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Editor’s Choice Articles

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

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15 pages, 852 KB  
Review
Epigenetic Mechanisms of Senescence in Plants
by Matin Miryeganeh
Cells 2022, 11(2), 251; https://doi.org/10.3390/cells11020251 - 12 Jan 2022
Cited by 24 | Viewed by 6580
Abstract
Senescence is a major developmental transition in plants that requires a massive reprogramming of gene expression and includes various layers of regulations. Senescence is either an age-dependent or a stress-induced process, and is under the control of complex regulatory networks that interact with [...] Read more.
Senescence is a major developmental transition in plants that requires a massive reprogramming of gene expression and includes various layers of regulations. Senescence is either an age-dependent or a stress-induced process, and is under the control of complex regulatory networks that interact with each other. It has been shown that besides genetic reprogramming, which is an important aspect of plant senescence, transcription factors and higher-level mechanisms, such as epigenetic and small RNA-mediated regulators, are also key factors of senescence-related genes. Epigenetic mechanisms are an important layer of this multilevel regulatory system that change the activity of transcription factors (TFs) and play an important role in modulating the expression of senescence-related gene. They include chromatin remodeling, DNA methylation, histone modification, and the RNA-mediated control of transcription factors and genes. This review provides an overview of the known epigenetic regulation of plant senescence, which has mostly been studied in the form of leaf senescence, and it also covers what has been reported about whole-plant senescence. Full article
(This article belongs to the Special Issue Epigenetic Mechanisms of Longevity and Aging)
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26 pages, 1798 KB  
Review
One-Carbon Metabolism: Pulling the Strings behind Aging and Neurodegeneration
by Eirini Lionaki, Christina Ploumi and Nektarios Tavernarakis
Cells 2022, 11(2), 214; https://doi.org/10.3390/cells11020214 - 9 Jan 2022
Cited by 70 | Viewed by 23975
Abstract
One-carbon metabolism (OCM) is a network of biochemical reactions delivering one-carbon units to various biosynthetic pathways. The folate cycle and methionine cycle are the two key modules of this network that regulate purine and thymidine synthesis, amino acid homeostasis, and epigenetic mechanisms. Intersection [...] Read more.
One-carbon metabolism (OCM) is a network of biochemical reactions delivering one-carbon units to various biosynthetic pathways. The folate cycle and methionine cycle are the two key modules of this network that regulate purine and thymidine synthesis, amino acid homeostasis, and epigenetic mechanisms. Intersection with the transsulfuration pathway supports glutathione production and regulation of the cellular redox state. Dietary intake of micronutrients, such as folates and amino acids, directly contributes to OCM, thereby adapting the cellular metabolic state to environmental inputs. The contribution of OCM to cellular proliferation during development and in adult proliferative tissues is well established. Nevertheless, accumulating evidence reveals the pivotal role of OCM in cellular homeostasis of non-proliferative tissues and in coordination of signaling cascades that regulate energy homeostasis and longevity. In this review, we summarize the current knowledge on OCM and related pathways and discuss how this metabolic network may impact longevity and neurodegeneration across species. Full article
(This article belongs to the Special Issue Role of Mitochondria in Environmentally and Dietary Modulated Age-Associated Diseases)
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16 pages, 2813 KB  
Article
Native and Oxidized Low-Density Lipoproteins Increase the Expression of the LDL Receptor and the LOX-1 Receptor, Respectively, in Arterial Endothelial Cells
by Rusan Catar, Lei Chen, Hongfan Zhao, Dashan Wu, Julian Kamhieh-Milz, Christian Lücht, Daniel Zickler, Alexander W. Krug, Christian G. Ziegler, Henning Morawietz and Janusz Witowski
Cells 2022, 11(2), 204; https://doi.org/10.3390/cells11020204 - 8 Jan 2022
Cited by 21 | Viewed by 7863
Abstract
Atherosclerotic artery disease is the major cause of death and an immense burden on healthcare systems worldwide. The formation of atherosclerotic plaques is promoted by high levels of low-density lipoproteins (LDL) in the blood, especially in the oxidized form. Circulating LDL is taken [...] Read more.
Atherosclerotic artery disease is the major cause of death and an immense burden on healthcare systems worldwide. The formation of atherosclerotic plaques is promoted by high levels of low-density lipoproteins (LDL) in the blood, especially in the oxidized form. Circulating LDL is taken up by conventional and non-classical endothelial cell receptors and deposited in the vessel wall. The exact mechanism of LDL interaction with vascular endothelial cells is not fully understood. Moreover, it appears to depend on the type and location of the vessel affected and the receptor involved. Here, we analyze how native LDL (nLDL) and oxidized LDL (oxLDL) modulate the expression of their receptors—classical LDLR and alternative LOX-1—in endothelial cells derived from human umbilical artery (HUAECs), used as an example of a medium-sized vessel, which is typically affected by atherosclerosis. Exposure of HUAECs to nLDL resulted in moderate nLDL uptake and gradual increase in LDLR, but not LOX-1, expression over 24 h. Conversely, exposure of HUAECs to oxLDL, led to significant accumulation of oxLDL and rapid induction of LOX-1, but not LDLR, within 7 h. These activation processes were associated with phosphorylation of protein kinases ERK1/2 and p38, followed by activation of the transcription factor AP-1 and its binding to the promoters of the respective receptor genes. Both nLDL-induced LDLR mRNA expression and oxLDL-induced LOX-1 mRNA expression were abolished by blocking ERK1/2, p-38 or AP-1. In addition, oxLDL, but not nLDL, was capable of inducing LOX-1 through the NF-κB-controlled pathway. These observations indicate that in arterial endothelial cells nLDL and oxLDL signal mainly via LDLR and LOX-1 receptors, respectively, and engage ERK1/2 and p38 kinases, and AP-1, as well as NF-κB transcription factors to exert feed-forward regulation and increase the expression of these receptors, which may perpetuate endothelial dysfunction in atherosclerosis. Full article
(This article belongs to the Collection Endothelial Cell Dysfunction and Multi-Organ Injury: From Molecular Mechanisms to Therapeutic Interventions)
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12 pages, 1691 KB  
Article
Transient Exposure of Endothelial Cells to Doxorubicin Leads to Long-Lasting Vascular Endothelial Growth Factor Receptor 2 Downregulation
by Silvia Graziani, Luca Scorrano and Giovanna Pontarin
Cells 2022, 11(2), 210; https://doi.org/10.3390/cells11020210 - 8 Jan 2022
Cited by 21 | Viewed by 5226
Abstract
Doxorubicin (Dox) is an effective antineoplastic drug with serious cardiotoxic side effects that persist after drug withdrawal and can lead to heart failure. Dysregulation of vascular endothelium has been linked to the development of Dox-induced cardiotoxicity, but it is unclear whether and how [...] Read more.
Doxorubicin (Dox) is an effective antineoplastic drug with serious cardiotoxic side effects that persist after drug withdrawal and can lead to heart failure. Dysregulation of vascular endothelium has been linked to the development of Dox-induced cardiotoxicity, but it is unclear whether and how transient exposure to Dox leads to long-term downregulation of Endothelial Vascular Endothelial Growth Factor Receptor type2 (VEGFR2), essential for endothelial cells function. Using an in vitro model devised to study the long-lasting effects of brief endothelial cells exposure to Dox, we show that Dox leads to sustained protein synthesis inhibition and VEGFR2 downregulation. Transient Dox treatment led to the development of long-term senescence associated with a reduction in VEGFR2 levels that persisted days after drug withdrawal. By analyzing VEGFR2 turnover, we ruled out that its downregulation was depended on Dox-induced autophagy. Conversely, Dox induced p53 expression, reduced mTOR-dependent translation, and inhibited global protein synthesis. Our data contribute to a mechanistic basis to the permanent damage caused to endothelial cells by short-term Dox treatment. Full article
(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Organelle Function)
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22 pages, 1214 KB  
Review
Methodologies to Isolate and Purify Clinical Grade Extracellular Vesicles for Medical Applications
by Asma Akbar, Farzaneh Malekian, Neda Baghban, Sai Priyanka Kodam and Mujib Ullah
Cells 2022, 11(2), 186; https://doi.org/10.3390/cells11020186 - 6 Jan 2022
Cited by 112 | Viewed by 10442
Abstract
The use of extracellular vesicles (EV) in nano drug delivery has been demonstrated in many previous studies. In this study, we discuss the sources of extracellular vesicles, including plant, salivary and urinary sources which are easily available but less sought after compared with [...] Read more.
The use of extracellular vesicles (EV) in nano drug delivery has been demonstrated in many previous studies. In this study, we discuss the sources of extracellular vesicles, including plant, salivary and urinary sources which are easily available but less sought after compared with blood and tissue. Extensive research in the past decade has established that the breadth of EV applications is wide. However, the efforts on standardizing the isolation and purification methods have not brought us to a point that can match the potential of extracellular vesicles for clinical use. The standardization can open doors for many researchers and clinicians alike to experiment with the proposed clinical uses with lesser concerns regarding untraceable side effects. It can make it easier to identify the mechanism of therapeutic benefits and to track the mechanism of any unforeseen effects observed. Full article
(This article belongs to the Special Issue Stem Cells and Extracellular Vesicles)
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15 pages, 1095 KB  
Review
Role of MicroRNAs and Long Non-Coding RNAs in Sarcopenia
by Jihui Lee and Hara Kang
Cells 2022, 11(2), 187; https://doi.org/10.3390/cells11020187 - 6 Jan 2022
Cited by 26 | Viewed by 5192
Abstract
Sarcopenia is an age-related pathological process characterized by loss of muscle mass and function, which consequently affects the quality of life of the elderly. There is growing evidence that non-coding RNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), play a key role [...] Read more.
Sarcopenia is an age-related pathological process characterized by loss of muscle mass and function, which consequently affects the quality of life of the elderly. There is growing evidence that non-coding RNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), play a key role in skeletal muscle physiology. Alterations in the expression levels of miRNAs and lncRNAs contribute to muscle atrophy and sarcopenia by regulating various signaling pathways. This review summarizes the recent findings regarding non-coding RNAs associated with sarcopenia and provides an overview of sarcopenia pathogenesis promoted by multiple non-coding RNA-mediated signaling pathways. In addition, we discuss the impact of exercise on the expression patterns of non-coding RNAs involved in sarcopenia. Identifying non-coding RNAs associated with sarcopenia and understanding the molecular mechanisms that regulate skeletal muscle dysfunction during aging will provide new insights to develop potential treatment strategies. Full article
(This article belongs to the Special Issue Role of Non-coding RNA in Health and Disease)
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32 pages, 2696 KB  
Article
Co-Expression Analysis of microRNAs and Proteins in Brain of Alzheimer’s Disease Patients
by Callum N. Watson, Ghazala Begum, Emma Ashman, Daniella Thorn, Kamal M. Yakoub, Moustafa Al Hariri, Ali Nehme, Stefania Mondello, Firas Kobeissy, Antonio Belli and Valentina Di Pietro
Cells 2022, 11(1), 163; https://doi.org/10.3390/cells11010163 - 4 Jan 2022
Cited by 12 | Viewed by 5303
Abstract
Alzheimer’s disease (AD) is the most common form of dementia globally; however, the aetiology of AD remains elusive hindering the development of effective therapeutics. MicroRNAs (miRNAs) are regulators of gene expression and have been of growing interest in recent studies in many pathologies [...] Read more.
