Editor’s Choice Articles

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

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23 pages, 6926 KiB  
Article
Neurological Enhancement Effects of Melatonin against Brain Injury-Induced Oxidative Stress, Neuroinflammation, and Neurodegeneration via AMPK/CREB Signaling
by Shafiq Ur Rehman, Muhammad Ikram, Najeeb Ullah, Sayed Ibrar Alam, Hyun Young Park, Haroon Badshah, Kyonghwan Choe and Myeong Ok Kim
Cells 2019, 8(7), 760; https://doi.org/10.3390/cells8070760 - 21 Jul 2019
Cited by 135 | Viewed by 11882
Abstract
Oxidative stress and energy imbalance strongly correlate in neurodegenerative diseases. Repeated concussion is becoming a serious public health issue with uncontrollable adverse effects in the human population, which involve cognitive dysfunction and even permanent disability. Here, we demonstrate that traumatic brain injury (TBI) [...] Read more.
Oxidative stress and energy imbalance strongly correlate in neurodegenerative diseases. Repeated concussion is becoming a serious public health issue with uncontrollable adverse effects in the human population, which involve cognitive dysfunction and even permanent disability. Here, we demonstrate that traumatic brain injury (TBI) evokes oxidative stress, disrupts brain energy homeostasis, and boosts neuroinflammation, which further contributes to neuronal degeneration and cognitive dysfunction in the mouse brain. We also demonstrate that melatonin (an anti-oxidant agent) treatment exerts neuroprotective effects, while overcoming oxidative stress and energy depletion and reducing neuroinflammation and neurodegeneration. Male C57BL/6N mice were used as a model for repetitive mild traumatic brain injury (rmTBI) and were treated with melatonin. Protein expressions were examined via Western blot analysis, immunofluorescence, and ELISA; meanwhile, behavior analysis was performed through a Morris water maze test, and Y-maze and beam-walking tests. We found elevated oxidative stress, depressed phospho-5′AMP-activated protein kinase (p-AMPK) and phospho- CAMP-response element-binding (p-CREB) levels, and elevated p-NF-κB in rmTBI mouse brains, while melatonin treatment significantly regulated p-AMPK, p-CREB, and p-NF-κB in the rmTBI mouse brain. Furthermore, rmTBI mouse brains showed a deregulated mitochondrial system, abnormal amyloidogenic pathway activation, and cognitive functions which were significantly regulated by melatonin treatment in the mice. These findings provide evidence, for the first time, that rmTBI induces brain energy imbalance and reduces neuronal cell survival, and that melatonin treatment overcomes energy depletion and protects against brain damage via the regulation of p-AMPK/p-CREB signaling pathways in the mouse brain. Full article
(This article belongs to the Special Issue Melatonin in Human Health and Diseases)
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26 pages, 4055 KiB  
Review
Targeting the Canonical WNT/β-Catenin Pathway in Cancer Treatment Using Non-Steroidal Anti-Inflammatory Drugs
by Alexandre Vallée, Yves Lecarpentier and Jean-Noël Vallée
Cells 2019, 8(7), 726; https://doi.org/10.3390/cells8070726 - 15 Jul 2019
Cited by 71 | Viewed by 9415
Abstract
Chronic inflammation and oxidative stress are common and co-substantial pathological processes accompanying and contributing to cancers. Numerous epidemiological studies have indicated that non-steroidal anti-inflammatory drugs (NSAIDs) could have a positive effect on both the prevention of cancer and tumor therapy. Numerous hypotheses have [...] Read more.
Chronic inflammation and oxidative stress are common and co-substantial pathological processes accompanying and contributing to cancers. Numerous epidemiological studies have indicated that non-steroidal anti-inflammatory drugs (NSAIDs) could have a positive effect on both the prevention of cancer and tumor therapy. Numerous hypotheses have postulated that NSAIDs could slow tumor growth by acting on both chronic inflammation and oxidative stress. This review takes a closer look at these hypotheses. In the cancer process, one of the major signaling pathways involved is the WNT/β-catenin pathway, which appears to be upregulated. This pathway is closely associated with both chronic inflammation and oxidative stress in cancers. The administration of NSAIDs has been observed to help in the downregulation of the WNT/β-catenin pathway and thus in the control of tumor growth. NSAIDs act as PPARγ agonists. The WNT/β-catenin pathway and PPARγ act in opposing manners. PPARγ agonists can promote cell cycle arrest, cell differentiation, and apoptosis, and can reduce inflammation, oxidative stress, proliferation, invasion, and cell migration. In parallel, the dysregulation of circadian rhythms (CRs) contributes to cancer development through the upregulation of the canonical WNT/β-catenin pathway. By stimulating PPARγ expression, NSAIDs can control CRs through the regulation of many key circadian genes. The administration of NSAIDs in cancer treatment would thus appear to be an interesting therapeutic strategy, which acts through their role in regulating WNT/β-catenin pathway and PPARγ activity levels. Full article
(This article belongs to the Special Issue Wnt Signaling in Health and Diseases)
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24 pages, 894 KiB  
Review
Overview of Extracellular Vesicles, Their Origin, Composition, Purpose, and Methods for Exosome Isolation and Analysis
by Laura M. Doyle and Michael Zhuo Wang
Cells 2019, 8(7), 727; https://doi.org/10.3390/cells8070727 - 15 Jul 2019
Cited by 1931 | Viewed by 49614
Abstract
The use of extracellular vesicles, specifically exosomes, as carriers of biomarkers in extracellular spaces has been well demonstrated. Despite their promising potential, the use of exosomes in the clinical setting is restricted due to the lack of standardization in exosome isolation and analysis [...] Read more.
The use of extracellular vesicles, specifically exosomes, as carriers of biomarkers in extracellular spaces has been well demonstrated. Despite their promising potential, the use of exosomes in the clinical setting is restricted due to the lack of standardization in exosome isolation and analysis methods. The purpose of this review is to not only introduce the different types of extracellular vesicles but also to summarize their differences and similarities, and discuss different methods of exosome isolation and analysis currently used. A thorough understanding of the isolation and analysis methods currently being used could lead to some standardization in the field of exosomal research, allowing the use of exosomes in the clinical setting to become a reality. Full article
(This article belongs to the Section Intracellular and Plasma Membranes)
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12 pages, 1143 KiB  
Review
Never Travel Alone: The Crosstalk of Circulating Tumor Cells and the Blood Microenvironment
by Simon Heeke, Baharia Mograbi, Catherine Alix-Panabières and Paul Hofman
Cells 2019, 8(7), 714; https://doi.org/10.3390/cells8070714 - 13 Jul 2019
Cited by 104 | Viewed by 8942
Abstract
Commonly, circulating tumor cells (CTCs) are described as source of metastasis in cancer patients. However, in this process cancer cells of the primary tumor site need to survive the physical and biological challenges in the blood stream before leaving the circulation to become [...] Read more.
Commonly, circulating tumor cells (CTCs) are described as source of metastasis in cancer patients. However, in this process cancer cells of the primary tumor site need to survive the physical and biological challenges in the blood stream before leaving the circulation to become the seed of a new metastatic site in distant parenchyma. Most of the CTCs released in the blood stream will not resist those challenges and will consequently fail to induce metastasis. A few of them, however, interact closely with other blood cells, such as neutrophils, platelets, and/or macrophages to survive in the blood stream. Recent studies demonstrated that the interaction and modulation of the blood microenvironment by CTCs is pivotal for the development of new metastasis, making it an interesting target for potential novel treatment strategies. This review will discuss the recent research on the processes in the blood microenvironment with CTCs and will outline currently investigated treatment strategies. Full article
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15 pages, 2106 KiB  
Article
Convolutional Neural Network and Bidirectional Long Short-Term Memory-Based Method for Predicting Drug–Disease Associations
by Ping Xuan, Yilin Ye, Tiangang Zhang, Lianfeng Zhao and Chang Sun
Cells 2019, 8(7), 705; https://doi.org/10.3390/cells8070705 - 11 Jul 2019
Cited by 40 | Viewed by 4767
Abstract
Identifying novel indications for approved drugs can accelerate drug development and reduce research costs. Most previous studies used shallow models for prioritizing the potential drug-related diseases and failed to deeply integrate the paths between drugs and diseases which may contain additional association information. [...] Read more.
Identifying novel indications for approved drugs can accelerate drug development and reduce research costs. Most previous studies used shallow models for prioritizing the potential drug-related diseases and failed to deeply integrate the paths between drugs and diseases which may contain additional association information. A deep-learning-based method for predicting drug–disease associations by integrating useful information is needed. We proposed a novel method based on a convolutional neural network (CNN) and bidirectional long short-term memory (BiLSTM)—CBPred—for predicting drug-related diseases. Our method deeply integrates similarities and associations between drugs and diseases, and paths among drug-disease pairs. The CNN-based framework focuses on learning the original representation of a drug-disease pair from their similarities and associations. As the drug-disease association possibility also depends on the multiple paths between them, the BiLSTM-based framework mainly learns the path representation of the drug-disease pair. In addition, considering that different paths have discriminate contributions to the association prediction, an attention mechanism at path level is constructed. Our method, CBPred, showed better performance and retrieved more real associations in the front of the results, which is more important for biologists. Case studies further confirmed that CBPred can discover potential drug-disease associations. Full article
(This article belongs to the Special Issue Biocomputing and Synthetic Biology in Cells)
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25 pages, 2238 KiB  
Review
Mitochondrial Homeostasis and Cellular Senescence
by Panagiotis V.S. Vasileiou, Konstantinos Evangelou, Konstantinos Vlasis, Georgios Fildisis, Mihalis I. Panayiotidis, Efstathios Chronopoulos, Panagiotis-Georgios Passias, Mirsini Kouloukoussa, Vassilis G. Gorgoulis and Sophia Havaki
Cells 2019, 8(7), 686; https://doi.org/10.3390/cells8070686 - 6 Jul 2019
Cited by 163 | Viewed by 11261
Abstract
Cellular senescence refers to a stress response aiming to preserve cellular and, therefore, organismal homeostasis. Importantly, deregulation of mitochondrial homeostatic mechanisms, manifested as impaired mitochondrial biogenesis, metabolism and dynamics, has emerged as a hallmark of cellular senescence. On the other hand, impaired mitostasis [...] Read more.
Cellular senescence refers to a stress response aiming to preserve cellular and, therefore, organismal homeostasis. Importantly, deregulation of mitochondrial homeostatic mechanisms, manifested as impaired mitochondrial biogenesis, metabolism and dynamics, has emerged as a hallmark of cellular senescence. On the other hand, impaired mitostasis has been suggested to induce cellular senescence. This review aims to provide an overview of homeostatic mechanisms operating within mitochondria and a comprehensive insight into the interplay between cellular senescence and mitochondrial dysfunction. Full article
(This article belongs to the Section Intracellular and Plasma Membranes)
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23 pages, 1737 KiB  
Review
Melatonin in Medicinal and Food Plants: Occurrence, Bioavailability, and Health Potential for Humans
by Bahare Salehi, Farukh Sharopov, Patrick Valere Tsouh Fokou, Agnieszka Kobylinska, Lilian de Jonge, Kathryn Tadio, Javad Sharifi-Rad, Malgorzata M. Posmyk, Miquel Martorell, Natália Martins and Marcello Iriti
Cells 2019, 8(7), 681; https://doi.org/10.3390/cells8070681 - 5 Jul 2019
Cited by 123 | Viewed by 17101
Abstract
Melatonin is a widespread molecule among living organisms involved in multiple biological, hormonal, and physiological processes at cellular, tissue, and organic levels. It is well-known for its ability to cross the blood–brain barrier, and renowned antioxidant effects, acting as a free radical scavenger, [...] Read more.
