Cells

17 pages, 2647 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 28 | Viewed by 5700

Abstract

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

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

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

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18 pages, 1006 KiB

Open AccessEditor’s ChoiceArticle

VEGF Triggers Transient Induction of Autophagy in Endothelial Cells via AMPKα1

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

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

Cited by 37 | Viewed by 4962

Abstract

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

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

(This article belongs to the Section Autophagy)

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22 pages, 9422 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 20 | Viewed by 5225

Abstract

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

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

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

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17 pages, 2309 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 32 | Viewed by 6401

Abstract

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

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

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

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32 pages, 2039 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 125 | Viewed by 14172

Abstract

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

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

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

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21 pages, 504 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Astrocyte and Oligodendrocyte Cross-Talk in the Central Nervous System

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

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

Cited by 108 | Viewed by 15583

Abstract

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

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

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

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29 pages, 3774 KiB

Open AccessEditor’s ChoiceReview

Myeloid-Derived Suppressor Cells as a Therapeutic Target for Cancer

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

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

Cited by 321 | Viewed by 19229

Abstract

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

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

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

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21 pages, 3916 KiB

Open AccessEditor’s ChoiceArticle

Stress Reshapes the Physiological Response of Halophile Fungi to Salinity

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

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

Cited by 39 | Viewed by 5924

Abstract

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

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

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

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22 pages, 3412 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 46 | Viewed by 4213

Abstract

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

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

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

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11 pages, 698 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 26 | Viewed by 7474

Abstract

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

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

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

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32 pages, 541 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 785 | Viewed by 20387

Abstract

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

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

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

22 pages, 3107 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 208 | Viewed by 26592

Abstract

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

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

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

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17 pages, 2989 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 22 | Viewed by 5061

Abstract

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

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

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

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28 pages, 762 KiB

Open AccessEditor’s ChoiceReview

miRNAs as Influencers of Cell–Cell Communication in Tumor Microenvironment

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

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

Cited by 59 | Viewed by 8138

Abstract

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

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

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

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19 pages, 2870 KiB

Open AccessEditor’s ChoiceArticle

Hippocampal Neurogenesis Is Enhanced in Adult Tau Deficient Mice

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

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

Cited by 24 | Viewed by 5767

Abstract

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

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

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

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19 pages, 6856 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 91 | Viewed by 6287

Abstract

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

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

(This article belongs to the Section Cellular Pathology)

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27 pages, 1939 KiB

Open AccessEditor’s ChoiceReview

RNA-Based Therapeutics: From Antisense Oligonucleotides to miRNAs

by Sarah Bajan and Gyorgy Hutvagner

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

Cited by 258 | Viewed by 18748

Abstract

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

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

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

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13 pages, 1165 KiB

Open AccessEditor’s ChoiceArticle

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

by Hilal Tayara and Kil To Chong

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

Cited by 18 | Viewed by 4194

Abstract

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

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

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

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15 pages, 2810 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 17 | Viewed by 6984

Abstract

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

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

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

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20 pages, 3414 KiB

Open AccessFeature PaperEditor’s ChoiceReview

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

by Christiaan J. Stavast and Stefan J. Erkeland

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

Cited by 269 | Viewed by 11209

Abstract

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

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

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

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33 pages, 2540 KiB

Open AccessEditor’s ChoiceReview

MicroRNAs Contribute to Breast Cancer Invasiveness

by Ivana Fridrichova and Iveta Zmetakova

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

Cited by 116 | Viewed by 10040

Abstract

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

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

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

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20 pages, 3334 KiB

Open AccessEditor’s ChoiceArticle

Improved Motor Nerve Regeneration by SIRT1/Hif1a-Mediated Autophagy

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

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

Cited by 26 | Viewed by 5338

Abstract

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

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

(This article belongs to the Section Autophagy)

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22 pages, 2112 KiB

Open AccessFeature PaperEditor’s ChoiceReview

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

by Daria Sicari, Aeid Igbaria and Eric Chevet

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

Cited by 30 | Viewed by 9660

Abstract

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

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

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

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15 pages, 3111 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 86 | Viewed by 4739

Abstract

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

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

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

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14 pages, 3059 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 9 | Viewed by 31953

Abstract

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

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

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

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21 pages, 19459 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 142 | Viewed by 11628

Abstract

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

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

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

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10 pages, 1359 KiB

Open AccessFeature PaperEditor’s ChoiceReview

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

by Takafumi Yokota

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

Cited by 11 | Viewed by 9029

Abstract

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

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

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

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33 pages, 2337 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 813 | Viewed by 38982

Abstract

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

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

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

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28 pages, 1031 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 137 | Viewed by 16415

Abstract

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

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

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

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35 pages, 1887 KiB

Open AccessEditor’s ChoiceReview

Trends and Challenges in Tumor Anti-Angiogenic Therapies

by József Jászai and Mirko H.H. Schmidt

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

Cited by 161 | Viewed by 15411

Abstract

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

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

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

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21 pages, 2515 KiB

Open AccessEditor’s ChoiceArticle

Fatty Acid-Treated Induced Pluripotent Stem Cell-Derived Human Cardiomyocytes Exhibit Adult Cardiomyocyte-Like Energy Metabolism Phenotypes

by Yuichi Horikoshi, Yasheng Yan, Maia Terashvili, Clive Wells, Hisako Horikoshi, Satoshi Fujita, Zeljko J. Bosnjak and Xiaowen Bai

Cells 2019, 8(9), 1095; https://doi.org/10.3390/cells8091095 - 17 Sep 2019

Cited by 105 | Viewed by 13093

Abstract

Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) (iPSC-CMs) are a promising cell source for myocardial regeneration, disease modeling and drug assessment. However, iPSC-CMs exhibit immature fetal CM-like characteristics that are different from adult CMs in several aspects, including cellular structure and metabolism. [...] Read more.

Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) (iPSC-CMs) are a promising cell source for myocardial regeneration, disease modeling and drug assessment. However, iPSC-CMs exhibit immature fetal CM-like characteristics that are different from adult CMs in several aspects, including cellular structure and metabolism. As an example, glycolysis is a major energy source for immature CMs. As CMs mature, the mitochondrial oxidative capacity increases, with fatty acid β-oxidation becoming a key energy source to meet the heart’s high energy demand. The immaturity of iPSC-CMs thereby limits their applications. The aim of this study was to investigate whether the energy substrate fatty acid-treated iPSC-CMs exhibit adult CM-like metabolic properties. After 20 days of differentiation from human iPSCs, iPSC-CMs were sequentially cultured with CM purification medium (lactate+/glucose-) for 7 days and maturation medium (fatty acids+/glucose-) for 3–7 days by mimicking the adult CM’s preference of utilizing fatty acids as a major metabolic substrate. The purity and maturity of iPSC-CMs were characterized via the analysis of: (1) Expression of CM-specific markers (e.g., troponin T, and sodium and potassium channels) using RT-qPCR, Western blot or immunofluorescence staining and electron microscopy imaging; and (2) cell energy metabolic profiles using the XF96 Extracellular Flux Analyzer. iPSCs-CMs (98% purity) cultured in maturation medium exhibited enhanced elongation, increased mitochondrial numbers with more aligned Z-lines, and increased expression of matured CM-related genes, suggesting that fatty acid-contained medium promotes iPSC-CMs to undergo maturation. In addition, the oxygen consumption rate (OCR) linked to basal respiration, ATP production, and maximal respiration and spare respiratory capacity (representing mitochondrial function) was increased in matured iPSC-CMs. Mature iPSC-CMs also displayed a larger change in basal and maximum respirations due to the utilization of exogenous fatty acids (palmitate) compared with non-matured control iPSC-CMs. Etomoxir (a carnitine palmitoyltransferase 1 inhibitor) but not 2-deoxyglucose (an inhibitor of glycolysis) abolished the palmitate pretreatment-mediated OCR increases in mature iPSC-CMs. Collectively, our data demonstrate for the first time that fatty acid treatment promotes metabolic maturation of iPSC-CMs (as evidenced by enhanced mitochondrial oxidative function and strong capacity of utilizing fatty acids as energy source). These matured iPSC-CMs might be a promising human CM source for broad biomedical application. Full article

(This article belongs to the Special Issue Stem Cell-based Therapy and Disease Modeling)

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18 pages, 4207 KiB

Open AccessEditor’s ChoiceArticle

Melatonin Effects on Non-Alcoholic Fatty Liver Disease Are Related to MicroRNA-34a-5p/Sirt1 Axis and Autophagy

by Alessandra Stacchiotti, Ilaria Grossi, Raquel García-Gómez, Gaurangkumar Arvindbhai Patel, Alessandro Salvi, Antonio Lavazza, Giuseppina De Petro, Maria Monsalve and Rita Rezzani

Cells 2019, 8(9), 1053; https://doi.org/10.3390/cells8091053 - 8 Sep 2019

Cited by 67 | Viewed by 8497

Abstract

Melatonin, an indole produced by pineal and extrapineal tissues, but also taken with a vegetarian diet, has strong anti-oxidant, anti-inflammatory and anti-obesogenic potentials. Non-alcoholic fatty liver disease (NAFLD) is the hepatic side of the metabolic syndrome. NAFLD is a still reversible phase but [...] Read more.

Melatonin, an indole produced by pineal and extrapineal tissues, but also taken with a vegetarian diet, has strong anti-oxidant, anti-inflammatory and anti-obesogenic potentials. Non-alcoholic fatty liver disease (NAFLD) is the hepatic side of the metabolic syndrome. NAFLD is a still reversible phase but may evolve into steatohepatitis (NASH), cirrhosis and carcinoma. Currently, an effective therapy for blocking NAFLD staging is lacking. Silent information regulator 1 (SIRT1), a NAD+ dependent histone deacetylase, modulates the energetic metabolism in the liver. Micro-RNA-34a-5p, a direct inhibitor of SIRT1, is an emerging indicator of NAFLD grading. Thus, here we analyzed the effects of oral melatonin against NAFLD and underlying molecular mechanisms, focusing on steatosis, ER stress, mitochondrial shape and autophagy. Male C57BL/6J (WT) and SIRT1 heterozygous (HET) mice were placed either on a high-fat diet (58.4% energy from lard) (HFD) or on a standard maintenance diet (8.4% energy from lipids) for 16 weeks, drinking melatonin (10 mg/kg) or not. Indirect calorimetry, glucose tolerance, steatosis, inflammation, ER stress, mitochondrial changes, autophagy and microRNA-34a-5p expression were estimated. Melatonin improved hepatic metabolism and steatosis, influenced ER stress and mitochondrial shape, and promoted autophagy in WT HFD mice. Conversely, melatonin was ineffective in HET HFD mice, maintaining NASH changes. Indeed, autophagy was inconsistent in HET HFD or starved mice, as indicated by LC3II/LC3I ratio, p62/SQSTM1 and autophagosomes estimation. The beneficial role of melatonin in dietary induced NAFLD/NASH in mice was related to reduced expression of microRNA-34a-5p and sterol regulatory element-binding protein (SREBP1) but only in the presence of full SIRT1 availability. Full article

