Cells

19 pages, 3102 KB

Open AccessEditor’s ChoiceArticle

Circular RNA Encoded Amyloid Beta peptides—A Novel Putative Player in Alzheimer’s Disease

by Dingding Mo, Xinping Li, Carsten A. Raabe, Timofey S. Rozhdestvensky, Boris V. Skryabin and Juergen Brosius

Cells 2020, 9(10), 2196; https://doi.org/10.3390/cells9102196 - 29 Sep 2020

Cited by 49 | Viewed by 6615

Abstract

Alzheimer’s disease (AD) is an age-related detrimental dementia. Amyloid beta peptides (Aβ) play a crucial role in the pathology of AD. In familial AD, Aβ are generated from the full-length amyloid beta precursor protein (APP) via dysregulated proteolytic processing; however, in the case [...] Read more.

Alzheimer’s disease (AD) is an age-related detrimental dementia. Amyloid beta peptides (Aβ) play a crucial role in the pathology of AD. In familial AD, Aβ are generated from the full-length amyloid beta precursor protein (APP) via dysregulated proteolytic processing; however, in the case of sporadic AD, the mechanism of Aβ biogenesis remains elusive. circRNAs are a class of transcripts preferentially expressed in brain. We identified a circRNA harboring the Aβ-coding region of the APP gene termed circAβ-a. This circular RNA was detected in the brains of AD patients and non-dementia controls. With the aid of our recently established approach for analysis of circRNA functions, we demonstrated that circAβ-a is efficiently translated into a novel Aβ-containing Aβ175 polypeptide (19.2 KDa) in both cultured cells and human brain. Furthermore, Aβ175 was shown to be processed into Aβ peptides—a hallmark of AD. In summary, our analysis revealed an alternative pathway of Aβ biogenesis. Consequently, circAβ-a and its corresponding translation product could potentially represent novel therapeutic targets for AD treatment. Importantly, our data point to yet another evolutionary route for potentially increasing proteome complexity by generating additional polypeptide variants using back-splicing of primary transcripts that yield circular RNA templates. Full article

(This article belongs to the Special Issue Circular RNAs: Non-canonical Observations on Non-canonical RNAs)

► Show Figures

Figure 1

17 pages, 1911 KB

Open AccessEditor’s ChoiceArticle

Disharmonic Inflammatory Signatures in COVID-19: Augmented Neutrophils’ but Impaired Monocytes’ and Dendritic Cells’ Responsiveness

by Zuzana Parackova, Irena Zentsova, Marketa Bloomfield, Petra Vrabcova, Jitka Smetanova, Adam Klocperk, Grigorij Mesežnikov, Luis Fernando Casas Mendez, Tomas Vymazal and Anna Sediva

Cells 2020, 9(10), 2206; https://doi.org/10.3390/cells9102206 - 29 Sep 2020

Cited by 113 | Viewed by 6540

Abstract

COVID-19, caused by SARS-CoV-2 virus, emerged as a pandemic disease posing a severe threat to global health. To date, sporadic studies have demonstrated that innate immune mechanisms, specifically neutrophilia, NETosis, and neutrophil-associated cytokine responses, are involved in COVID-19 pathogenesis; however, our understanding of [...] Read more.

COVID-19, caused by SARS-CoV-2 virus, emerged as a pandemic disease posing a severe threat to global health. To date, sporadic studies have demonstrated that innate immune mechanisms, specifically neutrophilia, NETosis, and neutrophil-associated cytokine responses, are involved in COVID-19 pathogenesis; however, our understanding of the exact nature of this aspect of host–pathogen interaction is limited. Here, we present a detailed dissection of the features and functional profiles of neutrophils, dendritic cells, and monocytes in COVID-19. We portray the crucial role of neutrophils as drivers of hyperinflammation associated with COVID-19 disease via the shift towards their immature forms, enhanced degranulation, cytokine production, and augmented interferon responses. We demonstrate the impaired functionality of COVID-19 dendritic cells and monocytes, particularly their low expression of maturation markers, increased PD-L1 levels, and their inability to upregulate phenotype upon stimulation. In summary, our work highlights important data that prompt further research, as therapeutic targeting of neutrophils and their associated products may hold the potential to reduce the severity of COVID-19. Full article

(This article belongs to the Special Issue Understanding Molecular Actors of SARS-Cov-2 Virulence to Tackle COVID19 Outbreak)

► Show Figures

Graphical abstract

21 pages, 1502 KB

Open AccessEditor’s ChoiceReview

Neuron-Glia Interactions in Neurodevelopmental Disorders

by Yoo Sung Kim, Juwon Choi and Bo-Eun Yoon

Cells 2020, 9(10), 2176; https://doi.org/10.3390/cells9102176 - 27 Sep 2020

Cited by 112 | Viewed by 14824

Abstract

Recent studies have revealed synaptic dysfunction to be a hallmark of various psychiatric diseases, and that glial cells participate in synapse formation, development, and plasticity. Glial cells contribute to neuroinflammation and synaptic homeostasis, the latter being essential for maintaining the physiological function of [...] Read more.

Recent studies have revealed synaptic dysfunction to be a hallmark of various psychiatric diseases, and that glial cells participate in synapse formation, development, and plasticity. Glial cells contribute to neuroinflammation and synaptic homeostasis, the latter being essential for maintaining the physiological function of the central nervous system (CNS). In particular, glial cells undergo gliotransmission and regulate neuronal activity in tripartite synapses via ion channels (gap junction hemichannel, volume regulated anion channel, and bestrophin-1), receptors (for neurotransmitters and cytokines), or transporters (GLT-1, GLAST, and GATs) that are expressed on glial cell membranes. In this review, we propose that dysfunction in neuron-glia interactions may contribute to the pathogenesis of neurodevelopmental disorders. Understanding the mechanisms of neuron-glia interaction for synapse formation and maturation will contribute to the development of novel therapeutic targets of neurodevelopmental disorders. Full article

(This article belongs to the Special Issue Neuron-Glia Interactions)

► Show Figures

Figure 1

22 pages, 1396 KB

Open AccessEditor’s ChoiceReview

Rho GTPases: Big Players in Breast Cancer Initiation, Metastasis and Therapeutic Responses

by Brock Humphries, Zhishan Wang and Chengfeng Yang

Cells 2020, 9(10), 2167; https://doi.org/10.3390/cells9102167 - 25 Sep 2020

Cited by 55 | Viewed by 7050

Abstract

Rho GTPases, a family of the Ras GTPase superfamily, are key regulators of the actin cytoskeleton. They were originally thought to primarily affect cell migration and invasion; however, recent advances in our understanding of the biology and function of Rho GTPases have demonstrated [...] Read more.

Rho GTPases, a family of the Ras GTPase superfamily, are key regulators of the actin cytoskeleton. They were originally thought to primarily affect cell migration and invasion; however, recent advances in our understanding of the biology and function of Rho GTPases have demonstrated their diverse roles within the cell, including membrane trafficking, gene transcription, migration, invasion, adhesion, survival and growth. As these processes are critically involved in cancer initiation, metastasis and therapeutic responses, it is not surprising that studies have demonstrated important roles of Rho GTPases in cancer. Although the majority of data indicates an oncogenic role of Rho GTPases, tumor suppressor functions of Rho GTPases have also been revealed, suggesting a context and cell-type specific function for Rho GTPases in cancer. This review aims to summarize recent progresses in our understanding of the regulation and functions of Rho GTPases, specifically in the context of breast cancer. The potential of Rho GTPases as therapeutic targets and prognostic tools for breast cancer patients are also discussed. Full article

(This article belongs to the Special Issue Rho family of GTPases in Model Organisms and Systems)

► Show Figures

Figure 1

11 pages, 10614 KB

Open AccessEditor’s ChoiceArticle

NIR-Triggered Hyperthermal Effect of Polythiophene Nanoparticles Synthesized by Surfactant-Free Oxidative Polymerization Method on Colorectal Carcinoma Cells

by Deval Prasad Bhattarai and Beom Su Kim

Cells 2020, 9(9), 2122; https://doi.org/10.3390/cells9092122 - 18 Sep 2020

Cited by 17 | Viewed by 3138

Abstract

In this work, polythiophene nanoparticles (PTh–NPs) were synthesized by a surfactant-free oxidative chemical polymerization method at 60 °C, using ammonium persulphate as an oxidant. Various physicochemical properties were studied in terms of field emission scanning electron microscopy (FESEM), X-ray diffraction (XRD), Fourier transform [...] Read more.

In this work, polythiophene nanoparticles (PTh–NPs) were synthesized by a surfactant-free oxidative chemical polymerization method at 60 °C, using ammonium persulphate as an oxidant. Various physicochemical properties were studied in terms of field emission scanning electron microscopy (FESEM), X-ray diffraction (XRD), Fourier transform infra-red (FT-IR) spectroscopy, and differential scanning calorimetry (DSC)/thermogravimetric analysis (TGA). Photothermal performance of the as-synthesized PTh–NPs was studied by irradiating near infra-red of 808 nm under different concentration of the substrate and power supply. The photothermal stability of PTh–NPs was also studied. Photothermal effects of the as-synthesized PTh–NPs on colorectal cancer cells (CT-26) were studied at 100 µg/mL concentration and 808 nm NIR irradiation of 2.0 W/cm² power. Our in vitro results showed remarkable NIR laser-triggered photothermal apoptotic cell death by PTh–NPs. Based on the experimental findings, it is revealed that PTh–NPs can act as a heat mediator and can be an alternative material for photothermal therapy in cancer treatment. Full article

(This article belongs to the Collection Recent Advances in Oncology Nanomedicine: Toward Novel Personalized Medicine Tools to Fight Human Cancer)

► Show Figures

Figure 1

19 pages, 913 KB

Open AccessEditor’s ChoiceReview

Ivermectin as a Broad-Spectrum Host-Directed Antiviral: The Real Deal?

by David A. Jans and Kylie M. Wagstaff

Cells 2020, 9(9), 2100; https://doi.org/10.3390/cells9092100 - 15 Sep 2020

Cited by 54 | Viewed by 44495

Abstract

The small molecule macrocyclic lactone ivermectin, approved by the US Food and Drug Administration for parasitic infections, has received renewed attention in the last eight years due to its apparent exciting potential as an antiviral. It was identified in a high-throughput chemical screen [...] Read more.

The small molecule macrocyclic lactone ivermectin, approved by the US Food and Drug Administration for parasitic infections, has received renewed attention in the last eight years due to its apparent exciting potential as an antiviral. It was identified in a high-throughput chemical screen as inhibiting recognition of the nuclear localizing Human Immunodeficiency Virus-1 (HIV-1) integrase protein by the host heterodimeric importin (IMP) α/β1 complex, and has since been shown to bind directly to IMPα to induce conformational changes that prevent its normal function in mediating nuclear import of key viral and host proteins. Excitingly, cell culture experiments show robust antiviral action towards HIV-1, dengue virus (DENV), Zika virus, West Nile virus, Venezuelan equine encephalitis virus, Chikungunya virus, Pseudorabies virus, adenovirus, and SARS-CoV-2 (COVID-19). Phase III human clinical trials have been completed for DENV, with >50 trials currently in progress worldwide for SARS-CoV-2. This mini-review discusses the case for ivermectin as a host-directed broad-spectrum antiviral agent for a range of viruses, including SARS-CoV-2. Full article

(This article belongs to the Section Cell Nuclei: Function, Transport and Receptors)

► Show Figures

Figure 1

17 pages, 1104 KB

Open AccessEditor’s ChoiceReview

Precision Medicine: Steps along the Road to Combat Human Cancer

by Samuel F. Nassar, Khadir Raddassi, Baljit Ubhi, Joseph Doktorski and Ahmad Abulaban

Cells 2020, 9(9), 2056; https://doi.org/10.3390/cells9092056 - 9 Sep 2020

Cited by 35 | Viewed by 6570

Abstract

The diagnosis and treatment of diseases such as cancer is becoming more accurate and specialized with the advent of precision medicine techniques, research and treatments. Reaching down to the cellular and even sub-cellular level, diagnostic tests can pinpoint specific, individual information from each [...] Read more.