Alzheimer’s disease (AD) is the most common form of dementia globally; however, the aetiology of AD remains elusive hindering the development of effective therapeutics. MicroRNAs (miRNAs) are regulators of gene expression and have been of growing interest in recent studies in many pathologies including AD not only for their use as biomarkers but also for their implications in the therapeutic field. In this study, miRNA and protein profiles were obtained from brain tissues of different stage (Braak III-IV and Braak V-VI) of AD patients and compared to matched controls. The aim of the study was to identify in the late stage of AD, the key dysregulated pathways that may contribute to pathogenesis and then to evaluate whether any of these pathways could be detected in the early phase of AD, opening new opportunity for early treatment that could stop or delay the pathology. Six common pathways were found regulated by miRNAs and proteins in the late stage of AD, with one of them (Rap1 signalling) activated since the early phase. MiRNAs and proteins were also compared to explore an inverse trend of expression which could lead to the identification of new therapeutic targets. These results suggest that specific miRNA changes could represent molecular fingerprint of neurodegenerative processes and potential therapeutic targets for early intervention. Full article
(This article belongs to the Special Issue MicroRNA-Mediated Silencing Pathways in the Nervous System and Neurological Diseases)
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29 pages, 3204 KB  
Review
Overview of Polyamines as Nutrients for Human Healthy Long Life and Effect of Increased Polyamine Intake on DNA Methylation
by Kuniyasu Soda
Cells 2022, 11(1), 164; https://doi.org/10.3390/cells11010164 - 4 Jan 2022
Cited by 56 | Viewed by 13220
Abstract
Polyamines, spermidine and spermine, are synthesized in every living cell and are therefore contained in foods, especially in those that are thought to contribute to health and longevity. They have many physiological activities similar to those of antioxidant and anti-inflammatory substances such as [...] Read more.
Polyamines, spermidine and spermine, are synthesized in every living cell and are therefore contained in foods, especially in those that are thought to contribute to health and longevity. They have many physiological activities similar to those of antioxidant and anti-inflammatory substances such as polyphenols. These include antioxidant and anti-inflammatory properties, cell and gene protection, and autophagy activation. We have first reported that increased polyamine intake (spermidine much more so than spermine) over a long period increased blood spermine levels and inhibited aging-associated pathologies and pro-inflammatory status in humans and mice and extended life span of mice. However, it is unlikely that the life-extending effect of polyamines is exerted by the same bioactivity as polyphenols because most studies using polyphenols and antioxidants have failed to demonstrate their life-extending effects. Recent investigations revealed that aging-associated pathologies and lifespan are closely associated with DNA methylation, a regulatory mechanism of gene expression. There is a close relationship between polyamine metabolism and DNA methylation. We have shown that the changes in polyamine metabolism affect the concentrations of substances and enzyme activities involved in DNA methylation. I consider that the increased capability of regulation of DNA methylation by spermine is a key of healthy long life of humans. Full article
(This article belongs to the Special Issue Epigenetic Mechanisms of Longevity and Aging)
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17 pages, 3902 KB  
Article
Matrix Metalloproteinases Inhibition by Doxycycline Rescues Extracellular Matrix Organization and Partly Reverts Myofibroblast Differentiation in Hypermobile Ehlers-Danlos Syndrome Dermal Fibroblasts: A Potential Therapeutic Target?
by Nicola Chiarelli, Nicoletta Zoppi, Marina Venturini, Daniele Capitanio, Cecilia Gelfi, Marco Ritelli and Marina Colombi
Cells 2021, 10(11), 3236; https://doi.org/10.3390/cells10113236 - 19 Nov 2021
Cited by 14 | Viewed by 9457
Abstract
Hypermobile Ehlers-Danlos syndrome (hEDS) is the most frequent type of EDS and is characterized by generalized joint hypermobility and musculoskeletal manifestations which are associated with chronic pain, and mild skin involvement along with the presence of more than a few comorbid conditions. Despite [...] Read more.
Hypermobile Ehlers-Danlos syndrome (hEDS) is the most frequent type of EDS and is characterized by generalized joint hypermobility and musculoskeletal manifestations which are associated with chronic pain, and mild skin involvement along with the presence of more than a few comorbid conditions. Despite numerous research efforts, no causative gene(s) or validated biomarkers have been identified and insights into the disease-causing mechanisms remain scarce. Variability in the spectrum and severity of symptoms and progression of hEDS patients’ phenotype likely depend on a combination of age, gender, lifestyle, and the probable multitude of genes involved in hEDS. However, considering the clinical overlap with other EDS forms, which lead to abnormalities in extracellular matrix (ECM), it is plausible that the mechanisms underlying hEDS pathogenesis also affect the ECM to a certain extent. Herein, we performed a series of in vitro studies on the secretome of hEDS dermal fibroblasts that revealed a matrix metalloproteinases (MMPs) dysfunction as one of the major disease drivers by causing a detrimental feedback loop of excessive ECM degradation coupled with myofibroblast differentiation. We demonstrated that doxycycline-mediated inhibition of MMPs rescues in hEDS cells a control-like ECM organization and induces a partial reversal of their myofibroblast-like features, thus offering encouraging clues for translational studies confirming MMPs as a potential therapeutic target in hEDS with the expectation to improve patients’ quality of life and alleviate their disabilities. Full article
(This article belongs to the Special Issue Common Denominators of Extracellular Matrix across Tissues as Inter-Tissue Messengers and Targets for Drug Repurposing)
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24 pages, 6393 KB  
Article
Resveratrol Contrasts LPA-Induced Ovarian Cancer Cell Migration and Platinum Resistance by Rescuing Hedgehog-Mediated Autophagy
by Alessandra Ferraresi, Andrea Esposito, Carlo Girone, Letizia Vallino, Amreen Salwa, Ian Ghezzi, Suyanee Thongchot, Chiara Vidoni, Danny N. Dhanasekaran and Ciro Isidoro
Cells 2021, 10(11), 3213; https://doi.org/10.3390/cells10113213 - 17 Nov 2021
Cited by 62 | Viewed by 5574
Abstract
Background: Ovarian cancer progression and invasiveness are promoted by a range of soluble factors released by cancer cells and stromal cells within the tumor microenvironment. Our previous studies demonstrated that resveratrol (RV), a nutraceutical and caloric restriction mimetic with tumor-suppressive properties, counteracts [...] Read more.
Background: Ovarian cancer progression and invasiveness are promoted by a range of soluble factors released by cancer cells and stromal cells within the tumor microenvironment. Our previous studies demonstrated that resveratrol (RV), a nutraceutical and caloric restriction mimetic with tumor-suppressive properties, counteracts cancer cell motility induced by stromal IL-6 by upregulating autophagy. Lysophosphatidic acid (LPA), a bioactive phospholipid that shows elevated levels in the tumor microenvironment and the ascites of ovarian cancers, stimulates the growth and tissue invasion of cancer cells. Whether LPA elicits these effects by inhibiting autophagy and through which pathway and whether RV can counteract the same remain obscure. Aims: To investigate the molecular pathways involved in LPA-induced ovarian cancer malignancy, particularly focusing on the role of autophagy, and the ability of RV to counteract LPA activity. Results: LPA stimulated while RV inhibited ovarian cancer cell migration. Transcriptomic and bioinformatic analyses showed an opposite regulation by LPA and RV of genes linked to epithelial-to-mesenchymal transition (EMT) and autophagy with involvement of the PI3K-AKT, JAK-STAT and Hedgehog (Hh) pathways. LPA upregulated the Hh and EMT members GLI1, BMI-1, SNAIL-1 and TWIST1 and inhibited autophagy, while RV did the opposite. Similar to the inhibitors of the Hh pathway, RV inhibited LPA-induced cancer cell migration and 3D growth of ovarian cancer cells. BMI-1 silencing prevented LPA-induced EMT, restored autophagy and hampered cell migration, resembling the effects of RV. TCGA data analyses indicated that patients with low expression of Hh/EMT-related genes together with active autophagy flux tended to have a better prognosis and this correlates with a more effective response to platinum therapy. In in vitro 3D spheroids, LPA upregulated BMI-1, downregulated autophagy and inhibited platinum toxicity while RV and Hh inhibitors restored autophagy and favored BAX-mediated cell death in response to platinum. Conclusions: By inhibiting the Hh pathway and restoration of autophagy, RV counteracts LPA-induced malignancy, supporting its inclusion in the therapy of ovarian cancer for limiting metastasis and chemoresistance. Full article
(This article belongs to the Collection Cell-to-Cell Metabolic Cross-Talk in Physiology and Pathology)
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18 pages, 2150 KB  
Article
Highly Specific Memory B Cells Generation after the 2nd Dose of BNT162b2 Vaccine Compensate for the Decline of Serum Antibodies and Absence of Mucosal IgA
by Eva Piano Mortari, Cristina Russo, Maria Rosaria Vinci, Sara Terreri, Ane Fernandez Salinas, Livia Piccioni, Claudia Alteri, Luna Colagrossi, Luana Coltella, Stefania Ranno, Giulia Linardos, Marilena Agosta, Christian Albano, Chiara Agrati, Concetta Castilletti, Silvia Meschi, Paolo Romania, Giuseppe Roscilli, Emiliano Pavoni, Vincenzo Camisa, Annapaola Santoro, Rita Brugaletta, Nicola Magnavita, Alessandra Ruggiero, Nicola Cotugno, Donato Amodio, Marta Luisa Ciofi Degli Atti, Daniela Giorgio, Nicoletta Russo, Guglielmo Salvatori, Tiziana Corsetti, Franco Locatelli, Carlo Federico Perno, Salvatore Zaffina and Rita Carsettiadd Show full author list remove Hide full author list
Cells 2021, 10(10), 2541; https://doi.org/10.3390/cells10102541 - 26 Sep 2021
Cited by 63 | Viewed by 14409
Abstract
Specific memory B cells and antibodies are a reliable read-out of vaccine efficacy. We analysed these biomarkers after one and two doses of BNT162b2 vaccine. The second dose significantly increases the level of highly specific memory B cells and antibodies. Two months after [...] Read more.
Specific memory B cells and antibodies are a reliable read-out of vaccine efficacy. We analysed these biomarkers after one and two doses of BNT162b2 vaccine. The second dose significantly increases the level of highly specific memory B cells and antibodies. Two months after the second dose, specific antibody levels decline, but highly specific memory B cells continue to increase, thus predicting a sustained protection from COVID-19. We show that although mucosal IgA is not induced by the vaccination, memory B cells migrate in response to inflammation and secrete IgA at mucosal sites. We show that the first vaccine dose may lead to an insufficient number of highly specific memory B cells and low concentration of serum antibodies, thus leaving vaccinees without the immune robustness needed to ensure viral elimination and herd immunity. We also clarify that the reduction of serum antibodies does not diminish the force and duration of the immune protection induced by vaccination. The vaccine does not induce sterilizing immunity. Infection after vaccination may be caused by the lack of local preventive immunity because of the absence of mucosal IgA. Full article
(This article belongs to the Collection Cellular Immunology and COVID-19)
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15 pages, 1138 KB  
Review
Circadian Organelles: Rhythms at All Scales
by Rona Aviram, Yaarit Adamovich and Gad Asher
Cells 2021, 10(9), 2447; https://doi.org/10.3390/cells10092447 - 16 Sep 2021
Cited by 12 | Viewed by 5184
Abstract
Circadian clocks have evolved in most light-sensitive organisms, from unicellular organisms to mammals. Consequently, a myriad of biological functions exhibits circadian rhythmicity, from behavior to physiology, through tissue and cellular functions to subcellular processes. Circadian rhythms in intracellular organelles are an emerging and [...] Read more.
Circadian clocks have evolved in most light-sensitive organisms, from unicellular organisms to mammals. Consequently, a myriad of biological functions exhibits circadian rhythmicity, from behavior to physiology, through tissue and cellular functions to subcellular processes. Circadian rhythms in intracellular organelles are an emerging and exciting research arena. We summarize herein the current literature for rhythmicity in major intracellular organelles in mammals. These include changes in the morphology, content, and functions of different intracellular organelles. While these data highlight the presence of rhythmicity in these organelles, a gap remains in our knowledge regarding the underlying molecular mechanisms and their functional significance. Finally, we discuss the importance and challenges faced by spatio-temporal studies on these organelles and speculate on the presence of oscillators in organelles and their potential mode of communication. As circadian biology has been and continues to be studied throughout temporal and spatial axes, circadian organelles appear to be the next frontier. Full article
(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Organelle Function)
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18 pages, 639 KB  
Review
Microgravity Effects on the Matrisome
by Ludmila Buravkova, Irina Larina, Elena Andreeva and Anatoly Grigoriev
Cells 2021, 10(9), 2226; https://doi.org/10.3390/cells10092226 - 27 Aug 2021
Cited by 23 | Viewed by 4673
Abstract
Gravity is fundamental factor determining all processes of development and vital activity on Earth. During evolution, a complex mechanism of response to gravity alterations was formed in multicellular organisms. It includes the “gravisensors” in extracellular and intracellular spaces. Inside the cells, the cytoskeleton [...] Read more.