(This article belongs to the Special Issue Melatonin in Human Health and Diseases)

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20 pages, 1572 KiB

Open AccessEditor’s ChoiceReview

Membrane-Bound Meet Membraneless in Health and Disease

by Chujun Zhang and Catherine Rabouille

Cells 2019, 8(9), 1000; https://doi.org/10.3390/cells8091000 - 29 Aug 2019

Cited by 17 | Viewed by 6191

Abstract

Membraneless organelles (MLOs) are defined as cellular structures that are not sealed by a lipidic membrane and are shown to form by phase separation. They exist in both the nucleus and the cytoplasm that is also heavily populated by numerous membrane-bound organelles. Even [...] Read more.

Membraneless organelles (MLOs) are defined as cellular structures that are not sealed by a lipidic membrane and are shown to form by phase separation. They exist in both the nucleus and the cytoplasm that is also heavily populated by numerous membrane-bound organelles. Even though the name membraneless suggests that MLOs are free of membrane, both membrane and factors regulating membrane trafficking steps are emerging as important components of MLO formation and function. As a result, we name them biocondensates. In this review, we examine the relationships between biocondensates and membrane. First, inhibition of membrane trafficking in the early secretory pathway leads to the formation of biocondensates (P-bodies and Sec bodies). In the same vein, stress granules have a complex relationship with the cyto-nuclear transport machinery. Second, membrane contributes to the regulated formation of phase separation in the cells and we will present examples including clustering at the plasma membrane and at the synapse. Finally, the whole cell appears to transit from an interphase phase-separated state to a mitotic diffuse state in a DYRK3 dependent manner. This firmly establishes a crosstalk between the two types of cell organization that will need to be further explored. Full article

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

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19 pages, 1741 KiB

Open AccessEditor’s ChoiceReview

Physiology, Pathology and Regeneration of Salivary Glands

by Cristina Porcheri and Thimios A. Mitsiadis

Cells 2019, 8(9), 976; https://doi.org/10.3390/cells8090976 - 26 Aug 2019

Cited by 115 | Viewed by 22616

Abstract

Salivary glands are essential structures in the oral cavity. A variety of diseases, such as cancer, autoimmune diseases, infections and physical traumas, can alter the functionality of these glands, greatly impacting the quality of life of patients. To date, no definitive therapeutic approach [...] Read more.

Salivary glands are essential structures in the oral cavity. A variety of diseases, such as cancer, autoimmune diseases, infections and physical traumas, can alter the functionality of these glands, greatly impacting the quality of life of patients. To date, no definitive therapeutic approach can compensate the impairment of salivary glands, and treatment are purely symptomatic. Understanding the cellular and molecular control of salivary glands function is, therefore, highly relevant for therapeutic purposes. In this review, we provide a starting platform for future studies in basic biology and clinical research, reporting classical ideas on salivary gland physiology and recently developed technology to guide regeneration, reconstruction and substitution of the functional organs. Full article

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

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17 pages, 2413 KiB

Open AccessEditor’s ChoiceArticle

A Novel Computational Model for Predicting microRNA–Disease Associations Based on Heterogeneous Graph Convolutional Networks

by Chunyan Li, Hongju Liu, Qian Hu, Jinlong Que and Junfeng Yao

Cells 2019, 8(9), 977; https://doi.org/10.3390/cells8090977 - 26 Aug 2019

Cited by 39 | Viewed by 5849

Abstract

Identifying the interactions between disease and microRNA (miRNA) can accelerate drugs development, individualized diagnosis, and treatment for various human diseases. However, experimental methods are time-consuming and costly. So computational approaches to predict latent miRNA–disease interactions are eliciting increased attention. But most previous studies [...] Read more.

Identifying the interactions between disease and microRNA (miRNA) can accelerate drugs development, individualized diagnosis, and treatment for various human diseases. However, experimental methods are time-consuming and costly. So computational approaches to predict latent miRNA–disease interactions are eliciting increased attention. But most previous studies have mainly focused on designing complicated similarity-based methods to predict latent interactions between miRNAs and diseases. In this study, we propose a novel computational model, termed heterogeneous graph convolutional network for miRNA–disease associations (HGCNMDA), which is based on known human protein–protein interaction (PPI) and integrates four biological networks: miRNA–disease, miRNA–gene, disease–gene, and PPI network. HGCNMDA achieved reliable performance using leave-one-out cross-validation (LOOCV). HGCNMDA is then compared to three state-of-the-art algorithms based on five-fold cross-validation. HGCNMDA achieves an AUC of 0.9626 and an average precision of 0.9660, respectively, which is ahead of other competitive algorithms. We further analyze the top-10 unknown interactions between miRNA and disease. In summary, HGCNMDA is a useful computational model for predicting miRNA–disease interactions. Full article

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

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30 pages, 3370 KiB

Open AccessEditor’s ChoiceReview

TGFβ/BMP Signaling Pathway in Cartilage Homeostasis

by Nathalie G.M. Thielen, Peter M. van der Kraan and Arjan P.M. van Caam

Cells 2019, 8(9), 969; https://doi.org/10.3390/cells8090969 - 24 Aug 2019

Cited by 177 | Viewed by 14648

Abstract

Cartilage homeostasis is governed by articular chondrocytes via their ability to modulate extracellular matrix production and degradation. In turn, chondrocyte activity is regulated by growth factors such as those of the transforming growth factor β (TGFβ) family. Members of this family include the [...] Read more.