Melatonin is a widespread molecule among living organisms involved in multiple biological, hormonal, and physiological processes at cellular, tissue, and organic levels. It is well-known for its ability to cross the blood–brain barrier, and renowned antioxidant effects, acting as a free radical scavenger, up-regulating antioxidant enzymes, reducing mitochondrial electron leakage, and interfering with proinflammatory signaling pathways. Detected in various medicinal and food plants, its concentration is widely variable. Plant generative organs (e.g., flowers, fruits), and especially seeds, have been proposed as having the highest melatonin concentrations, markedly higher than those found in vertebrate tissues. In addition, seeds are also rich in other substances (lipids, sugars, and proteins), constituting the energetic reserve for a potentially growing seedling and beneficial for the human diet. Thus, given that dietary melatonin is absorbed in the gastrointestinal tract and transported into the bloodstream, the ingestion of medicinal and plant foods by mammals as a source of melatonin may be conceived as a key step in serum melatonin modulation and, consequently, health promotion. Full article
(This article belongs to the Special Issue Melatonin in Human Health and Diseases)
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35 pages, 2870 KiB  
Review
Myasthenia Gravis: Pathogenic Effects of Autoantibodies on Neuromuscular Architecture
by Inga Koneczny and Ruth Herbst
Cells 2019, 8(7), 671; https://doi.org/10.3390/cells8070671 - 2 Jul 2019
Cited by 106 | Viewed by 14744
Abstract
Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction (NMJ). Autoantibodies target key molecules at the NMJ, such as the nicotinic acetylcholine receptor (AChR), muscle-specific kinase (MuSK), and low-density lipoprotein receptor-related protein 4 (Lrp4), that lead by a range of different [...] Read more.
Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction (NMJ). Autoantibodies target key molecules at the NMJ, such as the nicotinic acetylcholine receptor (AChR), muscle-specific kinase (MuSK), and low-density lipoprotein receptor-related protein 4 (Lrp4), that lead by a range of different pathogenic mechanisms to altered tissue architecture and reduced densities or functionality of AChRs, reduced neuromuscular transmission, and therefore a severe fatigable skeletal muscle weakness. In this review, we give an overview of the history and clinical aspects of MG, with a focus on the structure and function of myasthenic autoantigens at the NMJ and how they are affected by the autoantibodies’ pathogenic mechanisms. Furthermore, we give a short overview of the cells that are implicated in the production of the autoantibodies and briefly discuss diagnostic challenges and treatment strategies. Full article
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16 pages, 2872 KiB  
Article
Prognostic Significance of TWIST1, CD24, CD44, and ALDH1 Transcript Quantification in EpCAM-Positive Circulating Tumor Cells from Early Stage Breast Cancer Patients
by Areti Strati, Michail Nikolaou, Vassilis Georgoulias and Evi S. Lianidou
Cells 2019, 8(7), 652; https://doi.org/10.3390/cells8070652 - 29 Jun 2019
Cited by 44 | Viewed by 6025
Abstract
(1) Background: The aim of the study was to evaluate the prognostic significance of EMT-associated (TWIST1) and stem-cell (SC) transcript (CD24, CD44, ALDH1) quantification in EpCAM+ circulating tumor cells (CTCs) of early breast cancer patients. (2) Methods: 100 [...] Read more.
(1) Background: The aim of the study was to evaluate the prognostic significance of EMT-associated (TWIST1) and stem-cell (SC) transcript (CD24, CD44, ALDH1) quantification in EpCAM+ circulating tumor cells (CTCs) of early breast cancer patients. (2) Methods: 100 early stage breast cancer patients and 19 healthy donors were enrolled in the study. CD24, CD44, and ALDH1 transcripts of EpCAM+ cells were quantified using a novel highly sensitive and specific quadraplex RT-qPCR, while TWIST1 transcripts were quantified by single RT-qPCR. All patients were followed up for more than 5 years. (3) Results: A significant positive correlation between overexpression of TWIST1 and CD24−/low/CD44high profile was found. Kaplan–Meier analysis revealed that the ER/PR-negative (HR-) patients and those patients with more than 3 positive lymph nodes that overexpressed TWIST1 in EpCAM+ cells had a significant lower DFI (log rank test; p < 0.001, p < 0.001) and OS (log rank test; p = 0.006, p < 0.001). Univariate and multivariate analysis also revealed the prognostic value of TWIST1 overexpression and CD24−/low/CD44high and CD24−/low/ALDH1high profile for both DFI and OS. (4) Conclusions: Detection of TWIST1 overexpression and stem-cell (CD24, CD44, ALDH1) transcripts in EpCAM+ CTCs provides prognostic information in early stage breast cancer patients. Full article
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17 pages, 597 KiB  
Review
Patient-Derived Xenograft Models of Breast Cancer and Their Application
by Takahiko Murayama and Noriko Gotoh
Cells 2019, 8(6), 621; https://doi.org/10.3390/cells8060621 - 20 Jun 2019
Cited by 95 | Viewed by 13346
Abstract
Recently, patient-derived xenograft (PDX) models of many types of tumors including breast cancer have emerged as a powerful tool for predicting drug efficacy and for understanding tumor characteristics. PDXs are established by the direct transfer of human tumors into highly immunodeficient mice and [...] Read more.
Recently, patient-derived xenograft (PDX) models of many types of tumors including breast cancer have emerged as a powerful tool for predicting drug efficacy and for understanding tumor characteristics. PDXs are established by the direct transfer of human tumors into highly immunodeficient mice and then maintained by passaging from mouse to mouse. The ability of PDX models to maintain the original features of patient tumors and to reflect drug sensitivity has greatly improved both basic and clinical study outcomes. However, current PDX models cannot completely predict drug efficacy because they do not recapitulate the tumor microenvironment of origin, a failure which puts emphasis on the necessity for the development of the next generation PDX models. In this article, we summarize the advantages and limitations of current PDX models and discuss the future directions of this field. Full article
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22 pages, 1334 KiB  
Review
Regulation of TEAD Transcription Factors in Cancer Biology
by Hyunbin D. Huh, Dong Hyeon Kim, Han-Sol Jeong and Hyun Woo Park
Cells 2019, 8(6), 600; https://doi.org/10.3390/cells8060600 - 17 Jun 2019
Cited by 165 | Viewed by 17658
Abstract
Transcriptional enhanced associate domain (TEAD) transcription factors play important roles during development, cell proliferation, regeneration, and tissue homeostasis. TEAD integrates with and coordinates various signal transduction pathways including Hippo, Wnt, transforming growth factor beta (TGFβ), and epidermal growth factor receptor (EGFR) pathways. TEAD [...] Read more.
Transcriptional enhanced associate domain (TEAD) transcription factors play important roles during development, cell proliferation, regeneration, and tissue homeostasis. TEAD integrates with and coordinates various signal transduction pathways including Hippo, Wnt, transforming growth factor beta (TGFβ), and epidermal growth factor receptor (EGFR) pathways. TEAD deregulation affects well-established cancer genes such as KRAS, BRAF, LKB1, NF2, and MYC, and its transcriptional output plays an important role in tumor progression, metastasis, cancer metabolism, immunity, and drug resistance. To date, TEADs have been recognized to be key transcription factors of the Hippo pathway. Therefore, most studies are focused on the Hippo kinases and YAP/TAZ, whereas the Hippo-dependent and Hippo-independent regulators and regulations governing TEAD only emerged recently. Deregulation of the TEAD transcriptional output plays important roles in tumor progression and serves as a prognostic biomarker due to high correlation with clinicopathological parameters in human malignancies. In addition, discovering the molecular mechanisms of TEAD, such as post-translational modifications and nucleocytoplasmic shuttling, represents an important means of modulating TEAD transcriptional activity. Collectively, this review highlights the role of TEAD in multistep-tumorigenesis by interacting with upstream oncogenic signaling pathways and controlling downstream target genes, which provides unprecedented insight and rationale into developing TEAD-targeted anticancer therapeutics. Full article
(This article belongs to the Special Issue Disease and the Hippo Pathway: Cellular and Molecular Mechanisms)
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20 pages, 1329 KiB  
Review
Genome Organization in and around the Nucleolus
by Cristiana Bersaglieri and Raffaella Santoro
Cells 2019, 8(6), 579; https://doi.org/10.3390/cells8060579 - 12 Jun 2019
Cited by 80 | Viewed by 10755
Abstract
The nucleolus is the largest substructure in the nucleus, where ribosome biogenesis takes place, and forms around the nucleolar organizer regions (NORs) that comprise ribosomal RNA (rRNA) genes. Each cell contains hundreds of rRNA genes, which are organized in three distinct chromatin and [...] Read more.
The nucleolus is the largest substructure in the nucleus, where ribosome biogenesis takes place, and forms around the nucleolar organizer regions (NORs) that comprise ribosomal RNA (rRNA) genes. Each cell contains hundreds of rRNA genes, which are organized in three distinct chromatin and transcriptional states—silent, inactive and active. Increasing evidence indicates that the role of the nucleolus and rRNA genes goes beyond the control of ribosome biogenesis. Recent results highlighted the nucleolus as a compartment for the location and regulation of repressive genomic domains and, together with the nuclear lamina, represents the hub for the organization of the inactive heterochromatin. In this review, we aim to describe the crosstalk between the nucleolus and the rest of the genome and how distinct rRNA gene chromatin states affect nucleolus structure and are implicated in genome stability, genome architecture, and cell fate decision. Full article
(This article belongs to the Special Issue Nucleolar Organization and Functions in Health and Disease)
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21 pages, 1246 KiB  
Review
Insights on CTC Biology and Clinical Impact Emerging from Advances in Capture Technology
by Patrick C. Bailey and Stuart S. Martin
Cells 2019, 8(6), 553; https://doi.org/10.3390/cells8060553 - 6 Jun 2019
Cited by 39 | Viewed by 10100
Abstract
Circulating tumor cells (CTCs) and circulating tumor microemboli (CTM) have been shown to correlate negatively with patient survival. Actual CTC counts before and after treatment can be used to aid in the prognosis of patient outcomes. The presence of circulating tumor materials (CTMat) [...] Read more.
Circulating tumor cells (CTCs) and circulating tumor microemboli (CTM) have been shown to correlate negatively with patient survival. Actual CTC counts before and after treatment can be used to aid in the prognosis of patient outcomes. The presence of circulating tumor materials (CTMat) can advertise the presence of metastasis before clinical presentation, enabling the early detection of relapse. Importantly, emerging evidence is indicating that cancer treatments can actually increase the incidence of CTCs and metastasis in pre-clinical models. Subsequently, the study of CTCs, their biology and function are of vital importance. Emerging technologies for the capture of CTC/CTMs and CTMat are elucidating vitally important biological and functional information that can lead to important alterations in how therapies are administered. This paves the way for the development of a “liquid biopsy” where treatment decisions can be informed by information gleaned from tumor cells and tumor cell debris in the blood. Full article
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21 pages, 1769 KiB  
Review
Glycosylation in the Tumor Microenvironment: Implications for Tumor Angiogenesis and Metastasis
by Kevin Brown Chandler, Catherine E. Costello and Nader Rahimi
Cells 2019, 8(6), 544; https://doi.org/10.3390/cells8060544 - 5 Jun 2019
Cited by 81 | Viewed by 8098
Abstract
Just as oncogene activation and tumor suppressor loss are hallmarks of tumor development, emerging evidence indicates that tumor microenvironment-mediated changes in glycosylation play a crucial functional role in tumor progression and metastasis. Hypoxia and inflammatory events regulate protein glycosylation in tumor cells and [...] Read more.
