. Here, we review the physiological functions of CRT and its involvement in the ICD appearance in malignant disease. Moreover, we also focus on the ability of various anti-cancer drugs to induce expression of surface CRT on ovarian cancer cells. The second aim of this work is to discuss and summarize the prognostic/predictive value of CRT in ovarian cancer patients.
      Citation: Cells
      PubDate: 2021-01-11
      DOI: 10.3390/cells10010130
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 131: Apoptosis in the Extraosseous Calcification

    • Authors: Federica Boraldi, Francesco Demetrio Lofaro, Daniela Quaglino
      First page: 131
      Abstract: Extraosseous calcification is a pathologic mineralization process occurring in soft connective tissues (e.g., skin, vessels, tendons, and cartilage). It can take place on a genetic basis or as a consequence of acquired chronic diseases. In this last case, the etiology is multifactorial, including both extra- and intracellular mechanisms, such as the formation of membrane vesicles (e.g., matrix vesicles and apoptotic bodies), mitochondrial alterations, and oxidative stress. This review is an overview of extraosseous calcification mechanisms focusing on the relationships between apoptosis and mineralization in cartilage and vascular tissues, as these are the two tissues mostly affected by a number of age-related diseases having a progressively increased impact in Western Countries.
      Citation: Cells
      PubDate: 2021-01-12
      DOI: 10.3390/cells10010131
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 132: Unraveling the In Vivo Protein Corona

    • Authors: Johanna Simon, Gabor Kuhn, Michael Fichter, Stephan Gehring, Katharina Landfester, Volker Mailänder
      First page: 132
      Abstract: Understanding the behavior of nanoparticles upon contact with a physiological environment is of urgent need in order to improve their properties for a successful therapeutic application. Most commonly, the interaction of nanoparticles with plasma proteins are studied under in vitro conditions. However, this has been shown to not reflect the complex situation after in vivo administration. Therefore, here we focused on the investigation of magnetic nanoparticles with blood proteins under in vivo conditions. Importantly, we observed a radically different proteome in vivo in comparison to the in vitro situation underlining the significance of in vivo protein corona studies. Next to this, we found that the in vivo corona profile does not significantly change over time. To mimic the in vivo situation, we established an approach, which we termed “ex vivo” as it uses whole blood freshly prepared from an animal. Overall, we present a comprehensive analysis focusing on the interaction between nanoparticles and blood proteins under in vivo conditions and how to mimic this situation with our ex vivo approach. This knowledge is needed to characterize the true biological identity of nanoparticles.
      Citation: Cells
      PubDate: 2021-01-12
      DOI: 10.3390/cells10010132
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 133: Ligands and Receptors Involved in the
           Sperm-Zona Pellucida Interactions in Mammals

    • Authors: Lucie Tumova, Michal Zigo, Peter Sutovsky, Marketa Sedmikova, Pavla Postlerova
      First page: 133
      Abstract: Sperm-zona pellucida (ZP) interaction, involving the binding of sperm surface ligands to complementary carbohydrates of ZP, is the first direct gamete contact event crucial for subsequent gamete fusion and successful fertilization in mammals. It is a complex process mediated by the coordinated engagement of multiple ZP receptors forming high-molecular-weight (HMW) protein complexes at the acrosomal region of the sperm surface. The present article aims to review the current understanding of sperm-ZP binding in the four most studied mammalian models, i.e., murine, porcine, bovine, and human, and summarizes the candidate ZP receptors with established ZP affinity, including their origins and the mechanisms of ZP binding. Further, it compares and contrasts the ZP structure and carbohydrate composition in the aforementioned model organisms. The comprehensive understanding of sperm-ZP interaction mechanisms is critical for the diagnosis of infertility and thus becomes an integral part of assisted reproductive therapies/technologies.
      Citation: Cells
      PubDate: 2021-01-12
      DOI: 10.3390/cells10010133
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 134: Neuron–Glia Interactions in Tuberous

    • Authors: Stephanie Dooves, Arianne J. H. van Velthoven, Linda G. Suciati, Vivi M. Heine
      First page: 134
      Abstract: Tuberous sclerosis complex (TSC) is a genetic disease affecting the brain. Neurological symptoms like epilepsy and neurodevelopmental issues cause a significant burden on patients. Both neurons and glial cells are affected by TSC mutations. Previous studies have shown changes in the excitation/inhibition balance (E/I balance) in TSC. Astrocytes are known to be important for neuronal development, and astrocytic dysfunction can cause changes in the E/I balance. We hypothesized that astrocytes affect the synaptic balance in TSC. TSC patient-derived stem cells were differentiated into astrocytes, which showed increased proliferation compared to control astrocytes. RNA sequencing revealed changes in gene expression, which were related to epidermal growth factor (EGF) signaling and enriched for genes that coded for secreted or transmembrane proteins. Control neurons were cultured in astrocyte-conditioned medium (ACM) of TSC and control astrocytes. After culture in TSC ACM, neurons showed an altered synaptic balance, with an increase in the percentage of VGAT+ synapses. These findings were confirmed in organoids, presenting a spontaneous 3D organization of neurons and glial cells. To conclude, this study shows that TSC astrocytes are affected and secrete factors that alter the synaptic balance. As an altered E/I balance may underlie many of the neurological TSC symptoms, astrocytes may provide new therapeutic targets.
      Citation: Cells
      PubDate: 2021-01-12
      DOI: 10.3390/cells10010134
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 135: Radiation-Activated PI3K/AKT Pathway Promotes
           the Induction of Cancer Stem-Like Cells via the Upregulation of SOX2 in
           Colorectal Cancer

    • Authors: Ji-Hye Park, Young-Heon Kim, Sehwan Shim, Areumnuri Kim, Hyosun Jang, Su-Jae Lee, Sunhoo Park, Songwon Seo, Won Il Jang, Seung Bum Lee, Min-Jung Kim
      First page: 135
      Abstract: The current treatment strategy for patients with aggressive colorectal cancer has been hampered by resistance to radiotherapy and chemotherapy due to the existence of cancer stem-like cells (CSCs). Recent studies have shown that SOX2 expression plays an important role in the maintenance of CSC properties in colorectal cancer. In this study, we investigated the induction and regulatory role of SOX2 following the irradiation of radioresistant and radiosensitive colorectal cancer cells. We used FACS and western blotting to analyze SOX2 expression in cells. Among the markers of colorectal CSCs, the expression of CD44 increased upon irradiation in radioresistant cells. Further analysis revealed the retention of CSC properties with an upregulation of SOX2 as shown by enhanced resistance to radiation and metastatic potential in vitro. Interestingly, both the knockdown and overexpression of SOX2 led to increase in CD44+ population and induction of CSC properties in colorectal cancer following irradiation. Furthermore, selective genetic and pharmacological inhibition of the PI3K/AKT pathway, but not the MAPK pathway, attenuated SOX2-dependent CD44 expression and metastatic potential upon irradiation in vitro. Our findings suggested that SOX2 regulated by radiation-induced activation of PI3K/AKT pathway contributes to the induction of colorectal CSCs, thereby highlighting its potential as a therapeutic target.
      Citation: Cells
      PubDate: 2021-01-12
      DOI: 10.3390/cells10010135
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 136: Double Duty: Mitotic Kinesins and Their
           Post-Mitotic Functions in Neurons

    • Authors: Nadine F. Joseph, Supriya Swarnkar, Sathyanarayanan V Puthanveettil
      First page: 136
      Abstract: Neurons, regarded as post-mitotic cells, are characterized by their extensive dendritic and axonal arborization. This unique architecture imposes challenges to how to supply materials required at distal neuronal components. Kinesins are molecular motor proteins that mediate the active delivery of cellular materials along the microtubule cytoskeleton for facilitating the local biochemical and structural changes at the synapse. Recent studies have made intriguing observations that some kinesins that function during neuronal mitosis also have a critical role in post-mitotic neurons. However, we know very little about the function and regulation of such kinesins. Here, we summarize the known cellular and biochemical functions of mitotic kinesins in post-mitotic neurons.
      Citation: Cells
      PubDate: 2021-01-12
      DOI: 10.3390/cells10010136
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 137: Single-Cell Profiling of Coding and Noncoding
           Genes in Human Dopamine Neuron Differentiation

    • Authors: Fredrik Nilsson, Petter Storm, Edoardo Sozzi, David Hidalgo Gil, Marcella Birtele, Yogita Sharma, Malin Parmar, Alessandro Fiorenzano
      First page: 137
      Abstract: Dopaminergic (DA) neurons derived from human pluripotent stem cells (hPSCs) represent a renewable and available source of cells useful for understanding development, developing disease models, and stem-cell therapies for Parkinson’s disease (PD). To assess the utility of stem cell cultures as an in vitro model system of human DA neurogenesis, we performed high-throughput transcriptional profiling of ~20,000 ventral midbrain (VM)-patterned stem cells at different stages of maturation using droplet-based single-cell RNA sequencing (scRNAseq). Using this dataset, we defined the cellular composition of human VM cultures at different timepoints and found high purity DA progenitor formation at an early stage of differentiation. DA neurons sharing similar molecular identities to those found in authentic DA neurons derived from human fetal VM were the major cell type after two months in culture. We also developed a bioinformatic pipeline that provided a comprehensive long noncoding RNA landscape based on temporal and cell-type specificity, which may contribute to unraveling the intricate regulatory network of coding and noncoding genes in DA neuron differentiation. Our findings serve as a valuable resource to elucidate the molecular steps of development, maturation, and function of human DA neurons, and to identify novel candidate coding and noncoding genes driving specification of progenitors into functionally mature DA neurons.
      Citation: Cells
      PubDate: 2021-01-12
      DOI: 10.3390/cells10010137
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 138: Identification of Cathepsin D as a Plasma
           Biomarker for Alzheimer’s Disease

    • Authors: Jae-Whan Kim, Soon-Young Jung, Youngbin Kim, Hansol Heo, Chang-Hyung Hong, Sang-Won Seo, Seong-Hye Choi, Sang-Joon Son, Seongju Lee, Jaerak Chang
      First page: 138
      Abstract: Although Alzheimer’s disease (AD) is the most common neurodegenerative disease, there are still no drugs available to treat or prevent AD effectively. Here, we examined changes in levels of selected proteins implicated in the pathogenesis of AD using plasma samples of control subjects and patients with cognition impairment. To precisely categorize the disease, fifty-six participants were examined with clinical cognitive tests, amyloid positron emission tomography (PET) scan, and white matter hyperintensities scored by magnetic resonance imaging. Plasma cathepsin D levels of the subjects were examined by immunoblotting and enzyme-linked immunosorbent assay (ELISA). Correlation of plasma cathepsin D levels with AD-related factors and clinical characteristics were examined by statistical analysis. By analyzing quantitative immunoblot and ELISA, we found that the plasma level of cathepsin D, a major lysosomal protease, was decreased in the group with amyloid plaque deposition at the brain compared to the control group. The level of plasma cathepsin D was negatively correlated with clinical dementia rating scale sum of boxes (CDR-SB) scores. In addition, our integrated multivariable logistic regression model suggests the high performance of plasma cathepsin D level for discriminating AD from non-AD. These results suggest that the plasma cathepsin D level could be developed as a diagnostic biomarker candidate for AD.
      Citation: Cells
      PubDate: 2021-01-12
      DOI: 10.3390/cells10010138
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 139: Seeding Propensity and Characteristics of
           Pathogenic αSyn Assemblies in Formalin-Fixed Human Tissue from the
           Enteric Nervous System, Olfactory Bulb, and Brainstem in Cases Staged for
           Parkinson’s Disease

    • Authors: Alexis Fenyi, Charles Duyckaerts, Luc Bousset, Heiko Braak, Kelly Del Tredici, Ronald Melki, on behalf of the Brainbank Neuro-CEB Neuropathology Network
      First page: 139
      Abstract: We investigated α-synuclein’s (αSyn) seeding activity in tissue from the brain and enteric nervous system. Specifically, we assessed the seeding propensity of pathogenic αSyn in formalin-fixed tissue from the gastric cardia and five brain regions of 29 individuals (12 Parkinson’s disease, 8 incidental Lewy body disease, 9 controls) using a protein misfolding cyclic amplification assay. The structural characteristics of the resultant αSyn assemblies were determined by limited proteolysis and transmission electron microscopy. We show that fixed tissue from Parkinson’s disease (PD) and incidental Lewy body disease (ILBD) seeds the aggregation of monomeric αSyn into fibrillar assemblies. Significant variations in the characteristics of fibrillar assemblies derived from different regions even within the same individual were observed. This finding suggests that fixation stabilizes seeds with an otherwise limited seeding propensity, that yield assemblies with different intrinsic structures (i.e., strains). The lag phase preceding fibril assembly for patients ≥80 was significantly shorter than in other age groups, suggesting the existence of increased numbers of seeds or a higher seeding potential of pathogenic αSyn with time. Seeding activity did not diminish in late-stage disease. No statistically significant difference in the seeding efficiency of specific regions was found, nor was there a relationship between seeding efficiency and the load of pathogenic αSyn in a particular region at a given neuropathological stage.
      Citation: Cells
      PubDate: 2021-01-12
      DOI: 10.3390/cells10010139
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 140: Calcium Signalling in Alzheimer’s Disease:
           From Pathophysiological Regulation to Therapeutic Approaches