Gravity is fundamental factor determining all processes of development and vital activity on Earth. During evolution, a complex mechanism of response to gravity alterations was formed in multicellular organisms. It includes the “gravisensors” in extracellular and intracellular spaces. Inside the cells, the cytoskeleton molecules are the principal gravity-sensitive structures, and outside the cells these are extracellular matrix (ECM) components. The cooperation between the intracellular and extracellular compartments is implemented through specialized protein structures, integrins. The gravity-sensitive complex is a kind of molecular hub that coordinates the functions of various tissues and organs in the gravitational environment. The functioning of this system is of particular importance under extremal conditions, such as spaceflight microgravity. This review covers the current understanding of ECM and associated molecules as the matrisome, the features of the above components in connective tissues, and the role of the latter in the cell and tissue responses to the gravity alterations. Special attention is paid to contemporary methodological approaches to the matrisome composition analysis under real space flights and ground-based simulation of its effects on Earth. Full article
(This article belongs to the Section Cell Microenvironment)
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13 pages, 3620 KB  
Article
Cognitive Impairment in Frail Hypertensive Elderly Patients: Role of Hyperglycemia
by Pasquale Mone, Jessica Gambardella, Antonella Pansini, Antonio de Donato, Giuseppe Martinelli, Eugenio Boccalone, Alessandro Matarese, Salvatore Frullone and Gaetano Santulli
Cells 2021, 10(8), 2115; https://doi.org/10.3390/cells10082115 - 17 Aug 2021
Cited by 57 | Viewed by 5508
Abstract
Endothelial dysfunction is a key hallmark of hypertension, which is a leading risk factor for cognitive decline in older adults with or without frailty. Similarly, hyperglycemia is known to impair endothelial function and is a predictor of severe cardiovascular outcomes, independent of the [...] Read more.
Endothelial dysfunction is a key hallmark of hypertension, which is a leading risk factor for cognitive decline in older adults with or without frailty. Similarly, hyperglycemia is known to impair endothelial function and is a predictor of severe cardiovascular outcomes, independent of the presence of diabetes. On these grounds, we designed a study to assess the effects of high-glucose and metformin on brain microvascular endothelial cells (ECs) and on cognitive impairment in frail hypertensive patients. We tested the effects of metformin on high-glucose-induced cell death, cell permeability, and generation of reactive oxygen species in vitro, in human brain microvascular ECs. To investigate the consequences of hyperglycemia and metformin in the clinical scenario, we recruited frail hypertensive patients and we evaluated their Montreal Cognitive Assessment (MoCA) scores, comparing them according to the glycemic status (normoglycemic vs. hyperglycemic) and the use of metformin. We enrolled 376 patients, of which 209 successfully completed the study. We observed a significant correlation between MoCA score and glycemia. We found that hyperglycemic patients treated with metformin had a significantly better MoCA score than hyperglycemic patients treated with insulin (18.32 ± 3.9 vs. 14.94 ± 3.8; p < 0.001). Our in vitro assays confirmed the beneficial effects of metformin on human brain microvascular ECs. To our knowledge, this is the first study correlating MoCA score and glycemia in frail and hypertensive older adults, showing that hyperglycemia aggravates cognitive impairment. Full article
(This article belongs to the Special Issue Cellular Senescence in Age-Related Diseases: Molecular Bases and Therapeutic Interventions)
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17 pages, 2913 KB  
Article
Kinetics of Anti-SARS-CoV-2 Antibody Responses 3 Months Post Complete Vaccination with BNT162b2; A Prospective Study in 283 Health Workers
by Evangelos Terpos, Ioannis P. Trougakos, Vangelis Karalis, Ioannis Ntanasis-Stathopoulos, Sentiljana Gumeni, Filia Apostolakou, Aimilia D. Sklirou, Maria Gavriatopoulou, Stamatia Skourti, Efstathios Kastritis, Eleni Korompoki, Ioannis Papassotiriou and Meletios A. Dimopoulos
Cells 2021, 10(8), 1942; https://doi.org/10.3390/cells10081942 - 30 Jul 2021
Cited by 36 | Viewed by 4218
Abstract
The aim of this study was to investigate the kinetics of neutralizing antibodies (NAbs) and anti-SARS-CoV-2 anti-S-RBD IgGs up to three months after the second vaccination dose with the BNT162b2 mRNA vaccine. NAbs and anti-S-RBD levels were measured on days 1 (before the [...] Read more.
The aim of this study was to investigate the kinetics of neutralizing antibodies (NAbs) and anti-SARS-CoV-2 anti-S-RBD IgGs up to three months after the second vaccination dose with the BNT162b2 mRNA vaccine. NAbs and anti-S-RBD levels were measured on days 1 (before the first vaccine shot), 8, 22 (before the second shot), 36, 50, and three months after the second vaccination (D111) (NCT04743388). 283 health workers were included in this study. NAbs showed a rapid increase from D8 to D36 at a constant rate of about 3% per day and reached a median (SD) of 97.2% (4.7) at D36. From D36 to D50, a slight decrease in NAbs values was detected and it became more prominent between D50 and D111 when the rate of decline was determined at −0.11 per day. The median (SD) NAbs value at D111 was 92.7% (11.8). A similar pattern was also observed for anti-S-RBD antibodies. Anti-S-RBDs showed a steeper increase during D22–D36 and a lower decline rate during D36–D111. Prior COVID-19 infection and younger age were associated with superior antibody responses over time. In conclusion, we found a persistent but declining anti-SARS-CoV-2 humoral immunity at 3 months following full vaccination with BNT162b2 in healthy individuals. Full article
(This article belongs to the Collection Cellular Immunology and COVID-19)
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19 pages, 1583 KB  
Review
The Role of DNA Damage Response in Dysbiosis-Induced Colorectal Cancer
by Antonio Rivas-Domínguez, Nuria Pastor, Laura Martínez-López, Julia Colón-Pérez, Beatriz Bermúdez and Manuel Luis Orta
Cells 2021, 10(8), 1934; https://doi.org/10.3390/cells10081934 - 29 Jul 2021
Cited by 43 | Viewed by 6156
Abstract
The high incidence of colorectal cancer (CRC) in developed countries indicates a predominant role of the environment as a causative factor. Natural gut microbiota provides multiple benefits to humans. Dysbiosis is characterized by an unbalanced microbiota and causes intestinal damage and inflammation. The [...] Read more.
The high incidence of colorectal cancer (CRC) in developed countries indicates a predominant role of the environment as a causative factor. Natural gut microbiota provides multiple benefits to humans. Dysbiosis is characterized by an unbalanced microbiota and causes intestinal damage and inflammation. The latter is a common denominator in many cancers including CRC. Indeed, in an inflammation scenario, cellular growth is promoted and immune cells release Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS), which cause DNA damage. Apart from that, many metabolites from the diet are converted into DNA damaging agents by microbiota and some bacteria deliver DNA damaging toxins in dysbiosis conditions as well. The interactions between diet, microbiota, inflammation, and CRC are not the result of a straightforward relationship, but rather a network of multifactorial interactions that deserve deep consideration, as their consequences are not yet fully elucidated. In this paper, we will review the influence of dysbiosis in the induction of DNA damage and CRC. Full article
(This article belongs to the Special Issue Double-Strand DNA Break Repair and Human Disease)
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16 pages, 5452 KB  
Article
Microglia Depletion-Induced Remodeling of Extracellular Matrix and Excitatory Synapses in the Hippocampus of Adult Mice
by Luisa Strackeljan, Ewa Baczynska, Carla Cangalaya, David Baidoe-Ansah, Jakub Wlodarczyk, Rahul Kaushik and Alexander Dityatev
Cells 2021, 10(8), 1862; https://doi.org/10.3390/cells10081862 - 22 Jul 2021
Cited by 48 | Viewed by 7478
Abstract
The extracellular matrix (ECM) plays a key role in synaptogenesis and the regulation of synaptic functions in the central nervous system. Recent studies revealed that in addition to dopaminergic and serotoninergic neuromodulatory systems, microglia also contribute to the regulation of ECM remodeling. In [...] Read more.
The extracellular matrix (ECM) plays a key role in synaptogenesis and the regulation of synaptic functions in the central nervous system. Recent studies revealed that in addition to dopaminergic and serotoninergic neuromodulatory systems, microglia also contribute to the regulation of ECM remodeling. In the present work, we investigated the physiological role of microglia in the remodeling of perineuronal nets (PNNs), predominantly associated with parvalbumin-immunopositive (PV+) interneurons, and the perisynaptic ECM around pyramidal neurons in the hippocampus. Adult mice were treated with PLX3397 (pexidartinib), as the inhibitor of colony-stimulating factor 1 receptor (CSF1-R), to deplete microglia. Then, confocal analysis of the ECM and synapses was performed. Although the elimination of microglia did not alter the overall number or intensity of PNNs in the CA1 region of the hippocampus, it decreased the size of PNN holes and elevated the expression of the surrounding ECM. In the neuropil area in the CA1 str. radiatum, the depletion of microglia increased the expression of perisynaptic ECM proteoglycan brevican, which was accompanied by the elevated expression of presynaptic marker vGluT1 and the increased density of dendritic spines. Thus, microglia regulate the homeostasis of pre- and postsynaptic excitatory terminals and the surrounding perisynaptic ECM as well as the fine structure of PNNs enveloping perisomatic—predominantly GABAergic—synapses. Full article
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16 pages, 3765 KB  
Review
The Interactome of the VAP Family of Proteins: An Overview
by Christina James and Ralph H. Kehlenbach
Cells 2021, 10(7), 1780; https://doi.org/10.3390/cells10071780 - 14 Jul 2021
Cited by 42 | Viewed by 8218
Abstract
Membrane contact sites (MCS) are sites of close apposition of two organelles that help in lipid transport and synthesis, calcium homeostasis and several other biological processes. The VAMP-associated proteins (VAPs) VAPA, VAPB, MOSPD2 and the recently described MOSPD1 and MOSPD3 are tether proteins [...] Read more.
Membrane contact sites (MCS) are sites of close apposition of two organelles that help in lipid transport and synthesis, calcium homeostasis and several other biological processes. The VAMP-associated proteins (VAPs) VAPA, VAPB, MOSPD2 and the recently described MOSPD1 and MOSPD3 are tether proteins of MCSs that are mainly found at the endoplasmic reticulum (ER). VAPs interact with various proteins with a motif called FFAT (two phenylalanines in an acidic tract), recruiting the associated organelle to the ER. In addition to the conventional FFAT motif, the recently described FFNT (two phenylalanines in a neutral tract) and phospho-FFAT motifs contribute to the interaction with VAPs. In this review, we summarize and compare the recent interactome studies described for VAPs, including in silico and proximity labeling methods. Collectively, the interaction repertoire of VAPs is very diverse and highlights the complexity of interactions mediated by the different FFAT motifs to the VAPs. Full article
(This article belongs to the Section Cell Microenvironment)
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15 pages, 1556 KB  
Review
Salivary Gland Tissue Engineering Approaches: State of the Art and Future Directions
by Lindsay R. Piraino, Danielle S. W. Benoit and Lisa A. DeLouise
Cells 2021, 10(7), 1723; https://doi.org/10.3390/cells10071723 - 8 Jul 2021
Cited by 19 | Viewed by 10121
Abstract
Salivary gland regeneration is important for developing treatments for radiation-induced xerostomia, Sjögren’s syndrome, and other conditions that cause dry mouth. Culture conditions adopted from tissue engineering strategies have been used to recapitulate gland structure and function to study and regenerate the salivary glands. [...] Read more.