Just as oncogene activation and tumor suppressor loss are hallmarks of tumor development, emerging evidence indicates that tumor microenvironment-mediated changes in glycosylation play a crucial functional role in tumor progression and metastasis. Hypoxia and inflammatory events regulate protein glycosylation in tumor cells and associated stromal cells in the tumor microenvironment, which facilitates tumor progression and also modulates a patient’s response to anti-cancer therapeutics. In this review, we highlight the impact of altered glycosylation on angiogenic signaling and endothelial cell adhesion, and the critical consequences of these changes in tumor behavior. Full article
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24 pages, 3377 KiB  
Review
Recent Data on Cellular Component Turnover: Focus on Adaptations to Physical Exercise
by Anthony MJ Sanchez, Robin Candau and Henri Bernardi
Cells 2019, 8(6), 542; https://doi.org/10.3390/cells8060542 - 5 Jun 2019
Cited by 33 | Viewed by 8582
Abstract
Significant progress has expanded our knowledge of the signaling pathways coordinating muscle protein turnover during various conditions including exercise. In this manuscript, the multiple mechanisms that govern the turnover of cellular components are reviewed, and their overall roles in adaptations to exercise training [...] Read more.
Significant progress has expanded our knowledge of the signaling pathways coordinating muscle protein turnover during various conditions including exercise. In this manuscript, the multiple mechanisms that govern the turnover of cellular components are reviewed, and their overall roles in adaptations to exercise training are discussed. Recent studies have highlighted the central role of the energy sensor (AMP)-activated protein kinase (AMPK), forkhead box class O subfamily protein (FOXO) transcription factors and the kinase mechanistic (or mammalian) target of rapamycin complex (MTOR) in the regulation of autophagy for organelle maintenance during exercise. A new cellular trafficking involving the lysosome was also revealed for full activation of MTOR and protein synthesis during recovery. Other emerging candidates have been found to be relevant in organelle turnover, especially Parkin and the mitochondrial E3 ubiquitin protein ligase (Mul1) pathways for mitochondrial turnover, and the glycerolipids diacylglycerol (DAG) for protein translation and FOXO regulation. Recent experiments with autophagy and mitophagy flux assessment have also provided important insights concerning mitochondrial turnover during ageing and chronic exercise. However, data in humans are often controversial and further investigations are needed to clarify the involvement of autophagy in exercise performed with additional stresses, such as hypoxia, and to understand the influence of exercise modality. Improving our knowledge of these pathways should help develop therapeutic ways to counteract muscle disorders in pathological conditions. Full article
(This article belongs to the Special Issue Autophagy in Tissue Injury and Homeostasis)
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18 pages, 3066 KiB  
Article
Fecal Microbiota Transplantation Controls Murine Chronic Intestinal Inflammation by Modulating Immune Cell Functions and Gut Microbiota Composition
by Claudia Burrello, Maria Rita Giuffrè, Angeli Dominique Macandog, Angelica Diaz-Basabe, Fulvia Milena Cribiù, Gianluca Lopez, Francesca Borgo, Luigi Nezi, Flavio Caprioli, Maurizio Vecchi and Federica Facciotti
Cells 2019, 8(6), 517; https://doi.org/10.3390/cells8060517 - 28 May 2019
Cited by 54 | Viewed by 8073
Abstract
Different gastrointestinal disorders, including inflammatory bowel diseases (IBD), have been linked to alterations of the gut microbiota composition, namely dysbiosis. Fecal microbiota transplantation (FMT) is considered an encouraging therapeutic approach for ulcerative colitis patients, mostly as a consequence of normobiosis restoration. We recently [...] Read more.
Different gastrointestinal disorders, including inflammatory bowel diseases (IBD), have been linked to alterations of the gut microbiota composition, namely dysbiosis. Fecal microbiota transplantation (FMT) is considered an encouraging therapeutic approach for ulcerative colitis patients, mostly as a consequence of normobiosis restoration. We recently showed that therapeutic effects of FMT during acute experimental colitis are linked to functional modulation of the mucosal immune system and of the gut microbiota composition. Here we analysed the effects of therapeutic FMT administration during chronic experimental colitis, a condition more similar to that of IBD patients, on immune-mediated mucosal inflammatory pathways. Mucus and feces from normobiotic donors were orally administered to mice with established chronic Dextran Sodium Sulphate (DSS)-induced colitis. Immunophenotypes and functions of infiltrating colonic immune cells were evaluated by cytofluorimetric analysis. Compositional differences in the intestinal microbiome were analyzed by 16S rRNA sequencing. Therapeutic FMT in mice undergoing chronic intestinal inflammation was capable to decrease colonic inflammation by modulating the expression of pro-inflammatory genes, antimicrobial peptides, and mucins. Innate and adaptive mucosal immune cells manifested a reduced pro-inflammatory profile in FMT-treated mice. Finally, restoration of a normobiotic core ecology contributed to the resolution of inflammation. Thus, FMT is capable of controlling chronic intestinal experimental colitis by inducing a concerted activation of anti-inflammatory immune pathways, mechanistically supporting the positive results of FMT treatment reported in ulcerative colitis patients. Full article
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17 pages, 941 KiB  
Review
Current Status of Patient-Derived Ovarian Cancer Models
by Yoshiaki Maru and Yoshitaka Hippo
Cells 2019, 8(5), 505; https://doi.org/10.3390/cells8050505 - 25 May 2019
Cited by 74 | Viewed by 8079
Abstract
Ovarian cancer (OC) is one of the leading causes of female cancer death. Recent studies have documented its extensive variations as a disease entity, in terms of cell or tissue of origin, pre-cancerous lesions, common mutations, and therapeutic responses, leading to the notion [...] Read more.
Ovarian cancer (OC) is one of the leading causes of female cancer death. Recent studies have documented its extensive variations as a disease entity, in terms of cell or tissue of origin, pre-cancerous lesions, common mutations, and therapeutic responses, leading to the notion that OC is a generic term referring to a whole range of different cancer subtypes. Despite such heterogeneity, OC treatment is stereotypic; aggressive surgery followed by conventional chemotherapy could result in chemo-resistant diseases. Whereas molecular-targeted therapies will become shortly available for a subset of OC, there still remain many patients without effective drugs, requiring development of groundbreaking therapeutic agents. In preclinical studies for drug discovery, cancer cell lines used to be the gold standard, but now this has declined due to frequent failure in predicting therapeutic responses in patients. In this regard, patient-derived cells and tumors are gaining more attention in precise and physiological modeling of in situ tumors, which could also pave the way to implementation of precision medicine. In this article, we comprehensively overviewed the current status of various platforms for patient-derived OC models. We highly appreciate the potentials of organoid culture in achieving high success rate and retaining tumor heterogeneity. Full article
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10 pages, 2521 KiB  
Article
Single Cell RNA Sequencing Identifies Subsets of Hepatic Stellate Cells and Myofibroblasts in Liver Fibrosis
by Oliver Krenkel, Jana Hundertmark, Thomas P. Ritz, Ralf Weiskirchen and Frank Tacke
Cells 2019, 8(5), 503; https://doi.org/10.3390/cells8050503 - 24 May 2019
Cited by 145 | Viewed by 16576
Abstract
Activation of hepatic stellate cells (HSCs) and their trans-differentiation towards collagen-secreting myofibroblasts (MFB) promote liver fibrosis progression. During chronic liver disease, resting HSCs become activated by inflammatory and injury signals. However, HSCs/MFB not only produce collagen, but also secrete cytokines, participate in metabolism, [...] Read more.
Activation of hepatic stellate cells (HSCs) and their trans-differentiation towards collagen-secreting myofibroblasts (MFB) promote liver fibrosis progression. During chronic liver disease, resting HSCs become activated by inflammatory and injury signals. However, HSCs/MFB not only produce collagen, but also secrete cytokines, participate in metabolism, and have biomechanical properties. We herein aimed to characterize the heterogeneity of these liver mesenchymal cells by single cell RNA sequencing. In vivo resting HSCs or activated MFB were isolated from C57BL6/J mice challenged by carbon tetrachloride (CCl4) intraperitoneally for 3 weeks to induce liver fibrosis and compared to in vitro cultivated MFB. While resting HSCs formed a homogenous population characterized by high platelet derived growth factor receptor β (PDGFRβ) expression, in vivo and in vitro activated MFB split into heterogeneous populations, characterized by α-smooth muscle actin (α-SMA), collagens, or immunological markers. S100 calcium binding protein A6 (S100A6) was a universal marker of activated MFB on both the gene and protein expression level. Compared to the heterogeneity of in vivo MFB, MFB in vitro sequentially and only transiently expressed marker genes, such as chemokines, during culture activation. Taken together, our data demonstrate the heterogeneity of HSCs and MFB, indicating the existence of functionally relevant subsets in hepatic fibrosis. Full article
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17 pages, 2189 KiB  
Article
Anti-Inflammatory Effects by Pharmacological Inhibition or Knockdown of Fatty Acid Amide Hydrolase in BV2 Microglial Cells
by Mikiei Tanaka, Kazuya Yagyu, Scott Sackett and Yumin Zhang
Cells 2019, 8(5), 491; https://doi.org/10.3390/cells8050491 - 22 May 2019
Cited by 28 | Viewed by 6220
Abstract
Fatty acid amide hydrolase (FAAH) has been recognized as a therapeutic target for several neurological diseases because its inhibition can exert neuroprotective and anti-inflammatory effects by boosting the endogenous levels of N-acylethanolamines. However, previous studies have shown inconsistent results by pharmacological inhibition [...] Read more.
Fatty acid amide hydrolase (FAAH) has been recognized as a therapeutic target for several neurological diseases because its inhibition can exert neuroprotective and anti-inflammatory effects by boosting the endogenous levels of N-acylethanolamines. However, previous studies have shown inconsistent results by pharmacological inhibition and genetic deletion of FAAH in response to inflammation. In this study we used two inhibitors, PF3845 and URB597, together with siRNA knockdown to characterize further the effects of FAAH inhibition in BV2 microglial cells. Treatment with PF3845 suppressed lipopolysaccharide (LPS)-induced prostaglandin E2 (PGE2) production, and down-regulated cyclooxygenase-2 and microsomal PGE synthase. PF3845 reduced the expression of pro-inflammatory cytokines but had no effect on the expression of anti-inflammatory cytokines. The anti-inflammatory effects of URB597 were not as potent as those of PF3845. Knockdown of FAAH also suppressed PGE2 production and pro-inflammatory gene expression. Interestingly, FAAH knockdown enhanced expression of anti-inflammatory molecules in both the absence and presence of LPS treatment. The anti-inflammatory effects of FAAH inhibition and knockdown were not affected by the cannabinoid receptor antagonists or the peroxisome proliferator-activated receptor (PPAR) antagonists. Although inhibition and knockdown of FAAH have potent anti-inflammatory effects and possibly lead to the dynamic change of microglial gene regulation, the underlying mechanisms remain to be elucidated. Full article
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18 pages, 19224 KiB  
Article
An In Vitro System for Evaluating Molecular Targeted Drugs Using Lung Patient-Derived Tumor Organoids
by Nobuhiko Takahashi, Hirotaka Hoshi, Arisa Higa, Gen Hiyama, Hirosumi Tamura, Mayu Ogawa, Kosuke Takagi, Kazuhito Goda, Naoyuki Okabe, Satoshi Muto, Hiroyuki Suzuki, Kenju Shimomura, Shinya Watanabe and Motoki Takagi
Cells 2019, 8(5), 481; https://doi.org/10.3390/cells8050481 - 20 May 2019
Cited by 40 | Viewed by 10915
Abstract
Patient-derived tumor organoids (PDOs) represent a promising preclinical cancer model that better replicates disease, compared with traditional cell culture models. We have established PDOs from various human tumors to accurately and efficiently recapitulate the tissue architecture and function. Molecular targeted therapies with remarkable [...] Read more.