    • Authors: Mounia Chami
      First page: 140
      Abstract: Alzheimer’s disease (AD) is a neurodegenerative pathology representing a socioeconomic challenge, however, the complex mechanism behind the disease is not yet fully understood [...]
      Citation: Cells
      PubDate: 2021-01-12
      DOI: 10.3390/cells10010140
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 141: Mimicking Tumor Hypoxia in Non-Small Cell Lung
           Cancer Employing Three-Dimensional In Vitro Models

    • Authors: Iwona Ziółkowska-Suchanek
      First page: 141
      Abstract: Hypoxia is the most common microenvironment feature of lung cancer tumors, which affects cancer progression, metastasis and metabolism. Oxygen induces both proteomic and genomic changes within tumor cells, which cause many alternations in the tumor microenvironment (TME). This review defines current knowledge in the field of tumor hypoxia in non-small cell lung cancer (NSCLC), including biology, biomarkers, in vitro and in vivo studies and also hypoxia imaging and detection. While classic two-dimensional (2D) in vitro research models reveal some hypoxia dependent manifestations, three-dimensional (3D) cell culture models more accurately replicate the hypoxic TME. In this study, a systematic review of the current NSCLC 3D models that have been able to mimic the hypoxic TME is presented. The multicellular tumor spheroid, organoids, scaffolds, microfluidic devices and 3D bioprinting currently being utilized in NSCLC hypoxia studies are reviewed. Additionally, the utilization of 3D in vitro models for exploring biological and therapeutic parameters in the future is described.
      Citation: Cells
      PubDate: 2021-01-12
      DOI: 10.3390/cells10010141
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 142: The WNT/ROR Pathway in Cancer: From Signaling
           to Therapeutic Intervention

    • Authors: Kerstin Menck, Saskia Heinrichs, Cornelia Baden, Annalen Bleckmann
      First page: 142
      Abstract: The WNT pathway is one of the major signaling cascades frequently deregulated in human cancer. While research had initially focused on signal transduction centered on β-catenin as a key effector activating a pro-tumorigenic transcriptional response, nowadays it is known that WNT ligands can also induce a multitude of β-catenin-independent cellular pathways. Traditionally, these comprise WNT/planar cell polarity (PCP) and WNT/Ca2+ signaling. In addition, signaling via the receptor tyrosine kinase-like orphan receptors (RORs) has gained increasing attention in cancer research due to their overexpression in a multitude of tumor entities. Active WNT/ROR signaling has been linked to processes driving tumor development and progression, such as cell proliferation, survival, invasion, or therapy resistance. In adult tissue, the RORs are largely absent, which has spiked the interest in them for targeted cancer therapy. Promising results in preclinical and initial clinical studies are beginning to unravel the great potential of such treatment approaches. In this review, we summarize seminal findings on the structure and expression of the RORs in cancer, their downstream signaling, and its output in regard to tumor cell function. Furthermore, we present the current clinical anti-ROR treatment strategies and discuss the state-of-the-art, as well as the challenges of the different approaches.
      Citation: Cells
      PubDate: 2021-01-12
      DOI: 10.3390/cells10010142
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 143: Exercise Ameliorates Spinal Cord Injury by
           Changing DNA Methylation

    • Authors: Ganchimeg Davaa, Jin Young Hong, Tae Uk Kim, Seong Jae Lee, Seo Young Kim, Kwonho Hong, Jung Keun Hyun
      First page: 143
      Abstract: Exercise training is a traditional method to maximize remaining function in patients with spinal cord injury (SCI), but the exact mechanism by which exercise promotes recovery after SCI has not been identified; whether exercise truly has a beneficial effect on SCI also remains unclear. Previously, we showed that epigenetic changes in the brain motor cortex occur after SCI and that a treatment leading to epigenetic modulation effectively promotes functional recovery after SCI. We aimed to determine how exercise induces functional improvement in rats subjected to SCI and whether epigenetic changes are engaged in the effects of exercise. A spinal cord contusion model was established in rats, which were then subjected to treadmill exercise for 12 weeks. We found that the size of the lesion cavity and the number of macrophages were decreased more in the exercise group than in the control group after 12 weeks of injury. Immunofluorescence and DNA dot blot analysis revealed that levels of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) in the brain motor cortex were increased after exercise. Accordingly, the expression of ten-eleven translocation (Tet) family members (Tet1, Tet2, and Tet3) in the brain motor cortex also elevated. However, no macrophage polarization was induced by exercise. Locomotor function, including Basso, Beattie, and Bresnahan (BBB) and ladder scores, also improved in the exercise group compared to the control group. We concluded that treadmill exercise facilitates functional recovery in rats with SCI, and mechanistically epigenetic changes in the brain motor cortex may contribute to exercise-induced improvements.
      Citation: Cells
      PubDate: 2021-01-12
      DOI: 10.3390/cells10010143
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 144: The Inhibition of CDK8/19 Mediator Kinases
           Prevents the Development of Resistance to EGFR-Targeting Drugs

    • Authors: Amanda C. Sharko, Chang-Uk Lim, Martina S. J. McDermott, Chuck Hennes, Kingsavanh P. Philavong, Tiffanie Aiken, Victor V. Tatarskiy, Igor B. Roninson, Eugenia V. Broude
      First page: 144
      Abstract: Drug resistance is the main obstacle to achieving cures with both conventional and targeted anticancer drugs. The emergence of acquired drug resistance is initially mediated by non-genetic transcriptional changes, which occur at a much higher frequency than mutations and may involve population-scale transcriptomic adaptation. CDK8/19 kinases, through association with transcriptional Mediator complex, regulate transcriptional reprogramming by co-operating with different signal-responsive transcription factors. Here we tested if CDK8/19 inhibition could prevent adaptation to drugs acting on epidermal growth factor receptor (EGFR/ERBB1/HER1). The development of resistance was analyzed following long-term exposure of BT474 and SKBR3 breast cancer cells to EGFR-targeting small molecules (gefitinib, erlotinib) and of SW48 colon cancer cells to an anti-EGFR monoclonal antibody cetuximab. In all cases, treatment of small cell populations (~105 cells) with a single dose of the drug initially led to growth inhibition that was followed by the resumption of proliferation and development of drug resistance in the adapted populations. However, this adaptation was always prevented by the addition of selective CDK8/19 inhibitors, even though such inhibitors alone had only moderate or no effect on cell growth. These results indicate that combining EGFR-targeting drugs with CDK8/19 inhibitors may delay or prevent the development of tumor resistance to therapy.
      Citation: Cells
      PubDate: 2021-01-12
      DOI: 10.3390/cells10010144
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 145: IL-33 and Superantigenic Activation of Human
           Lung Mast Cells Induce the Release of Angiogenic and Lymphangiogenic

    • Authors: Leonardo Cristinziano, Remo Poto, Gjada Criscuolo, Anne Lise Ferrara, Maria Rosaria Galdiero, Luca Modestino, Stefania Loffredo, Amato de de Paulis, Gianni Marone, Giuseppe Spadaro, Gilda Varricchi
      First page: 145
      Abstract: Human lung mast cells (HLMCs) express the high-affinity receptor FcεRI for IgE and are strategically located in different compartments of human lung, where they play a role in several inflammatory disorders and cancer. Immunoglobulin superantigens (e.g., protein A of Staphylococcus aureus and protein L of Peptostreptococcus magnus) bind to the variable regions of either the heavy (VH3) or light chain (κ) of IgE. IL-33 is a cytokine expressed by epithelial cells that exerts pleiotropic functions in the lung. The present study investigated whether immunoglobulin superantigens protein A and protein L and IL-33 caused the release of inflammatory (histamine), angiogenic (VEGF-A) and lymphangiogenic (VEGF-C) factors from HLMCs. The results show that protein A and protein L induced the rapid (30 min) release of preformed histamine from HLMCs. By contrast, IL-33 did not induce the release of histamine from lung mast cells. Prolonged incubation (12 h) of HLMCs with superantigens and IL-33 induced the release of VEGF-A and VEGF-C. Preincubation with IL-33 potentiated the superantigenic release of histamine, angiogenic and lymphangiogenic factors from HLMCs. Our results suggest that IL-33 might enhance the inflammatory, angiogenic and lymphangiogenic activities of lung mast cells in pulmonary disorders.
      Citation: Cells
      PubDate: 2021-01-12
      DOI: 10.3390/cells10010145
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 146: β2-Adrenergic Signaling Modulates
           Mitochondrial Function and Morphology in Skeletal Muscle in Response to
           Aerobic Exercise

    • Authors: Vanessa Azevedo Voltarelli, Michael Coronado, Larissa Gonçalves Fernandes, Juliane Cruz Campos, Paulo Roberto Jannig, Julio Cesar Batista Ferreira, Giovanni Fajardo, Patricia Chakur Brum, Daniel Bernstein
      First page: 146
      Abstract: The molecular mechanisms underlying skeletal muscle mitochondrial adaptations induced by aerobic exercise (AE) are not fully understood. We have previously shown that AE induces mitochondrial adaptations in cardiac muscle, mediated by sympathetic stimulation. Since direct sympathetic innervation of neuromuscular junctions influences skeletal muscle homeostasis, we tested the hypothesis that β2-adrenergic receptor (β2-AR)-mediated sympathetic activation induces mitochondrial adaptations to AE in skeletal muscle. Male FVB mice were subjected to a single bout of AE on a treadmill (80% Vmax, 60 min) under β2-AR blockade with ICI 118,551 (ICI) or vehicle, and parameters of mitochondrial function and morphology/dynamics were evaluated. An acute bout of AE significantly increased maximal mitochondrial respiration in tibialis anterior (TA) isolated fiber bundles, which was prevented by β2-AR blockade. This increased mitochondrial function after AE was accompanied by a change in mitochondrial morphology towards fusion, associated with increased Mfn1 protein expression and activity. β2-AR blockade fully prevented the increase in Mfn1 activity and reduced mitochondrial elongation. To determine the mechanisms involved in mitochondrial modulation by β2-AR activation in skeletal muscle during AE, we used C2C12 myotubes, treated with the non-selective β-AR agonist isoproterenol (ISO) in the presence of the specific β2-AR antagonist ICI or during protein kinase A (PKA) and Gαi protein blockade. Our in vitro data show that β-AR activation significantly increases mitochondrial respiration in myotubes, and this response was dependent on β2-AR activation through a Gαs-PKA signaling cascade. In conclusion, we provide evidence for AE-induced β2-AR activation as a major mechanism leading to alterations in mitochondria function and morphology/dynamics. β2-AR signaling is thus a key-signaling pathway that contributes to skeletal muscle plasticity in response to exercise.
      Citation: Cells
      PubDate: 2021-01-13
      DOI: 10.3390/cells10010146
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 147: Function of the Porcine TRPC1 Gene in
           Myogenesis and Muscle Growth

    • Authors: Yu Fu, Peng Shang, Bo Zhang, Xiaolong Tian, Ruixue Nie, Ran Zhang, Hao Zhang
      First page: 147
      Abstract: In animals, muscle growth is a quantitative trait controlled by multiple genes. Previously, we showed that the transient receptor potential channel 1 (TRPC1) gene was differentially expressed in muscle tissues between pig breeds with divergent growth traits base on RNA-seq. Here, we characterized TRPC1 expression profiles in different tissues and pig breeds and showed that TRPC1 was highly expressed in the muscle. We found two single nucleotide polymorphisms (SNPs) (C-1763T and C-1604T) in TRPC1 that could affect the promoter region activity and regulate pig growth rate. Functionally, we used RNAi and overexpression to illustrate that TRPC1 promotes myoblast proliferation, migration, differentiation, fusion, and muscle hypertrophy while inhibiting muscle degradation. These processes may be mediated by the activation of Wnt signaling pathways. Altogether, our results revealed that TRPC1 might promote muscle growth and development and plays a key role in Wnt-mediated myogenesis.
      Citation: Cells
      PubDate: 2021-01-13
      DOI: 10.3390/cells10010147
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 148: Complement as a Therapeutic Target in Systemic
           Autoimmune Diseases