The diagnosis and treatment of diseases such as cancer is becoming more accurate and specialized with the advent of precision medicine techniques, research and treatments. Reaching down to the cellular and even sub-cellular level, diagnostic tests can pinpoint specific, individual information from each patient, and guide providers to a more accurate plan of treatment. With this advanced knowledge, researchers and providers can better gauge the effectiveness of drugs, radiation, and other therapies, which is bound to lead to a more accurate, if not more positive, prognosis. As precision medicine becomes more established, new techniques, equipment, materials and testing methods will be required. Herein, we will examine the recent innovations in assays, devices and software, along with next generation sequencing in genomics diagnostics which are in use or are being developed for personalized medicine. So as to avoid duplication and produce the fullest possible benefit, all involved must be strongly encouraged to collaborate, across national borders, public and private sectors, science, medicine and academia alike. In this paper we will offer recommendations for tools, research and development, along with ideas for implementation. We plan to begin with discussion of the lessons learned to date, and the current research on pharmacogenomics. Given the steady stream of advances in imaging mass spectrometry and nanoLC-MS/MS, and use of genomic, proteomic and metabolomics biomarkers to distinguish healthy tissue from diseased cells, there is great potential to utilize pharmacogenomics to tailor a drug or drugs to a particular cohort of patients. Such efforts very well may bring increased hope for small groups of non-responders and those who have demonstrated adverse reactions to current treatments. Full article

(This article belongs to the Collection Recent Advances in Oncology Nanomedicine: Toward Novel Personalized Medicine Tools to Fight Human Cancer)

► Show Figures

Figure A1

31 pages, 3218 KB

Open AccessEditor’s ChoiceReview

The Roles of Ubiquitin in Mediating Autophagy

by Zhangyuan Yin, Hana Popelka, Yuchen Lei, Ying Yang and Daniel J. Klionsky

Cells 2020, 9(9), 2025; https://doi.org/10.3390/cells9092025 - 2 Sep 2020

Cited by 85 | Viewed by 10310

Abstract

Ubiquitination, the post-translational modification essential for various intracellular processes, is implicated in multiple aspects of autophagy, the major lysosome/vacuole-dependent degradation pathway. The autophagy machinery adopted the structural architecture of ubiquitin and employs two ubiquitin-like protein conjugation systems for autophagosome biogenesis. Ubiquitin chains that [...] Read more.

Ubiquitination, the post-translational modification essential for various intracellular processes, is implicated in multiple aspects of autophagy, the major lysosome/vacuole-dependent degradation pathway. The autophagy machinery adopted the structural architecture of ubiquitin and employs two ubiquitin-like protein conjugation systems for autophagosome biogenesis. Ubiquitin chains that are attached as labels to protein aggregates or subcellular organelles confer selectivity, allowing autophagy receptors to simultaneously bind ubiquitinated cargos and autophagy-specific ubiquitin-like modifiers (Atg8-family proteins). Moreover, there is tremendous crosstalk between autophagy and the ubiquitin-proteasome system. Ubiquitination of autophagy-related proteins or regulatory components plays significant roles in the precise control of the autophagy pathway. In this review, we summarize and discuss the molecular mechanisms and functions of ubiquitin and ubiquitination, in the process and regulation of autophagy. Full article

(This article belongs to the Special Issue Ubiquitin and Autophagy)

► Show Figures

Figure 1

25 pages, 4157 KB

Open AccessEditor’s ChoiceReview

Atg8-Family Proteins—Structural Features and Molecular Interactions in Autophagy and Beyond

by Nicole Wesch, Vladimir Kirkin and Vladimir V. Rogov

Cells 2020, 9(9), 2008; https://doi.org/10.3390/cells9092008 - 1 Sep 2020

Cited by 65 | Viewed by 8279

Abstract

Autophagy is a common name for a number of catabolic processes, which keep the cellular homeostasis by removing damaged and dysfunctional intracellular components. Impairment or misbalance of autophagy can lead to various diseases, such as neurodegeneration, infection diseases, and cancer. A central axis [...] Read more.

Autophagy is a common name for a number of catabolic processes, which keep the cellular homeostasis by removing damaged and dysfunctional intracellular components. Impairment or misbalance of autophagy can lead to various diseases, such as neurodegeneration, infection diseases, and cancer. A central axis of autophagy is formed along the interactions of autophagy modifiers (Atg8-family proteins) with a variety of their cellular counter partners. Besides autophagy, Atg8-proteins participate in many other pathways, among which membrane trafficking and neuronal signaling are the most known. Despite the fact that autophagy modifiers are well-studied, as the small globular proteins show similarity to ubiquitin on a structural level, the mechanism of their interactions are still not completely understood. A thorough analysis and classification of all known mechanisms of Atg8-protein interactions could shed light on their functioning and connect the pathways involving Atg8-proteins. In this review, we present our views of the key features of the Atg8-proteins and describe the basic principles of their recognition and binding by interaction partners. We discuss affinity and selectivity of their interactions as well as provide perspectives for discovery of new Atg8-interacting proteins and therapeutic approaches to tackle major human diseases. Full article

(This article belongs to the Special Issue Ubiquitin and Autophagy)

► Show Figures

Graphical abstract

16 pages, 2333 KB

Open AccessEditor’s ChoiceArticle

DNC4mC-Deep: Identification and Analysis of DNA N4-Methylcytosine Sites Based on Different Encoding Schemes By Using Deep Learning

by Abdul Wahab, Omid Mahmoudi, Jeehong Kim and Kil To Chong

Cells 2020, 9(8), 1756; https://doi.org/10.3390/cells9081756 - 22 Jul 2020

Cited by 32 | Viewed by 4883

Abstract

N4-methylcytosine as one kind of modification of DNA has a critical role which alters genetic performance such as protein interactions, conformation, stability in DNA as well as the regulation of gene expression same cell developmental and genomic imprinting. Some different 4mC site identifiers [...] Read more.

N4-methylcytosine as one kind of modification of DNA has a critical role which alters genetic performance such as protein interactions, conformation, stability in DNA as well as the regulation of gene expression same cell developmental and genomic imprinting. Some different 4mC site identifiers have been proposed for various species. Herein, we proposed a computational model, DNC4mC-Deep, including six encoding techniques plus a deep learning model to predict 4mC sites in the genome of F. vesca, R. chinensis, and Cross-species dataset. It was demonstrated by the 10-fold cross-validation test to get superior performance. The DNC4mC-Deep obtained 0.829 and 0.929 of MCC on F. vesca and R. chinensis training dataset, respectively, and 0.814 on cross-species. This means the proposed method outperforms the state-of-the-art predictors at least 0.284 and 0.265 on F. vesca and R. chinensis training dataset in turn. Furthermore, the DNC4mC-Deep achieved 0.635 and 0.565 of MCC on F. vesca and R. chinensis independent dataset, respectively, and 0.562 on cross-species which shows it can achieve the best performance to predict 4mC sites as compared to the state-of-the-art predictor. Full article

(This article belongs to the Special Issue Biocomputing and Synthetic Biology in Cells)

► Show Figures

Figure 1

10 pages, 3855 KB

Open AccessEditor’s ChoiceCommunication

Blocking Notch-Signaling Increases Neurogenesis in the Striatum after Stroke

by Giuseppe Santopolo, Jens P. Magnusson, Olle Lindvall, Zaal Kokaia and Jonas Frisén

Cells 2020, 9(7), 1732; https://doi.org/10.3390/cells9071732 - 20 Jul 2020

Cited by 34 | Viewed by 5728

Abstract

Stroke triggers neurogenesis in the striatum in mice, with new neurons deriving in part from the nearby subventricular zone and in part from parenchymal astrocytes. The initiation of neurogenesis by astrocytes within the striatum is triggered by reduced Notch-signaling, and blocking this signaling [...] Read more.

Stroke triggers neurogenesis in the striatum in mice, with new neurons deriving in part from the nearby subventricular zone and in part from parenchymal astrocytes. The initiation of neurogenesis by astrocytes within the striatum is triggered by reduced Notch-signaling, and blocking this signaling pathway by deletion of the gene encoding the obligate Notch coactivator Rbpj is sufficient to activate neurogenesis by striatal astrocytes in the absence of an injury. Here we report that blocking Notch-signaling in stroke increases the neurogenic response to stroke 3.5-fold in mice. Deletion of Rbpj results in the recruitment of a larger number of parenchymal astrocytes to neurogenesis and over larger areas of the striatum. These data suggest inhibition of Notch-signaling as a potential translational strategy to promote neuronal regeneration after stroke. Full article

(This article belongs to the Special Issue Neuron-Glia Interactions)

► Show Figures

Figure 1

17 pages, 6154 KB

Open AccessFeature PaperEditor’s ChoiceArticle

Development of Artificial Plasma Membranes Derived Nanovesicles Suitable for Drugs Encapsulation

by Carolina Martinelli, Fabio Gabriele, Elena Dini, Francesca Carriero, Giorgia Bresciani, Bianca Slivinschi, Marco Dei Giudici, Lisa Zanoletti, Federico Manai, Mayra Paolillo, Sergio Schinelli, Alberto Azzalin and Sergio Comincini

Cells 2020, 9(7), 1626; https://doi.org/10.3390/cells9071626 - 6 Jul 2020

Cited by 20 | Viewed by 4805

Abstract

Extracellular vesicles (EVs) are considered as promising nanoparticle theranostic tools in many pathological contexts. The increasing clinical employment of therapeutic nanoparticles is contributing to the development of a new research area related to the design of artificial EVs. To this aim, different approaches [...] Read more.

Extracellular vesicles (EVs) are considered as promising nanoparticle theranostic tools in many pathological contexts. The increasing clinical employment of therapeutic nanoparticles is contributing to the development of a new research area related to the design of artificial EVs. To this aim, different approaches have been described to develop mimetic biologically functional nanovescicles. In this paper, we suggest a simplified procedure to generate plasma membrane-derived nanovesicles with the possibility to efficiently encapsulate different drugs during their spontaneously assembly. After physical and molecular characterization by Tunable Resistive Pulse Sensing (TRPS) technology, transmission electron microscopy, and flow cytometry, as a proof of principle, we have loaded into mimetic EVs the isoquinoline alkaloid Berberine chloride and the chemotherapy compounds Temozolomide or Givinostat. We demonstrated the fully functionality of these nanoparticles in drug encapsulation and cell delivery, showing, in particular, a similar cytotoxic effect of direct cell culture administration of the anticancer drugs. In conclusion, we have documented the possibility to easily generate scalable nanovesicles with specific therapeutic cargo modifications useful in different drug delivery contexts. Full article

(This article belongs to the Collection Recent Advances in Oncology Nanomedicine: Toward Novel Personalized Medicine Tools to Fight Human Cancer)

► Show Figures

Graphical abstract

19 pages, 2122 KB

Open AccessFeature PaperEditor’s ChoiceReview

Progress and Challenges in the Use of MAP1LC3 as a Legitimate Marker for Measuring Dynamic Autophagy In Vivo

by Srinivasa Reddy Bonam, Jagadeesh Bayry, Mario P. Tschan and Sylviane Muller

Cells 2020, 9(5), 1321; https://doi.org/10.3390/cells9051321 - 25 May 2020

Cited by 37 | Viewed by 6040

Abstract

Tremendous efforts have been made these last decades to increase our knowledge of intracellular degradative systems, especially in the field of autophagy. The role of autophagy in the maintenance of cell homeostasis is well documented and the existence of defects in the autophagic [...] Read more.

Tremendous efforts have been made these last decades to increase our knowledge of intracellular degradative systems, especially in the field of autophagy. The role of autophagy in the maintenance of cell homeostasis is well documented and the existence of defects in the autophagic machinery has been largely described in diseases and aging. Determining the alterations occurring in the many forms of autophagy that coexist in cells and tissues remains complicated, as this cellular process is highly dynamic in nature and can vary from organ to organ in the same individual. Although autophagy is extensively studied, its functioning in different tissues and its links with other biological processes is still poorly understood. Several assays have been developed to monitor autophagy activity in vitro, ex vivo, and in vivo, based on different markers, the use of various inhibitors and activators, and distinct techniques. This review emphasizes the methods applied to measure (macro-)autophagy in tissue samples and in vivo via a protein, which centrally intervenes in the autophagy pathway, the microtubule-associated protein 1A/1B-light chain 3 (MAP1LC3), which is the most widely used marker and the first identified to associate with autophagosomal structures. These approaches are presented and discussed in terms of pros and cons. Some recommendations are provided to improve the reliability of the interpretation of results. Full article

(This article belongs to the Section Autophagy)

► Show Figures

Figure 1

20 pages, 2856 KB

Open AccessEditor’s ChoiceArticle

Lung Tumor Cell-Derived Exosomes Promote M2 Macrophage Polarization

by Alexandra Pritchard, Sultan Tousif, Yong Wang, Kenneth Hough, Saad Khan, John Strenkowski, Balu K. Chacko, Victor M. Darley-Usmar and Jessy S. Deshane

Cells 2020, 9(5), 1303; https://doi.org/10.3390/cells9051303 - 24 May 2020

Cited by 160 | Viewed by 13270

Abstract

Cellular cross-talk within the tumor microenvironment (TME) by exosomes is known to promote tumor progression. Tumor promoting macrophages with an M2 phenotype are suppressors of anti-tumor immunity. However, the impact of tumor-derived exosomes in modulating macrophage polarization in the lung TME is largely [...] Read more.