Patient-derived tumor organoids (PDOs) represent a promising preclinical cancer model that better replicates disease, compared with traditional cell culture models. We have established PDOs from various human tumors to accurately and efficiently recapitulate the tissue architecture and function. Molecular targeted therapies with remarkable efficacy are currently in use against various tumors. Thus, there is a need for in vitro functional-potency assays that can be used to test the efficacy of molecular targeted drugs and model complex interactions between immune cells and tumor cells to evaluate the potential for cancer immunotherapy. This study represents an in vitro evaluation of different classes of molecular targeted drugs, including small-molecule inhibitors, monoclonal antibodies, and an antibody-drug conjugate, using lung PDOs. We evaluated epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2) inhibitors using a suitable high-throughput assay system. Next, the antibody-dependent cellular cytotoxicity (ADCC) activity of an anti-HER2 monoclonal antibody was evaluated to visualize the interactions of immune cells with PDOs during ADCC responses. Moreover, an evaluation system was developed for the immune checkpoint inhibitors, nivolumab and pembrolizumab, using PDOs. Our results demonstrate that the in vitro assay systems using PDOs were suitable for evaluating molecular targeted drugs under conditions that better reflect pathological conditions. Full article
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21 pages, 389 KiB  
Review
Advances in Regenerative Stem Cell Therapy in Androgenic Alopecia and Hair Loss: Wnt Pathway, Growth-Factor, and Mesenchymal Stem Cell Signaling Impact Analysis on Cell Growth and Hair Follicle Development
by Pietro Gentile and Simone Garcovich
Cells 2019, 8(5), 466; https://doi.org/10.3390/cells8050466 - 16 May 2019
Cited by 206 | Viewed by 28508
Abstract
The use of stem cells has been reported to improve hair regrowth in several therapeutic strategies, including reversing the pathological mechanisms, that contribute to hair loss, regeneration of hair follicles, or creating hair using the tissue-engineering approach. Although various promising stem cell approaches [...] Read more.
The use of stem cells has been reported to improve hair regrowth in several therapeutic strategies, including reversing the pathological mechanisms, that contribute to hair loss, regeneration of hair follicles, or creating hair using the tissue-engineering approach. Although various promising stem cell approaches are progressing via pre-clinical models to clinical trials, intraoperative stem cell treatments with a one-step procedure offer a quicker result by incorporating an autologous cell source without manipulation, which may be injected by surgeons through a well-established clinical practice. Many authors have concentrated on adipose-derived stromal vascular cells due to their ability to separate into numerous cell genealogies, platelet-rich plasma for its ability to enhance cell multiplication and neo-angiogenesis, as well as human follicle mesenchymal stem cells. In this paper, the significant improvements in intraoperative stem cell approaches, from in vivo models to clinical investigations, are reviewed. The potential regenerative instruments and functions of various cell populaces in the hair regrowth process are discussed. The addition of Wnt signaling in dermal papilla cells is considered a key factor in stimulating hair growth. Mesenchymal stem cell-derived signaling and growth factors obtained by platelets influence hair growth through cellular proliferation to prolong the anagen phase (FGF-7), induce cell growth (ERK activation), stimulate hair follicle development (β-catenin), and suppress apoptotic cues (Bcl-2 release and Akt activation). Full article
(This article belongs to the Special Issue Advances in Stem Cells and Regenerative Medicine)
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34 pages, 3236 KiB  
Review
Molecular Mechanisms Responsible for Therapeutic Potential of Mesenchymal Stem Cell-Derived Secretome
by Carl Randall Harrell, Crissy Fellabaum, Nemanja Jovicic, Valentin Djonov, Nebojsa Arsenijevic and Vladislav Volarevic
Cells 2019, 8(5), 467; https://doi.org/10.3390/cells8050467 - 16 May 2019
Cited by 335 | Viewed by 14945
Abstract
Mesenchymal stem cell (MSC)-sourced secretome, defined as the set of MSC-derived bioactive factors (soluble proteins, nucleic acids, lipids and extracellular vesicles), showed therapeutic effects similar to those observed after transplantation of MSCs. MSC-derived secretome may bypass many side effects of MSC-based therapy, including [...] Read more.
Mesenchymal stem cell (MSC)-sourced secretome, defined as the set of MSC-derived bioactive factors (soluble proteins, nucleic acids, lipids and extracellular vesicles), showed therapeutic effects similar to those observed after transplantation of MSCs. MSC-derived secretome may bypass many side effects of MSC-based therapy, including unwanted differentiation of engrafted MSCs. In contrast to MSCs which had to be expanded in culture to reach optimal cell number for transplantation, MSC-sourced secretome is immediately available for treatment of acute conditions, including fulminant hepatitis, cerebral ischemia and myocardial infarction. Additionally, MSC-derived secretome could be massively produced from commercially available cell lines avoiding invasive cell collection procedure. In this review article we emphasized molecular and cellular mechanisms that were responsible for beneficial effects of MSC-derived secretomes in the treatment of degenerative and inflammatory diseases of hepatobiliary, respiratory, musculoskeletal, gastrointestinal, cardiovascular and nervous system. Results obtained in a large number of studies suggested that administration of MSC-derived secretomes represents a new, cell-free therapeutic approach for attenuation of inflammatory and degenerative diseases. Therapeutic effects of MSC-sourced secretomes relied on their capacity to deliver genetic material, growth and immunomodulatory factors to the target cells enabling activation of anti-apoptotic and pro-survival pathways that resulted in tissue repair and regeneration. Full article
(This article belongs to the Special Issue Immunomodulation by Mesenchymal Stem Cells)
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19 pages, 2355 KiB  
Review
Hippo Pathway in Mammalian Adaptive Immune System
by Takayoshi Yamauchi and Toshiro Moroishi
Cells 2019, 8(5), 398; https://doi.org/10.3390/cells8050398 - 30 Apr 2019
Cited by 61 | Viewed by 19047
Abstract
The Hippo pathway was originally identified as an evolutionarily-conserved signaling mechanism that contributes to the control of organ size. It was then rapidly expanded as a key pathway in the regulation of tissue development, regeneration, and cancer pathogenesis. The increasing amount of evidence [...] Read more.
The Hippo pathway was originally identified as an evolutionarily-conserved signaling mechanism that contributes to the control of organ size. It was then rapidly expanded as a key pathway in the regulation of tissue development, regeneration, and cancer pathogenesis. The increasing amount of evidence in recent years has also connected this pathway to the regulation of innate and adaptive immune responses. Notably, the Hippo pathway has been revealed to play a pivotal role in adaptive immune cell lineages, as represented by the patients with T- and B-cell lymphopenia exhibiting defective expressions of the pathway component. The complex regulatory mechanisms of and by the Hippo pathway have also been evident as alternative signal transductions are employed in some immune cell types. In this review article, we summarize the current understanding of the emerging roles of the Hippo pathway in adaptive immune cell development and differentiation. We also highlight the recent findings concerning the dual functions of the Hippo pathway in autoimmunity and anti-cancer immune responses and discuss the key open questions in the interplay between the Hippo pathway and the mammalian immune system. Full article
(This article belongs to the Special Issue Disease and the Hippo Pathway: Cellular and Molecular Mechanisms)
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12 pages, 3702 KiB  
Article
A Cleared View on Retinal Organoids
by Virginia Cora, Jasmin Haderspeck, Lena Antkowiak, Ulrich Mattheus, Peter H. Neckel, Andreas F. Mack, Sylvia Bolz, Marius Ueffing, Natalia Pashkovskaia, Kevin Achberger and Stefan Liebau
Cells 2019, 8(5), 391; https://doi.org/10.3390/cells8050391 - 28 Apr 2019
Cited by 38 | Viewed by 9231
Abstract
Human induced pluripotent stem cell (hiPSC)-derived organoids mimicking tissues and organs in vitro have advanced medical research, as they opened up new possibilities for in-depth basic research on human organ development as well as providing a human in vitro model for personalized therapeutic [...] Read more.
Human induced pluripotent stem cell (hiPSC)-derived organoids mimicking tissues and organs in vitro have advanced medical research, as they opened up new possibilities for in-depth basic research on human organ development as well as providing a human in vitro model for personalized therapeutic approaches. hiPSC-derived retinal organoids have proven to be of great value for modeling the human retina featuring a very similar cellular composition, layering, and functionality. The technically challenging imaging of three-dimensional structures such as retinal organoids has, however, raised the need for robust whole-organoid imaging techniques. To improve imaging of retinal organoids we optimized a passive clearing technique (PACT), which enables high-resolution visualization of fragile intra-tissue structures. Using cleared retinal organoids, we could greatly enhance the antibody labeling efficiency and depth of imaging at high resolution, thereby improving the three-dimensional microscopy output. In that course, we were able to identify the spatial morphological shape and organization of, e.g., photoreceptor cells and bipolar cell layers. Moreover, we used the synaptic protein CtBP2/Ribeye to visualize the interconnection points of photoreceptor and bipolar cells forming the retinal-specific ribbon synapses. Full article
(This article belongs to the Special Issue Stem Cells in Personalized Medicine)
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29 pages, 6468 KiB  
Article
Rainbow Trout Red Blood Cells Exposed to Viral Hemorrhagic Septicemia Virus Up-Regulate Antigen-Processing Mechanisms and MHC I&II, CD86, and CD83 Antigen-presenting Cell Markers
by Ivan Nombela, Ricardo Requena-Platek, Byron Morales-Lange, Veronica Chico, Sara Puente-Marin, Sergio Ciordia, Maria Carmen Mena, Julio Coll, Luis Perez, Luis Mercado and Maria del Mar Ortega-Villaizan
Cells 2019, 8(5), 386; https://doi.org/10.3390/cells8050386 - 27 Apr 2019
Cited by 28 | Viewed by 8259
Abstract
Nucleated teleost red blood cells (RBCs) are known to express molecules from the major histocompatibility complex and peptide-generating processes such as autophagy and proteasomes, but the role of RBCs in antigen presentation of viruses have not been studied yet. In this study, RBCs [...] Read more.