    • Authors: María Galindo-Izquierdo, José Luis Pablos Alvarez
      First page: 148
      Abstract: The complement system (CS) includes more than 50 proteins and its main function is to recognize and protect against foreign or damaged molecular components. Other homeostatic functions of CS are the elimination of apoptotic debris, neurological development, and the control of adaptive immune responses. Pathological activation plays prominent roles in the pathogenesis of most autoimmune diseases such as systemic lupus erythematosus, antiphospholipid syndrome, rheumatoid arthritis, dermatomyositis, and ANCA-associated vasculitis. In this review, we will review the main rheumatologic autoimmune processes in which complement plays a pathogenic role and its potential relevance as a therapeutic target.
      Citation: Cells
      PubDate: 2021-01-13
      DOI: 10.3390/cells10010148
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 149: Influence of Magnetic Field with Schumann
           Resonance Frequencies on Photosynthetic Light Reactions in Wheat and Pea

    • Authors: Vladimir Sukhov, Ekaterina Sukhova, Yulia Sinitsyna, Ekaterina Gromova, Natalia Mshenskaya, Anastasiia Ryabkova, Nikolay lin, Vladimir Vodeneev, Evgeny Маreev, Colin Price
      First page: 149
      Abstract: Photosynthesis is an important target of action of numerous environmental factors; in particular, stressors can strongly affect photosynthetic light reactions. Considering relations of photosynthetic light reactions to electron and proton transport, it can be supposed that extremely low frequency magnetic field (ELFMF) may influence these reactions; however, this problem has been weakly investigated. In this paper, we experimentally tested a hypothesis about the potential influence of ELFMF of 18 µT intensity with Schumann resonance frequencies (7.8, 14.3, and 20.8 Hz) on photosynthetic light reactions in wheat and pea seedlings. It was shown that ELFMF decreased non-photochemical quenching in wheat and weakly influenced quantum yield of photosystem II at short-term treatment; in contrast, the changes in potential and effective quantum yields of photosystem II were observed mainly under chronic action of ELFMF. It is interesting that both short-term and chronic treatment decreased the time periods for 50% activation of quantum yield and non-photochemical quenching under illumination. Influence of ELFMF on pea was not observed at both short-term and chronic treatment. Thus, we showed that ELFMF with Schumann resonance frequencies could influence photosynthetic light processes; however, this effect depends on plant species (wheat or pea) and type of treatment (short-term or chronic).
      Citation: Cells
      PubDate: 2021-01-13
      DOI: 10.3390/cells10010149
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 150: Microglial Turnover in Ageing-Related

    • Authors: Shofiul Azam, Md. Ezazul Haque, In-Su Kim, Dong-Kug Choi
      First page: 150
      Abstract: Microglia are brain-dwelling macrophages and major parts of the neuroimmune system that broadly contribute to brain development, homeostasis, ageing and injury repair in the central nervous system (CNS). Apart from other brain macrophages, they have the ability to constantly sense changes in the brain’s microenvironment, functioning as housekeepers for neuronal well-being and providing neuroprotection in normal physiology. Microglia use a set of genes for these functions that involve proinflammatory cytokines. In response to specific stimuli, they release these proinflammatory cytokines, which can damage and kill neurons via neuroinflammation. However, alterations in microglial functioning are a common pathophysiology in age-related neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, Huntington’s and prion diseases, as well as amyotrophic lateral sclerosis, frontotemporal dementia and chronic traumatic encephalopathy. When their sentinel or housekeeping functions are severely disrupted, they aggravate neuropathological conditions by overstimulating their defensive function and through neuroinflammation. Several pathways are involved in microglial functioning, including the Trem2, Cx3cr1 and progranulin pathways, which keep the microglial inflammatory response under control and promote clearance of injurious stimuli. Over time, an imbalance in this system leads to protective microglia becoming detrimental, initiating or exacerbating neurodegeneration. Correcting such imbalances might be a potential mode of therapeutic intervention in neurodegenerative diseases.
      Citation: Cells
      PubDate: 2021-01-14
      DOI: 10.3390/cells10010150
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 151: Significance of NETs Formation in COVID-19

    • Authors: Karolina Janiuk, Ewa Jabłońska, Marzena Garley
      First page: 151
      Abstract: Severe contagious respiratory disease—COVID-19—caused by the SARS-CoV-2 coronavirus, can lead to fatal respiratory failure associated with an excessive inflammatory response. Infiltration and spread of SARS-CoV-2 are based on the interaction between the virus’ structural protein S and the cell’s receptor–angiotensin-converting enzyme 2 (ACE2), with the simultaneous involvement of human trans-membrane protease, serine 2 (TMPRSS2). Many scientific reports stress the importance of elevated recruitment and activity of neutrophils, which can form extracellular neutrophil traps (NETs) playing a significant role in the mechanism of combating pathogens, in the pathogenesis of COVID-19. Excessive generation of NETs during prolonged periods of inflammation predisposes for the occurrence of undesirable reactions including thromboembolic complications and damage to surrounding tissues and organs. Within the present manuscript, we draw attention to the impact of NET generation on the severe course of COVID-19 in patients with concurrent cardiovascular and metabolic diseases. Additionally, we indicate the necessity to explore not only the cellular but also the molecular bases of COVID-19 pathogenesis, which may aid the development of dedicated therapies meant to improve chances for the successful treatment of patients. We also present new directions of research into medications that display NETs formation regulatory properties as potential significant therapeutic strategies in the progress of COVID-19.
      Citation: Cells
      PubDate: 2021-01-14
      DOI: 10.3390/cells10010151
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 152: Evaluation of Production Protocols for the
           Generation of NY-ESO-1-Specific T Cells

    • Authors: Wenjie Gong, Lei Wang, Sophia Stock, Ming Ni, Maria-Luisa Schubert, Brigitte Neuber, Christian Kleist, Angela Hückelhoven-Krauss, Depei Wu, Carsten Müller-Tidow, Anita Schmitt, Hiroshi Shiku, Michael Schmitt, Leopold Sellner
      First page: 152
      Abstract: NY-ESO-1-specific T cells have shown promising activity in the treatment of soft tissue sarcoma (STS). However, standardized protocols for their generation are limited. Particularly, cost-effectiveness considerations of cell production protocols are of importance for conducting clinical studies. In this study, two different NY-ESO-1-specific T cell production protocols were compared. Major differences between protocols 1 and 2 include culture medium, interleukin-2 and retronectin concentrations, T cell activation strategy, and the transduction process. NY-ESO-1-specific T cells generated according to the two protocols were investigated for differences in cell viability, transduction efficiency, T cell expansion, immunophenotype as well as functionality. NY-ESO-1-specific T cells showed similar viability and transduction efficiency between both protocols. Protocol 1 generated higher absolute numbers of NY-ESO-1-specific T cells. However, there was no difference in absolute numbers of NY-ESO-1-specific T cell subsets with less-differentiated phenotypes accounting for efficient in vivo expansion and engraftment. Furthermore, cells generated according to protocol 1 displayed higher capacity of TNF-α generation, but lower cytotoxic capacities. Overall, both protocols provided functional NY-ESO-1-specific T cells. However, compared to protocol 1, protocol 2 is advantageous in terms of cost-effectiveness. Cell production protocols should be designed diligently to achieve a cost-effective cellular product for further clinical evaluation.
      Citation: Cells
      PubDate: 2021-01-14
      DOI: 10.3390/cells10010152
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 153: Nuclear Pore Complexes Cluster in Dysmorphic
           Nuclei of Normal and Progeria Cells during Replicative Senescence

    • Authors: Jennifer M. Röhrl, Rouven Arnold, Karima Djabali
      First page: 153
      Abstract: Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disease caused by a mutation in LMNA. A G608G mutation in exon 11 of LMNA is responsible for most HGPS cases, generating a truncated protein called “progerin”. Progerin is permanently farnesylated and accumulates in HGPS cells, causing multiple cellular defects such as nuclear dysmorphism, a thickened lamina, loss of heterochromatin, premature senescence, and clustering of Nuclear Pore Complexes (NPC). To identify the mechanism of NPC clustering in HGPS cells, we evaluated post-mitotic NPC assembly in control and HGPS cells and found no defects. Next, we examined the occurrence of NPC clustering in control and HGPS cells during replicative senescence. We reported that NPC clustering occurs solely in the dysmorphic nuclei of control and HGPS cells. Hence, NPC clustering occurred at a higher frequency in HGPS cells compared to control cells at early passages; however, in late cultures with similar senescence index, NPCs clustering occurred at a similar rate in both control and HGPS. Our results show that progerin does not disrupt post-mitotic reassembly of NPCs. However, NPCs frequently cluster in dysmorphic nuclei with a high progerin content. Additionally, nuclear envelope defects that arise during replicative senescence cause NPC clustering in senescent cells with dysmorphic nuclei.
      Citation: Cells
      PubDate: 2021-01-14
      DOI: 10.3390/cells10010153
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 154: GRKs and Epac1 Interaction in Cardiac
           Remodeling and Heart Failure

    • Authors: Marion Laudette, Karina Formoso, Frank Lezoualc’h
      First page: 154
      Abstract: β-adrenergic receptors (β-ARs) play a major role in the physiological regulation of cardiac function through signaling routes tightly controlled by G protein-coupled receptor kinases (GRKs). Although the acute stimulation of β-ARs and the subsequent production of cyclic AMP (cAMP) have beneficial effects on cardiac function, chronic stimulation of β-ARs as observed under sympathetic overdrive promotes the development of pathological cardiac remodeling and heart failure (HF), a leading cause of mortality worldwide. This is accompanied by an alteration in cAMP compartmentalization and the activation of the exchange protein directly activated by cAMP 1 (Epac1) signaling. Among downstream signals of β-ARs, compelling evidence indicates that GRK2, GRK5, and Epac1 represent attractive therapeutic targets for cardiac disease. Here, we summarize the pathophysiological roles of GRK2, GRK5, and Epac1 in the heart. We focus on their signalosome and describe how under pathological settings, these proteins can cross-talk and are part of scaffolded nodal signaling systems that contribute to a decreased cardiac function and HF development.
      Citation: Cells
      PubDate: 2021-01-14
      DOI: 10.3390/cells10010154
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 155: Alteration of Neural Stem Cell Functions in
           Ataxia and Male Sterility Mice: A Possible Role of β-Tubulin
           Glutamylation in Neurodegeneration

    • Authors: Abdullah Md. Sheikh, Shozo Yano, Shatera Tabassum, Koji Omura, Asuka Araki, Shingo Mitaki, Yoshie Ito, Shuai Huang, Atsushi Nagai
      First page: 155
      Abstract: Ataxia and Male Sterility (AMS) is a mutant mouse strain that contains a missense mutation in the coding region of Nna1, a gene that encodes a deglutamylase. AMS mice exhibit early cerebellar Purkinje cell degeneration and an ataxic phenotype in an autosomal recessive manner. To understand the underlying mechanism, we generated neuronal stem cell (NSC) lines from wild-type (NMW7), Nna1 mutation heterozygous (NME), and Nna1 mutation homozygous (NMO1) mouse brains. The NNA1 levels were decreased, and the glutamylated tubulin levels were increased in NMO1 cultures as well as in the cerebellum of AMS mice at both 15 and 30 days of age. However, total β-tubulin protein levels were not altered in the AMS cerebellum. In NMO1 neurosphere cultures, β-tubulin protein levels were increased without changes at the transcriptional level. NMO1 grew faster than other NSC lines, and some of the neurospheres were attached to the plate after 3 days. Immunostaining revealed that SOX2 and nestin levels were decreased in NMO1 neurospheres and that the neuronal differentiation potentials were reduced in NMO1 cells compared to NME or NMW7 cells. These results demonstrate that the AMS mutation decreased the NNA1 levels and increased glutamylation in the cerebellum of AMS mice. The observed changes in glutamylation might alter NSC properties and the neuron maturation process, leading to Purkinje cell death in AMS mice.
      Citation: Cells
      PubDate: 2021-01-14
      DOI: 10.3390/cells10010155
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 156: MRGPRX2 Activation by Rocuronium: Insights from
           Studies with Human Skin Mast Cells and Missense Variants