Cellular cross-talk within the tumor microenvironment (TME) by exosomes is known to promote tumor progression. Tumor promoting macrophages with an M2 phenotype are suppressors of anti-tumor immunity. However, the impact of tumor-derived exosomes in modulating macrophage polarization in the lung TME is largely unknown. Herein, we investigated if lung tumor-derived exosomes alter transcriptional and bioenergetic signatures of M0 macrophages and polarize them to an M2 phenotype. The concentration of exosomes produced by p53 null H358 lung tumor cells was significantly reduced compared to A549 (p53 wild-type) lung tumor cells, consistent with p53-mediated regulation of exosome production. In co-culture studies, M0 macrophages internalized tumor-derived exosomes, and differentiated into M2 phenotype. Importantly, we demonstrate that tumor-derived exosomes enhance the oxygen consumption rate of macrophages, altering their bioenergetic state consistent with that of M2 macrophages. In vitro co-cultures of M0 macrophages with H358 exosomes demonstrated that exosome-induced M2 polarization may be p53 independent. Murine bone marrow cells and bone marrow-derived myeloid-derived suppressor cells (MDSCs) co-cultured with lewis lung carcinoma (LLC)-derived exosomes differentiated to M2 macrophages. Collectively, these studies provide evidence for a novel role for lung tumor-exosomes in M2 macrophage polarization, which then offers new therapeutic targets for immunotherapy of lung cancer. Full article

(This article belongs to the Special Issue Leukocytes in Inflammation, Resolution of Inflammation, Autoimmune Diseases and Cancer)

► Show Figures

Figure 1

22 pages, 4622 KB

Open AccessEditor’s ChoiceReview

A Structural View of SARS-CoV-2 RNA Replication Machinery: RNA Synthesis, Proofreading and Final Capping

by Maria Romano, Alessia Ruggiero, Flavia Squeglia, Giovanni Maga and Rita Berisio

Cells 2020, 9(5), 1267; https://doi.org/10.3390/cells9051267 - 20 May 2020

Cited by 415 | Viewed by 33460

Abstract

The current coronavirus disease-2019 (COVID-19) pandemic is due to the novel coronavirus SARS-CoV-2. The scientific community has mounted a strong response by accelerating research and innovation, and has quickly set the foundation for understanding the molecular determinants of the disease for the development [...] Read more.

The current coronavirus disease-2019 (COVID-19) pandemic is due to the novel coronavirus SARS-CoV-2. The scientific community has mounted a strong response by accelerating research and innovation, and has quickly set the foundation for understanding the molecular determinants of the disease for the development of targeted therapeutic interventions. The replication of the viral genome within the infected cells is a key stage of the SARS-CoV-2 life cycle. It is a complex process involving the action of several viral and host proteins in order to perform RNA polymerization, proofreading and final capping. This review provides an update of the structural and functional data on the key actors of the replicatory machinery of SARS-CoV-2, to fill the gaps in the currently available structural data, which is mainly obtained through homology modeling. Moreover, learning from similar viruses, we collect data from the literature to reconstruct the pattern of interactions among the protein actors of the SARS-CoV-2 RNA polymerase machinery. Here, an important role is played by co-factors such as Nsp8 and Nsp10, not only as allosteric activators but also as molecular connectors that hold the entire machinery together to enhance the efficiency of RNA replication. Full article

(This article belongs to the Special Issue Understanding Molecular Actors of SARS-Cov-2 Virulence to Tackle COVID19 Outbreak)

► Show Figures

Figure 1

16 pages, 8139 KB

Open AccessEditor’s ChoiceArticle

Progerin Expression Induces Inflammation, Oxidative Stress and Senescence in Human Coronary Endothelial Cells

by Guillaume Bidault, Marie Garcia, Jacqueline Capeau, Romain Morichon, Corinne Vigouroux and Véronique Béréziat

Cells 2020, 9(5), 1201; https://doi.org/10.3390/cells9051201 - 12 May 2020

Cited by 55 | Viewed by 6785

Abstract

Hutchinson–Gilford progeria syndrome (HGPS) is a rare premature aging disorder notably characterized by precocious and deadly atherosclerosis. Almost 90% of HGPS patients carry a LMNA p.G608G splice variant that leads to the expression of a permanently farnesylated abnormal form of prelamin-A, referred to [...] Read more.

Hutchinson–Gilford progeria syndrome (HGPS) is a rare premature aging disorder notably characterized by precocious and deadly atherosclerosis. Almost 90% of HGPS patients carry a LMNA p.G608G splice variant that leads to the expression of a permanently farnesylated abnormal form of prelamin-A, referred to as progerin. Endothelial dysfunction is a key determinant of atherosclerosis, notably during aging. Previous studies have shown that progerin accumulates in HGPS patients’ endothelial cells but also during vascular physiological aging. However, whether progerin expression in human endothelial cells can recapitulate features of endothelial dysfunction is currently unknown. Herein, we evaluated the direct impact of exogenously expressed progerin and wild-type lamin-A on human endothelial cell function and senescence. Our data demonstrate that progerin, but not wild-type lamin-A, overexpression induces endothelial cell dysfunction, characterized by increased inflammation and oxidative stress together with persistent DNA damage, increased cell cycle arrest protein expression and cellular senescence. Inhibition of progerin prenylation using a pravastatin–zoledronate combination partly prevents these defects. Our data suggest a direct proatherogenic role of progerin in human endothelial cells, which could contribute to HGPS-associated early atherosclerosis and also potentially be involved in physiological endothelial aging participating to age-related cardiometabolic diseases. Full article

(This article belongs to the Collection Lamins and Laminopathies)

► Show Figures

Graphical abstract

14 pages, 3480 KB

Open AccessEditor’s ChoiceArticle

p62 is Negatively Implicated in the TRAF6-BECN1 Signaling Axis for Autophagy Activation and Cancer Progression by Toll-Like Receptor 4 (TLR4)

by Mi-Jeong Kim, Yoon Min, Ji Seon Im, Juhee Son, Joo Sang Lee and Ki-Young Lee

Cells 2020, 9(5), 1142; https://doi.org/10.3390/cells9051142 - 6 May 2020

Cited by 33 | Viewed by 5768

Abstract

Toll-like receptors (TLRs) induce the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and autophagy through the TNF (Tumor necrosis factor) receptor-associated factor 6 (TRAF6)-evolutionarily conserved signaling intermediate in Toll pathways (ECSIT) and TRAF6-BECN1 signaling axes, respectively. Having shown that p62 [...] Read more.

Toll-like receptors (TLRs) induce the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and autophagy through the TNF (Tumor necrosis factor) receptor-associated factor 6 (TRAF6)-evolutionarily conserved signaling intermediate in Toll pathways (ECSIT) and TRAF6-BECN1 signaling axes, respectively. Having shown that p62 negatively regulates Toll-like receptor 4 (TLR4)-mediated signaling via TRAF6-ECSIT signaling axis, we herein investigated whether p62 is functionally implicated in the TRAF6-BECN1 signaling axis, thereby regulating cancer cell migration and invasion. p62 interacted with TRAF6 and BECN1, to interrupt the functional associations required for TRAF6-BECN1 complex formation, leading to inhibitions of BECN1 ubiquitination and autophagy activation. Importantly, p62-deficient cancer cells, such as p62-knockdown (p62^KD) SK-HEP-1, p62^KD MDA-MB-231, and p62-knockout (p62^KO) A549 cells, showed increased activation of autophagy induced by TLR4 stimulation, suggesting that p62 negatively regulates autophagy activation. Moreover, these p62-deficient cancer cells exhibited marked increases in cell migration and invasion in response to TLR4 stimulation. Collectively, these results suggest that p62 is negatively implicated in the TRAF6-BECN1 signaling axis, thereby inhibiting cancer cell migration and invasion regulated by autophagy activation in response to TLR4 stimulation. Full article

(This article belongs to the Special Issue Ubiquitin and Autophagy)

► Show Figures

Figure 1

20 pages, 9513 KB

Open AccessEditor’s ChoiceArticle

Comparative Application of BioID and TurboID for Protein-Proximity Biotinylation

by Danielle G. May, Kelsey L. Scott, Alexandre R. Campos and Kyle J. Roux

Cells 2020, 9(5), 1070; https://doi.org/10.3390/cells9051070 - 25 Apr 2020

Cited by 124 | Viewed by 30163

Abstract

BioID is a well-established method for identifying protein–protein interactions and has been utilized within live cells and several animal models. However, the conventional labeling period requires 15–18 h for robust biotinylation which may not be ideal for some applications. Recently, two new ligases [...] Read more.

BioID is a well-established method for identifying protein–protein interactions and has been utilized within live cells and several animal models. However, the conventional labeling period requires 15–18 h for robust biotinylation which may not be ideal for some applications. Recently, two new ligases termed TurboID and miniTurbo were developed using directed evolution of the BioID ligase and were able to produce robust biotinylation following a 10 min incubation with excess biotin. However, there is reported concern about inducibility of biotinylation, cellular toxicity, and ligase stability. To further investigate the practical applications of TurboID and ascertain strengths and weaknesses compared to BioID, we developed several stable cell lines expressing BioID and TurboID fusion proteins and analyzed them via immunoblot, immunofluorescence, and biotin-affinity purification-based proteomics. For TurboID we observed signs of protein instability, persistent biotinylation in the absence of exogenous biotin, and an increase in the practical labeling radius. However, TurboID enabled robust biotinylation in the endoplasmic reticulum lumen compared to BioID. Induction of biotinylation could be achieved by combining doxycycline-inducible expression with growth in biotin depleted culture media. These studies should help inform investigators utilizing BioID-based methods as to the appropriate ligase and experimental protocol for their particular needs. Full article

(This article belongs to the Collection Feature Papers in Cell Nuclei: Function, Transport and Receptors)

► Show Figures

Figure 1

13 pages, 655 KB

Open AccessEditor’s ChoiceReview

Microautophagy in Plants: Consideration of Its Molecular Mechanism

by Katarzyna Sieńko, Andisheh Poormassalehgoo, Kenji Yamada and Shino Goto-Yamada

Cells 2020, 9(4), 887; https://doi.org/10.3390/cells9040887 - 4 Apr 2020

Cited by 54 | Viewed by 7989

Abstract

Microautophagy is a type of autophagy. It is characterized by direct enclosing with the vacuolar/lysosomal membrane, which completes the isolation and uptake of cell components in the vacuole. Several publications present evidence that plants exhibit microautophagy. Plant microautophagy is involved in anthocyanin accumulation [...] Read more.

Microautophagy is a type of autophagy. It is characterized by direct enclosing with the vacuolar/lysosomal membrane, which completes the isolation and uptake of cell components in the vacuole. Several publications present evidence that plants exhibit microautophagy. Plant microautophagy is involved in anthocyanin accumulation in the vacuole, eliminating damaged chloroplasts and degrading cellular components during starvation. However, information on the molecular mechanism of microautophagy is less available than that on the general macroautophagy, because the research focusing on microautophagy has not been widely reported. In yeast and animals, it is suggested that microautophagy can be classified into several types depending on morphology and the requirements of autophagy-related (ATG) genes. This review summarizes the studies on plant microautophagy and discusses possible techniques for a future study in this field while taking into account the information on microautophagy obtained from yeast and animals. Full article

(This article belongs to the Special Issue Advances in the Plant Autophagy)

► Show Figures

Graphical abstract

43 pages, 1301 KB

Open AccessEditor’s ChoiceReview

Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

by Natascha Roehlen, Emilie Crouchet and Thomas F. Baumert

Cells 2020, 9(4), 875; https://doi.org/10.3390/cells9040875 - 3 Apr 2020

Cited by 968 | Viewed by 50973

Abstract

Liver fibrosis due to viral or metabolic chronic liver diseases is a major challenge of global health. Correlating with liver disease progression, fibrosis is a key factor for liver disease outcome and risk of hepatocellular carcinoma (HCC). Despite different mechanism of primary liver [...] Read more.

