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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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23 pages, 1791 KB  
Review
GBA Variants and Parkinson Disease: Mechanisms and Treatments
by Laura Smith and Anthony H. V. Schapira
Cells 2022, 11(8), 1261; https://doi.org/10.3390/cells11081261 - 8 Apr 2022
Cited by 140 | Viewed by 17491
Abstract
The GBA gene encodes for the lysosomal enzyme glucocerebrosidase (GCase), which maintains glycosphingolipid homeostasis. Approximately 5–15% of PD patients have mutations in the GBA gene, making it numerically the most important genetic risk factor for Parkinson disease (PD). Clinically, GBA-associated PD is [...] Read more.
The GBA gene encodes for the lysosomal enzyme glucocerebrosidase (GCase), which maintains glycosphingolipid homeostasis. Approximately 5–15% of PD patients have mutations in the GBA gene, making it numerically the most important genetic risk factor for Parkinson disease (PD). Clinically, GBA-associated PD is identical to sporadic PD, aside from the earlier age at onset (AAO), more frequent cognitive impairment and more rapid progression. Mutations in GBA can be associated with loss- and gain-of-function mechanisms. A key hallmark of PD is the presence of intraneuronal proteinaceous inclusions named Lewy bodies, which are made up primarily of alpha-synuclein. Mutations in the GBA gene may lead to loss of GCase activity and lysosomal dysfunction, which may impair alpha-synuclein metabolism. Models of GCase deficiency demonstrate dysfunction of the autophagic-lysosomal pathway and subsequent accumulation of alpha-synuclein. This dysfunction can also lead to aberrant lipid metabolism, including the accumulation of glycosphingolipids, glucosylceramide and glucosylsphingosine. Certain mutations cause GCase to be misfolded and retained in the endoplasmic reticulum (ER), activating stress responses including the unfolded protein response (UPR), which may contribute to neurodegeneration. In addition to these mechanisms, a GCase deficiency has also been associated with mitochondrial dysfunction and neuroinflammation, which have been implicated in the pathogenesis of PD. This review discusses the pathways associated with GBA-PD and highlights potential treatments which may act to target GCase and prevent neurodegeneration. Full article
(This article belongs to the Special Issue Parkinson’s Disease (PD): Molecular Mechanisms and Novel Treatment Strategies)
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23 pages, 3565 KB  
Review
Brain Microvascular Pericytes—More than Bystanders in Breast Cancer Brain Metastasis
by Danyyl Ippolitov, Leanne Arreza, Maliha Nuzhat Munir and Sabine Hombach-Klonisch
Cells 2022, 11(8), 1263; https://doi.org/10.3390/cells11081263 - 8 Apr 2022
Cited by 9 | Viewed by 5214
Abstract
Brain tissue contains the highest number of perivascular pericytes compared to other organs. Pericytes are known to regulate brain perfusion and to play an important role within the neurovascular unit (NVU). The high phenotypic and functional plasticity of pericytes make this cell type [...] Read more.
Brain tissue contains the highest number of perivascular pericytes compared to other organs. Pericytes are known to regulate brain perfusion and to play an important role within the neurovascular unit (NVU). The high phenotypic and functional plasticity of pericytes make this cell type a prime candidate to aid physiological adaptations but also propose pericytes as important modulators in diverse pathologies in the brain. This review highlights known phenotypes of pericytes in the brain, discusses the diverse markers for brain pericytes, and reviews current in vitro and in vivo experimental models to study pericyte function. Our current knowledge of pericyte phenotypes as it relates to metastatic growth patterns in breast cancer brain metastasis is presented as an example for the crosstalk between pericytes, endothelial cells, and metastatic cells. Future challenges lie in establishing methods for real-time monitoring of pericyte crosstalk to understand causal events in the brain metastatic process. Full article
(This article belongs to the Section Cell Microenvironment)
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24 pages, 5474 KB  
Article
Proteomics and Metabolomics Profiling of Platelets and Plasma Mediators of Thrombo-Inflammation in Gestational Hypertension and Preeclampsia
by Luiz Gustavo N. de Almeida, Daniel Young, Lorraine Chow, Joshua Nicholas, Adrienne Lee, Man-Chiu Poon, Antoine Dufour and Ejaife O. Agbani
Cells 2022, 11(8), 1256; https://doi.org/10.3390/cells11081256 - 7 Apr 2022
Cited by 33 | Viewed by 7121
Abstract
Platelets may be pivotal mediators of the thrombotic and coagulopathic complications of preeclampsia (PE), linking inflammation and thrombosis with endothelial and vascular dysfunction. Both PE and gestational hypertension (GH) fall within the spectrum of hypertensive complications of pregnancy, with GH being a risk [...] Read more.