Nucleated teleost red blood cells (RBCs) are known to express molecules from the major histocompatibility complex and peptide-generating processes such as autophagy and proteasomes, but the role of RBCs in antigen presentation of viruses have not been studied yet. In this study, RBCs exposed ex vivo to viral hemorrhagic septicemia virus (VHSV) were evaluated by means of transcriptomic and proteomic approaches. Genes and proteins related to antigen presentation molecules, proteasome degradation, and autophagy were up-regulated. VHSV induced accumulation of ubiquitinated proteins in ex vivo VHSV-exposed RBCs and showed at the same time a decrease of proteasome activity. Furthermore, induction of autophagy was detected by evaluating LC3 protein levels. Sequestosome-1/p62 underwent degradation early after VHSV exposure, and it may be a link between ubiquitination and autophagy activation. Inhibition of autophagosome degradation with niclosamide resulted in intracellular detection of N protein of VHSV (NVHSV) and p62 accumulation. In addition, antigen presentation cell markers, such as major histocompatibility complex (MHC) class I & II, CD83, and CD86, increased at the transcriptional and translational level in rainbow trout RBCs exposed to VHSV. In summary, we show that nucleated rainbow trout RBCs can degrade VHSV while displaying an antigen-presenting cell (APC)-like profile. Full article
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18 pages, 2571 KiB  
Article
MAGI1 Mediates eNOS Activation and NO Production in Endothelial Cells in Response to Fluid Shear Stress
by Kedar Ghimire, Jelena Zaric, Begoña Alday-Parejo, Jochen Seebach, Mélanie Bousquenaud, Jimmy Stalin, Grégory Bieler, Hans-Joachim Schnittler and Curzio Rüegg
Cells 2019, 8(5), 388; https://doi.org/10.3390/cells8050388 - 27 Apr 2019
Cited by 38 | Viewed by 8071
Abstract
Fluid shear stress stimulates endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO) production through multiple kinases, including protein kinase A (PKA), AMP-activated protein kinase (AMPK), AKT and Ca2+/calmodulin-dependent protein kinase II (CaMKII). Membrane-associated guanylate kinase (MAGUK) with inverted domain [...] Read more.
Fluid shear stress stimulates endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO) production through multiple kinases, including protein kinase A (PKA), AMP-activated protein kinase (AMPK), AKT and Ca2+/calmodulin-dependent protein kinase II (CaMKII). Membrane-associated guanylate kinase (MAGUK) with inverted domain structure-1 (MAGI1) is an adaptor protein that stabilizes epithelial and endothelial cell-cell contacts. The aim of this study was to assess the unknown role of endothelial cell MAGI1 in response to fluid shear stress. We show constitutive expression and co-localization of MAGI1 with vascular endothelial cadherin (VE-cadherin) in endothelial cells at cellular junctions under static and laminar flow conditions. Fluid shear stress increases MAGI1 expression. MAGI1 silencing perturbed flow-dependent responses, specifically, Krüppel-like factor 4 (KLF4) expression, endothelial cell alignment, eNOS phosphorylation and NO production. MAGI1 overexpression had opposite effects and induced phosphorylation of PKA, AMPK, and CAMKII. Pharmacological inhibition of PKA and AMPK prevented MAGI1-mediated eNOS phosphorylation. Consistently, MAGI1 silencing and PKA inhibition suppressed the flow-induced NO production. Endothelial cell-specific transgenic expression of MAGI1 induced PKA and eNOS phosphorylation in vivo and increased NO production ex vivo in isolated endothelial cells. In conclusion, we have identified endothelial cell MAGI1 as a previously unrecognized mediator of fluid shear stress-induced and PKA/AMPK dependent eNOS activation and NO production. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis of Cardiovascular Disease)
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22 pages, 1769 KiB  
Review
Protein Hydroxylation by Hypoxia-Inducible Factor (HIF) Hydroxylases: Unique or Ubiquitous?
by Moritz J. Strowitzki, Eoin P. Cummins and Cormac T. Taylor
Cells 2019, 8(5), 384; https://doi.org/10.3390/cells8050384 - 26 Apr 2019
Cited by 145 | Viewed by 12585
Abstract
All metazoans that utilize molecular oxygen (O2) for metabolic purposes have the capacity to adapt to hypoxia, the condition that arises when O2 demand exceeds supply. This is mediated through activation of the hypoxia-inducible factor (HIF) pathway. At physiological oxygen [...] Read more.
All metazoans that utilize molecular oxygen (O2) for metabolic purposes have the capacity to adapt to hypoxia, the condition that arises when O2 demand exceeds supply. This is mediated through activation of the hypoxia-inducible factor (HIF) pathway. At physiological oxygen levels (normoxia), HIF-prolyl hydroxylases (PHDs) hydroxylate proline residues on HIF-α subunits leading to their destabilization by promoting ubiquitination by the von-Hippel Lindau (VHL) ubiquitin ligase and subsequent proteasomal degradation. HIF-α transactivation is also repressed in an O2-dependent way due to asparaginyl hydroxylation by the factor-inhibiting HIF (FIH). In hypoxia, the O2-dependent hydroxylation of HIF-α subunits by PHDs and FIH is reduced, resulting in HIF-α accumulation, dimerization with HIF-β and migration into the nucleus to induce an adaptive transcriptional response. Although HIFs are the canonical substrates for PHD- and FIH-mediated protein hydroxylation, increasing evidence indicates that these hydroxylases may also have alternative targets. In addition to PHD-conferred alterations in protein stability, there is now evidence that hydroxylation can affect protein activity and protein/protein interactions for alternative substrates. PHDs can be pharmacologically inhibited by a new class of drugs termed prolyl hydroxylase inhibitors which have recently been approved for the treatment of anemia associated with chronic kidney disease. The identification of alternative targets of HIF hydroxylases is important in order to fully elucidate the pharmacology of hydroxylase inhibitors (PHI). Despite significant technical advances, screening, detection and verification of alternative functional targets for PHDs and FIH remain challenging. In this review, we discuss recently proposed non-HIF targets for PHDs and FIH and provide an overview of the techniques used to identify these. Full article
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45 pages, 915 KiB  
Review
Role of Hedgehog Signaling in Breast Cancer: Pathogenesis and Therapeutics
by Natalia A. Riobo-Del Galdo, Ángela Lara Montero and Eva V. Wertheimer
Cells 2019, 8(4), 375; https://doi.org/10.3390/cells8040375 - 25 Apr 2019
Cited by 94 | Viewed by 8280
Abstract
Breast cancer (BC) is the leading cause of cancer-related mortality in women, only followed by lung cancer. Given the importance of BC in public health, it is essential to identify biomarkers to predict prognosis, predetermine drug resistance and provide treatment guidelines that include [...] Read more.
Breast cancer (BC) is the leading cause of cancer-related mortality in women, only followed by lung cancer. Given the importance of BC in public health, it is essential to identify biomarkers to predict prognosis, predetermine drug resistance and provide treatment guidelines that include personalized targeted therapies. The Hedgehog (Hh) signaling pathway plays an essential role in embryonic development, tissue regeneration, and stem cell renewal. Several lines of evidence endorse the important role of canonical and non-canonical Hh signaling in BC. In this comprehensive review we discuss the role of Hh signaling in breast development and homeostasis and its contribution to tumorigenesis and progression of different subtypes of BC. We also examine the efficacy of agents targeting different components of the Hh pathway both in preclinical models and in clinical trials. The contribution of the Hh pathway in BC tumorigenesis and progression, its prognostic role, and its value as a therapeutic target vary according to the molecular, clinical, and histopathological characteristics of the BC patients. The evidence presented here highlights the relevance of the Hh signaling in BC, and suggest that this pathway is key for BC progression and metastasis. Full article
(This article belongs to the Collection Hedgehog Signal Transduction in Physiology and Disease)
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27 pages, 1047 KiB  
Review
Hepatitis C Virus Infection: Host–Virus Interaction and Mechanisms of Viral Persistence
by DeGaulle I. Chigbu, Ronak Loonawat, Mohit Sehgal, Dip Patel and Pooja Jain
Cells 2019, 8(4), 376; https://doi.org/10.3390/cells8040376 - 25 Apr 2019
Cited by 95 | Viewed by 17304
Abstract
Hepatitis C (HCV) is a major cause of liver disease, in which a third of individuals with chronic HCV infections may develop liver cirrhosis. In a chronic HCV infection, host immune factors along with the actions of HCV proteins that promote viral persistence [...] Read more.
Hepatitis C (HCV) is a major cause of liver disease, in which a third of individuals with chronic HCV infections may develop liver cirrhosis. In a chronic HCV infection, host immune factors along with the actions of HCV proteins that promote viral persistence and dysregulation of the immune system have an impact on immunopathogenesis of HCV-induced hepatitis. The genome of HCV encodes a single polyprotein, which is translated and processed into structural and nonstructural proteins. These HCV proteins are the target of the innate and adaptive immune system of the host. Retinoic acid-inducible gene-I (RIG-I)-like receptors and Toll-like receptors are the main pattern recognition receptors that recognize HCV pathogen-associated molecular patterns. This interaction results in a downstream cascade that generates antiviral cytokines including interferons. The cytolysis of HCV-infected hepatocytes is mediated by perforin and granzyme B secreted by cytotoxic T lymphocyte (CTL) and natural killer (NK) cells, whereas noncytolytic HCV clearance is mediated by interferon gamma (IFN-γ) secreted by CTL and NK cells. A host–HCV interaction determines whether the acute phase of an HCV infection will undergo complete resolution or progress to the development of viral persistence with a consequential progression to chronic HCV infection. Furthermore, these host–HCV interactions could pose a challenge to developing an HCV vaccine. This review will focus on the role of the innate and adaptive immunity in HCV infection, the failure of the immune response to clear an HCV infection, and the factors that promote viral persistence. Full article
(This article belongs to the Special Issue Hepatitis C Virus and Host Interactions)
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14 pages, 1811 KiB  
Article
Combined Inhibition of TGF-β Signaling and the PD-L1 Immune Checkpoint Is Differentially Effective in Tumor Models
by Heng Sheng Sow, Jiang Ren, Marcel Camps, Ferry Ossendorp and Peter ten Dijke
Cells 2019, 8(4), 320; https://doi.org/10.3390/cells8040320 - 5 Apr 2019
Cited by 84 | Viewed by 10783
Abstract
Antibodies blocking the programmed death-ligand 1 (PD-L1) have shown impressive and durable responses in clinical studies. However, this type of immunotherapy is only effective in a subset of patients and not sufficient for rejection of all tumor types. In this study, we explored [...] Read more.
Antibodies blocking the programmed death-ligand 1 (PD-L1) have shown impressive and durable responses in clinical studies. However, this type of immunotherapy is only effective in a subset of patients and not sufficient for rejection of all tumor types. In this study, we explored in two mouse tumor models whether the antitumor effect could be enhanced by the combined blockade of PD-L1 and transforming growth factor-β (TGF-β), a potent immunosuppressive cytokine. The effect of anti-PD-L1 mouse monoclonal (mAb) and a TGF-β type I receptor small molecule kinase inhibitor (LY364947) was evaluated in the highly immunogenic mouse MC38 colon adenocarcinoma and the poorly immunogenic mouse KPC1 pancreatic tumor model. In the MC38 tumor model, LY364947 monotherapy did not show any antitumor effect, whereas treatment with anti-PD-L1 mAb significantly delayed tumor outgrowth. However, combination therapy showed the strongest therapeutic efficacy, resulting in improved long-term survival compared with anti-PD-L1 mAb monotherapy. This improved survival was associated with an increased influx of CD8+ T cells in the tumor microenvironment. In the KPC1 tumor model, LY364947 did not enhance the antitumor effect of anti-PD-L1 mAb. Despite this, delayed KPC1 tumor outgrowth was observed in the LY364947-treated group and this treatment led to a significant reduction of CD4+ T cells in the tumor microenvironment. Together, our data indicate that an additive anti-tumor response of dual targeting PD-L1 and TGF-β is dependent on the tumor model used, highlighting the importance of selecting appropriate cancer types, using in-depth analysis of the tumor microenvironment, which can benefit from combinatorial immunotherapy regimens. Full article
(This article belongs to the Special Issue TGF-beta/BMP Signaling Pathway)
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17 pages, 14461 KiB  
Article
Hepatitis C Virus Non-Structural Protein 5A (NS5A) Disrupts Mitochondrial Dynamics and Induces Mitophagy
by Alagie Jassey, Ching-Hsuan Liu, Chun A. Changou, Christopher D. Richardson, Hsue-Yin Hsu and Liang-Tzung Lin
Cells 2019, 8(4), 290; https://doi.org/10.3390/cells8040290 - 29 Mar 2019
Cited by 52 | Viewed by 6680
Abstract
Mitophagy is a selective form of autophagy, targeting damaged mitochondria for lysosomal degradation. Although HCV infection has been shown to induce mitophagy, the precise underlying mechanism and the effector protein responsible remain unclear. Herein, we demonstrated that the HCV non-structural protein 5A (NS5A) [...] Read more.