Liver fibrosis due to viral or metabolic chronic liver diseases is a major challenge of global health. Correlating with liver disease progression, fibrosis is a key factor for liver disease outcome and risk of hepatocellular carcinoma (HCC). Despite different mechanism of primary liver injury and disease-specific cell responses, the progression of fibrotic liver disease follows shared patterns across the main liver disease etiologies. Scientific discoveries within the last decade have transformed the understanding of the mechanisms of liver fibrosis. Removal or elimination of the causative agent such as control or cure of viral infection has shown that liver fibrosis is reversible. However, reversal often occurs too slowly or too infrequent to avoid life-threatening complications particularly in advanced fibrosis. Thus, there is a huge unmet medical need for anti-fibrotic therapies to prevent liver disease progression and HCC development. However, while many anti-fibrotic candidate agents have shown robust effects in experimental animal models, their anti-fibrotic effects in clinical trials have been limited or absent. Thus, no approved therapy exists for liver fibrosis. In this review we summarize cellular drivers and molecular mechanisms of fibrogenesis in chronic liver diseases and discuss their impact for the development of urgently needed anti-fibrotic therapies. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

► Show Figures

Figure 1

17 pages, 2647 KB

Open AccessEditor’s ChoiceArticle

Lamin A/C Assembly Defects in LMNA-Congenital Muscular Dystrophy Is Responsible for the Increased Severity of the Disease Compared with Emery–Dreifuss Muscular Dystrophy

by Anne T. Bertrand, Astrid Brull, Feriel Azibani, Louise Benarroch, Khadija Chikhaoui, Colin L. Stewart, Ohad Medalia, Rabah Ben Yaou and Gisèle Bonne

Cells 2020, 9(4), 844; https://doi.org/10.3390/cells9040844 - 31 Mar 2020

Cited by 32 | Viewed by 6874

Abstract

LMNA encodes for Lamin A/C, type V intermediate filaments that polymerize under the inner nuclear membrane to form the nuclear lamina. A small fraction of Lamin A/C, less polymerized, is also found in the nucleoplasm. Lamin A/C functions include roles in nuclear resistance [...] Read more.

LMNA encodes for Lamin A/C, type V intermediate filaments that polymerize under the inner nuclear membrane to form the nuclear lamina. A small fraction of Lamin A/C, less polymerized, is also found in the nucleoplasm. Lamin A/C functions include roles in nuclear resistance to mechanical stress and gene regulation. LMNA mutations are responsible for a wide variety of pathologies, including Emery–Dreifuss (EDMD) and LMNA-related congenital muscular dystrophies (L-CMD) without clear genotype–phenotype correlations. Both diseases presented with striated muscle disorders although L-CMD symptoms appear much earlier and are more severe. Seeking for pathomechanical differences to explain the severity of L-CMD mutations, we performed an in silico analysis of the UMD-LMNA database and found that L-CMD mutations mainly affect residues involved in Lamin dimer and tetramer stability. In line with this, we found increased nucleoplasmic Lamin A/C in L-CMD patient fibroblasts and mouse myoblasts compared to the control and EDMD. L-CMD myoblasts show differentiation defects linked to their inability to upregulate muscle specific nuclear envelope (NE) proteins expression. NE proteins were mislocalized, leading to misshapen nuclei. We conclude that these defects are due to both the absence of Lamin A/C from the nuclear lamina and its maintenance in the nucleoplasm of myotubes. Full article

(This article belongs to the Special Issue The New Frontier of Therapies for Nuclear Envelope and Lamin-Related Diseases: Selected Papers from 2019 International Meeting on Laminopathies)

► Show Figures

Figure 1

18 pages, 1006 KB

Open AccessEditor’s ChoiceArticle

VEGF Triggers Transient Induction of Autophagy in Endothelial Cells via AMPKα1

by Katrin Spengler, Nderim Kryeziu, Silke Große, Alexander S. Mosig and Regine Heller

Cells 2020, 9(3), 687; https://doi.org/10.3390/cells9030687 - 11 Mar 2020

Cited by 46 | Viewed by 5606

Abstract

AMP-activated protein kinase (AMPK) is activated by vascular endothelial growth factor (VEGF) in endothelial cells and it is significantly involved in VEGF-induced angiogenesis. This study investigates whether the VEGF/AMPK pathway regulates autophagy in endothelial cells and whether this is linked to its pro-angiogenic [...] Read more.

AMP-activated protein kinase (AMPK) is activated by vascular endothelial growth factor (VEGF) in endothelial cells and it is significantly involved in VEGF-induced angiogenesis. This study investigates whether the VEGF/AMPK pathway regulates autophagy in endothelial cells and whether this is linked to its pro-angiogenic role. We show that VEGF leads to AMPKα1-dependent phosphorylation of Unc-51-like kinase 1 (ULK1) at its serine residue 556 and to the subsequent phosphorylation of the ULK1 substrate ATG14. This triggers initiation of autophagy as shown by phosphorylation of ATG16L1 and conjugation of the microtubule-associated protein light chain 3B, which indicates autophagosome formation; this is followed by increased autophagic flux measured in the presence of bafilomycin A1 and by reduced expression of the autophagy substrate p62. VEGF-induced autophagy is transient and probably terminated by mechanistic target of rapamycin (mTOR), which is activated by VEGF in a delayed manner. We show that functional autophagy is required for VEGF-induced angiogenesis and may have specific functions in addition to maintaining homeostasis. In line with this, inhibition of autophagy impaired VEGF-mediated formation of the Notch intracellular domain, a critical regulator of angiogenesis. Our study characterizes autophagy induction as a pro-angiogenic function of the VEGF/AMPK pathway and suggests that timely activation of autophagy-initiating pathways may help to initiate angiogenesis. Full article

(This article belongs to the Section Autophagy)

► Show Figures

Figure 1

22 pages, 9422 KB

Open AccessEditor’s ChoiceArticle

Overexpression of the Selective Autophagy Cargo Receptor NBR1 Modifies Plant Response to Sulfur Deficit

by Leszek Tarnowski, Milagros Collados Rodriguez, Jerzy Brzywczy, Dominik Cysewski, Anna Wawrzynska and Agnieszka Sirko

Cells 2020, 9(3), 669; https://doi.org/10.3390/cells9030669 - 10 Mar 2020

Cited by 21 | Viewed by 5856

Abstract

Plants exposed to sulfur deficit elevate the transcription of NBR1 what might reflect an increased demand for NBR1 in such conditions. Therefore, we investigated the role of this selective autophagy cargo receptor in plant response to sulfur deficit (-S). Transcriptome analysis of the [...] Read more.

Plants exposed to sulfur deficit elevate the transcription of NBR1 what might reflect an increased demand for NBR1 in such conditions. Therefore, we investigated the role of this selective autophagy cargo receptor in plant response to sulfur deficit (-S). Transcriptome analysis of the wild type and NBR1 overexpressing plants pointed out differences in gene expression in response to -S. Our attention focused particularly on the genes upregulated by -S in roots of both lines because of significant overrepresentation of cytoplasmic ribosomal gene family. Moreover, we noticed overrepresentation of the same family in the set of proteins co-purifying with NBR1 in -S. One of these ribosomal proteins, RPS6 was chosen for verification of its direct interaction with NBR1 and proven to bind outside the NBR1 ubiquitin binding domains. The biological significance of this novel interaction and the postulated role of NBR1 in ribosomes remodeling in response to starvation remain to be further investigated. Interestingly, NBR1 overexpressing seedlings have significantly shorter roots than wild type when grown in nutrient deficient conditions in the presence of TOR kinase inhibitors. This phenotype probably results from excessive autophagy induction by the additive effect of NBR1 overexpression, starvation, and TOR inhibition. Full article

(This article belongs to the Special Issue Advances in the Plant Autophagy)

► Show Figures

Figure 1

17 pages, 2309 KB

Open AccessEditor’s ChoiceArticle

The Lipid Virulence Factors of Mycobacterium tuberculosis Exert Multilayered Control over Autophagy-Related Pathways in Infected Human Macrophages

by Aïcha Bah, Merlin Sanicas, Jérôme Nigou, Christophe Guilhot, Catherine Astarie-Dequeker and Isabelle Vergne

Cells 2020, 9(3), 666; https://doi.org/10.3390/cells9030666 - 9 Mar 2020

Cited by 39 | Viewed by 7498

Abstract

Autophagy is an important innate immune defense mechanism that controls Mycobacterium tuberculosis (Mtb) growth inside macrophages. Autophagy machinery targets Mtb-containing phagosomes via xenophagy after damage to the phagosomal membrane due to the Type VII secretion system Esx-1 or via LC3-associated [...] Read more.

Autophagy is an important innate immune defense mechanism that controls Mycobacterium tuberculosis (Mtb) growth inside macrophages. Autophagy machinery targets Mtb-containing phagosomes via xenophagy after damage to the phagosomal membrane due to the Type VII secretion system Esx-1 or via LC3-associated phagocytosis without phagosomal damage. Conversely, Mtb restricts autophagy-related pathways via the production of various bacterial protein factors. Although bacterial lipids are known to play strategic functions in Mtb pathogenesis, their role in autophagy manipulation remains largely unexplored. Here, we report that the lipid virulence factors sulfoglycolipids (SLs) and phthiocerol dimycocerosates (DIMs) control autophagy-related pathways through distinct mechanisms in human macrophages. Using knock-out and knock-in mutants of Mtb and Mycobacterium bovis BCG (Bacille Calmette Guerin) and purified lipids, we found that (i) Mtb mutants with DIM and SL deficiencies promoted functional autophagy via an MyD88-dependent and phagosomal damage-independent pathway in human macrophages; (ii) SLs limited this pathway by acting as TLR2 antagonists; (iii) DIMs prevented phagosomal damage-independent autophagy while promoting Esx-1-dependent xenophagy; (iv) and DIMs, but not SLs, limited the acidification of LC3-positive Mtb compartments. In total, our study reveals an unexpected and intricate role for Mtb lipid virulence factors in controlling autophagy-related pathways in human macrophages, thus providing further insight into the autophagy manipulation tactics deployed by intracellular bacterial pathogens. Full article

(This article belongs to the Special Issue Autophagy in Antimicrobial Immunity)

► Show Figures

Figure 1

32 pages, 2039 KB

Open AccessEditor’s ChoiceReview

DNA Methylation-Based Testing in Liquid Biopsies as Detection and Prognostic Biomarkers for the Four Major Cancer Types

by Vera Constâncio, Sandra P. Nunes, Rui Henrique and Carmen Jerónimo

Cells 2020, 9(3), 624; https://doi.org/10.3390/cells9030624 - 5 Mar 2020

Cited by 161 | Viewed by 16717

Abstract

Lung, breast, colorectal, and prostate cancers are the most incident worldwide. Optimal population-based cancer screening methods remain an unmet need, since cancer detection at early stages increases the prospects of successful and curative treatment, leading to a lower incidence of recurrences. Moreover, the [...] Read more.

Lung, breast, colorectal, and prostate cancers are the most incident worldwide. Optimal population-based cancer screening methods remain an unmet need, since cancer detection at early stages increases the prospects of successful and curative treatment, leading to a lower incidence of recurrences. Moreover, the current parameters for cancer patients’ stratification have been associated with divergent outcomes. Therefore, new biomarkers that could aid in cancer detection and prognosis, preferably detected by minimally invasive methods are of major importance. Aberrant DNA methylation is an early event in cancer development and may be detected in circulating cell-free DNA (ccfDNA), constituting a valuable cancer biomarker. Furthermore, DNA methylation is a stable alteration that can be easily and rapidly quantified by methylation-specific PCR methods. Thus, the main goal of this review is to provide an overview of the most important studies that report methylation biomarkers for the detection and prognosis of the four major cancers after a critical analysis of the available literature. DNA methylation-based biomarkers show promise for cancer detection and management, with some studies describing a “PanCancer” detection approach for the simultaneous detection of several cancer types. Nonetheless, DNA methylation biomarkers still lack large-scale validation, precluding implementation in clinical practice. Full article

(This article belongs to the Special Issue Circulating DNA and Epigenetic Alterations as Biomarkers in Oncology)

► Show Figures

Figure 1

21 pages, 504 KB

Open AccessFeature PaperEditor’s ChoiceReview

Astrocyte and Oligodendrocyte Cross-Talk in the Central Nervous System

by Erik Nutma, Démi van Gent, Sandra Amor and Laura A. N. Peferoen

Cells 2020, 9(3), 600; https://doi.org/10.3390/cells9030600 - 3 Mar 2020

Cited by 140 | Viewed by 18311

Abstract

Over the last decade knowledge of the role of astrocytes in central nervous system (CNS) neuroinflammatory diseases has changed dramatically. Rather than playing a merely passive role in response to damage it is clear that astrocytes actively maintain CNS homeostasis by influencing pH, [...] Read more.