Salivary gland regeneration is important for developing treatments for radiation-induced xerostomia, Sjögren’s syndrome, and other conditions that cause dry mouth. Culture conditions adopted from tissue engineering strategies have been used to recapitulate gland structure and function to study and regenerate the salivary glands. The purpose of this review is to highlight current trends in the field, with an emphasis on soluble factors that have been shown to improve secretory function in vitro. A PubMed search was conducted to identify articles published in the last 10 years and articles were evaluated to identify the most promising approaches and areas for further research. Results showed increasing use of extracellular matrix mimetics, such as Matrigel®, collagen, and a variety of functionalized polymers. Soluble factors that provide supportive cues, including fibroblast growth factors (FGFs) and neurotrophic factors, as well as chemical inhibitors of Rho-associated kinase (ROCK), epidermal growth factor receptor (EGFR), and transforming growth factor β receptor (TGFβR) have shown increases in important markers including aquaporin 5 (Aqp5); muscle, intestine, and stomach expression 1 (Mist1); and keratin (K5). However, recapitulation of tissue function at in vivo levels is still elusive. A focus on identification of soluble factors, cells, and/or matrix cues tested in combination may further increase the maintenance of salivary gland secretory function in vitro. These approaches may also be amenable for translation in vivo to support successful regeneration of dysfunctional glands. Full article
(This article belongs to the Section Cell Microenvironment)
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30 pages, 10374 KB  
Article
Extracellular Vesicles Derived from Endothelial Progenitor Cells Protect Human Glomerular Endothelial Cells and Podocytes from Complement- and Cytokine-Mediated Injury
by Davide Medica, Rossana Franzin, Alessandra Stasi, Giuseppe Castellano, Massimiliano Migliori, Vincenzo Panichi, Federico Figliolini, Loreto Gesualdo, Giovanni Camussi and Vincenzo Cantaluppi
Cells 2021, 10(7), 1675; https://doi.org/10.3390/cells10071675 - 2 Jul 2021
Cited by 42 | Viewed by 6061
Abstract
Glomerulonephritis are renal inflammatory processes characterized by increased permeability of the Glomerular Filtration Barrier (GFB) with consequent hematuria and proteinuria. Glomerular endothelial cells (GEC) and podocytes are part of the GFB and contribute to the maintenance of its structural and functional integrity through [...] Read more.
Glomerulonephritis are renal inflammatory processes characterized by increased permeability of the Glomerular Filtration Barrier (GFB) with consequent hematuria and proteinuria. Glomerular endothelial cells (GEC) and podocytes are part of the GFB and contribute to the maintenance of its structural and functional integrity through the release of paracrine mediators. Activation of the complement cascade and pro-inflammatory cytokines (CK) such as Tumor Necrosis Factor α (TNF-α) and Interleukin-6 (IL-6) can alter GFB function, causing acute glomerular injury and progression toward chronic kidney disease. Endothelial Progenitor Cells (EPC) are bone-marrow-derived hematopoietic stem cells circulating in peripheral blood and able to induce angiogenesis and to repair injured endothelium by releasing paracrine mediators including Extracellular Vesicles (EVs), microparticles involved in intercellular communication by transferring proteins, lipids, and genetic material (mRNA, microRNA, lncRNA) to target cells. We have previously demonstrated that EPC-derived EVs activate an angiogenic program in quiescent endothelial cells and renoprotection in different experimental models. The aim of the present study was to evaluate in vitro the protective effect of EPC-derived EVs on GECs and podocytes cultured in detrimental conditions with CKs (TNF-α/IL-6) and the complement protein C5a. EVs were internalized in both GECs and podocytes mainly through a L-selectin-based mechanism. In GECs, EVs enhanced the formation of capillary-like structures and cell migration by modulating gene expression and inducing the release of growth factors such as VEGF-A and HGF. In the presence of CKs, and C5a, EPC-derived EVs protected GECs from apoptosis by decreasing oxidative stress and prevented leukocyte adhesion by inhibiting the expression of adhesion molecules (ICAM-1, VCAM-1, E-selectin). On podocytes, EVs inhibited apoptosis and prevented nephrin shedding induced by CKs and C5a. In a co-culture model of GECs/podocytes that mimicked GFB, EPC-derived EVs protected cell function and permeselectivity from inflammatory-mediated damage. Moreover, RNase pre-treatment of EVs abrogated their protective effects, suggesting the crucial role of RNA transfer from EVs to damaged glomerular cells. In conclusion, EPC-derived EVs preserved GFB integrity from complement- and cytokine-induced damage, suggesting their potential role as therapeutic agents for drug-resistant glomerulonephritis. Full article
(This article belongs to the Collection Cell-to-Cell Metabolic Cross-Talk in Physiology and Pathology)
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16 pages, 1146 KB  
Review
The Ultimate (Mis)match: When DNA Meets RNA
by Benoit Palancade and Rodney Rothstein
Cells 2021, 10(6), 1433; https://doi.org/10.3390/cells10061433 - 8 Jun 2021
Cited by 7 | Viewed by 9785
Abstract
RNA-containing structures, including ribonucleotide insertions, DNA:RNA hybrids and R-loops, have recently emerged as critical players in the maintenance of genome integrity. Strikingly, different enzymatic activities classically involved in genome maintenance contribute to their generation, their processing into genotoxic or repair intermediates, or their [...] Read more.
RNA-containing structures, including ribonucleotide insertions, DNA:RNA hybrids and R-loops, have recently emerged as critical players in the maintenance of genome integrity. Strikingly, different enzymatic activities classically involved in genome maintenance contribute to their generation, their processing into genotoxic or repair intermediates, or their removal. Here we review how this substrate promiscuity can account for the detrimental and beneficial impacts of RNA insertions during genome metabolism. We summarize how in vivo and in vitro experiments support the contribution of DNA polymerases and homologous recombination proteins in the formation of RNA-containing structures, and we discuss the role of DNA repair enzymes in their removal. The diversity of pathways that are thus affected by RNA insertions likely reflects the ancestral function of RNA molecules in genome maintenance and transmission. Full article
(This article belongs to the Special Issue DNA Repair, Genome Stability/Diversity, and Oxidative Stress and Aging, from Bacteria to Human Cells: A Themed Issue in Honor of Prof. Miroslav Radman)
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19 pages, 281 KB  
Review
Regulatory Effects of Cannabidiol on Mitochondrial Functions: A Review
by John Zewen Chan and Robin Elaine Duncan
Cells 2021, 10(5), 1251; https://doi.org/10.3390/cells10051251 - 19 May 2021
Cited by 53 | Viewed by 7585
Abstract
Cannabidiol (CBD) is part of a group of phytocannabinoids derived from Cannabissativa. Initial work on CBD presumed the compound was inactive, but it was later found to exhibit antipsychotic, anti-depressive, anxiolytic, and antiepileptic effects. In recent decades, evidence has indicated a role [...] Read more.
Cannabidiol (CBD) is part of a group of phytocannabinoids derived from Cannabissativa. Initial work on CBD presumed the compound was inactive, but it was later found to exhibit antipsychotic, anti-depressive, anxiolytic, and antiepileptic effects. In recent decades, evidence has indicated a role for CBD in the modulation of mitochondrial processes, including respiration and bioenergetics, mitochondrial DNA epigenetics, intrinsic apoptosis, the regulation of mitochondrial and intracellular calcium concentrations, mitochondrial fission, fusion and biogenesis, and mitochondrial ferritin concentration and mitochondrial monoamine oxidase activity regulation. Despite these advances, current data demonstrate contradictory findings with regard to not only the magnitude of effects mediated by CBD, but also to the direction of effects. For example, there are data indicating that CBD treatment can increase, decrease, or have no significant effect on intrinsic apoptosis. Differences between studies in cell type, cell-specific response to CBD, and, in some cases, dose of CBD may help to explain differences in outcomes. Most studies on CBD and mitochondria have utilized treatment concentrations that exceed the highest recorded plasma concentrations in humans, suggesting that future studies should focus on CBD treatments within a range observed in pharmacokinetic studies. This review focuses on understanding the mechanisms of CBD-mediated regulation of mitochondrial functions, with an emphasis on findings in neural cells and tissues and therapeutic relevance based on human pharmacokinetics. Full article
(This article belongs to the Collection Determinants of Neuronal Susceptibility to Mitochondrial Disease)
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22 pages, 1681 KB  
Review
Glutamatergic Mechanisms in Glioblastoma and Tumor-Associated Epilepsy
by Falko Lange, Max Frederik Hörnschemeyer and Timo Kirschstein
Cells 2021, 10(5), 1226; https://doi.org/10.3390/cells10051226 - 17 May 2021
Cited by 72 | Viewed by 8639
Abstract
The progression of glioblastomas is associated with a variety of neurological impairments, such as tumor-related epileptic seizures. Seizures are not only a common comorbidity of glioblastoma but often an initial clinical symptom of this cancer entity. Both, glioblastoma and tumor-associated epilepsy are closely [...] Read more.
The progression of glioblastomas is associated with a variety of neurological impairments, such as tumor-related epileptic seizures. Seizures are not only a common comorbidity of glioblastoma but often an initial clinical symptom of this cancer entity. Both, glioblastoma and tumor-associated epilepsy are closely linked to one another through several pathophysiological mechanisms, with the neurotransmitter glutamate playing a key role. Glutamate interacts with its ionotropic and metabotropic receptors to promote both tumor progression and excitotoxicity. In this review, based on its physiological functions, our current understanding of glutamate receptors and glutamatergic signaling will be discussed in detail. Furthermore, preclinical models to study glutamatergic interactions between glioma cells and the tumor-surrounding microenvironment will be presented. Finally, current studies addressing glutamate receptors in glioma and tumor-related epilepsy will be highlighted and future approaches to interfere with the glutamatergic network are discussed. Full article
(This article belongs to the Special Issue Molecular Biology in Glioblastoma Multiforme Treatment)
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19 pages, 5507 KB  
Article
Regulation of the Phosphoinositide Code by Phosphorylation of Membrane Readers
by Troy A. Kervin and Michael Overduin
Cells 2021, 10(5), 1205; https://doi.org/10.3390/cells10051205 - 14 May 2021
Cited by 12 | Viewed by 5761
Abstract
The genetic code that dictates how nucleic acids are translated into proteins is well known, however, the code through which proteins recognize membranes remains mysterious. In eukaryotes, this code is mediated by hundreds of membrane readers that recognize unique phosphatidylinositol phosphates (PIPs), which [...] Read more.
The genetic code that dictates how nucleic acids are translated into proteins is well known, however, the code through which proteins recognize membranes remains mysterious. In eukaryotes, this code is mediated by hundreds of membrane readers that recognize unique phosphatidylinositol phosphates (PIPs), which demark organelles to initiate localized trafficking and signaling events. The only superfamily which specifically detects all seven PIPs are the Phox homology (PX) domains. Here, we reveal that throughout evolution, these readers are universally regulated by the phosphorylation of their PIP binding surfaces based on our analysis of existing and modelled protein structures and phosphoproteomic databases. These PIP-stops control the selective targeting of proteins to organelles and are shown to be key determinants of high-fidelity PIP recognition. The protein kinases responsible include prominent cancer targets, underscoring the critical role of regulated membrane readership. Full article
(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Organelle Function)
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34 pages, 4131 KB  
Review
Molecular and Hormonal Mechanisms Regulating Fleshy Fruit Ripening
by Shan Li, Kunsong Chen and Donald Grierson
Cells 2021, 10(5), 1136; https://doi.org/10.3390/cells10051136 - 8 May 2021
Cited by 175 | Viewed by 15569
Abstract
This article focuses on the molecular and hormonal mechanisms underlying the control of fleshy fruit ripening and quality. Recent research on tomato shows that ethylene, acting through transcription factors, is responsible for the initiation of tomato ripening. Several other hormones, including abscisic acid [...] Read more.