Platelets may be pivotal mediators of the thrombotic and coagulopathic complications of preeclampsia (PE), linking inflammation and thrombosis with endothelial and vascular dysfunction. Both PE and gestational hypertension (GH) fall within the spectrum of hypertensive complications of pregnancy, with GH being a risk factor for preeclampsia. However, it is unclear what biomarkers distinguish PE from GH. Using a discovery size cohort, we aimed to characterize specific plasma and platelet thrombo-inflammatory drivers indicative of PE and differentiate PE from GH. We performed multiplex immunoassays, platelet and plasma quantitative proteomics and metabolomics of PE patients, comparing with non-pregnant (NP), healthy pregnant controls (PC) and GH participants. The expression pattern of plasma proteins and metabolites in PE/GH platelets was distinct from that of NP and PC. Whilst procoagulation in PC may be fibrinogen driven, inter-alpha-trypsin inhibitors ITIH2 and ITIH3 are likely mediators of thrombo-inflammation in GH and PE, and fibronectin and S100A8/9 may be major procoagulant agonists in PE only. Also enriched in PE were CCL1 and CCL27 plasma cytokines, and the platelet leucine-rich repeat-containing protein 27 and 42 (LRRC27/42), whose effects on platelets were explored using STRING analysis. Through protein-protein interactions analysis, we generated a new hypothesis for platelets’ contribution to the thrombo-inflammatory states of preeclampsia. Full article
(This article belongs to the Special Issue Platelets as Pathophysiological Drivers of Thrombo-Inflammation and Immune Response)
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18 pages, 3211 KB  
Article
Decellularized Organ-Derived Scaffold Is a Promising Carrier for Human Induced Pluripotent Stem Cells-Derived Hepatocytes
by Hideaki Kojima, Hiroshi Yagi, Hiroko Kushige, Yukiko Toda, Kazuo Takayama, Shinako Masuda, Toshinori Morisaku, Tomonori Tsuchida, Kohei Kuroda, Kazuya Hirukawa, Jumpei Inui, Kotaro Nishi, Yutaka Nakano, Masayuki Tanaka, Shutaro Hori, Yasushi Hasegawa, Yuta Abe, Minoru Kitago, Shungo Adachi, Masatoshi Tomi, Katsuhisa Matsuura, Hiroyuki Mizuguchi and Yuko Kitagawaadd Show full author list remove Hide full author list
Cells 2022, 11(8), 1258; https://doi.org/10.3390/cells11081258 - 7 Apr 2022
Cited by 10 | Viewed by 3975
Abstract
Human induced pluripotent stem cells (hiPSCs) are a promising cell source for elucidating disease pathology and therapy. The mass supply of hiPSC-derived cells is technically feasible. Carriers that can contain a large number of hiPSC-derived cells and evaluate their functions in vivo-like environments [...] Read more.