    • Authors: Chalatip Chompunud Na Ayudhya, Aetas Amponnawarat, Saptarshi Roy, Carole A. Oskeritzian, Hydar Ali
      First page: 156
      Abstract: Perioperative hypersensitivity (POH) to the neuromuscular blocking drug (NMBD) rocuronium was previously thought to be IgE and mast cell (MC)-mediated. However, the recent seminal observation that rocuronium induces degranulation in murine peritoneal MCs (PMCs) via Mas-related G protein-coupled receptor B2 (MrgprB2) led to the idea that POH to this drug involves the activation of MRGPRX2 (human ortholog of MrgprB2). Furthermore, based on the demonstration that a patient with POH to rocuronium displayed three missense mutations (M196I, L226P and L237P) in MRGPRX2’s transmembrane domains, it was proposed that this hypersensitivity reaction resulted from aberrant activation of this receptor. We found that rocuronium at 20 µg/mL caused degranulation in mouse PMCs via MrgprB2 but required at least 500 µg/mL to induce degranulation in human MCs via MRGPRX2. Furthermore, RBL-2H3 cells transiently expressing M196I, L226P and L237P variants did not display enhanced degranulation in response to rocuronium when compared to the wild-type receptor. These findings provide the first demonstration that rocuronium induces degranulation in human MCs via MRGPRX2. Furthermore, the important differences between MrgprB2 and MRGPRX2 and the inability of rocuronium to induce enhanced response in cells expressing MRGPRX2 variants suggest that the mechanism of its POH is more complex than previously thought.
      Citation: Cells
      PubDate: 2021-01-15
      DOI: 10.3390/cells10010156
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 157: The Cycling of Intracellular Calcium Released
           in Response to Fluid Shear Stress Is Critical for Migration-Associated
           Actin Reorganization in Eosinophils

    • Authors: Kiho Son, Amer Hussain, Roma Sehmi, Luke Janssen
      First page: 157
      Abstract: The magnitude of eosinophil mobilization into respiratory tissues drives the severity of inflammation in several airway diseases. In classical models of leukocyte extravasation, surface integrins undergo conformational switches to high-affinity states via chemokine binding activation. Recently, we learned that eosinophil integrins possess mechanosensitive properties that detect fluid shear stress, which alone was sufficient to induce activation. This mechanical stimulus triggered intracellular calcium release and hallmark migration-associated cytoskeletal reorganization including flattening for increased cell–substratum contact area and pseudopodia formation. The present study utilized confocal fluorescence microscopy to investigate the effects of pharmacological inhibitors to calcium signaling and actin polymerization pathways on shear stress-induced migration in vitro. Morphological changes (cell elongation, membrane protrusions) succeeded the calcium flux in untreated eosinophils within 2 min, suggesting that calcium signaling was upstream of actin cytoskeleton rearrangement. The inhibition of ryanodine receptors and endomembrane Ca2+-ATPases corroborated this idea, indicated by a significant increase in time between the calcium spike and actin polymerization. The impact of the temporal link is evident as the capacity of treated eosinophils to move across fibronectin-coated surfaces was significantly hampered relative to untreated eosinophils. Furthermore, we determined that the nature of cellular motility in response to fluid shear stress was nondirectional.
      Citation: Cells
      PubDate: 2021-01-15
      DOI: 10.3390/cells10010157
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 158: Unravelling Heterogeneity of Amplified Human
           Amniotic Fluid Stem Cells Sub-Populations

    • Authors: Francesca Casciaro, Silvia Zia, Mattia Forcato, Manuela Zavatti, Francesca Beretti, Emma Bertucci, Andrea Zattoni, Pierluigi Reschiglian, Francesco Alviano, Laura Bonsi, Matilde Yung Follo, Marco Demaria, Barbara Roda, Tullia Maraldi
      First page: 158
      Abstract: Human amniotic fluid stem cells (hAFSCs) are broadly multipotent immature progenitor cells with high self-renewal and no tumorigenic properties. These cells, even amplified, present very variable morphology, density, intracellular composition and stemness potential, and this heterogeneity can hinder their characterization and potential use in regenerative medicine. Celector® (Stem Sel ltd.) is a new technology that exploits the Non-Equilibrium Earth Gravity Assisted Field Flow Fractionation principles to characterize and label-free sort stem cells based on their solely physical characteristics without any manipulation. Viable cells are collected and used for further studies or direct applications. In order to understand the intrapopulation heterogeneity, various fractions of hAFSCs were isolated using the Celector® profile and live imaging feature. The gene expression profile of each fraction was analysed using whole-transcriptome sequencing (RNAseq). Gene Set Enrichment Analysis identified significant differential expression in pathways related to Stemness, DNA repair, E2F targets, G2M checkpoint, hypoxia, EM transition, mTORC1 signalling, Unfold Protein Response and p53 signalling. These differences were validated by RT-PCR, immunofluorescence and differentiation assays. Interestingly, the different fractions showed distinct and unique stemness properties. These results suggest the existence of deep intra-population differences that can influence the stemness profile of hAFSCs. This study represents a proof-of-concept of the importance of selecting certain cellular fractions with the highest potential to use in regenerative medicine.
      Citation: Cells
      PubDate: 2021-01-15
      DOI: 10.3390/cells10010158
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 159: Immune Cell-Associated Protein Expression Helps
           to Predict Survival in Muscle-Invasive Urothelial Bladder Cancer Patients
           after Radical Cystectomy and Optional Adjuvant Chemotherapy

    • Authors: Helge Taubert, Markus Eckstein, Elena Epple, Rudolf Jung, Katrin Weigelt, Verena Lieb, Danijel Sikic, Robert Stöhr, Carol Geppert, Veronika Weyerer, Simone Bertz, Astrid Kehlen, Arndt Hartmann, Bernd Wullich, Sven Wach
      First page: 159
      Abstract: Bladder cancer (BCa) is the tenth most commonly diagnosed malignant cancer worldwide. Although adjuvant chemotherapy following radical cystectomy is a common therapy for muscle invasive bladder cancer patients, no applicable biomarkers exist to predict which patients will benefit from chemotherapy. In this study, we examined three immune cell markers, the chemokine CC motif ligand 2 (CCL2), the pan macrophage marker cluster of differentiation 68 (CD68) and the M2 macrophage marker cluster of differentiation 163 (CD163), using immunohistochemistry to determine their predictive value for the chemotherapy response in different nodal stage (pN0 vs. pN1 + 2) and tumor stage subgroups (pT2 vs. pT3 + 4). The prognosis was studied in terms of the overall survival (OS), disease-specific survival (DSS), and recurrence-free-survival (RFS) in 168 muscle invasive BCa patients. Chemotherapy was associated with a poorer prognosis in patients with a higher expression of the immune markers CCL2 (RFS), CD68 (DSS and RFS), and CD163 (DSS and RFS) in the N0 group and with poorer survival in patients with a higher expression of the immune markers CCL2 (OS, DSS, and RFS), CD68 (OS, DSS, and RFS), and CD163 (OS, DSS, and RFS) in the pT2 group when compared with treatments without chemotherapy. In contrast, chemotherapy was associated with a better prognosis in patients with a low expression of the immune markers CCL2 (DSS and RFS), CD68 (OS, DSS, and RFS), and CD163 (OS) in the N1 + 2 group. In addition, chemotherapy was associated with improved survival in patients with a low expression of the immune marker CD68 (OS and DSS) and there was a trend for a better prognosis in patients with a low expression of CD163 (OS) in the pT3 + 4 group compared to patients not treated with chemotherapy. Interestingly, CD68 appeared to be the most applicable immune marker to stratify patients by the outcome of chemotherapy in the nodal stage and tumor stage groups. Overall, we suggest that, in addition to the clinical factors of tumor stage and nodal stage, it is also meaningful to consider the abundance of immune cells, such as macrophages, to better predict the response to chemotherapy for BCa patients after radical treatment.
      Citation: Cells
      PubDate: 2021-01-15
      DOI: 10.3390/cells10010159
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 160: Structural Insights into Membrane Fusion
           Mediated by Convergent Small Fusogens

    • Authors: Yiming Yang, Nandini Nagarajan Margam
      First page: 160
      Abstract: From lifeless viral particles to complex multicellular organisms, membrane fusion is inarguably the important fundamental biological phenomena. Sitting at the heart of membrane fusion are protein mediators known as fusogens. Despite the extensive functional and structural characterization of these proteins in recent years, scientists are still grappling with the fundamental mechanisms underlying membrane fusion. From an evolutionary perspective, fusogens follow divergent evolutionary principles in that they are functionally independent and do not share any sequence identity; however, they possess structural similarity, raising the possibility that membrane fusion is mediated by essential motifs ubiquitous to all. In this review, we particularly emphasize structural characteristics of small-molecular-weight fusogens in the hope of uncovering the most fundamental aspects mediating membrane–membrane interactions. By identifying and elucidating fusion-dependent functional domains, this review paves the way for future research exploring novel fusogens in health and disease.
      Citation: Cells
      PubDate: 2021-01-15
      DOI: 10.3390/cells10010160
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 161: PE_PGRS33, an Important Virulence Factor of
           Mycobacterium tuberculosis and Potential Target of Host Humoral Immune

    • Authors: Eliza Kramarska, Flavia Squeglia, Flavio De Maio, Giovanni Delogu, Rita Berisio
      First page: 161
      Abstract: PE_PGRS proteins are surface antigens of Mycobacterium tuberculosis (Mtb) and a few other pathogenic mycobacteria. The PE_PGRS33 protein is among the most studied PE_PGRSs. It is known that the PE domain of PE_PGRS33 is required for the protein translocation through the mycobacterial cell wall, where the PGRS domain remains available for interaction with host receptors. Interaction with Toll like receptor 2 (TLR2) promotes secretion of inflammatory chemokines and cytokines, which are key in the immunopathogenesis of tuberculosis (TB). In this review, we briefly address some key challenges in the development of a TB vaccine and attempt to provide a rationale for the development of new vaccines aimed at fostering a humoral response against Mtb. Using PE_PGRS33 as a model for a surface-exposed antigen, we exploit the availability of current structural data using homology modeling to gather insights on the PGRS domain features. Our study suggests that the PGRS domain of PE_PGRS33 exposes four PGII sandwiches on the outer surface, which, we propose, are directly involved through their loops in the interactions with the host receptors and, as such, are promising targets for a vaccination strategy aimed at inducing a humoral response.
      Citation: Cells
      PubDate: 2021-01-15
      DOI: 10.3390/cells10010161
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 162: GRIM19 Impedes Obesity by Regulating
           Inflammatory White Fat Browning and Promoting Th17/Treg Balance

    • Authors: JooYeon Jhun, Jin Seok Woo, Seung Hoon Lee, Jeong-Hee Jeong, KyungAh Jung, Wonhee Hur, Seon-Yeong Lee, Jae Yoon Ryu, Young-Mee Moon, Yoon Ju Jung, Kyo Young Song, Kiyuk Chang, Seung Kew Yoon, Sung-Hwan Park, Mi-La Cho
      First page: 162
      Abstract: Obesity, a condition characterized by excessive accumulation of body fat, is a metabolic disorder related to an increased risk of chronic inflammation. Obesity is mediated by signal transducer and activator of transcription (STAT) 3, which is regulated by genes associated with retinoid-interferon-induced mortality (GRIM) 19, a protein ubiquitously expressed in various human tissues. In this study, we investigated the role of GRIM19 in diet-induced obese C57BL/6 mice via intravenous or intramuscular administration of a plasmid encoding GRIM19. Splenocytes from wild-type and GRIM19-overexpressing mice were compared using enzyme-linked immunoassay, real-time polymerase chain reaction, Western blotting, flow cytometry, and histological analyses. GRIM19 attenuated the progression of obesity by regulating STAT3 activity and enhancing brown adipose tissue (BAT) differentiation. GRIM19 regulated the differentiation of mouse-derived 3T3-L1 preadipocytes into adipocytes, while modulating gene expression in white adipose tissue (WAT) and BAT. GRIM19 overexpression reduced diet-induced obesity and enhanced glucose and lipid metabolism in the liver. Moreover, GRIM19 overexpression reduced WAT differentiation and induced BAT differentiation in obese mice. GRIM19-transgenic mice exhibited reduced mitochondrial superoxide levels and a reciprocal balance between Th17 and Treg cells. These results suggest that GRIM19 attenuates the progression of obesity by controlling adipocyte differentiation.
      Citation: Cells
      PubDate: 2021-01-15
      DOI: 10.3390/cells10010162
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 163: A Dual Role of Heme Oxygenase-1 in Angiotensin
           II-Induced Abdominal Aortic Aneurysm in the Normolipidemic Mice