This article focuses on the molecular and hormonal mechanisms underlying the control of fleshy fruit ripening and quality. Recent research on tomato shows that ethylene, acting through transcription factors, is responsible for the initiation of tomato ripening. Several other hormones, including abscisic acid (ABA), jasmonic acid (JA) and brassinosteroids (BR), promote ripening by upregulating ethylene biosynthesis genes in different fruits. Changes to histone marks and DNA methylation are associated with the activation of ripening genes and are necessary for ripening initiation. Light, detected by different photoreceptors and operating through ELONGATED HYPOCOTYL 5(HY5), also modulates ripening. Re-evaluation of the roles of ‘master regulators’ indicates that MADS-RIN, NAC-NOR, Nor-like1 and other MADS and NAC genes, together with ethylene, promote the full expression of genes required for further ethylene synthesis and change in colour, flavour, texture and progression of ripening. Several different types of non-coding RNAs are involved in regulating expression of ripening genes, but further clarification of their diverse mechanisms of action is required. We discuss a model that integrates the main hormonal and genetic regulatory interactions governing the ripening of tomato fruit and consider variations in ripening regulatory circuits that operate in other fruits. Full article
(This article belongs to the Special Issue Molecular Regulation of Fruit-Set, Development, Maturation, Ripening and Shelf-Life)
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17 pages, 3003 KB  
Review
Coordinated and Independent Roles for MLH Subunits in DNA Repair
by Gianno Pannafino and Eric Alani
Cells 2021, 10(4), 948; https://doi.org/10.3390/cells10040948 - 20 Apr 2021
Cited by 23 | Viewed by 7682
Abstract
The MutL family of DNA mismatch repair proteins (MMR) acts to maintain genomic integrity in somatic and meiotic cells. In baker’s yeast, the MutL homolog (MLH) MMR proteins form three heterodimeric complexes, MLH1-PMS1, MLH1-MLH2, and MLH1-MLH3. The recent discovery of human PMS2 (homolog [...] Read more.
The MutL family of DNA mismatch repair proteins (MMR) acts to maintain genomic integrity in somatic and meiotic cells. In baker’s yeast, the MutL homolog (MLH) MMR proteins form three heterodimeric complexes, MLH1-PMS1, MLH1-MLH2, and MLH1-MLH3. The recent discovery of human PMS2 (homolog of baker’s yeast PMS1) and MLH3 acting independently of human MLH1 in the repair of somatic double-strand breaks questions the assumption that MLH1 is an obligate subunit for MLH function. Here we provide a summary of the canonical roles for MLH factors in DNA genomic maintenance and in meiotic crossover. We then present the phenotypes of cells lacking specific MLH subunits, particularly in meiotic recombination, and based on this analysis, propose a model for an independent early role for MLH3 in meiosis to promote the accurate segregation of homologous chromosomes in the meiosis I division. Full article
(This article belongs to the Special Issue DNA Repair, Genome Stability/Diversity, and Oxidative Stress and Aging, from Bacteria to Human Cells: A Themed Issue in Honor of Prof. Miroslav Radman)
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17 pages, 3151 KB  
Article
Alterations in the Gut-Microbial-Inflammasome-Brain Axis in a Mouse Model of Alzheimer’s Disease
by Pradeep K. Shukla, David F. Delotterie, Jianfeng Xiao, Joseph F. Pierre, RadhaKrishna Rao, Michael P. McDonald and Mohammad Moshahid Khan
Cells 2021, 10(4), 779; https://doi.org/10.3390/cells10040779 - 1 Apr 2021
Cited by 87 | Viewed by 8657
Abstract
Alzheimer’s disease (AD), a progressive neurodegenerative disorder characterized by memory loss and cognitive decline, is a major cause of death and disability among the older population. Despite decades of scientific research, the underlying etiological triggers are unknown. Recent studies suggested that gut microbiota [...] Read more.
Alzheimer’s disease (AD), a progressive neurodegenerative disorder characterized by memory loss and cognitive decline, is a major cause of death and disability among the older population. Despite decades of scientific research, the underlying etiological triggers are unknown. Recent studies suggested that gut microbiota can influence AD progression; however, potential mechanisms linking the gut microbiota with AD pathogenesis remain obscure. In the present study, we provided a potential mechanistic link between dysbiotic gut microbiota and neuroinflammation associated with AD progression. Using a mouse model of AD, we discovered that unfavorable gut microbiota are correlated with abnormally elevated expression of gut NLRP3 and lead to peripheral inflammasome activation, which in turn exacerbates AD-associated neuroinflammation. To this end, we observe significantly altered gut microbiota compositions in young and old 5xFAD mice compared to age-matched non-transgenic mice. Moreover, 5xFAD mice demonstrated compromised gut barrier function as evident from the loss of tight junction and adherens junction proteins compared to non-transgenic mice. Concurrently, we observed increased expression of NLRP3 inflammasome and IL-1β production in the 5xFAD gut. Consistent with our hypothesis, increased gut–microbial–inflammasome activation is positively correlated with enhanced astrogliosis and microglial activation, along with higher expression of NLRP3 inflammasome and IL-1β production in the brains of 5xFAD mice. These data indicate that the elevated expression of gut–microbial–inflammasome components may be an important trigger for subsequent downstream activation of inflammatory and potentially cytotoxic mediators, and gastrointestinal NLRP3 may promote NLRP3 inflammasome-mediated neuroinflammation. Thus, modulation of the gut microbiota may be a potential strategy for the treatment of AD-related neurological disorders in genetically susceptible hosts. Full article
(This article belongs to the Collection The Pathogenesis of Neurological Disorders)
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17 pages, 1183 KB  
Review
Microglial Pruning: Relevance for Synaptic Dysfunction in Multiple Sclerosis and Related Experimental Models
by Maria Concetta Geloso and Nadia D’Ambrosi
Cells 2021, 10(3), 686; https://doi.org/10.3390/cells10030686 - 20 Mar 2021
Cited by 54 | Viewed by 10253
Abstract
Microglia, besides being able to react rapidly to a wide range of environmental changes, are also involved in shaping neuronal wiring. Indeed, they actively participate in the modulation of neuronal function by regulating the elimination (or “pruning”) of weaker synapses in both physiologic [...] Read more.
Microglia, besides being able to react rapidly to a wide range of environmental changes, are also involved in shaping neuronal wiring. Indeed, they actively participate in the modulation of neuronal function by regulating the elimination (or “pruning”) of weaker synapses in both physiologic and pathologic processes. Mounting evidence supports their crucial role in early synaptic loss, which is emerging as a hallmark of several neurodegenerative diseases, including multiple sclerosis (MS) and its preclinical models. MS is an inflammatory, immune-mediated pathology of the white matter in which demyelinating lesions may cause secondary neuronal death. Nevertheless, primitive grey matter (GM) damage is emerging as an important contributor to patients’ long-term disability, since it has been associated with early and progressive cognitive decline (CD), which seriously worsens the quality of life of MS patients. Widespread synapse loss even in the absence of demyelination, axon degeneration and neuronal death has been demonstrated in different GM structures, thus raising the possibility that synaptic dysfunction could be an early and possibly independent event in the neurodegenerative process associated with MS. This review provides an overview of microglial-dependent synapse elimination in the neuroinflammatory process that underlies MS and its experimental models. Full article
(This article belongs to the Special Issue The Contribution of Non-Neuronal Cells in Neurodegeneration: From Molecular Pathogenesis to Therapeutic Challenges)
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15 pages, 1247 KB  
Article
The Relationship between the Antioxidant System and Proline Metabolism in the Leaves of Cucumber Plants Acclimated to Salt Stress
by Marcin Naliwajski and Maria Skłodowska
Cells 2021, 10(3), 609; https://doi.org/10.3390/cells10030609 - 10 Mar 2021
Cited by 84 | Viewed by 5425
Abstract
The study examines the effect of acclimation on the antioxidant system and proline metabolism in cucumber leaves subjected to 100 and 150 NaCl stress. The levels of protein carbonyl group, thiobarbituric acid reactive substances, α-tocopherol, and activity of ascorbate and glutathione peroxidases, catalase, [...] Read more.
The study examines the effect of acclimation on the antioxidant system and proline metabolism in cucumber leaves subjected to 100 and 150 NaCl stress. The levels of protein carbonyl group, thiobarbituric acid reactive substances, α-tocopherol, and activity of ascorbate and glutathione peroxidases, catalase, glutathione S-transferase, pyrroline-5-carboxylate: synthetase and reductase as well as proline dehydrogenase were determined after 24 and 72 h periods of salt stress in the acclimated and non-acclimated plants. Although both groups of plants showed high α-tocopherol levels, in acclimated plants was observed higher constitutive concentration of these compounds as well as after salt treatment. Furthermore, the activity of enzymatic antioxidants grew in response to salt stress, mainly in the acclimated plants. In the acclimated plants, protein carbonyl group levels collapsed on a constitutive level and in response to salt stress. Although both groups of plants showed a decrease in proline dehydrogenase activity, they differed with regard to the range and time. Differences in response to salt stress between the acclimated and non-acclimated plants may suggest a relationship between increased tolerance in acclimated plants and raised activity of antioxidant enzymes, high-level of α-tocopherol as well, as decrease enzyme activity incorporates in proline catabolism. Full article
(This article belongs to the Section Plant, Algae and Fungi Cell Biology)
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32 pages, 2195 KB  
Review
Oligodendrocyte Dysfunction in Amyotrophic Lateral Sclerosis: Mechanisms and Therapeutic Perspectives
by Stefano Raffaele, Marta Boccazzi and Marta Fumagalli
Cells 2021, 10(3), 565; https://doi.org/10.3390/cells10030565 - 5 Mar 2021
Cited by 65 | Viewed by 12815
Abstract
Myelin is the lipid-rich structure formed by oligodendrocytes (OLs) that wraps the axons in multilayered sheaths, assuring protection, efficient saltatory signal conduction and metabolic support to neurons. In the last few years, the impact of OL dysfunction and myelin damage has progressively received [...] Read more.
Myelin is the lipid-rich structure formed by oligodendrocytes (OLs) that wraps the axons in multilayered sheaths, assuring protection, efficient saltatory signal conduction and metabolic support to neurons. In the last few years, the impact of OL dysfunction and myelin damage has progressively received more attention and is now considered to be a major contributing factor to neurodegeneration in several neurological diseases, including amyotrophic lateral sclerosis (ALS). Upon OL injury, oligodendrocyte precursor cells (OPCs) of adult nervous tissue sustain the generation of new OLs for myelin reconstitution, but this spontaneous regeneration process fails to successfully counteract myelin damage. Of note, the functions of OPCs exceed the formation and repair of myelin, and also involve the trophic support to axons and the capability to exert an immunomodulatory role, which are particularly relevant in the context of neurodegeneration. In this review, we deeply analyze the impact of dysfunctional OLs in ALS pathogenesis. The possible mechanisms underlying OL degeneration, defective OPC maturation, and impairment in energy supply to motor neurons (MNs) have also been examined to provide insights on future therapeutic interventions. On this basis, we discuss the potential therapeutic utility in ALS of several molecules, based on their remyelinating potential or capability to enhance energy metabolism. Full article
(This article belongs to the Special Issue The Contribution of Non-Neuronal Cells in Neurodegeneration: From Molecular Pathogenesis to Therapeutic Challenges)
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19 pages, 2742 KB  
Review
Astrocytes in Alzheimer’s Disease: Pathological Significance and Molecular Pathways
by Pranav Preman, Maria Alfonso-Triguero, Elena Alberdi, Alexei Verkhratsky and Amaia M. Arranz
Cells 2021, 10(3), 540; https://doi.org/10.3390/cells10030540 - 4 Mar 2021
Cited by 130 | Viewed by 15969
Abstract
Astrocytes perform a wide variety of essential functions defining normal operation of the nervous system and are active contributors to the pathogenesis of neurodegenerative disorders such as Alzheimer’s among others. Recent data provide compelling evidence that distinct astrocyte states are associated with specific [...] Read more.