Human induced pluripotent stem cells (hiPSCs) are a promising cell source for elucidating disease pathology and therapy. The mass supply of hiPSC-derived cells is technically feasible. Carriers that can contain a large number of hiPSC-derived cells and evaluate their functions in vivo-like environments will become increasingly important for understanding disease pathogenesis or treating end-stage organ failure. hiPSC-derived hepatocyte-like cells (hiPSC-HLCs; 5 × 108) were seeded into decellularized organ-derived scaffolds under circumfusion culture. The scaffolds were implanted into immunodeficient microminiature pigs to examine their applicability in vivo. The seeded hiPSC-HLCs demonstrated increased albumin secretion and up-regulated cytochrome P450 activities compared with those in standard two-dimensional culture conditions. Moreover, they showed long-term survival accompanied by neovascularization in vivo. The decellularized organ-derived scaffold is a promising carrier for hiPSC-derived cells for ex vivo and in vivo use and is an essential platform for regenerative medicine and research. Full article
(This article belongs to the Special Issue Current Progress in Organ Regeneration: Cells, Organoids and Organs)
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19 pages, 29063 KB  
Article
CARD19 Interacts with Mitochondrial Contact Site and Cristae Organizing System Constituent Proteins and Regulates Cristae Morphology
by Kariana E. Rios, Ming Zhou, Nathaniel M. Lott, Chelsi R. Beauregard, Dennis P. McDaniel, Thomas P. Conrads and Brian C. Schaefer
Cells 2022, 11(7), 1175; https://doi.org/10.3390/cells11071175 - 31 Mar 2022
Cited by 4 | Viewed by 4699
Abstract
CARD19 is a mitochondrial protein of unknown function. While CARD19 was originally reported to regulate TCR-dependent NF-κB activation via interaction with BCL10, this function is not recapitulated ex vivo in primary murine CD8+ T cells. Here, we employ a combination of SIM, [...] Read more.
CARD19 is a mitochondrial protein of unknown function. While CARD19 was originally reported to regulate TCR-dependent NF-κB activation via interaction with BCL10, this function is not recapitulated ex vivo in primary murine CD8+ T cells. Here, we employ a combination of SIM, TEM, and confocal microscopy, along with proteinase K protection assays and proteomics approaches, to identify interacting partners of CARD19 in macrophages. Our data show that CARD19 is specifically localized to the outer mitochondrial membrane. Through deletion of functional domains, we demonstrate that both the distal C-terminus and transmembrane domain are required for mitochondrial targeting, whereas the CARD is not. Importantly, mass spectrometry analysis of 3×Myc-CARD19 immunoprecipitates reveals that CARD19 interacts with the components of the mitochondrial intermembrane bridge (MIB), consisting of mitochondrial contact site and cristae organizing system (MICOS) components MIC19, MIC25, and MIC60, and MICOS-interacting proteins SAMM50 and MTX2. These CARD19 interactions are in part dependent on a properly folded CARD. Consistent with previously reported phenotypes upon siRNA silencing of MICOS subunits, absence of CARD19 correlates with irregular cristae morphology. Based on these data, we propose that CARD19 is a previously unknown interacting partner of the MIB and the MIC19–MIC25–MIC60 MICOS subcomplex that regulates cristae morphology. Full article
(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Organelle Function)
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16 pages, 2490 KB  
Article
Alterations in Protein Translation and Carboxylic Acid Catabolic Processes in Diabetic Kidney Disease
by Kimberly S. Collins, Michael T. Eadon, Ying-Hua Cheng, Daria Barwinska, Ricardo Melo Ferreira, Thomas W. McCarthy, Danielle Janosevic, Farooq Syed, Bernhard Maier, Tarek M. El-Achkar, Katherine J. Kelly, Carrie L. Phillips, Takashi Hato, Timothy A. Sutton and Pierre C. Dagher
Cells 2022, 11(7), 1166; https://doi.org/10.3390/cells11071166 - 30 Mar 2022
Cited by 9 | Viewed by 3384
Abstract
Diabetic kidney disease (DKD) remains the leading cause of end-stage kidney disease despite decades of study. Alterations in the glomerulus and kidney tubules both contribute to the pathogenesis of DKD although the majority of investigative efforts have focused on the glomerulus. We sought [...] Read more.