    • Authors: Aleksandra Kopacz, Damian Klóska, Ewa Werner, Karolina Hajduk, Anna Grochot-Przęczek, Alicja Józkowicz, Aleksandra Piechota-Polańczyk
      First page: 163
      Abstract: Abdominal aortic aneurysm (AAA) bears a high risk of rupture and sudden death of the patient. The pathogenic mechanisms of AAA remain elusive, and surgical intervention represents the only treatment option. Heme oxygenase-1 (HO-1), a heme degrading enzyme, is induced in AAA, both in mice and humans. HO-1 was reported to mitigate AAA development in an angiotensin II (AngII)-induced model of AAA in hyperlipidemic ApoE-/- mice. Since the role of hyperlipidaemia in the pathogenesis of AAA remains controversial, we aimed to evaluate the significance of HO-1 in the development and progression of AAA in normolipidemic animals. The experiments were performed in HO-1-deficient mice and their wild-type counterparts. We demonstrated in non-hypercholesterolemic mice that the high-dose of AngII leads to the efficient formation of AAA, which is attenuated by HO-1 deficiency. Yet, if formed, they are significantly more prone to rupture upon HO-1 shortage. Differential susceptibility to AAA formation does not rely on enhanced inflammatory response or oxidative stress. AAA-resistant mice are characterized by an increase in regulators of aortic remodeling and angiotensin receptor-2 expression, significant medial thickening, and delayed blood pressure elevation in response to AngII. To conclude, we unveil a dual role of HO-1 deficiency in AAA in normolipidemic mice, where it protects against AAA development, but exacerbates the state of formed AAA.
      Citation: Cells
      PubDate: 2021-01-15
      DOI: 10.3390/cells10010163
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 164: Functional Heterogeneity and Therapeutic
           Targeting of Tissue-Resident Memory T Cells

    • Authors: Esmé T. I. van der Gracht, Felix M. Behr, Ramon Arens
      First page: 164
      Abstract: Tissue-resident memory T (TRM) cells mediate potent local innate and adaptive immune responses and provide long-lasting protective immunity. TRM cells localize to many different tissues, including barrier tissues, and play a crucial role in protection against infectious and malignant disease. The formation and maintenance of TRM cells are influenced by numerous factors, including inflammation, antigen triggering, and tissue-specific cues. Emerging evidence suggests that these signals also contribute to heterogeneity within the TRM cell compartment. Here, we review the phenotypic and functional heterogeneity of CD8+ TRM cells at different tissue sites and the molecular determinants defining CD8+ TRM cell subsets. We further discuss the possibilities of targeting the unique cell surface molecules, cytokine and chemokine receptors, transcription factors, and metabolic features of TRM cells for therapeutic purposes. Their crucial role in immune protection and their location at the frontlines of the immune defense make TRM cells attractive therapeutic targets. A better understanding of the possibilities to selectively modulate TRM cell populations may thus improve vaccination and immunotherapeutic strategies employing these potent immune cells.
      Citation: Cells
      PubDate: 2021-01-15
      DOI: 10.3390/cells10010164
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 165: TRPing to the Point of Clarity: Understanding
           the Function of the Complex TRPV4 Ion Channel

    • Authors: Trine L. Toft-Bertelsen, Nanna MacAulay
      First page: 165
      Abstract: The transient receptor potential vanilloid 4 channel (TRPV4) belongs to the mammalian TRP superfamily of cation channels. TRPV4 is ubiquitously expressed, activated by a disparate array of stimuli, interacts with a multitude of proteins, and is modulated by a range of post-translational modifications, the majority of which we are only just beginning to understand. Not surprisingly, a great number of physiological roles have emerged for TRPV4, as have various disease states that are attributable to the absence, or abnormal functioning, of this ion channel. This review will highlight structural features of TRPV4, endogenous and exogenous activators of the channel, and discuss the reported roles of TRPV4 in health and disease.
      Citation: Cells
      PubDate: 2021-01-15
      DOI: 10.3390/cells10010165
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 166: MMP-9 Signaling Pathways That Engage Rho
           GTPases in Brain Plasticity

    • Authors: Izabela Figiel, Patrycja K. Kruk, Monika Zaręba-Kozioł, Paulina Rybak, Monika Bijata, Jakub Wlodarczyk, Joanna Dzwonek
      First page: 166
      Abstract: The extracellular matrix (ECM) has been identified as a critical factor affecting synaptic function. It forms a functional scaffold that provides both the structural support and the reservoir of signaling molecules necessary for communication between cellular constituents of the central nervous system (CNS). Among numerous ECM components and modifiers that play a role in the physiological and pathological synaptic plasticity, matrix metalloproteinase 9 (MMP-9) has recently emerged as a key molecule. MMP-9 may contribute to the dynamic remodeling of structural and functional plasticity by cleaving ECM components and cell adhesion molecules. Notably, MMP-9 signaling was shown to be indispensable for long-term memory formation that requires synaptic remodeling. The core regulators of the dynamic reorganization of the actin cytoskeleton and cell adhesion are the Rho family of GTPases. These proteins have been implicated in the control of a wide range of cellular processes occurring in brain physiology and pathology. Here, we discuss the contribution of Rho GTPases to MMP-9-dependent signaling pathways in the brain. We also describe how the regulation of Rho GTPases by post-translational modifications (PTMs) can influence these processes.
      Citation: Cells
      PubDate: 2021-01-15
      DOI: 10.3390/cells10010166
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 167: The Metabolic Role of GRK2 in Insulin
           Resistance and Associated Conditions

    • Authors: Daniela Sorriento, Maria Rosaria Rusciano, Valeria Visco, Antonella Fiordelisi, Federica Andrea Cerasuolo, Paolo Poggio, Michele Ciccarelli, Guido Iaccarino
      First page: 167
      Abstract: Insulin resistance (IRES) is a pathophysiological condition characterized by the reduced response to insulin of several tissues, including myocardial and skeletal muscle. IRES is associated with obesity, glucose intolerance, dyslipidemia, and hypertension, evolves toward type 2 diabetes, and increases the risk of developing cardiovascular diseases. Several studies designed to explore the mechanisms involved in IRES allowed the identification of a multitude of potential molecular targets. Among the most promising, G Protein Coupled Receptor Kinase type 2 (GRK2) appears to be a suitable one given its functional implications in many cellular processes. In this review, we will discuss the metabolic role of GRK2 in those conditions that are characterized by insulin resistance (diabetes, hypertension, heart failure), and the potentiality of its inhibition as a therapeutic strategy to revert both insulin resistance and its associated phenotypes.
      Citation: Cells
      PubDate: 2021-01-15
      DOI: 10.3390/cells10010167
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 168: Detecting Resistance to Therapeutic ALK
           Inhibitors in Tumor Tissue and Liquid Biopsy Markers: An Update to a
           Clinical Routine Practice

    • Authors: Paul Hofman
      First page: 168
      Abstract: The survival of most patients with advanced stage non-small cell lung cancer is prolonged by several months when they are treated with first- and next-generation inhibitors targeting ALK rearrangements, but resistance inevitably emerges. Some of the mechanisms of resistance are sensitive to novel ALK inhibitors but after an initial tumor response, more or less long-term resistance sets in. Therefore, to adapt treatment it is necessary to repeat biological sampling over time to look for different mechanisms of resistance. To this aim it is essential to obtain liquid and/or tissue biopsies to detect therapeutic targets, in particular for the analysis of different genomic alterations. This review discusses the mechanisms of resistance to therapeutics targeting genomic alterations in ALK as well as the advantages and the limitations of liquid biopsies for their identification.
      Citation: Cells
      PubDate: 2021-01-15
      DOI: 10.3390/cells10010168
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 169: CD112 Regulates Angiogenesis and T Cell Entry
           into the Spleen

    • Authors: Erica Russo, Peter Runge, Neda Haghayegh Jahromi, Heidi Naboth, Angela Landtwing, Riccardo Montecchi, Noémie Leicht, Morgan Campbell Hunter, Yoshimi Takai, Cornelia Halin
      First page: 169
      Abstract: Junctional adhesion proteins play important roles in controlling angiogenesis, vascular permeability and leukocyte trafficking. CD112 (nectin-2) belongs to the immunoglobulin superfamily and was shown to engage in homophilic and heterophilic interactions with a variety of binding partners expressed on endothelial cells and on leukocytes. Recent in vitro studies suggested that CD112 regulates human endothelial cell migration and proliferation as well as transendothelial migration of leukocytes. However, so far, the role of CD112 in endothelial cell biology and in leukocyte trafficking has not been elucidated in vivo. We found CD112 to be expressed by lymphatic and blood endothelial cells in different murine tissues. In CD112-deficient mice, the blood vessel coverage in the retina and spleen was significantly enhanced. In functional in vitro studies, a blockade of CD112 modulated endothelial cell migration and significantly enhanced endothelial tube formation. An antibody-based blockade of CD112 also significantly reduced T cell transmigration across endothelial monolayers in vitro. Moreover, T cell homing to the spleen was significantly reduced in CD112-deficient mice. Overall, our results identify CD112 as a regulator of angiogenic processes in vivo and demonstrate a novel role for CD112 in T cell entry into the spleen.
      Citation: Cells
      PubDate: 2021-01-15
      DOI: 10.3390/cells10010169
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 170: The Predictive Value of miR-16, -29a and -134
           for Early Identification of Gestational Diabetes: A Nested Analysis of the
           DALI Cohort

    • Authors: Anja Sørensen, Mireille van Poppel, Gernot Desoye, Peter Damm, David Simmons, Dorte Jensen, Louise Dalgaard, The DALI Core Investigator Group
      First page: 170
      Abstract: Early identification of gestational diabetes mellitus (GDM) aims to reduce the risk of adverse maternal and perinatal outcomes. Currently, no circulating biomarker has proven clinically useful for accurate prediction of GDM. In this study, we tested if a panel of small non-coding circulating RNAs could improve early prediction of GDM. We performed a nested case-control study of participants from the European multicenter ‘Vitamin D and lifestyle intervention for GDM prevention (DALI)’ trial using serum samples from obese pregnant women (BMI ≥ 29 kg/m2) entailing 82 GDM cases (early- and late- GDM), and 41 age- and BMI-matched women with normal glucose tolerance (NGT) throughout pregnancy (controls). Anthropometric, clinical and biochemical characteristics were obtained at baseline (<20 weeks of gestation) and throughout gestation. Baseline serum microRNAs (miRNAs) were measured using quantitative real time PCR (qPCR). Elevated miR-16-5p, -29a-3p, and -134-5p levels were observed in women, who were NGT at baseline and later developed GDM, compared with controls who remained NGT. A combination of the three miRNAs could distinguish later GDM from NGT cases (AUC 0.717, p = 0.001, compared with fasting plasma glucose (AUC 0.687, p = 0.004)) as evaluated by area under the curves (AUCs) using Receiver Operator Characteristics (ROC) analysis. Elevated levels of individual miRNAs or a combination hereof were associated with higher odds ratios of GDM. Conclusively, circulating miRNAs early in pregnancy could serve as valuable predictive biomarkers of GDM.
      Citation: Cells
      PubDate: 2021-01-15
      DOI: 10.3390/cells10010170
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 171: Unravelling Genetic Factors Underlying
           Corticobasal Syndrome: A Systematic Review

    • Authors: Federica Arienti, Giulia Lazzeri, Maria Vizziello, Edoardo Monfrini, Nereo Bresolin, Maria Cristina Saetti, Marina Picillo, Giulia Franco, Alessio Di Fonzo
      First page: 171
      Abstract: Corticobasal syndrome (CBS) is an atypical parkinsonian presentation characterized by heterogeneous clinical features and different underlying neuropathology. Most CBS cases are sporadic; nevertheless, reports of families and isolated individuals with genetically determined CBS have been reported. In this systematic review, we analyze the demographical, clinical, radiological, and anatomopathological features of genetically confirmed cases of CBS. A systematic search was performed using the PubMed, EMBASE, and Cochrane Library databases, included all publications in English from 1 January, 1999 through 1 August, 2020. We found forty publications with fifty-eight eligible cases. A second search for publications dealing with genetic risk factors for CBS led to the review of eight additional articles. GRN was the most common gene involved in CBS, representing 28 out of 58 cases, followed by MAPT, C9ORF72, and PRNP. A set of symptoms was shown to be significantly more common in GRN-CBS patients, including visuospatial impairment, behavioral changes, aphasia, and language alterations. In addition, specific demographical, clinical, biochemical, and radiological features may suggest mutations in other genes. We suggest a diagnostic algorithm to help in identifying potential genetic cases of CBS in order to improve the diagnostic accuracy and to better understand the still poorly defined underlying pathogenetic process.
      Citation: Cells
      PubDate: 2021-01-15
      DOI: 10.3390/cells10010171
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 172: Future Directions in the Treatment of