Cartilage homeostasis is governed by articular chondrocytes via their ability to modulate extracellular matrix production and degradation. In turn, chondrocyte activity is regulated by growth factors such as those of the transforming growth factor β (TGFβ) family. Members of this family include the TGFβs, bone morphogenetic proteins (BMPs), and growth and differentiation factors (GDFs). Signaling by this protein family uniquely activates SMAD-dependent signaling and transcription but also activates SMAD-independent signaling via MAPKs such as ERK and TAK1. This review will address the pivotal role of the TGFβ family in cartilage biology by listing several TGFβ family members and describing their signaling and importance for cartilage maintenance. In addition, it is discussed how (pathological) processes such as aging, mechanical stress, and inflammation contribute to altered TGFβ family signaling, leading to disturbed cartilage metabolism and disease. Full article

(This article belongs to the Special Issue TGF-beta/BMP Signaling Pathway)

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20 pages, 2696 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Dynamics of Dynamin-Related Protein 1 in Alzheimer’s Disease and Other Neurodegenerative Diseases

by Darryll Oliver and P. Hemachandra Reddy

Cells 2019, 8(9), 961; https://doi.org/10.3390/cells8090961 - 23 Aug 2019

Cited by 124 | Viewed by 14477

Abstract

The purpose of this article is to highlight the role of dynamin-related protein 1 (Drp1) in abnormal mitochondrial dynamics, mitochondrial fragmentation, autophagy/mitophagy, and neuronal damage in Alzheimer’s disease (AD) and other neurological diseases, including Parkinson’s, Huntington’s, amyotrophic lateral sclerosis, multiple sclerosis, diabetes, and [...] Read more.

The purpose of this article is to highlight the role of dynamin-related protein 1 (Drp1) in abnormal mitochondrial dynamics, mitochondrial fragmentation, autophagy/mitophagy, and neuronal damage in Alzheimer’s disease (AD) and other neurological diseases, including Parkinson’s, Huntington’s, amyotrophic lateral sclerosis, multiple sclerosis, diabetes, and obesity. Dynamin-related protein 1 is one of the evolutionarily highly conserved large family of GTPase proteins. Drp1 is critical for mitochondrial division, size, shape, and distribution throughout the neuron, from cell body to axons, dendrites, and nerve terminals. Several decades of intense research from several groups revealed that Drp1 is enriched at neuronal terminals and involved in synapse formation and synaptic sprouting. Different phosphorylated forms of Drp1 acts as both increased fragmentation and/or increased fusion of mitochondria. Increased levels of Drp1 were found in diseased states and caused excessive fragmentation of mitochondria, leading to mitochondrial dysfunction and neuronal damage. In the last two decades, several Drp1 inhibitors have been developed, including Mdivi-1, Dynasore, P110, and DDQ and their beneficial effects tested using cell cultures and mouse models of neurodegenerative diseases. Recent research using genetic crossing studies revealed that a partial reduction of Drp1 is protective against mutant protein(s)-induced mitochondrial and synaptic toxicities. Based on findings from cell cultures, mouse models and postmortem brains of AD and other neurodegenerative disease, we cautiously conclude that reduced Drp1 is a promising therapeutic target for AD and other neurological diseases. Full article

(This article belongs to the Section Mitochondria)

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32 pages, 2359 KiB

Open AccessEditor’s ChoiceReview

Mechanisms of Chemotherapy Resistance in Triple-Negative Breast Cancer—How We Can Rise to the Challenge

by Milica Nedeljković and Ana Damjanović

Cells 2019, 8(9), 957; https://doi.org/10.3390/cells8090957 - 22 Aug 2019

Cited by 530 | Viewed by 31159

Abstract

Triple-negative (TNBC) is the most lethal subtype of breast cancer owing to high heterogeneity, aggressive nature, and lack of treatment options. Chemotherapy remains the standard of care for TNBC treatment, but unfortunately, patients frequently develop resistance. Accordingly, in recent years, tremendous effort has [...] Read more.

Triple-negative (TNBC) is the most lethal subtype of breast cancer owing to high heterogeneity, aggressive nature, and lack of treatment options. Chemotherapy remains the standard of care for TNBC treatment, but unfortunately, patients frequently develop resistance. Accordingly, in recent years, tremendous effort has been made into elucidating the mechanisms of TNBC chemoresistance with the goal of identifying new molecular targets. It has become evident that the development of TNBC chemoresistance is multifaceted and based on the elaborate interplay of the tumor microenvironment, drug efflux, cancer stem cells, and bulk tumor cells. Alterations of multiple signaling pathways govern these interactions. Moreover, TNBC’s high heterogeneity, highlighted in the existence of several molecular signatures, presents a significant obstacle to successful treatment. In the present, in-depth review, we explore the contribution of key mechanisms to TNBC chemoresistance as well as emerging strategies to overcome them. We discuss novel anti-tumor agents that target the components of these mechanisms and pay special attention to their current clinical development while emphasizing the challenges still ahead of successful TNBC management. The evidence presented in this review outlines the role of crucial pathways in TNBC survival following chemotherapy treatment and highlights the importance of using combinatorial drug strategies and incorporating biomarkers in clinical studies. Full article