Diabetic kidney disease (DKD) remains the leading cause of end-stage kidney disease despite decades of study. Alterations in the glomerulus and kidney tubules both contribute to the pathogenesis of DKD although the majority of investigative efforts have focused on the glomerulus. We sought to examine the differential expression signature of human DKD in the glomerulus and proximal tubule and corroborate our findings in the db/db mouse model of diabetes. A transcriptogram network analysis of RNAseq data from laser microdissected (LMD) human glomerulus and proximal tubule of DKD and reference nephrectomy samples revealed enriched pathways including rhodopsin-like receptors, olfactory signaling, and ribosome (protein translation) in the proximal tubule of human DKD biopsy samples. The translation pathway was also enriched in the glomerulus. Increased translation in diabetic kidneys was validated using polyribosomal profiling in the db/db mouse model of diabetes. Using single nuclear RNA sequencing (snRNAseq) of kidneys from db/db mice, we prioritized additional pathways identified in human DKD. The top overlapping pathway identified in the murine snRNAseq proximal tubule clusters and the human LMD proximal tubule compartment was carboxylic acid catabolism. Using ultra-performance liquid chromatography–mass spectrometry, the fatty acid catabolism pathway was also found to be dysregulated in the db/db mouse model. The Acetyl-CoA metabolite was down-regulated in db/db mice, aligning with the human differential expression of the genes ACOX1 and ACACB. In summary, our findings demonstrate that proximal tubular alterations in protein translation and carboxylic acid catabolism are key features in both human and murine DKD. Full article
(This article belongs to the Special Issue Metabolomics as a Tool for Functional Genomics)
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23 pages, 2557 KB  
Review
Vitamin D Receptor Influences Intestinal Barriers in Health and Disease
by Jun Sun and Yong-Guo Zhang
Cells 2022, 11(7), 1129; https://doi.org/10.3390/cells11071129 - 27 Mar 2022
Cited by 57 | Viewed by 9228
Abstract
Vitamin D receptor (VDR) executes most of the biological functions of vitamin D. Beyond this, VDR is a transcriptional factor regulating the expression levels of many target genes, such as genes for tight junction proteins claudin-2, -5, -12, and -15. In this review, [...] Read more.
Vitamin D receptor (VDR) executes most of the biological functions of vitamin D. Beyond this, VDR is a transcriptional factor regulating the expression levels of many target genes, such as genes for tight junction proteins claudin-2, -5, -12, and -15. In this review, we discuss the progress of research on VDR that influences intestinal barriers in health and disease. We searched PubMed and Google Scholar using key words vitamin D, VDR, tight junctions, cancer, inflammation, and infection. We summarize the literature and progress reports on VDR regulation of tight junction distribution, cellular functions, and mechanisms (directly or indirectly). We review the impacts of VDR on barriers in various diseases, e.g., colon cancer, infection, inflammatory bowel disease, and chronic inflammatory lung diseases. We also discuss the limits of current studies and future directions. Deeper understanding of the mechanisms by which the VDR signaling regulates intestinal barrier functions allow us to develop efficient and effective therapeutic strategies based on levels of tight junction proteins and vitamin D/VDR statuses for human diseases. Full article
(This article belongs to the Special Issue Cell-Cell Interactions and Cell Adhesion Signaling in Disease States)
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18 pages, 2050 KB  
Article
Activin A Causes Muscle Atrophy through MEF2C-Dependent Impaired Myogenesis
by Audrey Loumaye, Pascale Lause, Xiaoling Zhong, Teresa A. Zimmers, Laure B. Bindels and Jean-Paul Thissen
Cells 2022, 11(7), 1119; https://doi.org/10.3390/cells11071119 - 25 Mar 2022
Cited by 18 | Viewed by 4328
Abstract
Activin A (ActA) is considered to play a major role in cancer-induced cachexia (CC). Indeed, circulating ActA levels are elevated and predict survival in patients with CC. However, the mechanisms by which ActA mediates CC development and in particular skeletal muscle (SM) atrophy [...] Read more.