    • Authors: Alannah Smrke, Peter M. Anderson, Ashish Gulia, Spyridon Gennatas, Paul H. Huang, Robin L. Jones
      First page: 172
      Abstract: Osteosarcoma is the most common primary bone sarcoma and is often diagnosed in the 2nd–3rd decades of life. Response to the aggressive and highly toxic neoadjuvant methotrexate-doxorubicin-cisplatin (MAP) chemotherapy schedule is strongly predictive of outcome. Outcomes for patients with osteosarcoma have not significantly changed for over thirty years. There is a need for more effective treatment for patients with high risk features but also reduced treatment-related toxicity for all patients. Predictive biomarkers are needed to help inform clinicians to de-escalate or add therapy, including immune therapies, and to contribute to future clinical trial designs. Here, we review a variety of approaches to improve outcomes and quality of life for patients with osteosarcoma with a focus on incorporating toxicity reduction, immune therapy and molecular analysis to provide the most effective and least toxic osteosarcoma therapy.
      Citation: Cells
      PubDate: 2021-01-15
      DOI: 10.3390/cells10010172
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 173: Solution NMR Structure of the SH3 Domain of
           Human Caskin1 Validates the Lack of a Typical Peptide Binding Groove and
           Supports a Role in Lipid Mediator Binding

    • Authors: Orsolya Tőke, Kitti Koprivanacz, László Radnai, Balázs Merő, Tünde Juhász, Károly Liliom, László Buday
      First page: 173
      Abstract: SH3 domains constitute an important class of protein modules involved in a variety of cellular functions. They participate in protein-protein interactions via their canonical ligand binding interfaces composed of several evolutionarily conserved aromatic residues forming binding grooves for typical (PxxP) and atypical (PxxxPR, RxxK, RKxxY) binding motifs. The calcium/calmodulin-dependent serine protein kinase (CASK)-interacting protein 1, or Caskin1, a multidomain scaffold protein regulating the cortical actin filaments, is enriched in neural synapses in mammals. Based on its known interaction partners and knock-out animal studies, Caskin1 may play various roles in neural function and it is thought to participate in several pathological processes of the brain. Caskin1 has a single, atypical SH3 domain in which key aromatic residues are missing from the canonical binding groove. No protein interacting partner for this SH3 domain has been identified yet. Nevertheless, we have recently demonstrated the specific binding of this SH3 domain to the signaling lipid mediator lysophospatidic acid (LPA) in vitro. Here we report the solution NMR structure of the human Caskin1 SH3 domain and analyze its structural features in comparison with other SH3 domains exemplifying different strategies in target selectivity. The key differences revealed by our structural study show that the canonical binding groove found in typical SH3 domains accommodating proline-rich motifs is missing in Caskin1 SH3, most likely excluding a bona fide protein target for the domain. The LPA binding site is distinct from the altered protein binding groove. We conclude that the SH3 domain of Caskin1 might mediate the association of Caskin1 with membrane surfaces with locally elevated LPA content.
      Citation: Cells
      PubDate: 2021-01-16
      DOI: 10.3390/cells10010173
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 174: The Impact of HIV- and ART-Induced
           Mitochondrial Dysfunction in Cellular Senescence and Aging

    • Authors: Madison Schank, Juan Zhao, Jonathan P. Moorman, Zhi Q. Yao
      First page: 174
      Abstract: According to the WHO, 38 million individuals were living with human immunodeficiency virus (HIV), 25.4 million of which were using antiretroviral therapy (ART) at the end of 2019. Despite ART-mediated suppression of viral replication, ART is not a cure and is associated with viral persistence, residual inflammation, and metabolic disturbances. Indeed, due to the presence of viral reservoirs, lifelong ART therapy is required to control viremia and prevent disease progression into acquired immune deficiency syndrome (AIDS). Successful ART treatment allows people living with HIV (PLHIV) to achieve a similar life expectancy to uninfected individuals. However, recent studies have illustrated the presence of increased comorbidities, such as accelerated, premature immune aging, in ART-controlled PLHIV compared to uninfected individuals. Studies suggest that both HIV-infection and ART-treatment lead to mitochondrial dysfunction, ultimately resulting in cellular exhaustion, senescence, and apoptosis. Since mitochondria are essential cellular organelles for energy homeostasis and cellular metabolism, their compromise leads to decreased oxidative phosphorylation (OXPHOS), ATP synthesis, gluconeogenesis, and beta-oxidation, abnormal cell homeostasis, increased oxidative stress, depolarization of the mitochondrial membrane potential, and upregulation of mitochondrial DNA mutations and cellular apoptosis. The progressive mitochondrial damage induced by HIV-infection and ART-treatment likely contributes to accelerated aging, senescence, and cellular dysfunction in PLHIV. This review discusses the connections between mitochondrial compromise and cellular dysfunction associated with HIV- and ART-induced toxicities, providing new insights into how HIV and current ART directly impact mitochondrial functions and contribute to cellular senescence and aging in PLHIV. Identifying this nexus and potential mechanisms may be beneficial in developing improved therapeutics for treating PLHIV.
      Citation: Cells
      PubDate: 2021-01-16
      DOI: 10.3390/cells10010174
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 175: Exogenous Fatty Acids Modulate ER Lipid
           Composition and Metabolism in Breast Cancer Cells

    • Authors: Angela Maria Rizzo, Irma Colombo, Gigliola Montorfano, Stefania Zava, Paola Antonia Corsetto
      First page: 175
      Abstract: (1) Background: Lipid metabolism is a fundamental hallmark of all tumors, especially of breast cancer. Few studies describe the different lipid metabolisms and sensitivities to the microenvironment of breast cancer cell subtypes that influence the proliferation, aggressiveness, and success of therapy. This study describes the impact of lipid microenvironment on endoplasmic reticulum (ER) membrane and metabolic activity in two breast cancer cell lines with Luminal A and triple-negative breast cancer (TNBC) features. (2) Methods: We investigated the peculiar lipid phenotype of a TNBC cell line, MDA-MB-231, and a Luminal A cell line, MCF7, and their different sensitivity to exogenous fatty acids (i.e., palmitic acid (PA) and docosahexaenoic acid (DHA)). Moreover, we verified the impact of exogenous fatty acids on ER lipid composition. (3) Results: The data obtained demonstrate that MDA-MB-231 cells are more sensitive to the lipid microenvironment and that both PA and DHA are able to remodel their ER membranes with consequences on resident enzyme activity. On the contrary, MCF7 cells are less sensitive to PA, whereas they incorporate DHA, although less efficiently than MDA-MB-231 cells. (4) Conclusions: This study sustains the importance of lipid metabolism as an innovative hallmark to discriminate breast cancer subclasses and to develop personalized and innovative pharmacological strategies. The different sensitivities to the lipid environment shown by MCF7 and MDA-MB-231 cells might be related to cell malignancy and chemoresistance onset. In the future, this new approach could lead to a substantial decrease both in deleterious side effects for the patients and in the cost of entire therapeutic treatments coupled with increased therapy efficiency.
      Citation: Cells
      PubDate: 2021-01-16
      DOI: 10.3390/cells10010175
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 176: Circular RNA circMYL1 Inhibit Proliferation and
           Promote Differentiation of Myoblasts by Sponging miR-2400

    • Authors: Ibrahim Elsaeid Elnour, Xiaogang Wang, Toremurat Zhansaya, Zhanerke Akhatayeva, Rajwali Khan, Jie Cheng, Yongzhen Hung, Xianyong Lan, Chuzhao Lei, Hong Chen
      First page: 176
      Abstract: Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs (ncRNAs) involved in regulating skeletal muscle development by sponging miRNAs. In this study, we found that the circMYL1 expression was down-regulated during myoblast proliferation, while gradually up-regulated in myoblast differentiation. The potential role of circMYL1 was identified in the proliferation of bovine myoblast through mRNA and protein expression of proliferation marker genes (PCNA, CyclinD1, and CDK2), cell counting kit-8 assay, flow cytometry analysis, and 5-ethynyl 2′-deoxyuridine (EdU) assay. Analysis of the expression of differentiation marker genes (MyoD, MyoG, and MYH2) and immunofluorescence of Myosin heavy chain (MyHC) was used to assess cell differentiation. The proliferation analysis revealed that circMYL1 inhibited the proliferation of bovine primary myoblast. Furthermore, the differentiation analysis demonstrated that circMYL1 promoted the differentiation of bovine primary myoblast. The luciferase screening and RNA immunoprecipitation (RIP) assays found that circMYL1 could have interaction with miR-2400. Additionally, we demonstrated that miR-2400 promoted proliferation and inhibited differentiation of bovine primary myoblast, while circMYL1 may eliminate the effects of miR-2400, as showed by rescue experiments. Together, our results revealed that a novel circular RNA of circMYL1 could inhibit proliferation and promote differentiation of myoblast by sponging miR-2400.
      Citation: Cells
      PubDate: 2021-01-16
      DOI: 10.3390/cells10010176
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 177: Autophagy Involvement in the Postnatal
           Development of the Rat Retina

    • Authors: Noemi Anna Pesce, Alessio Canovai, Emma Lardner, Maurizio Cammalleri, Anders Kvanta, Helder André, Massimo Dal Monte
      First page: 177
      Abstract: During retinal development, a physiologic hypoxia stimulates endothelial cell proliferation. The hypoxic milieu warrants retina vascularization and promotes the activation of several mechanisms aimed to ensure homeostasis and energy balance of both endothelial and retinal cells. Autophagy is an evolutionarily conserved catabolic system that contributes to cellular adaptation to a variety of environmental changes and stresses. In association with the physiologic hypoxia, autophagy plays a crucial role during development. Autophagy expression profile was evaluated in the developing retina from birth to post-natal day 18 of rat pups, using qPCR, western blotting and immunostaining methodologies. The rat post-partum developing retina displayed increased active autophagy during the first postnatal days, correlating to the hypoxic phase. In latter stages of development, rat retinal autophagy decreases, reaching a normalization between post-natal days 14-18, when the retina is fully vascularized and mature. Collectively, the present study elaborates on the link between hypoxia and autophagy, and contributes to further elucidate the role of autophagy during retinal development.
      Citation: Cells
      PubDate: 2021-01-17
      DOI: 10.3390/cells10010177
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 178: SUMO-Activating Enzyme Subunit 1 (SAE1) Is a
           Promising Diagnostic Cancer Metabolism Biomarker of Hepatocellular

    • Authors: Jiann Ruey Ong, Oluwaseun Adebayo Bamodu, Nguyen Viet Khang, Yen-Kuang Lin, Chi-Tai Yeh, Wei-Hwa Lee, Yih-Giun Cherng
      First page: 178
      Abstract: Hepatocellular carcinoma (HCC) is one of the most diagnosed malignancies and a leading cause of cancer-related mortality globally. This is exacerbated by its highly aggressive phenotype, and limitation in early diagnosis and effective therapies. The SUMO-activating enzyme subunit 1 (SAE1) is a component of a heterodimeric small ubiquitin-related modifier that plays a vital role in SUMOylation, a post-translational modification involving in cellular events such as regulation of transcription, cell cycle and apoptosis. Reported overexpression of SAE1 in glioma in a stage-dependent manner suggests it has a probable role in cancer initiation and progression. In this study, hypothesizing that SAE1 is implicated in HCC metastatic phenotype and poor prognosis, we analyzed the expression of SAE1 in several cancer databases and to unravel the underlying molecular mechanism of SAE1-associated hepatocarcinogenesis. Here, we demonstrated that SAE1 is over-expressed in HCC samples compared to normal liver tissue, and this observed SAE1 overexpression is stage and grade-dependent and associated with poor survival. The receiver operating characteristic analysis of SAE1 in TCGA−LIHC patients (n = 421) showed an AUC of 0.925, indicating an excellent diagnostic value of SAE1 in HCC. Our protein-protein interaction analysis for SAE1 showed that SAE1 interacted with and activated oncogenes such as PLK1, CCNB1, CDK4 and CDK1, while simultaneously inhibiting tumor suppressors including PDK4, KLF9, FOXO1 and ALDH2. Immunohistochemical staining and clinicopathological correlate analysis of SAE1 in our TMU-SHH HCC cohort (n = 54) further validated the overexpression of SAE1 in cancerous liver tissues compared with ‘normal’ paracancerous tissue, and high SAE1 expression was strongly correlated with metastasis and disease progression. The oncogenic effect of upregulated SAE1 is associated with dysregulated cancer metabolic signaling. In conclusion, the present study demonstrates that SAE1 is a targetable cancer metabolic biomarker with high potential diagnostic and prognostic implications for patients with HCC.
      Citation: Cells
      PubDate: 2021-01-17
      DOI: 10.3390/cells10010178
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 179: A Splice Variant in SLC16A8 Gene Leads to
           Lactate Transport Deficit in Human iPS Cell-Derived Retinal Pigment
           Epithelial Cells