Mitophagy is a selective form of autophagy, targeting damaged mitochondria for lysosomal degradation. Although HCV infection has been shown to induce mitophagy, the precise underlying mechanism and the effector protein responsible remain unclear. Herein, we demonstrated that the HCV non-structural protein 5A (NS5A) plays a key role in regulating cellular mitophagy. Specifically, the expression of HCV NS5A in the hepatoma cells triggered hallmarks of mitophagy including mitochondrial fragmentation, loss of mitochondrial membrane potential, and Parkin translocation to the mitochondria. Furthermore, mitophagy induction through the expression of NS5A led to an increase in autophagic flux as demonstrated by an accumulation of LC3II in the presence of bafilomycin and a time-dependent decrease in p62 protein level. Intriguingly, the expression of NS5A concomitantly enhanced reactive oxygen species (ROS) production, and treatment with an antioxidant attenuated the NS5A-induced mitophagy event. These phenomena are similarly recapitulated in the NS5A-expressing HCV subgenomic replicon cells. Finally, we demonstrated that expression of HCV core, which has been documented to inhibit mitophagy, blocked the mitophagy induction both in cells harboring HCV replicating subgenomes or expressing NS5A alone. Our results, therefore, identified a new role for NS5A as an important regulator of HCV-induced mitophagy and have implications to broadening our understanding of the HCV-mitophagy interplay. Full article
(This article belongs to the Special Issue Hepatitis C Virus and Host Interactions)
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27 pages, 4449 KiB  
Review
Import of Non-Coding RNAs into Human Mitochondria: A Critical Review and Emerging Approaches
by Damien Jeandard, Anna Smirnova, Ivan Tarassov, Eric Barrey, Alexandre Smirnov and Nina Entelis
Cells 2019, 8(3), 286; https://doi.org/10.3390/cells8030286 - 26 Mar 2019
Cited by 61 | Viewed by 9631
Abstract
Mitochondria harbor their own genetic system, yet critically depend on the import of a number of nuclear-encoded macromolecules to ensure their expression. In all eukaryotes, selected non-coding RNAs produced from the nuclear genome are partially redirected into the mitochondria, where they participate in [...] Read more.
Mitochondria harbor their own genetic system, yet critically depend on the import of a number of nuclear-encoded macromolecules to ensure their expression. In all eukaryotes, selected non-coding RNAs produced from the nuclear genome are partially redirected into the mitochondria, where they participate in gene expression. Therefore, the mitochondrial RNome represents an intricate mixture of the intrinsic transcriptome and the extrinsic RNA importome. In this review, we summarize and critically analyze data on the nuclear-encoded transcripts detected in human mitochondria and outline the proposed molecular mechanisms of their mitochondrial import. Special attention is given to the various experimental approaches used to study the mitochondrial RNome, including some recently developed genome-wide and in situ techniques. Full article
(This article belongs to the Section Mitochondria)
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15 pages, 2863 KiB  
Article
Novel Flavivirus Antiviral That Targets the Host Nuclear Transport Importin α/β1 Heterodimer
by Sundy N. Y. Yang, Sarah C. Atkinson, Johanna E. Fraser, Chunxiao Wang, Belinda Maher, Noelia Roman, Jade K. Forwood, Kylie M. Wagstaff, Natalie A. Borg and David A. Jans
Cells 2019, 8(3), 281; https://doi.org/10.3390/cells8030281 - 24 Mar 2019
Cited by 33 | Viewed by 7703
Abstract
Dengue virus (DENV) threatens almost 70% of the world’s population, with no effective vaccine or therapeutic currently available. A key contributor to infection is nuclear localisation in the infected cell of DENV nonstructural protein 5 (NS5) through the action of the host importin [...] Read more.
Dengue virus (DENV) threatens almost 70% of the world’s population, with no effective vaccine or therapeutic currently available. A key contributor to infection is nuclear localisation in the infected cell of DENV nonstructural protein 5 (NS5) through the action of the host importin (IMP) α/β1 proteins. Here, we used a range of microscopic, virological and biochemical/biophysical approaches to show for the first time that the small molecule GW5074 has anti-DENV action through its novel ability to inhibit NS5–IMPα/β1 interaction in vitro as well as NS5 nuclear localisation in infected cells. Strikingly, GW5074 not only inhibits IMPα binding to IMPβ1, but can dissociate preformed IMPα/β1 heterodimer, through targeting the IMPα armadillo (ARM) repeat domain to impact IMPα thermal stability and α-helicity, as shown using analytical ultracentrifugation, thermostability analysis and circular dichroism measurements. Importantly, GW5074 has strong antiviral activity at low µM concentrations against not only DENV-2, but also zika virus and West Nile virus. This work highlights DENV NS5 nuclear targeting as a viable target for anti-flaviviral therapeutics. Full article
(This article belongs to the Special Issue Nuclear Transport in Ageing and Diseases)
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12 pages, 3836 KiB  
Article
Promethin Is a Conserved Seipin Partner Protein
by Inês G. Castro, Michal Eisenberg-Bord, Elisa Persiani, Justin J. Rochford, Maya Schuldiner and Maria Bohnert
Cells 2019, 8(3), 268; https://doi.org/10.3390/cells8030268 - 21 Mar 2019
Cited by 47 | Viewed by 7098
Abstract
Seipin (BSCL2/SPG17) is a key factor in lipid droplet (LD) biology, and its dysfunction results in severe pathologies, including the fat storage disease Berardinelli-Seip congenital lipodystrophy type 2, as well as several neurological seipinopathies. Despite its importance for human health, the molecular role [...] Read more.
Seipin (BSCL2/SPG17) is a key factor in lipid droplet (LD) biology, and its dysfunction results in severe pathologies, including the fat storage disease Berardinelli-Seip congenital lipodystrophy type 2, as well as several neurological seipinopathies. Despite its importance for human health, the molecular role of seipin is still enigmatic. Seipin is evolutionarily conserved from yeast to humans. In yeast, seipin was recently found to cooperate with the lipid droplet organization (LDO) proteins, Ldo16 and Ldo45, two structurally-related proteins involved in LD function and identity that display remote homology to the human protein promethin/TMEM159. In this study, we show that promethin is indeed an LD-associated protein that forms a complex with seipin, and its localization to the LD surface can be modulated by seipin expression levels. We thus identify promethin as a novel seipin partner protein. Full article
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16 pages, 378 KiB  
Review
Microbiome, Parkinson’s Disease and Molecular Mimicry
by Fabiana Miraglia and Emanuela Colla
Cells 2019, 8(3), 222; https://doi.org/10.3390/cells8030222 - 7 Mar 2019
Cited by 62 | Viewed by 7985
Abstract
Parkinson’s Disease (PD) is typically classified as a neurodegenerative disease affecting the motor system. Recent evidence, however, has uncovered the presence of Lewy bodies in locations outside the CNS, in direct contact with the external environment, including the olfactory bulbs and the enteric [...] Read more.
Parkinson’s Disease (PD) is typically classified as a neurodegenerative disease affecting the motor system. Recent evidence, however, has uncovered the presence of Lewy bodies in locations outside the CNS, in direct contact with the external environment, including the olfactory bulbs and the enteric nervous system. This, combined with the ability of alpha-synuclein (αS) to propagate in a prion-like manner, has supported the hypothesis that the resident microbial community, commonly referred to as microbiota, might play a causative role in the development of PD. In this article, we will be reviewing current knowledge on the importance of the microbiota in PD pathology, concentrating our investigation on mechanisms of microbiota-host interactions that might become harmful and favor the onset of PD. Such processes, which include the secretion of bacterial amyloid proteins or other metabolites, may influence the aggregation propensity of αS directly or indirectly, for example by favoring a pro-inflammatory environment in the gut. Thus, while the development of PD has not yet being associated with a unique microbial species, more data will be necessary to examine potential harmful interactions between the microbiota and the host, and to understand their relevance in PD pathogenesis. Full article
16 pages, 1042 KiB  
Review
Hypoxia-Inducible Factors and the Regulation of Lipid Metabolism
by Ilias Mylonis, George Simos and Efrosyni Paraskeva
Cells 2019, 8(3), 214; https://doi.org/10.3390/cells8030214 - 3 Mar 2019
Cited by 193 | Viewed by 12508
Abstract
Oxygen deprivation or hypoxia characterizes a number of serious pathological conditions and elicits a number of adaptive changes that are mainly mediated at the transcriptional level by the family of hypoxia-inducible factors (HIFs). The HIF target gene repertoire includes genes responsible for the [...] Read more.
Oxygen deprivation or hypoxia characterizes a number of serious pathological conditions and elicits a number of adaptive changes that are mainly mediated at the transcriptional level by the family of hypoxia-inducible factors (HIFs). The HIF target gene repertoire includes genes responsible for the regulation of metabolism, oxygen delivery and cell survival. Although the involvement of HIFs in the regulation of carbohydrate metabolism and the switch to anaerobic glycolysis under hypoxia is well established, their role in the control of lipid anabolism and catabolism remains still relatively obscure. Recent evidence indicates that many aspects of lipid metabolism are modified during hypoxia or in tumor cells in a HIF-dependent manner, contributing significantly to the pathogenesis and/or progression of cancer and metabolic disorders. However, direct transcriptional regulation by HIFs has been only demonstrated in relatively few cases, leaving open the exact and isoform-specific mechanisms that underlie HIF-dependency. This review summarizes the evidence for both direct and indirect roles of HIFs in the regulation of genes involved in lipid metabolism as well as the involvement of HIFs in various diseases as demonstrated by studies with transgenic animal models. Full article
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13 pages, 2513 KiB  
Article
Sigma-1 Receptor Activation Induces Autophagy and Increases Proteostasis Capacity In Vitro and In Vivo
by Maximilian G. Christ, Heike Huesmann, Heike Nagel, Andreas Kern and Christian Behl
Cells 2019, 8(3), 211; https://doi.org/10.3390/cells8030211 - 2 Mar 2019
Cited by 47 | Viewed by 11933
Abstract
Dysfunction of autophagy and disturbed protein homeostasis are linked to the pathogenesis of human neurodegenerative diseases and the modulation of autophagy as the protein clearance process has become one key pharmacological target. Due to the role of sigma-1 receptors (Sig-1R) in learning and [...] Read more.