Astrocytes perform a wide variety of essential functions defining normal operation of the nervous system and are active contributors to the pathogenesis of neurodegenerative disorders such as Alzheimer’s among others. Recent data provide compelling evidence that distinct astrocyte states are associated with specific stages of Alzheimer´s disease. The advent of transcriptomics technologies enables rapid progress in the characterisation of such pathological astrocyte states. In this review, we provide an overview of the origin, main functions, molecular and morphological features of astrocytes in physiological as well as pathological conditions related to Alzheimer´s disease. We will also explore the main roles of astrocytes in the pathogenesis of Alzheimer´s disease and summarize main transcriptional changes and altered molecular pathways observed in astrocytes during the course of the disease. Full article
(This article belongs to the Special Issue The Contribution of Non-Neuronal Cells in Neurodegeneration: From Molecular Pathogenesis to Therapeutic Challenges)
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17 pages, 3238 KB  
Article
The Temporal Order of DNA Replication Shaped by Mammalian DNA Methyltransferases
by Shin-ichiro Takebayashi, Tyrone Ryba, Kelsey Wimbish, Takuya Hayakawa, Morito Sakaue, Kenji Kuriya, Saori Takahashi, Shin Ogata, Ichiro Hiratani, Katsuzumi Okumura, Masaki Okano and Masato Ogata
Cells 2021, 10(2), 266; https://doi.org/10.3390/cells10020266 - 29 Jan 2021
Cited by 9 | Viewed by 5531
Abstract
Multiple epigenetic pathways underlie the temporal order of DNA replication (replication timing) in the contexts of development and disease. DNA methylation by DNA methyltransferases (Dnmts) and downstream chromatin reorganization and transcriptional changes are thought to impact DNA replication, yet this remains to be [...] Read more.
Multiple epigenetic pathways underlie the temporal order of DNA replication (replication timing) in the contexts of development and disease. DNA methylation by DNA methyltransferases (Dnmts) and downstream chromatin reorganization and transcriptional changes are thought to impact DNA replication, yet this remains to be comprehensively tested. Using cell-based and genome-wide approaches to measure replication timing, we identified a number of genomic regions undergoing subtle but reproducible replication timing changes in various Dnmt-mutant mouse embryonic stem (ES) cell lines that included a cell line with a drug-inducible Dnmt3a2 expression system. Replication timing within pericentromeric heterochromatin (PH) was shown to be correlated with redistribution of H3K27me3 induced by DNA hypomethylation: Later replicating PH coincided with H3K27me3-enriched regions. In contrast, this relationship with H3K27me3 was not evident within chromosomal arm regions undergoing either early-to-late (EtoL) or late-to-early (LtoE) switching of replication timing upon loss of the Dnmts. Interestingly, Dnmt-sensitive transcriptional up- and downregulation frequently coincided with earlier and later shifts in replication timing of the chromosomal arm regions, respectively. Our study revealed the previously unrecognized complex and diverse effects of the Dnmts loss on the mammalian DNA replication landscape. Full article
(This article belongs to the Special Issue DNA Replication Timing: From Basic Mechanisms to Biological Functions)
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15 pages, 2115 KB  
Review
Spermine: Its Emerging Role in Regulating Drought Stress Responses in Plants
by Md. Mahadi Hasan, Milan Skalicky, Mohammad Shah Jahan, Md. Nazmul Hossain, Zunaira Anwar, Zheng-Fei Nie, Nadiyah M. Alabdallah, Marian Brestic, Vaclav Hejnak and Xiang-Wen Fang
Cells 2021, 10(2), 261; https://doi.org/10.3390/cells10020261 - 28 Jan 2021
Cited by 143 | Viewed by 10744
Abstract
In recent years, research on spermine (Spm) has turned up a lot of new information about this essential polyamine, especially as it is able to counteract damage from abiotic stresses. Spm has been shown to protect plants from a variety of environmental insults, [...] Read more.
In recent years, research on spermine (Spm) has turned up a lot of new information about this essential polyamine, especially as it is able to counteract damage from abiotic stresses. Spm has been shown to protect plants from a variety of environmental insults, but whether it can prevent the adverse effects of drought has not yet been reported. Drought stress increases endogenous Spm in plants and exogenous application of Spm improves the plants’ ability to tolerate drought stress. Spm’s role in enhancing antioxidant defense mechanisms, glyoxalase systems, methylglyoxal (MG) detoxification, and creating tolerance for drought-induced oxidative stress is well documented in plants. However, the influences of enzyme activity and osmoregulation on Spm biosynthesis and metabolism are variable. Spm interacts with other molecules like nitric oxide (NO) and phytohormones such as abscisic acid, salicylic acid, brassinosteroids, and ethylene, to coordinate the reactions necessary for developing drought tolerance. This review focuses on the role of Spm in plants under severe drought stress. We have proposed models to explain how Spm interacts with existing defense mechanisms in plants to improve drought tolerance. Full article
(This article belongs to the Special Issue Plant Polyamines in Plant Stress Tolerance)
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26 pages, 1420 KB  
Review
Inflammatory Chemokines in Atherosclerosis
by Selin Gencer, Bryce R. Evans, Emiel P.C. van der Vorst, Yvonne Döring and Christian Weber
Cells 2021, 10(2), 226; https://doi.org/10.3390/cells10020226 - 25 Jan 2021
Cited by 144 | Viewed by 11892
Abstract
Atherosclerosis is a long-term, chronic inflammatory disease of the vessel wall leading to the formation of occlusive or rupture-prone lesions in large arteries. Complications of atherosclerosis can become severe and lead to cardiovascular diseases (CVD) with lethal consequences. During the last three decades, [...] Read more.
Atherosclerosis is a long-term, chronic inflammatory disease of the vessel wall leading to the formation of occlusive or rupture-prone lesions in large arteries. Complications of atherosclerosis can become severe and lead to cardiovascular diseases (CVD) with lethal consequences. During the last three decades, chemokines and their receptors earned great attention in the research of atherosclerosis as they play a key role in development and progression of atherosclerotic lesions. They orchestrate activation, recruitment, and infiltration of immune cells and subsequent phenotypic changes, e.g., increased uptake of oxidized low-density lipoprotein (oxLDL) by macrophages, promoting the development of foam cells, a key feature developing plaques. In addition, chemokines and their receptors maintain homing of adaptive immune cells but also drive pro-atherosclerotic leukocyte responses. Recently, specific targeting, e.g., by applying cell specific knock out models have shed new light on their functions in chronic vascular inflammation. This article reviews recent findings on the role of immunomodulatory chemokines in the development of atherosclerosis and their potential for targeting. Full article
(This article belongs to the Special Issue Inflammation and Atherosclerosis)
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23 pages, 3439 KB  
Article
Beyond the Warburg Effect: Oxidative and Glycolytic Phenotypes Coexist within the Metabolic Heterogeneity of Glioblastoma
by Tomás Duraj, Noemí García-Romero, Josefa Carrión-Navarro, Rodrigo Madurga, Ana Ortiz de Mendivil, Ricardo Prat-Acin, Lina Garcia-Cañamaque and Angel Ayuso-Sacido
Cells 2021, 10(2), 202; https://doi.org/10.3390/cells10020202 - 20 Jan 2021
Cited by 68 | Viewed by 9252
Abstract
Glioblastoma (GBM) is the most aggressive primary brain tumor, with a median survival at diagnosis of 16–20 months. Metabolism represents a new attractive therapeutic target; however, due to high intratumoral heterogeneity, the application of metabolic drugs in GBM is challenging. We characterized the [...] Read more.
Glioblastoma (GBM) is the most aggressive primary brain tumor, with a median survival at diagnosis of 16–20 months. Metabolism represents a new attractive therapeutic target; however, due to high intratumoral heterogeneity, the application of metabolic drugs in GBM is challenging. We characterized the basal bioenergetic metabolism and antiproliferative potential of metformin (MF), dichloroacetate (DCA), sodium oxamate (SOD) and diazo-5-oxo-L-norleucine (DON) in three distinct glioma stem cells (GSCs) (GBM18, GBM27, GBM38), as well as U87MG. GBM27, a highly oxidative cell line, was the most resistant to all treatments, except DON. GBM18 and GBM38, Warburg-like GSCs, were sensitive to MF and DCA, respectively. Resistance to DON was not correlated with basal metabolic phenotypes. In combinatory experiments, radiomimetic bleomycin exhibited therapeutically relevant synergistic effects with MF, DCA and DON in GBM27 and DON in all other cell lines. MF and DCA shifted the metabolism of treated cells towards glycolysis or oxidation, respectively. DON consistently decreased total ATP production. Our study highlights the need for a better characterization of GBM from a metabolic perspective. Metabolic therapy should focus on both glycolytic and oxidative subpopulations of GSCs. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Glioblastoma)
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22 pages, 3389 KB  
Article
Beneficial Effects of Akkermansia muciniphila Are Not Associated with Major Changes in the Circulating Endocannabinoidome but Linked to Higher Mono-Palmitoyl-Glycerol Levels as New PPARα Agonists
by Clara Depommier, Rosa Maria Vitale, Fabio Arturo Iannotti, Cristoforo Silvestri, Nicolas Flamand, Céline Druart, Amandine Everard, Rudy Pelicaen, Dominique Maiter, Jean-Paul Thissen, Audrey Loumaye, Michel P. Hermans, Nathalie M. Delzenne, Willem M. de Vos, Vincenzo Di Marzo and Patrice D. Cani
Cells 2021, 10(1), 185; https://doi.org/10.3390/cells10010185 - 19 Jan 2021
Cited by 57 | Viewed by 11932
Abstract
Akkermansia muciniphila is considered as one of the next-generation beneficial bacteria in the context of obesity and associated metabolic disorders. Although a first proof-of-concept of its beneficial effects has been established in the context of metabolic syndrome in humans, mechanisms are not yet [...] Read more.
Akkermansia muciniphila is considered as one of the next-generation beneficial bacteria in the context of obesity and associated metabolic disorders. Although a first proof-of-concept of its beneficial effects has been established in the context of metabolic syndrome in humans, mechanisms are not yet fully understood. This study aimed at deciphering whether the bacterium exerts its beneficial properties through the modulation of the endocannabinoidome (eCBome). Circulating levels of 25 endogenous endocannabinoid-related lipids were quantified by liquid chromatography with tandem mass spectrometry (LC-MS/MS) in the plasma of overweight or obese individuals before and after a 3 months intervention consisting of the daily ingestion of either alive or pasteurized A. muciniphila. Results from multivariate analyses suggested that the beneficial effects of A. muciniphila were not linked to an overall modification of the eCBome. However, subsequent univariate analysis showed that the decrease in 1-Palmitoyl-glycerol (1-PG) and 2-Palmitoyl-glycerol (2-PG), two eCBome lipids, observed in the placebo group was significantly counteracted by the alive bacterium, and to a lower extent by the pasteurized form. We also discovered that 1- and 2-PG are endogenous activators of peroxisome proliferator-activated receptor alpha (PPARα). We hypothesize that PPARα activation by mono-palmitoyl-glycerols may underlie part of the beneficial metabolic effects induced by A. muciniphila in human metabolic syndrome. Full article
(This article belongs to the Special Issue The Endocannabinoidome: A Pleiotropic Expanded Endocannabinoid System Controlling Cell Function)
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11 pages, 300 KB  
Review
Future Directions in the Treatment of Osteosarcoma
by Alannah Smrke, Peter M. Anderson, Ashish Gulia, Spyridon Gennatas, Paul H. Huang and Robin L. Jones
Cells 2021, 10(1), 172; https://doi.org/10.3390/cells10010172 - 15 Jan 2021
Cited by 183 | Viewed by 13248
Abstract
Osteosarcoma is the most common primary bone sarcoma and is often diagnosed in the 2nd–3rd decades of life. Response to the aggressive and highly toxic neoadjuvant methotrexate-doxorubicin-cisplatin (MAP) chemotherapy schedule is strongly predictive of outcome. Outcomes for patients with osteosarcoma have not significantly [...] Read more.
Osteosarcoma is the most common primary bone sarcoma and is often diagnosed in the 2nd–3rd decades of life. Response to the aggressive and highly toxic neoadjuvant methotrexate-doxorubicin-cisplatin (MAP) chemotherapy schedule is strongly predictive of outcome. Outcomes for patients with osteosarcoma have not significantly changed for over thirty years. There is a need for more effective treatment for patients with high risk features but also reduced treatment-related toxicity for all patients. Predictive biomarkers are needed to help inform clinicians to de-escalate or add therapy, including immune therapies, and to contribute to future clinical trial designs. Here, we review a variety of approaches to improve outcomes and quality of life for patients with osteosarcoma with a focus on incorporating toxicity reduction, immune therapy and molecular analysis to provide the most effective and least toxic osteosarcoma therapy. Full article
(This article belongs to the Special Issue Research Advances and Therapy of Human Osteosarcoma)
12 pages, 800 KB  
Review
Significance of NETs Formation in COVID-19
by Karolina Janiuk, Ewa Jabłońska and Marzena Garley
Cells 2021, 10(1), 151; https://doi.org/10.3390/cells10010151 - 14 Jan 2021
Cited by 80 | Viewed by 6719
Abstract
Severe contagious respiratory disease—COVID-19—caused by the SARS-CoV-2 coronavirus, can lead to fatal respiratory failure associated with an excessive inflammatory response. Infiltration and spread of SARS-CoV-2 are based on the interaction between the virus’ structural protein S and the cell’s receptor–angiotensin-converting enzyme 2 (ACE2), [...] Read more.