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

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23 pages, 1554 KiB

Open AccessEditor’s ChoiceReview

The Intricate Interplay between Epigenetic Events, Alternative Splicing and Noncoding RNA Deregulation in Colorectal Cancer

by Raheleh Amirkhah, Hojjat Naderi-Meshkin, Jaynish S. Shah, Philip D. Dunne and Ulf Schmitz

Cells 2019, 8(8), 929; https://doi.org/10.3390/cells8080929 - 19 Aug 2019

Cited by 35 | Viewed by 8799

Abstract

Colorectal cancer (CRC) results from a transformation of colonic epithelial cells into adenocarcinoma cells due to genetic and epigenetic instabilities, alongside remodelling of the surrounding stromal tumour microenvironment. Epithelial-specific epigenetic variations escorting this process include chromatin remodelling, histone modifications and aberrant DNA methylation, [...] Read more.

Colorectal cancer (CRC) results from a transformation of colonic epithelial cells into adenocarcinoma cells due to genetic and epigenetic instabilities, alongside remodelling of the surrounding stromal tumour microenvironment. Epithelial-specific epigenetic variations escorting this process include chromatin remodelling, histone modifications and aberrant DNA methylation, which influence gene expression, alternative splicing and function of non-coding RNA. In this review, we first highlight epigenetic modulators, modifiers and mediators in CRC, then we elaborate on causes and consequences of epigenetic alterations in CRC pathogenesis alongside an appraisal of the complex feedback mechanisms realized through alternative splicing and non-coding RNA regulation. An emphasis in our review is put on how this intricate network of epigenetic and post-transcriptional gene regulation evolves during the initiation, progression and metastasis formation in CRC. Full article

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26 pages, 2905 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Characterization of Cell Glycocalyx with Mass Spectrometry Methods

by Qiongyu Li, Yixuan Xie, Maurice Wong and Carlito B. Lebrilla

Cells 2019, 8(8), 882; https://doi.org/10.3390/cells8080882 - 13 Aug 2019

Cited by 27 | Viewed by 9647

Abstract

The cell membrane plays an important role in protecting the cell from its extracellular environment. As such, extensive work has been devoted to studying its structure and function. Crucial intercellular processes, such as signal transduction and immune protection, are mediated by cell surface [...] Read more.

The cell membrane plays an important role in protecting the cell from its extracellular environment. As such, extensive work has been devoted to studying its structure and function. Crucial intercellular processes, such as signal transduction and immune protection, are mediated by cell surface glycosylation, which is comprised of large biomolecules, including glycoproteins and glycosphingolipids. Because perturbations in glycosylation could result in dysfunction of cells and are related to diseases, the analysis of surface glycosylation is critical for understanding pathogenic mechanisms and can further lead to biomarker discovery. Different mass spectrometry-based techniques have been developed for glycan analysis, ranging from highly specific, targeted approaches to more comprehensive profiling studies. In this review, we summarized the work conducted for extensive analysis of cell membrane glycosylation, particularly those employing liquid chromatography with mass spectrometry (LC-MS) in combination with various sample preparation techniques. Full article

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23 pages, 1443 KiB

Open AccessEditor’s ChoiceReview

Current and Future Trends on Diagnosis and Prognosis of Glioblastoma: From Molecular Biology to Proteomics

by Artemiy S. Silantyev, Luca Falzone, Massimo Libra, Olga I. Gurina, Karina Sh. Kardashova, Taxiarchis K. Nikolouzakis, Alexander E. Nosyrev, Christopher W. Sutton, Panayiotis D. Mitsias and Aristides Tsatsakis

Cells 2019, 8(8), 863; https://doi.org/10.3390/cells8080863 - 9 Aug 2019

Cited by 177 | Viewed by 12071

Abstract

Glioblastoma multiforme is the most aggressive malignant tumor of the central nervous system. Due to the absence of effective pharmacological and surgical treatments, the identification of early diagnostic and prognostic biomarkers is of key importance to improve the survival rate of patients and [...] Read more.

Glioblastoma multiforme is the most aggressive malignant tumor of the central nervous system. Due to the absence of effective pharmacological and surgical treatments, the identification of early diagnostic and prognostic biomarkers is of key importance to improve the survival rate of patients and to develop new personalized treatments. On these bases, the aim of this review article is to summarize the current knowledge regarding the application of molecular biology and proteomics techniques for the identification of novel biomarkers through the analysis of different biological samples obtained from glioblastoma patients, including DNA, microRNAs, proteins, small molecules, circulating tumor cells, extracellular vesicles, etc. Both benefits and pitfalls of molecular biology and proteomics analyses are discussed, including the different mass spectrometry-based analytical techniques, highlighting how these investigation strategies are powerful tools to study the biology of glioblastoma, as well as to develop advanced methods for the management of this pathology. Full article