    • Authors: Laurence Klipfel, Marie Cordonnier, Léa Thiébault, Emmanuelle Clérin, Frédéric Blond, Géraldine Millet-Puel, Saddek Mohand-Saïd, Olivier Goureau, José-Alain Sahel, Emeline F. Nandrot, Thierry Léveillard
      First page: 179
      Abstract: Age-related macular degeneration (AMD) is a blinding disease for which most of the patients remain untreatable. Since the disease affects the macula at the center of the retina, a structure specific to the primate lineage, rodent models to study the pathophysiology of AMD and to develop therapies are very limited. Consequently, our understanding relies mostly on genetic studies highlighting risk alleles at many loci. We are studying the possible implication of a metabolic imbalance associated with risk alleles within the SLC16A8 gene that encodes for a retinal pigment epithelium (RPE)-specific lactate transporter MCT3 and its consequences for vision. As a first approach, we report here the deficit in transepithelial lactate transport of a rare SLC16A8 allele identified during a genome-wide association study. We produced induced pluripotent stem cells (iPSCs) from the unique patient in our cohort that carries two copies of this allele. After in vitro differentiation of the iPSCs into RPE cells and their characterization, we demonstrate that the rare allele results in the retention of intron 2 of the SLC16A8 gene leading to the absence of MCT3 protein. We show using a biochemical assay that these cells have a deficit in transepithelial lactate transport.
      Citation: Cells
      PubDate: 2021-01-18
      DOI: 10.3390/cells10010179
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 180: The Importance of Stromal Endometriosis in
           Thoracic Endometriosis

    • Authors: Ezekiel Mecha, Roselydiah Makunja, Jane B. Maoga, Agnes N. Mwaura, Muhammad A. Riaz, Charles O. A. Omwandho, Ivo Meinhold-Heerlein, Lutz Konrad
      First page: 180
      Abstract: Thoracic endometriosis (TE) is a rare type of endometriosis, where endometrial tissue is found in or around the lungs and is frequent among extra-pelvic endometriosis patients. Catamenial pneumothorax (CP) is the most common form of TE and is characterized by recurrent lung collapses around menstruation. In addition to histology, immunohistochemical evaluation of endometrial implants is used more frequently. In this review, we compared immunohistochemical (CPE) with histological (CPH) characterizations of TE/CP and reevaluated arguments in favor of the implantation theory of Sampson. A summary since the first immunohistochemical description in 1998 until 2019 is provided. The emphasis was on classification of endometrial implants into glands, stroma, and both together. The most remarkable finding is the very high percentage of stromal endometriosis of 52.7% (CPE) compared to 10.2% (CPH). Chest pain, dyspnea, right-sided preference, and diaphragmatic endometrial implants showed the highest percentages in both groups. No significant association was found between the recurrence rate and the various appearances of endometriosis. Sometimes in CPE (6.8%) and CPH (30.6%) no endometrial implants were identified underlining the importance of sensitive detection of endometriosis during and after surgery. We suggest that immunohistochemical evaluation should become mandatory and will improve diagnosis and classification of the disease.
      Citation: Cells
      PubDate: 2021-01-18
      DOI: 10.3390/cells10010180
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 181: Contribution of the CK2 Catalytic Isoforms α
           and α’ to the Glycolytic Phenotype of Tumor Cells

    • Authors: Francesca Zonta, Christian Borgo, Camila Paz Quezada Meza, Ionica Masgras, Andrea Rasola, Mauro Salvi, Lorenzo A. Pinna, Maria Ruzzene
      First page: 181
      Abstract: CK2 is a Ser/Thr protein kinase overexpressed in many cancers. It is usually present in cells as a tetrameric enzyme, composed of two catalytic (α or α’) and two regulatory (β) subunits, but it is active also in its monomeric form, and the specific role of the different isoforms is largely unknown. CK2 phosphorylates several substrates related to the uncontrolled proliferation, motility, and survival of cancer cells. As a consequence, tumor cells are addicted to CK2, relying on its activity more than healthy cells for their life, and exploiting it for developing multiple oncological hallmarks. However, little is known about CK2 contribution to the metabolic rewiring of cancer cells. With this study we aimed at shedding some light on it, especially focusing on the CK2 role in the glycolytic onco-phenotype. By analyzing neuroblastoma and osteosarcoma cell lines depleted of either one (α) or the other (α’) CK2 catalytic subunit, we also aimed at disclosing possible pro-tumor functions which are specific of a CK2 isoform. Our results suggest that both CK2 α and α’ contribute to cell proliferation, survival and tumorigenicity. The analyzed metabolic features disclosed a role of CK2 in tumor metabolism, and suggest prominent functions for CK2 α isoform. Results were also confirmed by CK2 pharmacological inhibition. Overall, our study provides new information on the mechanism of cancer cells addiction to CK2 and on its isoform-specific functions, with fundamental implications for improving future therapeutic strategies based on CK2 targeting.
      Citation: Cells
      PubDate: 2021-01-18
      DOI: 10.3390/cells10010181
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 182: Cytosolic 5′-Nucleotidase II Is a Sensor of
           Energy Charge and Oxidative Stress: A Possible Function as Metabolic

    • Authors: Rossana Pesi, Simone Allegrini, Francesco Balestri, Mercedes Garcia-Gil, Federico Cividini, Laura Colombaioni, Lars Petter Jordheim, Marcella Camici, Maria Grazia Tozzi
      First page: 182
      Abstract: Cytosolic 5′-nucleotidase II (NT5C2) is a highly regulated enzyme involved in the maintenance of intracellular purine and the pyrimidine compound pool. It dephosphorylates mainly IMP and GMP but is also active on AMP. This enzyme is highly expressed in tumors, and its activity correlates with a high rate of proliferation. In this paper, we show that the recombinant purified NT5C2, in the presence of a physiological concentration of the inhibitor inorganic phosphate, is very sensitive to changes in the adenylate energy charge, especially from 0.4 to 0.9. The enzyme appears to be very sensitive to pro-oxidant conditions; in this regard, the possible involvement of a disulphide bridge (C175-C547) was investigated by using a C547A mutant NT5C2. Two cultured cell models were used to further assess the sensitivity of the enzyme to oxidative stress conditions. NT5C2, differently from other enzyme activities, was inactivated and not rescued by dithiothreitol in a astrocytoma cell line (ADF) incubated with hydrogen peroxide. The incubation of a human lung carcinoma cell line (A549) with 2-deoxyglucose lowered the cell energy charge and impaired the interaction of NT5C2 with the ice protease-activating factor (IPAF), a protein involved in innate immunity and inflammation.
      Citation: Cells
      PubDate: 2021-01-18
      DOI: 10.3390/cells10010182
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 183: Putting Cells in Motion: Advantages of
           Endogenous Boosting of BDNF Production

    • Authors: Elvira Brattico, Leonardo Bonetti, Gabriella Ferretti, Peter Vuust, Carmela Matrone
      First page: 183
      Abstract: Motor exercise, such as sport or musical activities, helps with a plethora of diseases by modulating brain functions in neocortical and subcortical regions, resulting in behavioural changes related to mood regulation, well-being, memory, and even cognitive preservation in aging and neurodegenerative diseases. Although evidence is accumulating on the systemic neural mechanisms mediating these brain effects, the specific mechanisms by which exercise acts upon the cellular level are still under investigation. This is particularly the case for music training, a much less studied instance of motor exercise than sport. With regards to sport, consistent neurobiological research has focused on the brain-derived neurotrophic factor (BDNF), an essential player in the central nervous system. BDNF stimulates the growth and differentiation of neurons and synapses. It thrives in the hippocampus, the cortex, and the basal forebrain, which are the areas vital for memory, learning, and higher cognitive functions. Animal models and neurocognitive experiments on human athletes converge in demonstrating that physical exercise reliably boosts BDNF levels. In this review, we highlight comparable early findings obtained with animal models and elderly humans exposed to musical stimulation, showing how perceptual exposure to music might affect BDNF release, similar to what has been observed for sport. We subsequently propose a novel hypothesis that relates the neuroplastic changes in the human brains after musical training to genetically- and exercise-driven BDNF levels.
      Citation: Cells
      PubDate: 2021-01-18
      DOI: 10.3390/cells10010183
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 184: Hippo Signaling Pathway in Gliomas

    • Authors: Konstantin Masliantsev, Lucie Karayan-Tapon, Pierre-Olivier Guichet
      First page: 184
      Abstract: The Hippo signaling pathway is a highly conserved pathway involved in tissue development and regeneration that controls organ size through the regulation of cell proliferation and apoptosis. The core Hippo pathway is composed of a block of kinases, MST1/2 (Mammalian STE20-like protein kinase 1/2) and LATS1/2 (Large tumor suppressor 1/2), which inhibits nuclear translocation of YAP/TAZ (Yes-Associated Protein 1/Transcriptional co-activator with PDZ-binding motif) and its downstream association with the TEAD (TEA domain) family of transcription factors. This pathway was recently shown to be involved in tumorigenesis and metastasis in several cancers such as lung, breast, or colorectal cancers but is still poorly investigated in brain tumors. Gliomas are the most common and the most lethal primary brain tumors representing about 80% of malignant central nervous system neoplasms. Despite intensive clinical protocol, the prognosis for patients remains very poor due to systematic relapse and treatment failure. Growing evidence demonstrating the role of Hippo signaling in cancer biology and the lack of efficient treatments for malignant gliomas support the idea that this pathway could represent a potential target paving the way for alternative therapeutics. Based on recent advances in the Hippo pathway deciphering, the main goal of this review is to highlight the role of this pathway in gliomas by a state-of-the-art synthesis.
      Citation: Cells
      PubDate: 2021-01-18
      DOI: 10.3390/cells10010184
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 185: Beneficial Effects of Akkermansia muciniphila
           Are Not Associated with Major Changes in the Circulating
           Endocannabinoidome but Linked to Higher Mono-Palmitoyl-Glycerol Levels as
           New PPARα Agonists

    • Authors: Clara Depommier, Rosa Maria Vitale, Fabio Arturo Iannotti, Cristoforo Silvestri, Nicolas Flamand, Céline Druart, Amandine Everard, Rudy Pelicaen, Dominique Maiter, Jean-Paul Thissen, Audrey Loumaye, Michel P. Hermans, Nathalie M. Delzenne, Willem M. de Vos, Vincenzo Di Marzo, Patrice D. Cani
      First page: 185
      Abstract: Akkermansia muciniphila is considered as one of the next-generation beneficial bacteria in the context of obesity and associated metabolic disorders. Although a first proof-of-concept of its beneficial effects has been established in the context of metabolic syndrome in humans, mechanisms are not yet fully understood. This study aimed at deciphering whether the bacterium exerts its beneficial properties through the modulation of the endocannabinoidome (eCBome). Circulating levels of 25 endogenous endocannabinoid-related lipids were quantified by liquid chromatography with tandem mass spectrometry (LC-MS/MS) in the plasma of overweight or obese individuals before and after a 3 months intervention consisting of the daily ingestion of either alive or pasteurized A. muciniphila. Results from multivariate analyses suggested that the beneficial effects of A. muciniphila were not linked to an overall modification of the eCBome. However, subsequent univariate analysis showed that the decrease in 1-Palmitoyl-glycerol (1-PG) and 2-Palmitoyl-glycerol (2-PG), two eCBome lipids, observed in the placebo group was significantly counteracted by the alive bacterium, and to a lower extent by the pasteurized form. We also discovered that 1- and 2-PG are endogenous activators of peroxisome proliferator-activated receptor alpha (PPARα). We hypothesize that PPARα activation by mono-palmitoyl-glycerols may underlie part of the beneficial metabolic effects induced by A. muciniphila in human metabolic syndrome.
      Citation: Cells
      PubDate: 2021-01-19
      DOI: 10.3390/cells10010185
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 186: ICU Admission Levels of Endothelial Biomarkers
           as Predictors of Mortality in Critically Ill COVID-19 Patients