Severe contagious respiratory disease—COVID-19—caused by the SARS-CoV-2 coronavirus, can lead to fatal respiratory failure associated with an excessive inflammatory response. Infiltration and spread of SARS-CoV-2 are based on the interaction between the virus’ structural protein S and the cell’s receptor–angiotensin-converting enzyme 2 (ACE2), with the simultaneous involvement of human trans-membrane protease, serine 2 (TMPRSS2). Many scientific reports stress the importance of elevated recruitment and activity of neutrophils, which can form extracellular neutrophil traps (NETs) playing a significant role in the mechanism of combating pathogens, in the pathogenesis of COVID-19. Excessive generation of NETs during prolonged periods of inflammation predisposes for the occurrence of undesirable reactions including thromboembolic complications and damage to surrounding tissues and organs. Within the present manuscript, we draw attention to the impact of NET generation on the severe course of COVID-19 in patients with concurrent cardiovascular and metabolic diseases. Additionally, we indicate the necessity to explore not only the cellular but also the molecular bases of COVID-19 pathogenesis, which may aid the development of dedicated therapies meant to improve chances for the successful treatment of patients. We also present new directions of research into medications that display NETs formation regulatory properties as potential significant therapeutic strategies in the progress of COVID-19. Full article
(This article belongs to the Special Issue The Cell Biology of Coronavirus Infection)
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21 pages, 6129 KB  
Article
Nuclear Pore Complexes Cluster in Dysmorphic Nuclei of Normal and Progeria Cells during Replicative Senescence
by Jennifer M. Röhrl, Rouven Arnold and Karima Djabali
Cells 2021, 10(1), 153; https://doi.org/10.3390/cells10010153 - 14 Jan 2021
Cited by 17 | Viewed by 6512
Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disease caused by a mutation in LMNA. A G608G mutation in exon 11 of LMNA is responsible for most HGPS cases, generating a truncated protein called “progerin”. Progerin is permanently farnesylated and accumulates [...] Read more.
Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disease caused by a mutation in LMNA. A G608G mutation in exon 11 of LMNA is responsible for most HGPS cases, generating a truncated protein called “progerin”. Progerin is permanently farnesylated and accumulates in HGPS cells, causing multiple cellular defects such as nuclear dysmorphism, a thickened lamina, loss of heterochromatin, premature senescence, and clustering of Nuclear Pore Complexes (NPC). To identify the mechanism of NPC clustering in HGPS cells, we evaluated post-mitotic NPC assembly in control and HGPS cells and found no defects. Next, we examined the occurrence of NPC clustering in control and HGPS cells during replicative senescence. We reported that NPC clustering occurs solely in the dysmorphic nuclei of control and HGPS cells. Hence, NPC clustering occurred at a higher frequency in HGPS cells compared to control cells at early passages; however, in late cultures with similar senescence index, NPCs clustering occurred at a similar rate in both control and HGPS. Our results show that progerin does not disrupt post-mitotic reassembly of NPCs. However, NPCs frequently cluster in dysmorphic nuclei with a high progerin content. Additionally, nuclear envelope defects that arise during replicative senescence cause NPC clustering in senescent cells with dysmorphic nuclei. 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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23 pages, 1609 KB  
Review
The Mitochondrial Permeability Transition: Nexus of Aging, Disease and Longevity
by Hagai Rottenberg and Jan B. Hoek
Cells 2021, 10(1), 79; https://doi.org/10.3390/cells10010079 - 6 Jan 2021
Cited by 67 | Viewed by 9606
Abstract
The activity of the mitochondrial permeability transition pore, mPTP, a highly regulated multi-component mega-channel, is enhanced in aging and in aging-driven degenerative diseases. mPTP activity accelerates aging by releasing large amounts of cell-damaging reactive oxygen species, Ca2+ and NAD+. The [...] Read more.
The activity of the mitochondrial permeability transition pore, mPTP, a highly regulated multi-component mega-channel, is enhanced in aging and in aging-driven degenerative diseases. mPTP activity accelerates aging by releasing large amounts of cell-damaging reactive oxygen species, Ca2+ and NAD+. The various pathways that control the channel activity, directly or indirectly, can therefore either inhibit or accelerate aging or retard or enhance the progression of aging-driven degenerative diseases and determine lifespan and healthspan. Autophagy, a catabolic process that removes and digests damaged proteins and organelles, protects the cell against aging and disease. However, the protective effect of autophagy depends on mTORC2/SKG1 inhibition of mPTP. Autophagy is inhibited in aging cells. Mitophagy, a specialized form of autophagy, which retards aging by removing mitochondrial fragments with activated mPTP, is also inhibited in aging cells, and this inhibition leads to increased mPTP activation, which is a major contributor to neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases. The increased activity of mPTP in aging turns autophagy/mitophagy into a destructive process leading to cell aging and death. Several drugs and lifestyle modifications that enhance healthspan and lifespan enhance autophagy and inhibit the activation of mPTP. Therefore, elucidating the intricate connections between pathways that activate and inhibit mPTP, in the context of aging and degenerative diseases, could enhance the discovery of new drugs and lifestyle modifications that slow aging and degenerative disease. Full article
(This article belongs to the Section Mitochondria)
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20 pages, 5798 KB  
Review
Insights into Plant Programmed Cell Death Induced by Heavy Metals—Discovering a Terra Incognita
by Klaudia Sychta, Aneta Słomka and Elżbieta Kuta
Cells 2021, 10(1), 65; https://doi.org/10.3390/cells10010065 - 4 Jan 2021
Cited by 74 | Viewed by 8265
Abstract
Programmed cell death (PCD) is a process that plays a fundamental role in plant development and responses to biotic and abiotic stresses. Knowledge of plant PCD mechanisms is still very scarce and is incomparable to the large number of studies on PCD mechanisms [...] Read more.
Programmed cell death (PCD) is a process that plays a fundamental role in plant development and responses to biotic and abiotic stresses. Knowledge of plant PCD mechanisms is still very scarce and is incomparable to the large number of studies on PCD mechanisms in animals. Quick and accurate assays, e.g., the TUNEL assay, comet assay, and analysis of caspase-like enzyme activity, enable the differentiation of PCD from necrosis. Two main types of plant PCD, developmental (dPCD) regulated by internal factors, and environmental (ePCD) induced by external stimuli, are distinguished based on the differences in the expression of the conserved PCD-inducing genes. Abiotic stress factors, including heavy metals, induce necrosis or ePCD. Heavy metals induce PCD by triggering oxidative stress via reactive oxygen species (ROS) overproduction. ROS that are mainly produced by mitochondria modulate phytotoxicity mechanisms induced by heavy metals. Complex crosstalk between ROS, hormones (ethylene), nitric oxide (NO), and calcium ions evokes PCD, with proteases with caspase-like activity executing PCD in plant cells exposed to heavy metals. This pathway leads to very similar cytological hallmarks of heavy metal induced PCD to PCD induced by other abiotic factors. The forms, hallmarks, mechanisms, and genetic regulation of plant ePCD induced by abiotic stress are reviewed here in detail, with an emphasis on plant cell culture as a suitable model for PCD studies. The similarities and differences between plant and animal PCD are also discussed. Full article
(This article belongs to the Special Issue Programmed Cell Death Regulation in Plants)
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23 pages, 3632 KB  
Review
High Mobility Group Box-1 and Blood–Brain Barrier Disruption
by Masahiro Nishibori, Dengli Wang, Daiki Ousaka and Hidenori Wake
Cells 2020, 9(12), 2650; https://doi.org/10.3390/cells9122650 - 10 Dec 2020
Cited by 98 | Viewed by 9318
Abstract
Increasing evidence suggests that inflammatory responses are involved in the progression of brain injuries induced by a diverse range of insults, including ischemia, hemorrhage, trauma, epilepsy, and degenerative diseases. During the processes of inflammation, disruption of the blood–brain barrier (BBB) may play a [...] Read more.
Increasing evidence suggests that inflammatory responses are involved in the progression of brain injuries induced by a diverse range of insults, including ischemia, hemorrhage, trauma, epilepsy, and degenerative diseases. During the processes of inflammation, disruption of the blood–brain barrier (BBB) may play a critical role in the enhancement of inflammatory responses and may initiate brain damage because the BBB constitutes an interface between the brain parenchyma and the bloodstream containing blood cells and plasma. The BBB has a distinct structure compared with those in peripheral tissues: it is composed of vascular endothelial cells with tight junctions, numerous pericytes surrounding endothelial cells, astrocytic endfeet, and a basement membrane structure. Under physiological conditions, the BBB should function as an important element in the neurovascular unit (NVU). High mobility group box-1 (HMGB1), a nonhistone nuclear protein, is ubiquitously expressed in almost all kinds of cells. HMGB1 plays important roles in the maintenance of chromatin structure, the regulation of transcription activity, and DNA repair in nuclei. On the other hand, HMGB1 is considered to be a representative damage-associated molecular pattern (DAMP) because it is translocated and released extracellularly from different types of brain cells, including neurons and glia, contributing to the pathophysiology of many diseases in the central nervous system (CNS). The regulation of HMGB1 release or the neutralization of extracellular HMGB1 produces beneficial effects on brain injuries induced by ischemia, hemorrhage, trauma, epilepsy, and Alzheimer’s amyloidpathy in animal models and is associated with improvement of the neurological symptoms. In the present review, we focus on the dynamics of HMGB1 translocation in different disease conditions in the CNS and discuss the functional roles of extracellular HMGB1 in BBB disruption and brain inflammation. There might be common as well as distinct inflammatory processes for each CNS disease. This review will provide novel insights toward an improved understanding of a common pathophysiological process of CNS diseases, namely, BBB disruption mediated by HMGB1. It is proposed that HMGB1 might be an excellent target for the treatment of CNS diseases with BBB disruption. Full article
(This article belongs to the Special Issue Cell Biology: State-of-the-Art and Perspectives in Japan)
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19 pages, 7578 KB  
Article
Artesunate Impairs Growth in Cisplatin-Resistant Bladder Cancer Cells by Cell Cycle Arrest, Apoptosis and Autophagy Induction
by Fuguang Zhao, Olesya Vakhrusheva, Sascha D. Markowitsch, Kimberly S. Slade, Igor Tsaur, Jindrich Cinatl, Jr., Martin Michaelis, Thomas Efferth, Axel Haferkamp and Eva Juengel
Cells 2020, 9(12), 2643; https://doi.org/10.3390/cells9122643 - 9 Dec 2020
Cited by 99 | Viewed by 7156
Abstract
Cisplatin, which induces DNA damage, is standard chemotherapy for advanced bladder cancer (BCa). However, efficacy is limited due to resistance development. Since artesunate (ART), a derivative of artemisinin originating from Traditional Chinese Medicine, has been shown to exhibit anti-tumor activity, and to inhibit [...] Read more.