Activin A (ActA) is considered to play a major role in cancer-induced cachexia (CC). Indeed, circulating ActA levels are elevated and predict survival in patients with CC. However, the mechanisms by which ActA mediates CC development and in particular skeletal muscle (SM) atrophy in humans are not yet fully understood. In this work, we aimed to investigate the effects of ActA on human SM and in mouse models of CC. We used a model of human muscle cells in culture to explore how ActA acts towards human SM. In this model, recombinant ActA induced myotube atrophy associated with the decline of MyHC-β/slow, the main myosin isoform in human muscle cells studied. Moreover, ActA inhibited the expression and activity of MEF2C, the transcription factor regulating MYH7, the gene which codes for MyHC-β/slow. This decrease in MEF2C was involved in the decline of MyHC-β/slow expression, since inhibition of MEF2C by a siRNA leads to the decrease in MyHC-β/slow expression. The relevance of this ActA/MEF2C pathway in vivo was supported by the parallel decline of MEF2C expression and SM mass, which are both blunted by ActA inhibition, in animal models of CC. In this work, we showed that ActA is a potent negative regulator of SM mass by inhibiting MyHC-β/slow synthesis through downregulation of MEF2C. This observation highlights a novel interaction between ActA signaling and MEF2C transcriptional activity which contributes to SM atrophy in CC models. Full article
(This article belongs to the Special Issue Cancer-Induced Cachexia)
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15 pages, 2048 KB  
Review
Metabotropic Glutamate Receptors at Ribbon Synapses in the Retina and Cochlea
by Lisa Klotz-Weigand and Ralf Enz
Cells 2022, 11(7), 1097; https://doi.org/10.3390/cells11071097 - 24 Mar 2022
Cited by 5 | Viewed by 4740
Abstract
Our senses define our view of the world. They allow us to adapt to environmental stimuli and are essential for communication and social behaviour. For most humans, seeing and hearing are central senses for their daily life. Our eyes and ears respond to [...] Read more.
Our senses define our view of the world. They allow us to adapt to environmental stimuli and are essential for communication and social behaviour. For most humans, seeing and hearing are central senses for their daily life. Our eyes and ears respond to an extraordinary broad range of stimuli covering about 12 log units of light intensity or acoustic power, respectively. The cellular basis is represented by sensory cells (photoreceptors in the retina and inner hair cells in the cochlea) that convert sensory inputs into electrical signals. Photoreceptors and inner hair cells have developed a specific pre-synaptic structure, termed synaptic ribbon, that is decorated with numerous vesicles filled with the excitatory neurotransmitter glutamate. At these ribbon synapses, glutamatergic signal transduction is guided by distinct sets of metabotropic glutamate receptors (mGluRs). MGluRs belong to group II and III of the receptor classification can inhibit neuronal activity, thus protecting neurons from overstimulation and subsequent degeneration. Consequently, dysfunction of mGluRs is associated with vision and hearing disorders. In this review, we introduce the principle characteristics of ribbon synapses and describe group II and III mGluRs in these fascinating structures in the retina and cochlea. Full article
(This article belongs to the Special Issue The Role of Metabotropic Glutamate Receptors in Health and Disease)
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21 pages, 7496 KB  
Article
Protective Effect of Human-Neural-Crest-Derived Nasal Turbinate Stem Cells against Amyloid-β Neurotoxicity through Inhibition of Osteopontin in a Human Cerebral Organoid Model of Alzheimer’s Disease
by Jung Yeon Lim, Jung Eun Lee, Soon A Park, Sang In Park, Jung-Min Yon, Jeong-Ah Park, Sin-Soo Jeun, Seung Joon Kim, Hong Jun Lee, Sung Won Kim and Seung Ho Yang
Cells 2022, 11(6), 1029; https://doi.org/10.3390/cells11061029 - 18 Mar 2022
Cited by 11 | Viewed by 3857
Abstract
The aim of this study was to validate the use of human brain organoids (hBOs) to investigate the therapeutic potential and mechanism of human-neural-crest-derived nasal turbinate stem cells (hNTSCs) in models of Alzheimer’s disease (AD). We generated hBOs from human induced pluripotent stem [...] Read more.