Dysfunction of autophagy and disturbed protein homeostasis are linked to the pathogenesis of human neurodegenerative diseases and the modulation of autophagy as the protein clearance process has become one key pharmacological target. Due to the role of sigma-1 receptors (Sig-1R) in learning and memory, and the described pleiotropic neuroprotective effects in various experimental paradigms, Sig-1R activation is recognized as one potential approach for prevention and therapy of neurodegeneration and, interestingly, in amyotrophic lateral sclerosis associated with mutated Sig-1R, autophagy is disturbed. Here we analyzed the effects of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73), a muscarinic receptor ligand and Sig-1R agonist, on autophagy and proteostasis. We describe, at the molecular level, for the first time, that pharmacological Sig-1R activation a) enhances the autophagic flux in human cells and in Caenorhabditis elegans and b) increases proteostasis capacity, ultimately ameliorating paralysis caused by protein aggregation in C. elegans. ANAVEX2-73 is already in clinical investigation for the treatment of Alzheimer’s disease, and the novel activities of this compound on autophagy and proteostasis described here may have consequences for the use and further development of the Sig-1R as a drug target in the future. Moreover, our study defines the Sig-1R as an upstream modulator of canonical autophagy, which may have further implications for various conditions with dysfunctional autophagy, besides neurodegeneration. Full article
(This article belongs to the Special Issue Proteostasis and Autophagy)
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17 pages, 6930 KiB  
Article
Anti-Inflammatory Effect of Sulforaphane on LPS-Activated Microglia Potentially through JNK/AP-1/NF-κB Inhibition and Nrf2/HO-1 Activation
by Lalita Subedi, Jae Hyuk Lee, Silvia Yumnam, Eunhee Ji and Sun Yeou Kim
Cells 2019, 8(2), 194; https://doi.org/10.3390/cells8020194 - 22 Feb 2019
Cited by 202 | Viewed by 12505
Abstract
Sulforaphane (SFN), a potent nuclear factor erythroid 2-related factor 2 (Nrf2) activator, is present in the species of the Brassicaceae, especially in broccoli sprouts. In this study, the effects of SFN against microglial activation and inflammation, and the potential mechanisms involved, were analyzed. [...] Read more.
Sulforaphane (SFN), a potent nuclear factor erythroid 2-related factor 2 (Nrf2) activator, is present in the species of the Brassicaceae, especially in broccoli sprouts. In this study, the effects of SFN against microglial activation and inflammation, and the potential mechanisms involved, were analyzed. As mitogen-activated protein kinase (MAPK) signaling plays a key role in microglial activation and inflammation, we focused on the role of SFN in regulating the MAPK signaling regulation of the inflammatory and anti-inflammatory cascades in lipopolysaccharide (LPS)-activated microglia. The anti-inflammatory and immunomodulatory effects of SFN were explored by evaluating the expression and secretion of inflammatory proteins, cytokines, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and activator protein-1 (AP-1) under pre- and post-treatment conditions. Under the SFN pre- and post-treatment conditions, the MAPK phosphorylation levels were significantly reduced in both acutely and chronically activated microglial cells. SFN also reduced the c-Jun N-terminal kinase (JNK) phosphorylation levels, which subsequently reduced NF-κB and AP-1 signaling. As a result, the expression of the inflammatory mediators (iNOS, COX-2, NO, and PGE2) and proinflammatory cytokines (TNF-α, IL-6, and IL-1β) was decreased. At the same time, SFN increased the expression of Nrf2 and heme oxygenase-1 (HO-1) as well as the production of the anti-inflammatory cytokines IL-10 and IL-4. In conclusion, this study demonstrated that SFN exerts an anti-neuroinflammatory effect on microglia through JNK/AP-1/NF-κB pathway inhibition and Nrf2/HO-1 pathway activation. Full article
(This article belongs to the Section Cell Signaling)
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16 pages, 2520 KiB  
Article
Apolipoprotein E4 Alters Astrocyte Fatty Acid Metabolism and Lipid Droplet Formation
by Brandon C. Farmer, Jude Kluemper and Lance A. Johnson
Cells 2019, 8(2), 182; https://doi.org/10.3390/cells8020182 - 20 Feb 2019
Cited by 106 | Viewed by 13924
Abstract
Lipid droplets (LDs) serve as energy rich reservoirs and have been associated with apolipoprotein E (APOE) and neurodegeneration. The E4 allele of APOE (E4) is the strongest genetic risk factor for the development of late onset Alzheimer’s disease (AD). Since both [...] Read more.
Lipid droplets (LDs) serve as energy rich reservoirs and have been associated with apolipoprotein E (APOE) and neurodegeneration. The E4 allele of APOE (E4) is the strongest genetic risk factor for the development of late onset Alzheimer’s disease (AD). Since both E4 carriers and individuals with AD exhibit a state of cerebral lipid dyshomeostasis, we hypothesized that APOE may play a role in regulating LD metabolism. We found that astrocytes expressing E4 accumulate significantly more and smaller LDs compared to E3 astrocytes. Accordingly, expression of perilipin-2, an essential LD protein component, was higher in E4 astrocytes. We then probed fatty acid (FA) metabolism and found E4 astrocytes to exhibit decreased uptake of palmitate, and decreased oxidation of exogenously supplied oleate and palmitate. We then measured oxygen consumption rate, and found E4 astrocytes to consume more oxygen for endogenous FA oxidation and accumulate more LD-derived metabolites due to incomplete oxidation. Lastly, we found that E4 astrocytes are more sensitive to carnitine palmitoyltransferase-1 inhibition than E3 astrocytes. These findings offer the potential for further studies investigating the link between astrocyte lipid storage, utilization, and neurodegenerative disease as a function of APOE genotype. Full article
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17 pages, 564 KiB  
Review
Revisiting Telomere Shortening in Cancer
by Keiji Okamoto and Hiroyuki Seimiya
Cells 2019, 8(2), 107; https://doi.org/10.3390/cells8020107 - 31 Jan 2019
Cited by 106 | Viewed by 11497
Abstract
Telomeres, the protective structures of chromosome ends are gradually shortened by each cell division, eventually leading to senescence or apoptosis. Cancer cells maintain the telomere length for unlimited growth by telomerase reactivation or a recombination-based mechanism. Recent genome-wide analyses have unveiled genetic and [...] Read more.
Telomeres, the protective structures of chromosome ends are gradually shortened by each cell division, eventually leading to senescence or apoptosis. Cancer cells maintain the telomere length for unlimited growth by telomerase reactivation or a recombination-based mechanism. Recent genome-wide analyses have unveiled genetic and epigenetic alterations of the telomere maintenance machinery in cancer. While telomerase inhibition reveals that longer telomeres are more advantageous for cell survival, cancer cells often have paradoxically shorter telomeres compared with those found in the normal tissues. In this review, we summarize the latest knowledge about telomere length alterations in cancer and revisit its rationality. Finally, we discuss the potential utility of telomere length as a prognostic biomarker. Full article
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21 pages, 758 KiB  
Review
Mitochondrial DNA Integrity: Role in Health and Disease
by Priyanka Sharma and Harini Sampath
Cells 2019, 8(2), 100; https://doi.org/10.3390/cells8020100 - 29 Jan 2019
Cited by 160 | Viewed by 16132
Abstract
As the primary cellular location for respiration and energy production, mitochondria serve in a critical capacity to the cell. Yet, by virtue of this very function of respiration, mitochondria are subject to constant oxidative stress that can damage one of the unique features [...] Read more.
As the primary cellular location for respiration and energy production, mitochondria serve in a critical capacity to the cell. Yet, by virtue of this very function of respiration, mitochondria are subject to constant oxidative stress that can damage one of the unique features of this organelle, its distinct genome. Damage to mitochondrial DNA (mtDNA) and loss of mitochondrial genome integrity is increasingly understood to play a role in the development of both severe early-onset maladies and chronic age-related diseases. In this article, we review the processes by which mtDNA integrity is maintained, with an emphasis on the repair of oxidative DNA lesions, and the cellular consequences of diminished mitochondrial genome stability. Full article
(This article belongs to the Special Issue Mitochondrial Biology in Health and Disease)
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33 pages, 3140 KiB  
Review
Metabolic Reprogramming in Breast Cancer and Its Therapeutic Implications
by Nishant Gandhi and Gokul M Das
Cells 2019, 8(2), 89; https://doi.org/10.3390/cells8020089 - 26 Jan 2019
Cited by 151 | Viewed by 16694
Abstract
Current standard-of-care (SOC) therapy for breast cancer includes targeted therapies such as endocrine therapy for estrogen receptor-alpha (ERα) positive; anti-HER2 monoclonal antibodies for human epidermal growth factor receptor-2 (HER2)-enriched; and general chemotherapy for triple negative breast cancer (TNBC) subtypes. These therapies frequently fail [...] Read more.
Current standard-of-care (SOC) therapy for breast cancer includes targeted therapies such as endocrine therapy for estrogen receptor-alpha (ERα) positive; anti-HER2 monoclonal antibodies for human epidermal growth factor receptor-2 (HER2)-enriched; and general chemotherapy for triple negative breast cancer (TNBC) subtypes. These therapies frequently fail due to acquired or inherent resistance. Altered metabolism has been recognized as one of the major mechanisms underlying therapeutic resistance. There are several cues that dictate metabolic reprogramming that also account for the tumors’ metabolic plasticity. For metabolic therapy to be efficacious there is a need to understand the metabolic underpinnings of the different subtypes of breast cancer as well as the role the SOC treatments play in targeting the metabolic phenotype. Understanding the mechanism will allow us to identify potential therapeutic vulnerabilities. There are some very interesting questions being tackled by researchers today as they pertain to altered metabolism in breast cancer. What are the metabolic differences between the different subtypes of breast cancer? Do cancer cells have a metabolic pathway preference based on the site and stage of metastasis? How do the cell-intrinsic and -extrinsic cues dictate the metabolic phenotype? How do the nucleus and mitochondria coordinately regulate metabolism? How does sensitivity or resistance to SOC affect metabolic reprogramming and vice-versa? This review addresses these issues along with the latest updates in the field of breast cancer metabolism. Full article
(This article belongs to the Special Issue Mitochondrial Metabolic Reprogramming and Nuclear Crosstalk in Cancer)
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27 pages, 581 KiB  
Review
Application of Prostate Cancer Models for Preclinical Study: Advantages and Limitations of Cell Lines, Patient-Derived Xenografts, and Three-Dimensional Culture of Patient-Derived Cells
by Takeshi Namekawa, Kazuhiro Ikeda, Kuniko Horie-Inoue and Satoshi Inoue
Cells 2019, 8(1), 74; https://doi.org/10.3390/cells8010074 - 20 Jan 2019
Cited by 128 | Viewed by 21711
Abstract
Various preclinical models have been developed to clarify the pathophysiology of prostate cancer (PCa). Traditional PCa cell lines from clinical metastatic lesions, as exemplified by DU-145, PC-3, and LNCaP cells, are useful tools to define mechanisms underlying tumorigenesis and drug resistance. Cell line-based [...] Read more.