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23 pages, 2058 KiB

Open AccessEditor’s ChoiceReview

Current Status in Testing for Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH)

by Hannah K. Drescher, Sabine Weiskirchen and Ralf Weiskirchen

Cells 2019, 8(8), 845; https://doi.org/10.3390/cells8080845 - 7 Aug 2019

Cited by 101 | Viewed by 17936

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries with almost 25% affected adults worldwide. The growing public health burden is getting evident when considering that NAFLD-related liver transplantations are predicted to almost double within the next [...] Read more.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries with almost 25% affected adults worldwide. The growing public health burden is getting evident when considering that NAFLD-related liver transplantations are predicted to almost double within the next 20 years. Typically, hepatic alterations start with simple steatosis, which easily progresses to more advanced stages such as nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis. This course of disease finally leads to end-stage liver disease such as hepatocellular carcinoma, which is associated with increased morbidity and mortality. Although clinical trials show promising results, there is actually no pharmacological agent approved to treat NASH. Another important problem associated with NASH is that presently the liver biopsy is still the gold standard in diagnosis and for disease staging and grading. Because of its invasiveness, this technique is not well accepted by patients and the method is prone to sampling error. Therefore, an urgent need exists to find reliable, accurate and noninvasive biomarkers discriminating between different disease stages or to develop innovative imaging techniques to quantify steatosis. Full article

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

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33 pages, 1665 KiB

Open AccessEditor’s ChoiceReview

Role of miRNA-Regulated Cancer Stem Cells in the Pathogenesis of Human Malignancies

by Abdul Q. Khan, Eiman I. Ahmed, Noor R. Elareer, Kulsoom Junejo, Martin Steinhoff and Shahab Uddin

Cells 2019, 8(8), 840; https://doi.org/10.3390/cells8080840 - 5 Aug 2019

Cited by 226 | Viewed by 12815

Abstract

Recent biomedical discoveries have revolutionized the concept and understanding of carcinogenesis, a complex and multistep phenomenon which involves accretion of genetic, epigenetic, biochemical, and histological changes, with special reference to MicroRNAs (miRNAs) and cancer stem cells (CSCs). miRNAs are small noncoding molecules known [...] Read more.

Recent biomedical discoveries have revolutionized the concept and understanding of carcinogenesis, a complex and multistep phenomenon which involves accretion of genetic, epigenetic, biochemical, and histological changes, with special reference to MicroRNAs (miRNAs) and cancer stem cells (CSCs). miRNAs are small noncoding molecules known to regulate expression of more than 60% of the human genes, and their aberrant expression has been associated with the pathogenesis of human cancers and the regulation of stemness features of CSCs. CSCs are the small population of cells present in human malignancies well-known for cancer resistance, relapse, tumorigenesis, and poor clinical outcome which compels the development of novel and effective therapeutic protocols for better clinical outcome. Interestingly, the role of miRNAs in maintaining and regulating the functioning of CSCs through targeting various oncogenic signaling pathways, such as Notch, wingless (WNT)/β-Catenin, janus kinases/ signal transducer and activator of transcription (JAK/STAT), phosphatidylinositol 3-kinase/ protein kinase B (PI3/AKT), and nuclear factor kappa-light-chain-enhancer of activated B (NF-kB), is critical and poses a huge challenge to cancer treatment. Based on recent findings, here, we have documented the regulatory action or the underlying mechanisms of how miRNAs affect the signaling pathways attributed to stemness features of CSCs, such as self-renewal, differentiation, epithelial to mesenchymal transition (EMT), metastasis, resistance and recurrence etc., associated with the pathogenesis of various types of human malignancies including colorectal cancer, lung cancer, breast cancer, head and neck cancer, prostate cancer, liver cancer, etc. We also shed light on the fact that the targeted attenuation of deregulated functioning of miRNA related to stemness in human carcinogenesis could be a viable approach for cancer treatment. Full article

(This article belongs to the Special Issue CSCs Identification and Targeting Therapies: Advances and Challenges)

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32 pages, 1914 KiB

Open AccessEditor’s ChoiceReview

WNT Signaling in Disease

by Li Fang Ng, Prameet Kaur, Nawat Bunnag, Jahnavi Suresh, Isabelle Chiao Han Sung, Qian Hui Tan, Jan Gruber and Nicholas S. Tolwinski

Cells 2019, 8(8), 826; https://doi.org/10.3390/cells8080826 - 3 Aug 2019

Cited by 177 | Viewed by 17500

Abstract

Developmental signaling pathways control a vast array of biological processes during embryogenesis and in adult life. The WNT pathway was discovered simultaneously in cancer and development. Recent advances have expanded the role of WNT to a wide range of pathologies in humans. Here, [...] Read more.

Developmental signaling pathways control a vast array of biological processes during embryogenesis and in adult life. The WNT pathway was discovered simultaneously in cancer and development. Recent advances have expanded the role of WNT to a wide range of pathologies in humans. Here, we discuss the WNT pathway and its role in human disease and some of the advances in WNT-related treatments. Full article

(This article belongs to the Special Issue Wnt Signaling in Health and Diseases)

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33 pages, 7317 KiB

Open AccessEditor’s ChoiceReview

Role and Therapeutic Targeting of the PI3K/Akt/mTOR Signaling Pathway in Skin Cancer: A Review of Current Status and Future Trends on Natural and Synthetic Agents Therapy

by Jean Christopher Chamcheu, Tithi Roy, Mohammad Burhan Uddin, Sergette Banang-Mbeumi, Roxane-Cherille N. Chamcheu, Anthony L. Walker, Yong-Yu Liu and Shile Huang

Cells 2019, 8(8), 803; https://doi.org/10.3390/cells8080803 - 31 Jul 2019

Cited by 133 | Viewed by 12264

Abstract

The mammalian or mechanistic target of rapamycin (mTOR) and associated phosphatidyl-inositiol 3-kinase (PI3K)/protein kinase B (Akt) pathways regulate cell growth, differentiation, migration, and survival, as well as angiogenesis and metabolism. Dysregulation of these pathways is frequently associated with genetic/epigenetic alterations and predicts poor [...] Read more.