Over the last decade knowledge of the role of astrocytes in central nervous system (CNS) neuroinflammatory diseases has changed dramatically. Rather than playing a merely passive role in response to damage it is clear that astrocytes actively maintain CNS homeostasis by influencing pH, ion and water balance, the plasticity of neurotransmitters and synapses, cerebral blood flow, and are important immune cells. During disease astrocytes become reactive and hypertrophic, a response that was long considered to be pathogenic. However, recent studies reveal that astrocytes also have a strong tissue regenerative role. Whilst most astrocyte research focuses on modulating neuronal function and synaptic transmission little is known about the cross-talk between astrocytes and oligodendrocytes, the myelinating cells of the CNS. This communication occurs via direct cell-cell contact as well as via secreted cytokines, chemokines, exosomes, and signalling molecules. Additionally, this cross-talk is important for glial development, triggering disease onset and progression, as well as stimulating regeneration and repair. Its critical role in homeostasis is most evident when this communication fails. Here, we review emerging evidence of astrocyte-oligodendrocyte communication in health and disease. Understanding the pathways involved in this cross-talk will reveal important insights into the pathogenesis and treatment of CNS diseases. Full article

(This article belongs to the Collection Oligodendrocyte Physiology and Pathology Function)

► Show Figures

Graphical abstract

29 pages, 3774 KB

Open AccessEditor’s ChoiceReview

Myeloid-Derived Suppressor Cells as a Therapeutic Target for Cancer

by Andrew M. K. Law, Fatima Valdes-Mora and David Gallego-Ortega

Cells 2020, 9(3), 561; https://doi.org/10.3390/cells9030561 - 27 Feb 2020

Cited by 368 | Viewed by 21747

Abstract

The emergence of immunotherapy has been an astounding breakthrough in cancer treatments. In particular, immune checkpoint inhibitors, targeting PD-1 and CTLA-4, have shown remarkable therapeutic outcomes. However, response rates from immunotherapy have been reported to be varied, with some having pronounced success and [...] Read more.

The emergence of immunotherapy has been an astounding breakthrough in cancer treatments. In particular, immune checkpoint inhibitors, targeting PD-1 and CTLA-4, have shown remarkable therapeutic outcomes. However, response rates from immunotherapy have been reported to be varied, with some having pronounced success and others with minimal to no clinical benefit. An important aspect associated with this discrepancy in patient response is the immune-suppressive effects elicited by the tumour microenvironment (TME). Immune suppression plays a pivotal role in regulating cancer progression, metastasis, and reducing immunotherapy success. Most notably, myeloid-derived suppressor cells (MDSC), a heterogeneous population of immature myeloid cells, have potent mechanisms to inhibit T-cell and NK-cell activity to promote tumour growth, development of the pre-metastatic niche, and contribute to resistance to immunotherapy. Accumulating research indicates that MDSC can be a therapeutic target to alleviate their pro-tumourigenic functions and immunosuppressive activities to bolster the efficacy of checkpoint inhibitors. In this review, we provide an overview of the general immunotherapeutic approaches and discuss the characterisation, expansion, and activities of MDSCs with the current treatments used to target them either as a single therapeutic target or synergistically in combination with immunotherapy. Full article

(This article belongs to the Special Issue Tumor-Associated Myeloid Cells: From Basic Research to Clinical Application)

► Show Figures

Figure 1

21 pages, 3916 KB

Open AccessEditor’s ChoiceArticle

Stress Reshapes the Physiological Response of Halophile Fungi to Salinity

by Yordanis Pérez-Llano, Eya Caridad Rodríguez-Pupo, Irina S. Druzhinina, Komal Chenthamara, Feng Cai, Nina Gunde-Cimerman, Polona Zalar, Cene Gostinčar, Rok Kostanjšek, Jorge Luis Folch-Mallol, Ramón Alberto Batista-García and María del Rayo Sánchez-Carbente

Cells 2020, 9(3), 525; https://doi.org/10.3390/cells9030525 - 25 Feb 2020

Cited by 46 | Viewed by 7160

Abstract

(1) Background: Mechanisms of cellular and molecular adaptation of fungi to salinity have been commonly drawn from halotolerant strains and few studies in basidiomycete fungi. These studies have been conducted in settings where cells are subjected to stress, either hypo- or hyperosmotic, which [...] Read more.

(1) Background: Mechanisms of cellular and molecular adaptation of fungi to salinity have been commonly drawn from halotolerant strains and few studies in basidiomycete fungi. These studies have been conducted in settings where cells are subjected to stress, either hypo- or hyperosmotic, which can be a confounding factor in describing physiological mechanisms related to salinity. (2) Methods: We have studied transcriptomic changes in Aspergillus sydowii, a halophilic species, when growing in three different salinity conditions (No NaCl, 0.5 M, and 2.0 M NaCl). (3) Results: In this fungus, major physiological modifications occur under high salinity (2.0 M NaCl) and not when cultured under optimal conditions (0.5 M NaCl), suggesting that most of the mechanisms described for halophilic growth are a consequence of saline stress response and not an adaptation to saline conditions. Cell wall modifications occur exclusively at extreme salinity, with an increase in cell wall thickness and lamellar structure, which seem to involve a decrease in chitin content and an augmented content of alfa and beta-glucans. Additionally, three hydrophobin genes were differentially expressed under hypo- or hyperosmotic stress but not when the fungus grows optimally. Regarding compatible solutes, glycerol is the main compound accumulated in salt stress conditions, whereas trehalose is accumulated in the absence of salt. (4) Conclusions: Physiological responses to salinity vary greatly between optimal and high salt concentrations and are not a simple graded effect as the salt concentration increases. Our results highlight the influence of stress in reshaping the response of extremophiles to environmental challenges. Full article

(This article belongs to the Section Plant, Algae and Fungi Cell Biology)

► Show Figures

Graphical abstract

22 pages, 3412 KB

Open AccessEditor’s ChoiceArticle

PVPred-SCM: Improved Prediction and Analysis of Phage Virion Proteins Using a Scoring Card Method

by Phasit Charoenkwan, Sakawrat Kanthawong, Nalini Schaduangrat, Janchai Yana and Watshara Shoombuatong

Cells 2020, 9(2), 353; https://doi.org/10.3390/cells9020353 - 3 Feb 2020

Cited by 55 | Viewed by 4769

Abstract

Although, existing methods have been successful in predicting phage (or bacteriophage) virion proteins (PVPs) using various types of protein features and complex classifiers, such as support vector machine and naïve Bayes, these two methods do not allow interpretability. However, the characterization and analysis [...] Read more.

Although, existing methods have been successful in predicting phage (or bacteriophage) virion proteins (PVPs) using various types of protein features and complex classifiers, such as support vector machine and naïve Bayes, these two methods do not allow interpretability. However, the characterization and analysis of PVPs might be of great significance to understanding the molecular mechanisms of bacteriophage genetics and the development of antibacterial drugs. Hence, we herein proposed a novel method (PVPred-SCM) based on the scoring card method (SCM) in conjunction with dipeptide composition to identify and characterize PVPs. In PVPred-SCM, the propensity scores of 400 dipeptides were calculated using the statistical discrimination approach. Rigorous independent validation test showed that PVPred-SCM utilizing only dipeptide composition yielded an accuracy of 77.56%, indicating that PVPred-SCM performed well relative to the state-of-the-art method utilizing a number of protein features. Furthermore, the propensity scores of dipeptides were used to provide insights into the biochemical and biophysical properties of PVPs. Upon comparison, it was found that PVPred-SCM was superior to the existing methods considering its simplicity, interpretability, and implementation. Finally, in an effort to facilitate high-throughput prediction of PVPs, we provided a user-friendly web-server for identifying the likelihood of whether or not these sequences are PVPs. It is anticipated that PVPred-SCM will become a useful tool or at least a complementary existing method for predicting and analyzing PVPs. Full article

(This article belongs to the Special Issue Biocomputing and Synthetic Biology in Cells)

► Show Figures

Graphical abstract

11 pages, 698 KB

Open AccessEditor’s ChoiceReview

Regulation of Synaptic Development by Astrocyte Signaling Factors and Their Emerging Roles in Substance Abuse

by Christopher D. Walker, W. Christopher Risher and Mary-Louise Risher

Cells 2020, 9(2), 297; https://doi.org/10.3390/cells9020297 - 26 Jan 2020

Cited by 31 | Viewed by 8284

Abstract

Astrocytes have critical functions throughout the central nervous system (CNS) and have emerged as regulators of synaptic development and function. With their highly complex morphologies, they are able to interact with thousands of synapses via peripheral astrocytic processes (PAPs), ensheathing neuronal axons and [...] Read more.

Astrocytes have critical functions throughout the central nervous system (CNS) and have emerged as regulators of synaptic development and function. With their highly complex morphologies, they are able to interact with thousands of synapses via peripheral astrocytic processes (PAPs), ensheathing neuronal axons and dendrites to form the tripartite synapse. In this way, astrocytes engage in crosstalk with neurons to mediate a variety of CNS processes including the regulation of extracellular matrix protein signaling, formation and maintenance of the blood-brain barrier (BBB), axon growth and guidance, homeostasis of the synaptic microenvironment, synaptogenesis, and the promotion of synaptic diversity. In this review, we discuss several key astrocyte signaling factors (thrombospondins, netrins, apolipoproteins, neuregulins, bone morphogenetic proteins, and neuroligins) in the maintenance and regulation of synapse formation. We also explore how these astrocyte signaling factors are impacted by and contribute to substance abuse, particularly alcohol and cocaine use. Full article

(This article belongs to the Special Issue Astrocytes in Space and Time)

► Show Figures

Figure 1

32 pages, 541 KB

Open AccessEditor’s ChoiceReview

miRNAs as Biomarkers in Disease: Latest Findings Regarding Their Role in Diagnosis and Prognosis

by Carmen Elena Condrat, Dana Claudia Thompson, Madalina Gabriela Barbu, Oana Larisa Bugnar, Andreea Boboc, Dragos Cretoiu, Nicolae Suciu, Sanda Maria Cretoiu and Silviu Cristian Voinea

Cells 2020, 9(2), 276; https://doi.org/10.3390/cells9020276 - 23 Jan 2020

Cited by 1015 | Viewed by 23509

Abstract

MicroRNAs (miRNAs) represent a class of small, non-coding RNAs with the main roles of regulating mRNA through its degradation and adjusting protein levels. In recent years, extraordinary progress has been made in terms of identifying the origin and exact functions of miRNA, focusing [...] Read more.

MicroRNAs (miRNAs) represent a class of small, non-coding RNAs with the main roles of regulating mRNA through its degradation and adjusting protein levels. In recent years, extraordinary progress has been made in terms of identifying the origin and exact functions of miRNA, focusing on their potential use in both the research and the clinical field. This review aims at improving the current understanding of these molecules and their applicability in the medical field. A thorough analysis of the literature consulting resources available in online databases such as NCBI, PubMed, Medline, ScienceDirect, and UpToDate was performed. There is promising evidence that in spite of the lack of standardized protocols regarding the use of miRNAs in current clinical practice, they constitute a reliable tool for future use. These molecules meet most of the required criteria for being an ideal biomarker, such as accessibility, high specificity, and sensitivity. Despite present limitations, miRNAs as biomarkers for various conditions remain an impressive research field. As current techniques evolve, we anticipate that miRNAs will become a routine approach in the development of personalized patient profiles, thus permitting more specific therapeutic interventions. Full article

(This article belongs to the Special Issue microRNA as Biomarker)

22 pages, 3107 KB

Open AccessEditor’s ChoiceReview

Cellular and Molecular Differences between HFpEF and HFrEF: A Step Ahead in an Improved Pathological Understanding

by Steven J. Simmonds, Ilona Cuijpers, Stephane Heymans and Elizabeth A. V. Jones

Cells 2020, 9(1), 242; https://doi.org/10.3390/cells9010242 - 18 Jan 2020

Cited by 261 | Viewed by 32677

Abstract

Heart failure (HF) is the most rapidly growing cardiovascular health burden worldwide. HF can be classified into three groups based on the percentage of the ejection fraction (EF): heart failure with reduced EF (HFrEF), heart failure with mid-range—also called mildly reduced EF— (HFmrEF), [...] Read more.