Cisplatin, which induces DNA damage, is standard chemotherapy for advanced bladder cancer (BCa). However, efficacy is limited due to resistance development. Since artesunate (ART), a derivative of artemisinin originating from Traditional Chinese Medicine, has been shown to exhibit anti-tumor activity, and to inhibit DNA damage repair, the impact of artesunate on cisplatin-resistant BCa was evaluated. Cisplatin-sensitive (parental) and cisplatin-resistant BCa cells, RT4, RT112, T24, and TCCSup, were treated with ART (1–100 µM). Cell growth, proliferation, and cell cycle phases were investigated, as were apoptosis, necrosis, ferroptosis, autophagy, metabolic activity, and protein expression. Exposure to ART induced a time- and dose-dependent significant inhibition of tumor cell growth and proliferation of parental and cisplatin-resistant BCa cells. This inhibition was accompanied by a G0/G1 phase arrest and modulation of cell cycle regulating proteins. ART induced apoptos is by enhancing DNA damage, especially in the resistant cells. ART did not induce ferroptosis, but led to a disturbance of mitochondrial respiration and ATP generation. This impairment correlated with autophagy accompanied by a decrease in LC3B-I and an increase in LC3B-II. Since ART significantly inhibits proliferative and metabolic aspects of cisplatin-sensitive and cisplatin-resistant BCa cells, it may hold potential in treating advanced and therapy-resistant BCa. Full article
(This article belongs to the Special Issue Studying Drug Resistance Using Cancer Cell Lines)
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24 pages, 1445 KB  
Review
Linking Autism Risk Genes to Disruption of Cortical Development
by Marta Garcia-Forn, Andrea Boitnott, Zeynep Akpinar and Silvia De Rubeis
Cells 2020, 9(11), 2500; https://doi.org/10.3390/cells9112500 - 18 Nov 2020
Cited by 21 | Viewed by 8710
Abstract
Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by impairments in social communication and social interaction, and the presence of repetitive behaviors and/or restricted interests. In the past few years, large-scale whole-exome sequencing and genome-wide association studies have made enormous progress [...] Read more.
Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by impairments in social communication and social interaction, and the presence of repetitive behaviors and/or restricted interests. In the past few years, large-scale whole-exome sequencing and genome-wide association studies have made enormous progress in our understanding of the genetic risk architecture of ASD. While showing a complex and heterogeneous landscape, these studies have led to the identification of genetic loci associated with ASD risk. The intersection of genetic and transcriptomic analyses have also begun to shed light on functional convergences between risk genes, with the mid-fetal development of the cerebral cortex emerging as a critical nexus for ASD. In this review, we provide a concise summary of the latest genetic discoveries on ASD. We then discuss the studies in postmortem tissues, stem cell models, and rodent models that implicate recently identified ASD risk genes in cortical development. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neocortical Circuit Formation)
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20 pages, 1261 KB  
Review
Polyamines: Small Amines with Large Effects on Plant Abiotic Stress Tolerance
by Rubén Alcázar, Milagros Bueno and Antonio F. Tiburcio
Cells 2020, 9(11), 2373; https://doi.org/10.3390/cells9112373 - 29 Oct 2020
Cited by 204 | Viewed by 10754
Abstract
In recent years, climate change has altered many ecosystems due to a combination of frequent droughts, irregular precipitation, increasingly salinized areas and high temperatures. These environmental changes have also caused a decline in crop yield worldwide. Therefore, there is an urgent need to [...] Read more.
In recent years, climate change has altered many ecosystems due to a combination of frequent droughts, irregular precipitation, increasingly salinized areas and high temperatures. These environmental changes have also caused a decline in crop yield worldwide. Therefore, there is an urgent need to fully understand the plant responses to abiotic stress and to apply the acquired knowledge to improve stress tolerance in crop plants. The accumulation of polyamines (PAs) in response to many abiotic stresses is one of the most remarkable plant metabolic responses. In this review, we provide an update about the most significant achievements improving plant tolerance to drought, salinity, low and high temperature stresses by exogenous application of PAs or genetic manipulation of endogenous PA levels. We also provide some clues about possible mechanisms underlying PA functions, as well as known cross-talks with other stress signaling pathways. Finally, we discuss about the possible use of PAs for seed priming to induce abiotic stress tolerance in agricultural valuable crop plants. Full article
(This article belongs to the Special Issue Plant Polyamines in Plant Stress Tolerance)
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21 pages, 1294 KB  
Review
Development of Radiotracers for Breast Cancer—The Tumor Microenvironment as an Emerging Target
by Amelie Heesch, Jochen Maurer, Elmar Stickeler, Mohsen Beheshti, Felix M. Mottaghy and Agnieszka Morgenroth
Cells 2020, 9(10), 2334; https://doi.org/10.3390/cells9102334 - 21 Oct 2020
Cited by 18 | Viewed by 5397
Abstract
Molecular imaging plays an increasingly important role in the diagnosis and treatment of different malignancies. Radiolabeled probes enable the visualization of the primary tumor as well as the metastases and have been also employed in targeted therapy and theranostic approaches. With breast cancer [...] Read more.
Molecular imaging plays an increasingly important role in the diagnosis and treatment of different malignancies. Radiolabeled probes enable the visualization of the primary tumor as well as the metastases and have been also employed in targeted therapy and theranostic approaches. With breast cancer being the most common malignancy in women worldwide it is of special interest to develop novel targeted treatments. However, tumor microenvironment and escape mechanisms often limit their therapeutic potential. Addressing tumor stroma associated targets provides a promising option to inhibit tumor growth and angiogenesis and to disrupt tumor tissue architecture. This review describes recent developments on radiolabeled probes used in diagnosis and treatment of breast cancer especially in triple negative type with the focus on potential targets offered by the tumor microenvironment, like tumor associated macrophages, cancer associated fibroblasts, and endothelial cells. Full article
(This article belongs to the Collection Recent Advances in Oncology Nanomedicine: Toward Novel Personalized Medicine Tools to Fight Human Cancer)
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31 pages, 1552 KB  
Review
Cancer Metabolism: Phenotype, Signaling and Therapeutic Targets
by Jae Hyung Park, Woo Yang Pyun and Hyun Woo Park
Cells 2020, 9(10), 2308; https://doi.org/10.3390/cells9102308 - 16 Oct 2020
Cited by 380 | Viewed by 30955
Abstract
Aberrant metabolism is a major hallmark of cancer. Abnormal cancer metabolism, such as aerobic glycolysis and increased anabolic pathways, has important roles in tumorigenesis, metastasis, drug resistance, and cancer stem cells. Well-known oncogenic signaling pathways, such as phosphoinositide 3-kinase (PI3K)/AKT, Myc, and Hippo [...] Read more.
Aberrant metabolism is a major hallmark of cancer. Abnormal cancer metabolism, such as aerobic glycolysis and increased anabolic pathways, has important roles in tumorigenesis, metastasis, drug resistance, and cancer stem cells. Well-known oncogenic signaling pathways, such as phosphoinositide 3-kinase (PI3K)/AKT, Myc, and Hippo pathway, mediate metabolic gene expression and increase metabolic enzyme activities. Vice versa, deregulated metabolic pathways contribute to defects in cellular signal transduction pathways, which in turn provide energy, building blocks, and redox potentials for unrestrained cancer cell proliferation. Studies and clinical trials are being performed that focus on the inhibition of metabolic enzymes by small molecules or dietary interventions (e.g., fasting, calorie restriction, and intermittent fasting). Similar to genetic heterogeneity, the metabolic phenotypes of cancers are highly heterogeneous. This heterogeneity results from diverse cues in the tumor microenvironment and genetic mutations. Hence, overcoming metabolic plasticity is an important goal of modern cancer therapeutics. This review highlights recent findings on the metabolic phenotypes of cancer and elucidates the interactions between signal transduction pathways and metabolic pathways. We also provide novel rationales for designing the next-generation cancer metabolism drugs. Full article
(This article belongs to the Special Issue New Aspects of Targeting Cancer Metabolism in Therapeutic Approach)
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25 pages, 3739 KB  
Article
Cytotoxicity and Mitochondrial Dysregulation Caused by α-Synuclein in Dictyostelium discoideum
by Sanjanie Fernando, Claire Y. Allan, Katelyn Mroczek, Xavier Pearce, Oana Sanislav, Paul R. Fisher and Sarah J. Annesley
Cells 2020, 9(10), 2289; https://doi.org/10.3390/cells9102289 - 14 Oct 2020
Cited by 9 | Viewed by 3947
Abstract
Alpha synuclein has been linked to both sporadic and familial forms of Parkinson’s disease (PD) and is the most abundant protein in Lewy bodies a hallmark of Parkinson’s disease. The function of this protein and the molecular mechanisms underlying its toxicity are still [...] Read more.
Alpha synuclein has been linked to both sporadic and familial forms of Parkinson’s disease (PD) and is the most abundant protein in Lewy bodies a hallmark of Parkinson’s disease. The function of this protein and the molecular mechanisms underlying its toxicity are still unclear, but many studies have suggested that the mechanism of α-synuclein toxicity involves alterations to mitochondrial function. Here we expressed human α-synuclein and two PD-causing α-synuclein mutant proteins (with a point mutation, A53T, and a C-terminal 20 amino acid truncation) in the eukaryotic model Dictyostelium discoideum. Mitochondrial disease has been well studied in D. discoideum and, unlike in mammals, mitochondrial dysfunction results in a clear set of defective phenotypes. These defective phenotypes are caused by the chronic hyperactivation of the cellular energy sensor, AMP-activated protein kinase (AMPK). Expression of α-synuclein wild type and mutant forms was toxic to the cells and mitochondrial function was dysregulated. Some but not all of the defective phenotypes could be rescued by down regulation of AMPK revealing both AMPK-dependent and -independent mechanisms. Importantly, we also show that the C-terminus of α-synuclein is required and sufficient for the localisation of the protein to the cell cortex in D. discoideum. Full article
(This article belongs to the Special Issue Nonmammalian Models for Neurodegenerative and Neurological Disorders)
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27 pages, 10484 KB  
Review
Rho Family of Ras-Like GTPases in Early-Branching Animals
by Silvestar Beljan, Maja Herak Bosnar and Helena Ćetković
Cells 2020, 9(10), 2279; https://doi.org/10.3390/cells9102279 - 13 Oct 2020
Cited by 20 | Viewed by 5360
Abstract
Non-bilaterian animals consist of four phyla; Porifera, Cnidaria, Ctenophora, and Placozoa. These early-diverging animals are crucial for understanding the evolution of the entire animal lineage. The Rho family of proteins make up a major branch of the Ras superfamily of small GTPases, which [...] Read more.
Non-bilaterian animals consist of four phyla; Porifera, Cnidaria, Ctenophora, and Placozoa. These early-diverging animals are crucial for understanding the evolution of the entire animal lineage. The Rho family of proteins make up a major branch of the Ras superfamily of small GTPases, which function as key molecular switches that play important roles in converting and amplifying external signals into cellular responses. This review represents a compilation of the current knowledge on Rho-family GTPases in non-bilaterian animals, the available experimental data about their biochemical characteristics and functions, as well as original bioinformatics analysis, in order to gain a general insight into the evolutionary history of Rho-family GTPases in simple animals. Full article
(This article belongs to the Special Issue Rho family of GTPases in Model Organisms and Systems)
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18 pages, 1118 KB  
Review
Therapeutic miRNA-Enriched Extracellular Vesicles: Current Approaches and Future Prospects
by Javaria Munir, Jeong Kyo Yoon and Seongho Ryu
Cells 2020, 9(10), 2271; https://doi.org/10.3390/cells9102271 - 11 Oct 2020
Cited by 109 | Viewed by 8845
Abstract
Extracellular vesicles (EVs) are 50–300 nm vesicles secreted by eukaryotic cells. They can carry cargo (including miRNA) from the donor cell to the recipient cell. miRNAs in EVs can change the translational profile of the recipient cell and modulate cellular morphology. This endogenous [...] Read more.
Extracellular vesicles (EVs) are 50–300 nm vesicles secreted by eukaryotic cells. They can carry cargo (including miRNA) from the donor cell to the recipient cell. miRNAs in EVs can change the translational profile of the recipient cell and modulate cellular morphology. This endogenous mechanism has attracted the attention of the drug-delivery community in the last few years. EVs can be enriched with exogenous therapeutic miRNAs and used for treatment of diseases by targeting pathological recipient cells. However, there are some obstacles that need to be addressed before introducing therapeutic miRNA-enriched EVs in clinics. Here, we focused on the progress in the field of therapeutic miRNA enriched EVs, highlighted important areas where research is needed, and discussed the potential to use them as therapeutic miRNA carriers in the future. Full article
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