    • Authors: Alice G. Vassiliou, Chrysi Keskinidou, Edison Jahaj, Parisis Gallos, Ioanna Dimopoulou, Anastasia Kotanidou, Stylianos E. Orfanos
      First page: 186
      Abstract: Endotheliopathy is suggested to be an important feature of COVID-19 in hospitalized patients. To determine whether endotheliopathy is involved in COVID-19-associated mortality, markers of endothelial damage were assessed in critically ill COVID-19 patients upon intensive care unit (ICU) admission. Thirty-eight critically ill COVID-19 patients were included in this observational study, 10 of whom died in the ICU. Endothelial biomarkers, including soluble (s)E-selectin, sP-selectin, angiopoietin 1 and 2 (Ang-1 and Ang-2, respectively), soluble intercellular adhesion molecule 1 (sICAM-1), vascular endothelial growth factor (VEGF), soluble vascular endothelial (VE)-cadherin, and von Willebrand factor (vWf), were measured upon ICU admission. The ICU cohort was subsequently divided into survivors and non-survivors; Kaplan–Meier analysis was used to explore associations between biomarkers and survival, while receiver operating characteristic (ROC) curves were generated to determine their potential prognostic value. sE-selectin, sP-selectin, Ang-2, and sICAM-1 were significantly elevated in ICU non-survivors compared to survivors, and also associated with a higher mortality probability in the Kaplan–Meier analysis. The prognostic values of sE-selectin, Ang-2, and sICAM-1 from the generated ROC curves were greater than 0.85. Hence, we conclude that in our cohort, ICU non-survivors had higher levels of specific endothelial markers compared to survivors. Elevated levels of these markers upon ICU admission could possibly predict mortality in COVID-19.
      Citation: Cells
      PubDate: 2021-01-19
      DOI: 10.3390/cells10010186
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 187: mRNA-Enhanced Cell Therapy and Cardiovascular

    • Authors: Palas K. Chanda, Roman Sukhovershin, John P. Cooke
      First page: 187
      Abstract: mRNA has emerged as an important biomolecule in the global call for the development of therapies during the COVID-19 pandemic. Synthetic in vitro-transcribed (IVT) mRNA can be engineered to mimic naturally occurring mRNA and can be used as a tool to target “undruggable” diseases. Recent advancement in the field of RNA therapeutics have addressed the challenges inherent to this drug molecule and this approach is now being applied to several therapeutic modalities, from cancer immunotherapy to vaccine development. In this review, we discussed the use of mRNA for stem cell generation or enhancement for the purpose of cardiovascular regeneration.
      Citation: Cells
      PubDate: 2021-01-19
      DOI: 10.3390/cells10010187
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 188: Adenine-Based Purines and Related Metabolizing
           Enzymes: Evidence for Their Impact on Tumor Extracellular Vesicle

    • Authors: Patrizia Di Iorio, Renata Ciccarelli
      First page: 188
      Abstract: Extracellular vesicles (EVs), mainly classified as small and large EVs according to their size/origin, contribute as multi-signal messengers to intercellular communications in normal/pathological conditions. EVs are now recognized as critical players in cancer processes by promoting transformation, growth, invasion, and drug-resistance of tumor cells thanks to the release of molecules contained inside them (i.e., nucleic acids, lipids and proteins) into the tumor microenvironment (TME). Interestingly, secretion from donor cells and/or uptake of EVs/their content by recipient cells are regulated by extracellular signals present in TME. Among those able to modulate the EV-tumor crosstalk, purines, mainly the adenine-based ones, could be included. Indeed, TME is characterized by high levels of ATP/adenosine and by the presence of enzymes deputed to their turnover. Moreover, ATP/adenosine, interacting with their own receptors, can affect both host and tumor responses. However, studies on whether/how the purinergic system behaves as a modulator of EV biogenesis, release and functions in cancer are still poor. Thus, this review is aimed at collecting data so far obtained to stimulate further research in this regard. Hopefully, new findings on the impact of adenine purines/related enzymes on EV functions may be exploited in tumor management uncovering novel tumor biomarkers and/or druggable targets.
      Citation: Cells
      PubDate: 2021-01-19
      DOI: 10.3390/cells10010188
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 189: P2X7 Variants in Oncogenesis

    • Authors: Anna Pegoraro, Elena De Marchi, Elena Adinolfi
      First page: 189
      Abstract: The P2X7 receptor for extracellular ATP is a well-established mediator of tumoral development and progression both in solid cancers and hematological malignancies. The human P2X7 gene is highly polymorphic, and several splice variants of the receptor have been identified in time. P2X7 single-nucleotide polymorphisms (SNPs) have been broadly analyzed by studies relating them to pathologies as different as infectious, inflammatory, nervous, and bone diseases, among which cancer is included. Moreover, in the last years, an increasing number of reports concentrated on P2X7 splice variants’ different roles and their implications in pathological conditions, including oncogenesis. Here, we give an overview of established and recent literature demonstrating a role for human P2X7 gene products in oncological conditions, mainly focusing on current data emerging on P2X7 isoform B and nfP2X7. We explored the role of these and other genetic variants of P2X7 in cancer insurgence, dissemination, and progression, as well as the effect of chemotherapy on isoforms expression. The described literature strongly suggests that P2X7 variants are potential new biomarkers and therapeutical targets in oncological conditions and that their study in carcinogenesis deserves to be further pursued.
      Citation: Cells
      PubDate: 2021-01-19
      DOI: 10.3390/cells10010189
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 190: White Matter Interstitial Neurons in the Adult
           Human Brain: 3% of Cortical Neurons in Quest for Recognition

    • Authors: Goran Sedmak, Miloš Judaš
      First page: 190
      Abstract: White matter interstitial neurons (WMIN) are a subset of cortical neurons located in the subcortical white matter. Although they were fist described over 150 years ago, they are still largely unexplored and often considered a small, functionally insignificant neuronal population. WMIN are adult remnants of neurons located in the transient fetal subplate zone (SP). Following development, some of the SP neurons undergo apoptosis, and the remaining neurons are incorporated in the adult white matter as WMIN. In the adult human brain, WMIN are quite a large population of neurons comprising at least 3% of all cortical neurons (between 600 and 1100 million neurons). They include many of the morphological neuronal types that can be found in the overlying cerebral cortex. Furthermore, the phenotypic and molecular diversity of WMIN is similar to that of the overlying cortical neurons, expressing many glutamatergic and GABAergic biomarkers. WMIN are often considered a functionally unimportant subset of neurons. However, upon closer inspection of the scientific literature, it has been shown that WMIN are integrated in the cortical circuitry and that they exhibit diverse electrophysiological properties, send and receive axons from the cortex, and have active synaptic contacts. Based on these data, we are able to enumerate some of the potential WMIN roles, such as the control of the cerebral blood flow, sleep regulation, and the control of information flow through the cerebral cortex. Also, there is a number of studies indicating the involvement of WMIN in the pathophysiology of many brain disorders such as epilepsy, schizophrenia, Alzheimer’s disease, etc. All of these data indicate that WMIN are a large population with an important function in the adult brain. Further investigation of WMIN could provide us with novel data crucial for an improved elucidation of the pathophysiology of many brain disorders. In this review, we provide an overview of the current WMIN literature, with an emphasis on studies conducted on the human brain.
      Citation: Cells
      PubDate: 2021-01-19
      DOI: 10.3390/cells10010190
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 191: Towards a Functional Cure for Diabetes Using
           Stem Cell-Derived Beta Cells: Are We There Yet'

    • Authors: Stephanie Bourgeois, Toshiaki Sawatani, Annelore Van Mulders, Nico De Leu, Yves Heremans, Harry Heimberg, Miriam Cnop, Willem Staels
      First page: 191
      Abstract: Diabetes mellitus is a pandemic metabolic disorder that results from either the autoimmune destruction or the dysfunction of insulin-producing pancreatic beta cells. A promising cure is beta cell replacement through the transplantation of islets of Langerhans. However, donor shortage hinders the widespread implementation of this therapy. Human pluripotent stem cells, including embryonic stem cells and induced pluripotent stem cells, represent an attractive alternative beta cell source for transplantation. Although major advances over the past two decades have led to the generation of stem cell-derived beta-like cells that share many features with genuine beta cells, producing fully mature beta cells remains challenging. Here, we review the current status of beta cell differentiation protocols and highlight specific challenges that are associated with producing mature beta cells. We address the challenges and opportunities that are offered by monogenic forms of diabetes. Finally, we discuss the remaining hurdles for clinical application of stem cell-derived beta cells and the status of ongoing clinical trials.
      Citation: Cells
      PubDate: 2021-01-19
      DOI: 10.3390/cells10010191
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 192: Unlike Its Paralog LEDGF/p75, HRP-2 Is
           Dispensable for MLL-R Leukemogenesis but Important for Leukemic Cell

    • Authors: Siska Van Van Belle, Sara El Ashkar, Kateřina Čermáková, Filip Matthijssens, Steven Goossens, Alessandro Canella, Courtney H. Hodges, Frauke Christ, Jan De Rijck, Pieter Van Vlierberghe, Václav Veverka, Zeger Debyser
      First page: 192
      Abstract: HDGF-related protein 2 (HRP-2) is a member of the Hepatoma-Derived Growth Factor-related protein family that harbors the structured PWWP and Integrase Binding Domain, known to associate with methylated histone tails or cellular and viral proteins, respectively. Interestingly, HRP-2 is a paralog of Lens Epithelium Derived Growth Factor p75 (LEDGF/p75), which is essential for MLL-rearranged (MLL-r) leukemia but dispensable for hematopoiesis. Sequel to these findings, we investigated the role of HRP-2 in hematopoiesis and MLL-r leukemia. Protein interactions were investigated by co-immunoprecipitation and validated using recombinant proteins in NMR. A systemic knockout mouse model was used to study normal hematopoiesis and MLL-ENL transformation upon the different HRP-2 genotypes. The role of HRP-2 in MLL-r and other leukemic, human cell lines was evaluated by lentiviral-mediated miRNA targeting HRP-2. We demonstrate that MLL and HRP-2 interact through a conserved interface, although this interaction proved less dependent on menin than the MLL-LEDGF/p75 interaction. The systemic HRP-2 knockout mice only revealed an increase in neutrophils in the peripheral blood, whereas the depletion of HRP-2 in leukemic cell lines and transformed primary murine cells resulted in reduced colony formation independently of MLL-rearrangements. In contrast, primary murine HRP-2 knockout cells were efficiently transformed by the MLL-ENL fusion, indicating that HRP-2, unlike LEDGF/p75, is dispensable for the transformation of MLL-ENL leukemogenesis but important for leukemic cell survival.
      Citation: Cells
      PubDate: 2021-01-19
      DOI: 10.3390/cells10010192
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 193: New Prognostic Biomarkers in Metastatic
           Castration-Resistant Prostate Cancer

    • Authors: Vincenza Conteduca, Alessandra Mosca, Nicole Brighi, Ugo de Giorgi, Pasquale Rescigno
      First page: 193
      Abstract: Prostate cancer is one of the most frequent cancers in men and is a common cause of cancer-related death. Despite significant progress in the diagnosis and treatment of this tumor, patients who relapse after radical treatments inevitably develop metastatic disease. Patient stratification is therefore key in this type of cancer, and there is an urgent need for prognostic biomarkers that can define patients’ risk of cancer-related death. In the last 10 years, multiple prognostic factors have been identified and studied. Here, we review the literature available and discuss the most common aberrant genomic pathways in metastatic castration-resistant prostate cancer shown to have a prognostic relevance in this setting.
      Citation: Cells
      PubDate: 2021-01-19
      DOI: 10.3390/cells10010193
      Issue No: Vol. 10, No. 1 (2021)
  • Cells, Vol. 10, Pages 194: Advances in Plant Autophagy

    • Authors: Agnieszka Sirko, Céline Masclaux-Daubresse
      First page: 194
      Abstract: Ubiquitin–proteasome and lysosome–autophagy are the two main cellular degradation systems controlling cellular homeostasis in eukaryotes [...]
      Citation: Cells
      PubDate: 2021-01-19
      DOI: 10.3390/cells10010194
      Issue No: Vol. 10, No. 1 (2021)
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