Heart failure (HF) is the most rapidly growing cardiovascular health burden worldwide. HF can be classified into three groups based on the percentage of the ejection fraction (EF): heart failure with reduced EF (HFrEF), heart failure with mid-range—also called mildly reduced EF— (HFmrEF), and heart failure with preserved ejection fraction (HFpEF). HFmrEF can progress into either HFrEF or HFpEF, but its phenotype is dominated by coronary artery disease, as in HFrEF. HFrEF and HFpEF present with differences in both the development and progression of the disease secondary to changes at the cellular and molecular level. While recent medical advances have resulted in efficient and specific treatments for HFrEF, these treatments lack efficacy for HFpEF management. These differential response rates, coupled to increasing rates of HF, highlight the significant need to understand the unique pathogenesis of HFrEF and HFpEF. In this review, we summarize the differences in pathological development of HFrEF and HFpEF, focussing on disease-specific aspects of inflammation and endothelial function, cardiomyocyte hypertrophy and death, alterations in the giant spring titin, and fibrosis. We highlight the areas of difference between the two diseases with the aim of guiding research efforts for novel therapeutics in HFrEF and HFpEF. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis of Cardiovascular Disease)

► Show Figures

Figure 1

17 pages, 2989 KB

Open AccessEditor’s ChoiceArticle

Prevention of DNA Replication Stress by CHK1 Leads to Chemoresistance Despite a DNA Repair Defect in Homologous Recombination in Breast Cancer

by Felix Meyer, Saskia Becker, Sandra Classen, Ann Christin Parplys, Wael Yassin Mansour, Britta Riepen, Sara Timm, Claudia Ruebe, Maria Jasin, Harriet Wikman, Cordula Petersen, Kai Rothkamm and Kerstin Borgmann

Cells 2020, 9(1), 238; https://doi.org/10.3390/cells9010238 - 17 Jan 2020

Cited by 27 | Viewed by 5838

Abstract

Chromosomal instability not only has a negative effect on survival in triple-negative breast cancer, but also on the well treatable subgroup of luminal A tumors. This suggests a general mechanism independent of subtypes. Increased chromosomal instability (CIN) in triple-negative breast cancer (TNBC) is [...] Read more.

Chromosomal instability not only has a negative effect on survival in triple-negative breast cancer, but also on the well treatable subgroup of luminal A tumors. This suggests a general mechanism independent of subtypes. Increased chromosomal instability (CIN) in triple-negative breast cancer (TNBC) is attributed to a defect in the DNA repair pathway homologous recombination. Homologous recombination (HR) prevents genomic instability by repair and protection of replication. It is unclear whether genetic alterations actually lead to a repair defect or whether superior signaling pathways are of greater importance. Previous studies focused exclusively on the repair function of HR. Here, we show that the regulation of HR by the intra-S-phase damage response at the replication is of overriding importance. A damage response activated by Ataxia telangiectasia and Rad3 related-checkpoint kinase 1 (ATR-CHK1) can prevent replication stress and leads to resistance formation. CHK1 thus has a preferred role over HR in preventing replication stress in TNBC. The signaling cascade ATR-CHK1 can compensate for a double-strand break repair error and lead to resistance of HR-deficient tumors. Established methods for the identification of HR-deficient tumors for Poly(ADP-Ribose)-Polymerase 1 (PARP1) inhibitor therapies should be extended to include analysis of candidates for intra-S phase damage response. Full article

(This article belongs to the Special Issue Double-Strand DNA Break Repair and Human Disease)

► Show Figures

Figure 1

28 pages, 762 KB

Open AccessEditor’s ChoiceReview

miRNAs as Influencers of Cell–Cell Communication in Tumor Microenvironment

by Ilaria Conti, Gabriele Varano, Carolina Simioni, Ilaria Laface, Daniela Milani, Erika Rimondi and Luca M. Neri

Cells 2020, 9(1), 220; https://doi.org/10.3390/cells9010220 - 15 Jan 2020

Cited by 73 | Viewed by 9128

Abstract

microRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the posttranscriptional level, inducing the degradation of the target mRNA or translational repression. MiRNAs are involved in the control of a multiplicity of biological processes, and their absence or altered expression has [...] Read more.

microRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the posttranscriptional level, inducing the degradation of the target mRNA or translational repression. MiRNAs are involved in the control of a multiplicity of biological processes, and their absence or altered expression has been associated with a variety of human diseases, including cancer. Recently, extracellular miRNAs (ECmiRNAs) have been described as mediators of intercellular communication in multiple contexts, including tumor microenvironment. Cancer cells cooperate with stromal cells and elements of the extracellular matrix (ECM) to establish a comfortable niche to grow, to evade the immune system, and to expand. Within the tumor microenvironment, cells release ECmiRNAs and other factors in order to influence and hijack the physiological processes of surrounding cells, fostering tumor progression. Here, we discuss the role of miRNAs in the pathogenesis of multicomplex diseases, such as Alzheimer’s disease, obesity, and cancer, focusing on the contribution of both intracellular miRNAs, and of released ECmiRNAs in the establishment and development of cancer niche. We also review growing evidence suggesting the use of miRNAs as novel targets or potential tools for therapeutic applications. Full article

(This article belongs to the Collection Regulatory Functions of microRNAs)

► Show Figures

Graphical abstract

19 pages, 2870 KB

Open AccessEditor’s ChoiceArticle

Hippocampal Neurogenesis Is Enhanced in Adult Tau Deficient Mice

by Marangelie Criado-Marrero, Jonathan J. Sabbagh, Margaret R. Jones, Dale Chaput, Chad A. Dickey and Laura J. Blair

Cells 2020, 9(1), 210; https://doi.org/10.3390/cells9010210 - 14 Jan 2020

Cited by 25 | Viewed by 6489

Abstract

Tau dysfunction is common in several neurodegenerative diseases including Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Affective symptoms have often been associated with aberrant tau pathology and are commonly comorbid in patients with tauopathies, indicating a connection between tau functioning and mechanisms of [...] Read more.

Tau dysfunction is common in several neurodegenerative diseases including Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Affective symptoms have often been associated with aberrant tau pathology and are commonly comorbid in patients with tauopathies, indicating a connection between tau functioning and mechanisms of depression. The current study investigated depression-like behavior in Mapt^−/− mice, which contain a targeted deletion of the gene coding for tau. We show that 6-month Mapt^−/− mice are resistant to depressive behaviors, as evidenced by decreased immobility time in the forced swim and tail suspension tests, as well as increased escape behavior in a learned helplessness task. Since depression has also been linked to deficient adult neurogenesis, we measured neurogenesis in the hippocampal dentate gyrus and subventricular zone using 5-bromo-2-deoxyuridine (BrdU) labeling. We found that neurogenesis is increased in the dentate gyrus of 14-month-old Mapt^−/− brains compared to wild type, providing a potential mechanism for their behavioral phenotypes. In addition to the hippocampus, an upregulation of proteins involved in neurogenesis was observed in the frontal cortex and amygdala of the Mapt^−/− mice using proteomic mass spectrometry. All together, these findings suggest that tau may have a role in the depressive symptoms observed in many neurodegenerative diseases and identify tau as a potential molecular target for treating depression. Full article

(This article belongs to the Collection Functions of Nuclear Receptors)

► Show Figures

Figure 1

19 pages, 6856 KB

Open AccessEditor’s ChoiceArticle

Cholangiocyte-Derived Exosomal lncRNA H19 Promotes Macrophage Activation and Hepatic Inflammation under Cholestatic Conditions

by Xiaojiaoyang Li, Runping Liu, Yanyan Wang, Weiwei Zhu, Derrick Zhao, Xuan Wang, Hang Yang, Emily C. Gurley, Weidong Chen, Phillip B. Hylemon and Huiping Zhou

Cells 2020, 9(1), 190; https://doi.org/10.3390/cells9010190 - 11 Jan 2020

Cited by 100 | Viewed by 7139

Abstract

Activation of hepatic macrophages represents the critical driving force to promote cholestatic liver injury. Exosomes, as important small extracellular vesicles released by almost all types of cells, contribute to intercellular communication. We previously reported that cholangiocyte-derived exosomal long noncoding RNA (lncRNA) H19 plays [...] Read more.

Activation of hepatic macrophages represents the critical driving force to promote cholestatic liver injury. Exosomes, as important small extracellular vesicles released by almost all types of cells, contribute to intercellular communication. We previously reported that cholangiocyte-derived exosomal long noncoding RNA (lncRNA) H19 plays a vital role in disrupting bile acid homeostasis in hepatocytes and promoting the activation of hepatic stellate cells (HSCs). Exosomal H19 derived from cholangiocytes was rapidly taken up by Kupffer cells. However, the mechanistic links between exosomal lncRNA H19 and macrophage-driven inflammation in cholestasis remain unclear. Here, we reported that the hepatic H19 level was closely correlated with macrophage activation and hepatic fibrosis in both Mdr2^-/- and bile duct ligation (BDL) cholestatic mouse models, as well as in human primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) patients. Exosomal H19 significantly induced the expression and secretion of chemokine (C–C motif) ligand 2 (CCL-2) and interleukin 6 (IL-6) in Kupffer cells. H19-enriched exosomes enhanced the activation M1 polarization of Kupffer cells and promoted the recruitment and differentiation of bone marrow-derived macrophages, which were inhibited by a CCL-2 pharmacological inhibitor. In conclusion, Cholangiocyte-derived exosomal H19 played a critical role in macrophage activation, differentiation, and chemotaxis through CCL-2/CCR-2 signaling pathways, which represent a therapeutic target for cholestatic liver diseases. Full article

(This article belongs to the Section Cellular Pathology)

► Show Figures

Graphical abstract

27 pages, 1939 KB

Open AccessEditor’s ChoiceReview

RNA-Based Therapeutics: From Antisense Oligonucleotides to miRNAs

by Sarah Bajan and Gyorgy Hutvagner

Cells 2020, 9(1), 137; https://doi.org/10.3390/cells9010137 - 7 Jan 2020

Cited by 303 | Viewed by 21033

Abstract

The first therapeutic nucleic acid, a DNA oligonucleotide, was approved for clinical use in 1998. Twenty years later, in 2018, the first therapeutic RNA-based oligonucleotide was United States Food and Drug Administration (FDA) approved. This promises to be a rapidly expanding market, as [...] Read more.

The first therapeutic nucleic acid, a DNA oligonucleotide, was approved for clinical use in 1998. Twenty years later, in 2018, the first therapeutic RNA-based oligonucleotide was United States Food and Drug Administration (FDA) approved. This promises to be a rapidly expanding market, as many emerging biopharmaceutical companies are developing RNA interference (RNAi)-based, and RNA-based antisense oligonucleotide therapies. However, miRNA therapeutics are noticeably absent. miRNAs are regulatory RNAs that regulate gene expression. In disease states, the expression of many miRNAs is measurably altered. The potential of miRNAs as therapies and therapeutic targets has long been discussed and in the context of a wide variety of infections and diseases. Despite the great number of studies identifying miRNAs as potential therapeutic targets, only a handful of miRNA-targeting drugs (mimics or inhibitors) have entered clinical trials. In this review, we will discuss whether the investment in finding potential miRNA therapeutic targets has yielded feasible and practicable results, the benefits and obstacles of miRNAs as therapeutic targets, and the potential future of the field. Full article

(This article belongs to the Special Issue microRNA as Therapeutic Target)

► Show Figures

Figure 1

13 pages, 1165 KB

Open AccessEditor’s ChoiceArticle

Improving the Quantification of DNA Sequences Using Evolutionary Information Based on Deep Learning

by Hilal Tayara and Kil To Chong

Cells 2019, 8(12), 1635; https://doi.org/10.3390/cells8121635 - 14 Dec 2019

Cited by 19 | Viewed by 4584

Abstract

It is known that over 98% of the human genome is non-coding, and 93% of disease associated variants are located in these regions. Therefore, understanding the function of these regions is important. However, this task is challenging as most of these regions are [...] Read more.