The mammalian or mechanistic target of rapamycin (mTOR) and associated phosphatidyl-inositiol 3-kinase (PI3K)/protein kinase B (Akt) pathways regulate cell growth, differentiation, migration, and survival, as well as angiogenesis and metabolism. Dysregulation of these pathways is frequently associated with genetic/epigenetic alterations and predicts poor treatment outcomes in a variety of human cancers including cutaneous malignancies like melanoma and non-melanoma skin cancers. Recently, the enhanced understanding of the molecular and genetic basis of skin dysfunction in patients with skin cancers has provided a strong basis for the development of novel therapeutic strategies for these obdurate groups of skin cancers. This review summarizes recent advances in the roles of PI3K/Akt/mTOR and their targets in the development and progression of a broad spectrum of cutaneous cancers and discusses the current progress in preclinical and clinical studies for the development of PI3K/Akt/mTOR targeted therapies with nutraceuticals and synthetic small molecule inhibitors. Full article

(This article belongs to the Special Issue mTOR Signaling in Metabolism and Cancer)

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28 pages, 4164 KiB

Open AccessEditor’s ChoiceReview

Metabolic Plasticity of Acute Myeloid Leukemia

by Johanna Kreitz, Christine Schönfeld, Marcel Seibert, Verena Stolp, Islam Alshamleh, Thomas Oellerich, Björn Steffen, Harald Schwalbe, Frank Schnütgen, Nina Kurrle and Hubert Serve

Cells 2019, 8(8), 805; https://doi.org/10.3390/cells8080805 - 31 Jul 2019

Cited by 105 | Viewed by 11727

Abstract

Acute myeloid leukemia (AML) is one of the most common and life-threatening leukemias. A highly diverse and flexible metabolism contributes to the aggressiveness of the disease that is still difficult to treat. By using different sources of nutrients for energy and biomass supply, [...] Read more.

Acute myeloid leukemia (AML) is one of the most common and life-threatening leukemias. A highly diverse and flexible metabolism contributes to the aggressiveness of the disease that is still difficult to treat. By using different sources of nutrients for energy and biomass supply, AML cells gain metabolic plasticity and rapidly outcompete normal hematopoietic cells. This review aims to decipher the diverse metabolic strategies and the underlying oncogenic and environmental changes that sustain continuous growth, mediate redox homeostasis and induce drug resistance in AML. We revisit Warburg’s hypothesis and illustrate the role of glucose as a provider of cellular building blocks rather than as a supplier of the tricarboxylic acid (TCA) cycle for energy production. We discuss how the diversity of fuels for the TCA cycle, including glutamine and fatty acids, contributes to the metabolic plasticity of the disease and highlight the roles of amino acids and lipids in AML metabolism. Furthermore, we point out the potential of the different metabolic effectors to be used as novel therapeutic targets. Full article

(This article belongs to the Special Issue Metabolomics in Physiology and Diseases)

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14 pages, 1404 KiB

Open AccessEditor’s ChoiceReview

Short Overview of ROS as Cell Function Regulators and Their Implications in Therapy Concepts

by Lidija Milkovic, Ana Cipak Gasparovic, Marina Cindric, Pierre-Alexis Mouthuy and Neven Zarkovic

Cells 2019, 8(8), 793; https://doi.org/10.3390/cells8080793 - 30 Jul 2019

Cited by 225 | Viewed by 11264

Abstract

The importance of reactive oxygen species (ROS) has been gradually acknowledged over the last four decades. Initially perceived as unwanted products of detrimental oxidative stress, they have been upgraded since, and now ROS are also known to be essential for the regulation of [...] Read more.

The importance of reactive oxygen species (ROS) has been gradually acknowledged over the last four decades. Initially perceived as unwanted products of detrimental oxidative stress, they have been upgraded since, and now ROS are also known to be essential for the regulation of physiological cellular functions through redox signaling. In the majority of cases, metabolic demands, along with other stimuli, are vital for ROS formation and their actions. In this review, we focus on the role of ROS in regulating cell functioning and communication among themselves. The relevance of ROS in therapy concepts is also addressed here. Full article

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23 pages, 2076 KiB

Open AccessEditor’s ChoiceReview

Metabolic Dysregulations and Epigenetics: A Bidirectional Interplay that Drives Tumor Progression

by Fabiana Crispo, Valentina Condelli, Silvia Lepore, Tiziana Notarangelo, Alessandro Sgambato, Franca Esposito, Francesca Maddalena and Matteo Landriscina

Cells 2019, 8(8), 798; https://doi.org/10.3390/cells8080798 - 30 Jul 2019

Cited by 35 | Viewed by 6026

Abstract

Cancer has been considered, for a long time, a genetic disease where mutations in key regulatory genes drive tumor initiation, growth, metastasis, and drug resistance. Instead, the advent of high-throughput technologies has revolutionized cancer research, allowing to investigate molecular alterations at multiple levels, [...] Read more.