Various preclinical models have been developed to clarify the pathophysiology of prostate cancer (PCa). Traditional PCa cell lines from clinical metastatic lesions, as exemplified by DU-145, PC-3, and LNCaP cells, are useful tools to define mechanisms underlying tumorigenesis and drug resistance. Cell line-based experiments, however, have limitations for preclinical studies because those cells are basically adapted to 2-dimensional monolayer culture conditions, in which the majority of primary PCa cells cannot survive. Recent tissue engineering enables generation of PCa patient-derived xenografts (PDXs) from both primary and metastatic lesions. Compared with fresh PCa tissue transplantation in athymic mice, co-injection of PCa tissues with extracellular matrix in highly immunodeficient mice has remarkably improved the success rate of PDX generation. PDX models have advantages to appropriately recapitulate the molecular diversity, cellular heterogeneity, and histology of original patient tumors. In contrast to PDX models, patient-derived organoid and spheroid PCa models in 3-dimensional culture are more feasible tools for in vitro studies for retaining the characteristics of patient tumors. In this article, we review PCa preclinical model cell lines and their sublines, PDXs, and patient-derived organoid and spheroid models. These PCa models will be applied to the development of new strategies for cancer precision medicine. Full article
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19 pages, 518 KiB  
Review
Telomere Biology and Human Phenotype
by Kara J. Turner, Vimal Vasu and Darren K. Griffin
Cells 2019, 8(1), 73; https://doi.org/10.3390/cells8010073 - 19 Jan 2019
Cited by 249 | Viewed by 18526
Abstract
Telomeres are nucleoprotein structures that cap the end of each chromosome arm and function to maintain genome stability. The length of telomeres is known to shorten with each cell division and it is well-established that telomere attrition is related to replicative capacity in [...] Read more.
Telomeres are nucleoprotein structures that cap the end of each chromosome arm and function to maintain genome stability. The length of telomeres is known to shorten with each cell division and it is well-established that telomere attrition is related to replicative capacity in vitro. Moreover, telomere loss is also correlated with the process of aging in vivo. In this review, we discuss the mechanisms that lead to telomere shortening and summarise telomere homeostasis in humans throughout a lifetime. In addition, we discuss the available evidence that shows that telomere shortening is related to human aging and the onset of age-related disease. Full article
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23 pages, 2225 KiB  
Article
Carnosine Prevents Aβ-Induced Oxidative Stress and Inflammation in Microglial Cells: A Key Role of TGF-β1
by Giuseppe Caruso, Claudia G. Fresta, Nicolò Musso, Mariaconcetta Giambirtone, Margherita Grasso, Simona F. Spampinato, Sara Merlo, Filippo Drago, Giuseppe Lazzarino, Maria A. Sortino, Susan M. Lunte and Filippo Caraci
Cells 2019, 8(1), 64; https://doi.org/10.3390/cells8010064 - 17 Jan 2019
Cited by 90 | Viewed by 9084
Abstract
Carnosine (β-alanyl-L-histidine), a dipeptide, is an endogenous antioxidant widely distributed in excitable tissues like muscles and the brain. Carnosine is involved in cellular defense mechanisms against oxidative stress, including the inhibition of amyloid-beta (Aβ) aggregation and the scavenging of reactive species. Microglia play [...] Read more.
Carnosine (β-alanyl-L-histidine), a dipeptide, is an endogenous antioxidant widely distributed in excitable tissues like muscles and the brain. Carnosine is involved in cellular defense mechanisms against oxidative stress, including the inhibition of amyloid-beta (Aβ) aggregation and the scavenging of reactive species. Microglia play a central role in the pathogenesis of Alzheimer’s disease, promoting neuroinflammation through the secretion of inflammatory mediators and free radicals. However, the effects of carnosine on microglial cells and neuroinflammation are not well understood. In the present work, carnosine was tested for its ability to protect BV-2 microglial cells against oligomeric Aβ1-42-induced oxidative stress and inflammation. Carnosine prevented cell death in BV-2 cells challenged with Aβ oligomers through multiple mechanisms. Specifically, carnosine lowered the oxidative stress by decreasing NO and O2−• intracellular levels as well as the expression of iNOS and Nox enzymes. Carnosine also decreased the secretion of pro-inflammatory cytokines such as IL-1β, simultaneously rescuing IL-10 levels and increasing the expression and the release of TGF-β1. Carnosine also prevented Aβ-induced neurodegeneration in mixed neuronal cultures challenged with Aβ oligomers, and these neuroprotective effects were completely abolished by SB431542, a selective inhibitor of the type-1 TGF-β receptor. Our data suggest a multimodal mechanism of action of carnosine underlying its protective effects on microglial cells against Aβ toxicity with a key role of TGF-β1 in mediating these protective effects. Full article
(This article belongs to the Special Issue TGF-beta/BMP Signaling Pathway)
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32 pages, 2091 KiB  
Review
The Roles of Ubiquitin-Binding Protein Shuttles in the Degradative Fate of Ubiquitinated Proteins in the Ubiquitin-Proteasome System and Autophagy
by Katarzyna Zientara-Rytter and Suresh Subramani
Cells 2019, 8(1), 40; https://doi.org/10.3390/cells8010040 - 10 Jan 2019
Cited by 85 | Viewed by 13502
Abstract
The ubiquitin-proteasome system (UPS) and autophagy are the two major intracellular protein quality control (PQC) pathways that are responsible for cellular proteostasis (homeostasis of the proteome) by ensuring the timely degradation of misfolded, damaged, and unwanted proteins. Ubiquitination serves as the degradation signal [...] Read more.
The ubiquitin-proteasome system (UPS) and autophagy are the two major intracellular protein quality control (PQC) pathways that are responsible for cellular proteostasis (homeostasis of the proteome) by ensuring the timely degradation of misfolded, damaged, and unwanted proteins. Ubiquitination serves as the degradation signal in both these systems, but substrates are precisely targeted to one or the other pathway. Determining how and when cells target specific proteins to these two alternative PQC pathways and control the crosstalk between them are topics of considerable interest. The ubiquitin (Ub) recognition code based on the type of Ub-linked chains on substrate proteins was believed to play a pivotal role in this process, but an increasing body of evidence indicates that the PQC pathway choice is also made based on other criteria. These include the oligomeric state of the Ub-binding protein shuttles, their conformation, protein modifications, and the presence of motifs that interact with ATG8/LC3/GABARAP (autophagy-related protein 8/microtubule-associated protein 1A/1B-light chain 3/GABA type A receptor-associated protein) protein family members. In this review, we summarize the current knowledge regarding the Ub recognition code that is bound by Ub-binding proteasomal and autophagic receptors. We also discuss how cells can modify substrate fate by modulating the structure, conformation, and physical properties of these receptors to affect their shuttling between both degradation pathways. Full article
(This article belongs to the Special Issue Proteostasis and Autophagy)
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23 pages, 10506 KiB  
Article
Oxidative Stress Induces Telomere Dysfunction and Senescence by Replication Fork Arrest
by Elisa Coluzzi, Stefano Leone and Antonella Sgura
Cells 2019, 8(1), 19; https://doi.org/10.3390/cells8010019 - 3 Jan 2019
Cited by 97 | Viewed by 9522
Abstract
Oxidative DNA damage, particularly 8-oxoguanine, represents the most frequent DNA damage in human cells, especially at the telomeric level. The presence of oxidative lesions in the DNA can hinder the replication fork and is able to activate the DNA damage response. In this [...] Read more.
Oxidative DNA damage, particularly 8-oxoguanine, represents the most frequent DNA damage in human cells, especially at the telomeric level. The presence of oxidative lesions in the DNA can hinder the replication fork and is able to activate the DNA damage response. In this study, we wanted to understand the mechanisms by which oxidative damage causes telomere dysfunction and senescence in human primary fibroblasts. After acute oxidative stress at telomeres, our data demonstrated a reduction in TRF1 and TRF2, which are involved in proper telomere replication and T-loop formation, respectively. Furthermore, we observed a higher level of γH2AX with respect to 53BP1 at telomeres, suggesting a telomeric replication fork stall rather than double-strand breaks. To confirm this finding, we studied the replication of telomeres by Chromosome Orientation-FISH (CO-FISH). The data obtained show an increase in unreplicated telomeres after hydrogen peroxide treatment, corroborating the idea that the presence of 8-oxoG can induce replication fork arrest at telomeres. Lastly, we analyzed the H3K9me3 histone mark after oxidative stress at telomeres, and our results showed an increase of this marker, most likely inducing the heterochromatinization of telomeres. These results suggest that 8-oxoG is fundamental in oxidative stress-induced telomeric damage, principally causing replication fork arrest. Full article
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19 pages, 4251 KiB  
Article
A Rise in ATP, ROS, and Mitochondrial Content upon Glucose Withdrawal Correlates with a Dysregulated Mitochondria Turnover Mediated by the Activation of the Protein Deacetylase SIRT1
by Seon Beom Song and Eun Seong Hwang
Cells 2019, 8(1), 11; https://doi.org/10.3390/cells8010011 - 27 Dec 2018
Cited by 33 | Viewed by 9726
Abstract
Glucose withdrawal has been used as a model for the study of homeostatic defense mechanisms, especially for how cells cope with a shortage of nutrient supply by enhancing catabolism. However, detailed cellular responses to glucose withdrawal have been poorly studied, and are controversial. [...] Read more.
Glucose withdrawal has been used as a model for the study of homeostatic defense mechanisms, especially for how cells cope with a shortage of nutrient supply by enhancing catabolism. However, detailed cellular responses to glucose withdrawal have been poorly studied, and are controversial. In this study, we determined how glucose withdrawal affects mitochondrial activity, and the quantity and the role of SIRT1 in these changes. The results of our study indicate a substantial increase in ATP production from mitochondria, through an elevation of mitochondrial biogenesis, mediated by SIRT1 activation that is driven by increased NAD+/NADH ratio. Moreover, mitochondria persisted in the cells as elongated forms, and apparently evaded mitophagic removal. This led to a steady increase in mitochondria content and the reactive oxygen species (ROS) generated from them, indicating failure in ATP and ROS homeostasis, due to a misbalance in SIRT1-mediated mitochondria turnover in conditions of glucose withdrawal. Our results suggest that SIRT1 activation alone cannot properly manage energy homeostasis under certain metabolic crisis conditions. Full article
(This article belongs to the Special Issue Mitochondrial Biology in Health and Disease)
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18 pages, 1881 KiB  
Review
Impact of Autophagy of Innate Immune Cells on Inflammatory Bowel Disease
by Tomoya Iida, Yoshihiro Yokoyama, Kohei Wagatsuma, Daisuke Hirayama and Hiroshi Nakase
Cells 2019, 8(1), 7; https://doi.org/10.3390/cells8010007 - 22 Dec 2018
Cited by 30 | Viewed by 7122
Abstract
Autophagy, an intracellular degradation mechanism, has many immunological functions and is a constitutive process necessary for maintaining cellular homeostasis and organ structure. One of the functions of autophagy is to control the innate immune response. Many studies conducted in recent years have revealed [...] Read more.
Autophagy, an intracellular degradation mechanism, has many immunological functions and is a constitutive process necessary for maintaining cellular homeostasis and organ structure. One of the functions of autophagy is to control the innate immune response. Many studies conducted in recent years have revealed the contribution of autophagy to the innate immune response, and relationships between this process and various diseases have been reported. Inflammatory bowel disease is an intractable disorder with unknown etiology; however, immunological abnormalities in the intestines are known to be involved in the pathology of inflammatory bowel disease, as is dysfunction of autophagy. In Crohn’s disease, many associations with autophagy-related genes, such as ATG16L1, IRGM, NOD2, and others, have been reported. Abnormalities in the ATG16L1 gene, in particular, have been reported to cause autophagic dysfunction, resulting in enhanced production of inflammatory cytokines by macrophages as well as abnormal function of Paneth cells, which are important in intestinal innate immunity. In this review, we provide an overview of the autophagy mechanism in innate immune cells in inflammatory bowel disease. Full article
(This article belongs to the Special Issue Autophagy in Tissue Injury and Homeostasis)
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