It is known that over 98% of the human genome is non-coding, and 93% of disease associated variants are located in these regions. Therefore, understanding the function of these regions is important. However, this task is challenging as most of these regions are not well understood in terms of their functions. In this paper, we introduce a novel computational model based on deep neural networks, called DQDNN, for quantifying the function of non-coding DNA regions. This model combines convolution layers for capturing regularity motifs at multiple scales and recurrent layers for capturing long term dependencies between the captured motifs. In addition, we show that integrating evolutionary information with raw genomic sequences improves the performance of the predictor significantly. The proposed model outperforms the state-of-the-art ones using raw genomics sequences only and also by integrating evolutionary information with raw genomics sequences. More specifically, the proposed model improves 96.9% and 98% of the targets in terms of area under the receiver operating characteristic curve and the precision-recall curve, respectively. In addition, the proposed model improved the prioritization of functional variants of expression quantitative trait loci (eQTLs) compared with the state-of-the-art models. Full article

(This article belongs to the Special Issue Biocomputing and Synthetic Biology in Cells)

► Show Figures

Figure 1

15 pages, 2810 KB

Open AccessEditor’s ChoiceArticle

Sex Differences in High Fat Diet-Induced Metabolic Alterations Correlate with Changes in the Modulation of GRK2 Levels

by Alba C. Arcones, Marta Cruces-Sande, Paula Ramos, Federico Mayor and Cristina Murga

Cells 2019, 8(11), 1464; https://doi.org/10.3390/cells8111464 - 19 Nov 2019

Cited by 21 | Viewed by 7506

Abstract

A differential sex-related sensitivity has been reported in obesity and insulin resistance-related cardio-metabolic diseases, with a lower incidence of these pathologies being observed in young females when compared to age-matched males. However, such relative protection is lost with age. The mechanisms underlying such [...] Read more.

A differential sex-related sensitivity has been reported in obesity and insulin resistance-related cardio-metabolic diseases, with a lower incidence of these pathologies being observed in young females when compared to age-matched males. However, such relative protection is lost with age. The mechanisms underlying such sex and age-related changes in the susceptibility to diabetes and obesity are not fully understood. Herein, we report that the relative protection that is displayed by young female mice, as compared to male littermates, against some of the metabolic alterations that are induced by feeding a high fat diet (HFD), correlates with a lower upregulation of the protein levels of G protein-coupled receptor kinase (GRK2), which is a key regulator of both insulin and G protein-coupled receptor signaling, in the liver and adipose tissue. Interestingly, when the HFD is initiated in middle-aged (32 weeks) female mice, these animals are no longer protected and display a more overt obese and insulin-resistant phenotype, along with a more evident increase in the GRK2 protein levels in metabolically relevant tissues in such conditions. Our data suggest that GRK2 dosage might be involved in the sex and age-biased sensitivity to insulin resistance-related pathologies. Full article

(This article belongs to the Special Issue Emerging Paradigms of Insulin-Like Activities: From Pathophysiology to Targeted Therapy in Cancer and Diabetes)

► Show Figures

Figure 1

20 pages, 3414 KB

Open AccessFeature PaperEditor’s ChoiceReview

The Non-Canonical Aspects of MicroRNAs: Many Roads to Gene Regulation

by Christiaan J. Stavast and Stefan J. Erkeland

Cells 2019, 8(11), 1465; https://doi.org/10.3390/cells8111465 - 19 Nov 2019

Cited by 297 | Viewed by 12966

Abstract

MicroRNAs (miRNAs) are critical regulators of gene expression. As miRNAs are frequently deregulated in many human diseases, including cancer and immunological disorders, it is important to understand their biological functions. Typically, miRNA-encoding genes are transcribed by RNA Polymerase II and generate primary transcripts [...] Read more.

MicroRNAs (miRNAs) are critical regulators of gene expression. As miRNAs are frequently deregulated in many human diseases, including cancer and immunological disorders, it is important to understand their biological functions. Typically, miRNA-encoding genes are transcribed by RNA Polymerase II and generate primary transcripts that are processed by RNase III-endonucleases DROSHA and DICER into small RNAs of approximately 21 nucleotides. All miRNAs are loaded into Argonaute proteins in the RNA-induced silencing complex (RISC) and act as post-transcriptional regulators by binding to the 3′- untranslated region (UTR) of mRNAs. This seed-dependent miRNA binding inhibits the translation and/or promotes the degradation of mRNA targets. Surprisingly, recent data presents evidence for a target-mediated decay mechanism that controls the level of specific miRNAs. In addition, several non-canonical miRNA-containing genes have been recently described and unexpected functions of miRNAs have been identified. For instance, several miRNAs are located in the nucleus, where they are involved in the transcriptional activation or silencing of target genes. These epigenetic modifiers are recruited by RISC and guided by miRNAs to specific loci in the genome. Here, we will review non-canonical aspects of miRNA biology, including novel regulators of miRNA expression and functions of miRNAs in the nucleus. Full article

(This article belongs to the Collection Regulatory Functions of microRNAs)

► Show Figures

Figure 1

33 pages, 2540 KB

Open AccessEditor’s ChoiceReview

MicroRNAs Contribute to Breast Cancer Invasiveness

by Ivana Fridrichova and Iveta Zmetakova

Cells 2019, 8(11), 1361; https://doi.org/10.3390/cells8111361 - 31 Oct 2019

Cited by 130 | Viewed by 11090

Abstract

Cancer statistics in 2018 highlight an 8.6 million incidence in female cancers, and 4.2 million cancer deaths globally. Moreover, breast cancer is the most frequent malignancy in females and twenty percent of these develop metastasis. This provides only a small chance for successful [...] Read more.

Cancer statistics in 2018 highlight an 8.6 million incidence in female cancers, and 4.2 million cancer deaths globally. Moreover, breast cancer is the most frequent malignancy in females and twenty percent of these develop metastasis. This provides only a small chance for successful therapy, and identification of new molecular markers for the diagnosis and prognostic prediction of metastatic disease and development of innovative therapeutic molecules are therefore urgently required. Differentially expressed microRNAs (miRNAs) in cancers cause multiple changes in the expression of the tumorigenesis-promoting genes which have mostly been investigated in breast cancers. Herein, we summarize recent data on breast cancer-specific miRNA expression profiles and their participation in regulating invasive processes, in association with changes in cytoskeletal structure, cell-cell adhesion junctions, cancer cell-extracellular matrix interactions, tumor microenvironments, epithelial-to-mesenchymal transitions and cancer cell stem abilities. We then focused on the epigenetic regulation of individual miRNAs and their modified interactions with other regulatory genes, and reviewed the function of miRNA isoforms and exosome-mediated miRNA transfer in cancer invasiveness. Although research into miRNA’s function in cancer is still ongoing, results herein contribute to improved metastatic cancer management. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Breast Cancer)

► Show Figures

Figure 1

20 pages, 3334 KB

Open AccessEditor’s ChoiceArticle

Improved Motor Nerve Regeneration by SIRT1/Hif1a-Mediated Autophagy

by David Romeo-Guitart, Tatiana Leiva-Rodriguez, Joaquim Forés and Caty Casas

Cells 2019, 8(11), 1354; https://doi.org/10.3390/cells8111354 - 30 Oct 2019

Cited by 34 | Viewed by 5989

Abstract

Complete restoring of functional connectivity between neurons or target tissue after traumatic lesions is still an unmet medical need. Using models of nerve axotomy and compression, we investigated the effect of autophagy induction by genetic and pharmacological manipulation on motor nerve regeneration. ATG5 [...] Read more.

Complete restoring of functional connectivity between neurons or target tissue after traumatic lesions is still an unmet medical need. Using models of nerve axotomy and compression, we investigated the effect of autophagy induction by genetic and pharmacological manipulation on motor nerve regeneration. ATG5 or NAD⁺-dependent deacetylase sirtuin-1 (SIRT1) overexpression on spinal motoneurons stimulates mTOR-independent autophagy and facilitates a growth-competent state improving motor axonal regeneration with better electromyographic records after nerve transection and suture. In agreement with this, using organotypic spinal cord cultures and the human cell line SH-SY5Y, we observed that the activation of SIRT1 and autophagy by NeuroHeal increased neurite outgrowth and length extension and that this was mediated by downstream HIF1a. To conclude, SIRT1/Hifα-dependent autophagy confers a more pro-regenerative phenotype to motoneurons after peripheral nerve injury. Altogether, we provide evidence showing that autophagy induction by SIRT1/Hifα activation or NeuroHeal treatment is a novel therapeutic option for improving motor nerve regeneration and functional recovery after injury. Full article

(This article belongs to the Section Autophagy)

► Show Figures

Figure 1

22 pages, 2112 KB

Open AccessFeature PaperEditor’s ChoiceReview

Control of Protein Homeostasis in the Early Secretory Pathway: Current Status and Challenges

by Daria Sicari, Aeid Igbaria and Eric Chevet

Cells 2019, 8(11), 1347; https://doi.org/10.3390/cells8111347 - 29 Oct 2019

Cited by 31 | Viewed by 11341

Abstract

Discrimination between properly folded proteins and those that do not reach this state is necessary for cells to achieve functionality. Eukaryotic cells have evolved several mechanisms to ensure secretory protein quality control, which allows efficiency and fidelity in protein production. Among the actors [...] Read more.

Discrimination between properly folded proteins and those that do not reach this state is necessary for cells to achieve functionality. Eukaryotic cells have evolved several mechanisms to ensure secretory protein quality control, which allows efficiency and fidelity in protein production. Among the actors involved in such process, both endoplasmic reticulum (ER) and the Golgi complex play prominent roles in protein synthesis, biogenesis and secretion. ER and Golgi functions ensure that only properly folded proteins are allowed to flow through the secretory pathway while improperly folded proteins have to be eliminated to not impinge on cellular functions. Thus, complex quality control and degradation machineries are crucial to prevent the toxic accumulation of improperly folded proteins. However, in some instances, improperly folded proteins can escape the quality control systems thereby contributing to several human diseases. Herein, we summarize how the early secretory pathways copes with the accumulation of improperly folded proteins, and how insufficient handling can cause the development of several human diseases. Finally, we detail the genetic and pharmacologic approaches that could be used as potential therapeutic tools to treat these diseases. Full article

(This article belongs to the Special Issue Membrane Traffic in Health and Disease)

► Show Figures

Figure 1

15 pages, 3111 KB

Open AccessEditor’s ChoiceArticle

4mCpred-EL: An Ensemble Learning Framework for Identification of DNA N⁴-Methylcytosine Sites in the Mouse Genome

by Balachandran Manavalan, Shaherin Basith, Tae Hwan Shin, Da Yeon Lee, Leyi Wei and Gwang Lee

Cells 2019, 8(11), 1332; https://doi.org/10.3390/cells8111332 - 28 Oct 2019

Cited by 89 | Viewed by 5312

Abstract

DNA N⁴-methylcytosine (4mC) is one of the key epigenetic alterations, playing essential roles in DNA replication, differentiation, cell cycle, and gene expression. To better understand 4mC biological functions, it is crucial to gain knowledge on its genomic distribution. In recent times, [...] Read more.