Cancer has been considered, for a long time, a genetic disease where mutations in key regulatory genes drive tumor initiation, growth, metastasis, and drug resistance. Instead, the advent of high-throughput technologies has revolutionized cancer research, allowing to investigate molecular alterations at multiple levels, including genome, epigenome, transcriptome, proteome, and metabolome and showing the multifaceted aspects of this disease. The multi-omics approaches revealed an intricate molecular landscape where different cellular functions are interconnected and cooperatively contribute to shaping the malignant phenotype. Recent evidence has brought to light how metabolism and epigenetics are highly intertwined, and their aberrant crosstalk can contribute to tumorigenesis. The oncogene-driven metabolic plasticity of tumor cells supports the energetic and anabolic demands of proliferative tumor programs and secondary can alter the epigenetic landscape via modulating the production and/or the activity of epigenetic metabolites. Conversely, epigenetic mechanisms can regulate the expression of metabolic genes, thereby altering the metabolome, eliciting adaptive responses to rapidly changing environmental conditions, and sustaining malignant cell survival and progression in hostile niches. Thus, cancer cells take advantage of the epigenetics-metabolism crosstalk to acquire aggressive traits, promote cell proliferation, metastasis, and pluripotency, and shape tumor microenvironment. Understanding this bidirectional relationship is crucial to identify potential novel molecular targets for the implementation of robust anti-cancer therapeutic strategies. Full article

(This article belongs to the Special Issue Mitochondrial Metabolic Reprogramming and Nuclear Crosstalk in Cancer)

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22 pages, 5465 KiB

Open AccessEditor’s ChoiceArticle

Microglial Phenotyping in Neurodegenerative Disease Brains: Identification of Reactive Microglia with an Antibody to Variant of CD105/Endoglin

by Douglas G. Walker, Lih-Fen Lue, Thomas G. Beach and Ikuo Tooyama

Cells 2019, 8(7), 766; https://doi.org/10.3390/cells8070766 - 23 Jul 2019

Cited by 10 | Viewed by 7682

Abstract

Inflammation is considered a key pathological process in neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), but there are still mechanisms not understood. In the brain, most microglia are performing essential homeostatic functions, but can also respond to pathogenic stimuli by [...] Read more.

Inflammation is considered a key pathological process in neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), but there are still mechanisms not understood. In the brain, most microglia are performing essential homeostatic functions, but can also respond to pathogenic stimuli by producing harmful pro-inflammatory cytokines or free radicals. Distinguishing between damaging and homeostatic microglia in human diseased brain tissues is a challenge. This report describes findings using a monoclonal antibody to CD105/Endoglin (R&D Systems MAB1097) that identifies subtypes of activated microglia. CD105/Endoglin is a co-receptor for transforming growth factor beta (TGFβ) receptor that antagonizes TGFβ signaling. CD105/Endoglin is a marker for vascular endothelial cells, but was originally identified as a marker for activated macrophages. This antibody did not identify endothelial cells in brain sections, only microglia-like cells. In this study, we examined with this antibody tissue section from middle temporal gyrus derived from human brains from normal control subjects with low-plaque pathology, high-plaque pathology, and AD cases, and also substantia nigra samples from control and PD cases, in conjunction with antibodies to markers of pathology and microglia. In low-plaque pathology cases, CD105-positive microglia were mostly absent, but noticeably increased with increasing pathology. CD105-positive cells strongly colocalized with amyloid-beta plaques, but not phosphorylated tau positive tangles. In substantia nigra, strong microglial CD105 staining was observed in microglia associated with degenerating dopaminergic neurons and neuromelanin. In PD cases with few surviving dopaminergic neurons, this staining had decreased. By Western blot, this antibody identified polypeptide bands of 70 kDa in brain samples, and samples from microglia, macrophages, and brain endothelial cells. In comparison with other tested CD105 antibodies, this antibody did not recognize the glycosylated forms of CD105 on Western blots. Overall, the data indicate that this antibody and this marker could have utility for subtyping of microglia in pathologically-involved tissue. Full article

(This article belongs to the Special Issue Microglia in Neurodegenerative Diseases)

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17 pages, 3140 KiB

Open AccessEditor’s ChoiceArticle

Ensemble of Deep Recurrent Neural Networks for Identifying Enhancers via Dinucleotide Physicochemical Properties

by Kok Keng Tan, Nguyen Quoc Khanh Le, Hui-Yuan Yeh and Matthew Chin Heng Chua

Cells 2019, 8(7), 767; https://doi.org/10.3390/cells8070767 - 23 Jul 2019

Cited by 30 | Viewed by 5279

Abstract

Enhancers are short deoxyribonucleic acid fragments that assume an important part in the genetic process of gene expression. Due to their possibly distant location relative to the gene that is acted upon, the identification of enhancers is difficult. There are many published works [...] Read more.

Enhancers are short deoxyribonucleic acid fragments that assume an important part in the genetic process of gene expression. Due to their possibly distant location relative to the gene that is acted upon, the identification of enhancers is difficult. There are many published works focused on identifying enhancers based on their sequence information, however, the resulting performance still requires improvements. Using deep learning methods, this study proposes a model ensemble of classifiers for predicting enhancers based on deep recurrent neural networks. The input features of deep ensemble networks were generated from six types of dinucleotide physicochemical properties, which had outperformed the other features. In summary, our model which used this ensemble approach could identify enhancers with achieved sensitivity of 75.5%, specificity of 76%, accuracy of 75.5%, and MCC of 0.51. For classifying enhancers into strong or weak sequences, our model reached sensitivity of 83.15%, specificity of 45.61%, accuracy of 68.49%, and MCC of 0.312. Compared to the benchmark result, our results had higher performance in term of most measurement metrics. The results showed that deep model ensembles hold the potential for improving on the best results achieved to date using shallow machine learning methods. Full article

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

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