DNA N⁴-methylcytosine (4mC) is one of the key epigenetic alterations, playing essential roles in DNA replication, differentiation, cell cycle, and gene expression. To better understand 4mC biological functions, it is crucial to gain knowledge on its genomic distribution. In recent times, few computational studies, in particular machine learning (ML) approaches have been applied in the prediction of 4mC site predictions. Although ML-based methods are promising for 4mC identification in other species, none are available for detecting 4mCs in the mouse genome. Our novel computational approach, called 4mCpred-EL, is the first method for identifying 4mC sites in the mouse genome where four different ML algorithms with a wide range of seven feature encodings are utilized. Subsequently, those feature encodings predicted probabilistic values are used as a feature vector and are once again inputted to ML algorithms, whose corresponding models are integrated into ensemble learning. Our benchmarking results demonstrated that 4mCpred-EL achieved an accuracy and MCC values of 0.795 and 0.591, which significantly outperformed seven other classifiers by more than 1.5–5.9% and 3.2–11.7%, respectively. Additionally, 4mCpred-EL attained an overall accuracy of 79.80%, which is 1.8–5.1% higher than that yielded by seven other classifiers in the independent evaluation. We provided a user-friendly web server, namely 4mCpred-EL which could be implemented as a pre-screening tool for the identification of potential 4mC sites in the mouse genome. Full article

(This article belongs to the Special Issue Biocomputing and Synthetic Biology in Cells)

► Show Figures

Graphical abstract

14 pages, 3059 KB

Open AccessEditor’s ChoiceArticle

Dental Epithelial Stem Cells as a Source for Mammary Gland Regeneration and Milk Producing Cells In Vivo

by Lucia Jimenez-Rojo, Pierfrancesco Pagella, Hidemitsu Harada and Thimios A. Mitsiadis

Cells 2019, 8(10), 1302; https://doi.org/10.3390/cells8101302 - 22 Oct 2019

Cited by 11 | Viewed by 32877

Abstract

The continuous growth of rodent incisors is ensured by clusters of mesenchymal and epithelial stem cells that are located at the posterior part of these teeth. Genetic lineage tracing studies have shown that dental epithelial stem cells (DESCs) are able to generate all [...] Read more.

The continuous growth of rodent incisors is ensured by clusters of mesenchymal and epithelial stem cells that are located at the posterior part of these teeth. Genetic lineage tracing studies have shown that dental epithelial stem cells (DESCs) are able to generate all epithelial cell populations within incisors during homeostasis. However, it remains unclear whether these cells have the ability to adopt alternative fates in response to extrinsic factors. Here, we have studied the plasticity of DESCs in the context of mammary gland regeneration. Transplantation of DESCs together with mammary epithelial cells into the mammary stroma resulted in the formation of chimeric ductal epithelial structures in which DESCs adopted all the possible mammary fates including milk-producing alveolar cells. In addition, when transplanted without mammary epithelial cells, DESCs developed branching rudiments and cysts. These in vivo findings demonstrate that when outside their niche, DESCs redirect their fates according to their new microenvironment and thus can contribute to the regeneration of non-dental tissues. Full article

(This article belongs to the Special Issue Stem Cell Therapy in Oral and Maxillofacial Region)

► Show Figures

Figure 1

21 pages, 19459 KB

Open AccessEditor’s ChoiceArticle

Exosome Treatment Enhances Anti-Inflammatory M2 Macrophages and Reduces Inflammation-Induced Pyroptosis in Doxorubicin-Induced Cardiomyopathy

by Dinender K. Singla, Taylor A. Johnson and Zahra Tavakoli Dargani

Cells 2019, 8(10), 1224; https://doi.org/10.3390/cells8101224 - 9 Oct 2019

Cited by 164 | Viewed by 12595

Abstract

Doxorubicin (Dox) is an effective antineoplastic agent used to treat cancers, but its use is limited as Dox induces adverse cardiotoxic effects. Dox-induced cardiotoxicity (DIC) can lead to heart failure and death. There is no study that investigates whether embryonic stem cell-derived exosomes [...] Read more.

Doxorubicin (Dox) is an effective antineoplastic agent used to treat cancers, but its use is limited as Dox induces adverse cardiotoxic effects. Dox-induced cardiotoxicity (DIC) can lead to heart failure and death. There is no study that investigates whether embryonic stem cell-derived exosomes (ES-Exos) in DIC can attenuate inflammation-induced pyroptosis, pro-inflammatory M1 macrophages, inflammatory cell signaling, and adverse cardiac remodeling. For this purpose, we transplanted ES-Exos and compared with ES-cells (ESCs) to examine pyroptosis, inflammation, cell signaling, adverse cardiac remodeling, and their influence on DIC induced cardiac dysfunction. Therefore, we used C57BL/6J mice ages 10 ± 2 weeks and divided them into four groups (n = 6–8/group): Control, Dox, Dox + ESCs, and Dox + ES-Exos. Our data shows that the Dox treatment significantly increased expression of inflammasome markers (TLR4 and NLRP3), pyroptotic markers (caspase-1, IL1-β, and IL-18), cell signaling proteins (MyD88, p-P38, and p-JNK), pro-inflammatory M1 macrophages, and TNF-α cytokine. This increased pyroptosis, inflammation, and cell signaling proteins were inhibited with ES-Exos or ESCs. Moreover, ES-Exos or ESCs increased M2 macrophages and anti-inflammatory cytokine, IL-10. Additionally, ES-Exos or ESCs treatment inhibited significantly cytoplasmic vacuolization, myofibril loss, hypertrophy, and improved heart function. In conclusion, for the first time we demonstrated that Dox-induced pyroptosis and cardiac remodeling are ameliorated by ES-Exos or ESCs. Full article

(This article belongs to the Special Issue Cells in Cardiovascular Disease)

► Show Figures

Graphical abstract

10 pages, 1359 KB

Open AccessFeature PaperEditor’s ChoiceReview

“Hierarchy” and “Holacracy”; A Paradigm of the Hematopoietic System

by Takafumi Yokota

Cells 2019, 8(10), 1138; https://doi.org/10.3390/cells8101138 - 24 Sep 2019

Cited by 14 | Viewed by 10324

Abstract

The mammalian hematopoietic system has long been viewed as a hierarchical paradigm in which a small number of hematopoietic stem cells (HSCs) are located at the apex. HSCs were traditionally thought to be homogeneous and quiescent in a homeostatic state. However, recent observations, [...] Read more.

The mammalian hematopoietic system has long been viewed as a hierarchical paradigm in which a small number of hematopoietic stem cells (HSCs) are located at the apex. HSCs were traditionally thought to be homogeneous and quiescent in a homeostatic state. However, recent observations, through extramedullary hematopoiesis and clonal assays, have cast doubt on the validity of the conventional interpretation. A key issue is understanding the characteristics of HSCs from different viewpoints, including dynamic physics and social network theory. The aim of this literature review is to propose a new paradigm of our hematopoietic system, in which individual HSCs are actively involved. Full article

(This article belongs to the Special Issue Hematopoiesis and Stem Cells)

► Show Figures

Figure 1

33 pages, 2337 KB

Open AccessEditor’s ChoiceReview

The E-Cadherin and N-Cadherin Switch in Epithelial-to-Mesenchymal Transition: Signaling, Therapeutic Implications, and Challenges

by Chin-Yap Loh, Jian Yi Chai, Ting Fang Tang, Won Fen Wong, Gautam Sethi, Muthu Kumaraswamy Shanmugam, Pei Pei Chong and Chung Yeng Looi

Cells 2019, 8(10), 1118; https://doi.org/10.3390/cells8101118 - 20 Sep 2019

Cited by 1005 | Viewed by 47013

Abstract

Epithelial-to-Mesenchymal Transition (EMT) has been shown to be crucial in tumorigenesis where the EMT program enhances metastasis, chemoresistance and tumor stemness. Due to its emerging role as a pivotal driver of tumorigenesis, targeting EMT is of great therapeutic interest in counteracting metastasis and [...] Read more.

Epithelial-to-Mesenchymal Transition (EMT) has been shown to be crucial in tumorigenesis where the EMT program enhances metastasis, chemoresistance and tumor stemness. Due to its emerging role as a pivotal driver of tumorigenesis, targeting EMT is of great therapeutic interest in counteracting metastasis and chemoresistance in cancer patients. The hallmark of EMT is the upregulation of N-cadherin followed by the downregulation of E-cadherin, and this process is regulated by a complex network of signaling pathways and transcription factors. In this review, we summarized the recent understanding of the roles of E- and N-cadherins in cancer invasion and metastasis as well as the crosstalk with other signaling pathways involved in EMT. We also highlighted a few natural compounds with potential anti-EMT property and outlined the future directions in the development of novel intervention in human cancer treatments. We have reviewed 287 published papers related to this topic and identified some of the challenges faced in translating the discovery work from bench to bedside. Full article

(This article belongs to the Special Issue The Multifaceted Nature of Epithelial to Mesenchymal Transition (EMT): From Embryonic Development to Cellular Plasticity in Normal Tissue and Tumors)

► Show Figures

Figure 1

28 pages, 1031 KB

Open AccessEditor’s ChoiceReview

FOXO3a from the Nucleus to the Mitochondria: A Round Trip in Cellular Stress Response

by Candida Fasano, Vittoria Disciglio, Stefania Bertora, Martina Lepore Signorile and Cristiano Simone

Cells 2019, 8(9), 1110; https://doi.org/10.3390/cells8091110 - 19 Sep 2019

Cited by 171 | Viewed by 19807

Abstract

Cellular stress response is a universal mechanism that ensures the survival or negative selection of cells in challenging conditions. The transcription factor Forkhead box protein O3 (FOXO3a) is a core regulator of cellular homeostasis, stress response, and longevity since it can modulate a [...] Read more.

Cellular stress response is a universal mechanism that ensures the survival or negative selection of cells in challenging conditions. The transcription factor Forkhead box protein O3 (FOXO3a) is a core regulator of cellular homeostasis, stress response, and longevity since it can modulate a variety of stress responses upon nutrient shortage, oxidative stress, hypoxia, heat shock, and DNA damage. FOXO3a activity is regulated by post-translational modifications that drive its shuttling between different cellular compartments, thereby determining its inactivation (cytoplasm) or activation (nucleus and mitochondria). Depending on the stress stimulus and subcellular context, activated FOXO3a can induce specific sets of nuclear genes, including cell cycle inhibitors, pro-apoptotic genes, reactive oxygen species (ROS) scavengers, autophagy effectors, gluconeogenic enzymes, and others. On the other hand, upon glucose restriction, 5′-AMP-activated protein kinase (AMPK) and mitogen activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) -dependent FOXO3a mitochondrial translocation allows the transcription of oxidative phosphorylation (OXPHOS) genes, restoring cellular ATP levels, while in cancer cells, mitochondrial FOXO3a mediates survival upon genotoxic stress induced by chemotherapy. Interestingly, these target genes and their related pathways are diverse and sometimes antagonistic, suggesting that FOXO3a is an adaptable player in the dynamic homeostasis of normal and stressed cells. In this review, we describe the multiple roles of FOXO3a in cellular stress response, with a focus on both its nuclear and mitochondrial functions. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Stress Responses)

► Show Figures

Graphical abstract

35 pages, 1887 KB

Open AccessEditor’s ChoiceReview

Trends and Challenges in Tumor Anti-Angiogenic Therapies

by József Jászai and Mirko H.H. Schmidt

Cells 2019, 8(9), 1102; https://doi.org/10.3390/cells8091102 - 18 Sep 2019

Cited by 174 | Viewed by 17120

Abstract

Excessive abnormal angiogenesis plays a pivotal role in tumor progression and is a hallmark of solid tumors. This process is driven by an imbalance between pro- and anti-angiogenic factors dominated by the tissue hypoxia-triggered overproduction of vascular endothelial growth factor (VEGF). VEGF-mediated signaling [...] Read more.

Excessive abnormal angiogenesis plays a pivotal role in tumor progression and is a hallmark of solid tumors. This process is driven by an imbalance between pro- and anti-angiogenic factors dominated by the tissue hypoxia-triggered overproduction of vascular endothelial growth factor (VEGF). VEGF-mediated signaling has quickly become one of the most promising anti-angiogenic therapeutic targets in oncology. Nevertheless, the clinical efficacy of this approach is severely limited in certain tumor types or shows only transient efficacy in patients. Acquired or intrinsic therapy resistance associated with anti-VEGF monotherapeutic approaches indicates the necessity of a paradigm change when targeting neoangiogenesis in solid tumors. In this context, the elaboration of the conceptual framework of “vessel normalization” might be a promising approach to increase the efficacy of anti-angiogenic therapies and the survival rates of patients. Indeed, the promotion of vessel maturation instead of regressing tumors by vaso-obliteration could result in reduced tumor hypoxia and improved drug delivery. The implementation of such anti-angiogenic strategies, however, faces several pitfalls due to the potential involvement of multiple pro-angiogenic factors and modulatory effects of the innate and adaptive immune system. Thus, effective treatments bypassing relapses associated with anti-VEGF monotherapies or breaking the intrinsic therapy resistance of solid tumors might use combination therapies or agents with a multimodal mode of action. This review enumerates some of the current approaches and possible future directions of treating solid tumors by targeting neovascularization. Full article

(This article belongs to the Special Issue Angiogenesis in Cancer)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Editor’s Choice Articles

Further Information

Guidelines

MDPI Initiatives

Follow MDPI