The aim of this study was to validate the use of human brain organoids (hBOs) to investigate the therapeutic potential and mechanism of human-neural-crest-derived nasal turbinate stem cells (hNTSCs) in models of Alzheimer’s disease (AD). We generated hBOs from human induced pluripotent stem cells, investigated their characteristics according to neuronal markers and electrophysiological features, and then evaluated the protective effect of hNTSCs against amyloid-β peptide (Aβ1–42) neurotoxic activity in vitro in hBOs and in vivo in a mouse model of AD. Treatment of hBOs with Aβ1–42 induced neuronal cell death concomitant with decreased expression of neuronal markers, which was suppressed by hNTSCs cocultured under Aβ1–42 exposure. Cytokine array showed a significantly decreased level of osteopontin (OPN) in hBOs with hNTSC coculture compared with hBOs only in the presence of Aβ1–42. Silencing OPN via siRNA suppressed Aβ-induced neuronal cell death in cell culture. Notably, compared with PBS, hNTSC transplantation significantly enhanced performance on the Morris water maze, with reduced levels of OPN after transplantation in a mouse model of AD. These findings reveal that hBO models are useful to evaluate the therapeutic effect and mechanism of stem cells for application in treating AD. Full article
(This article belongs to the Section Stem Cells)
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14 pages, 989 KB  
Article
Cerebrospinal Fluid Proteome Alterations Associated with Neuropsychiatric Symptoms in Cognitive Decline and Alzheimer’s Disease
by Magdalena Mroczek, Christopher Clark, Loïc Dayon, Gene L. Bowman and Julius Popp
Cells 2022, 11(6), 1030; https://doi.org/10.3390/cells11061030 - 18 Mar 2022
Cited by 12 | Viewed by 3506
Abstract
Although neuropsychiatric symptoms (NPS) are common and severely affect older people with cognitive decline, little is known about their underlying molecular mechanisms and relationships with Alzheimer’s disease (AD). The aim of this study was to identify and characterize cerebrospinal fluid (CSF) proteome alterations [...] Read more.
Although neuropsychiatric symptoms (NPS) are common and severely affect older people with cognitive decline, little is known about their underlying molecular mechanisms and relationships with Alzheimer’s disease (AD). The aim of this study was to identify and characterize cerebrospinal fluid (CSF) proteome alterations related to NPS. In a longitudinally followed-up cohort of subjects with normal cognition and patients with cognitive impairment (MCI and mild dementia) from a memory clinic setting, we quantified a panel of 790 proteins in CSF using an untargeted shotgun proteomic workflow. Regression models and pathway enrichment analysis were used to investigate protein alterations related to NPS, and to explore relationships with AD pathology and cognitive decline at follow-up visits. Regression analysis selected 27 CSF proteins associated with NPS. These associations were independent of the presence of cerebral AD pathology (defined as CSF p-tau181/Aβ1–42 > 0.0779, center cutoff). Gene ontology enrichment showed abundance alterations of proteins related to cell adhesion, immune response, and lipid metabolism, among others, in relation to NPS. Out of the selected proteins, three were associated with accelerated cognitive decline at follow-up visits after controlling for possible confounders. Specific CSF proteome alterations underlying NPS may both represent pathophysiological processes independent from AD and accelerate clinical disease progression. Full article
(This article belongs to the Special Issue Alzheimer's Disease: Molecular Mechanisms and Novel Treatment Strategies)
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12 pages, 876 KB  
Review
Hydrogen Sulfide Produced by Gut Bacteria May Induce Parkinson’s Disease
by Kari Erik Murros
Cells 2022, 11(6), 978; https://doi.org/10.3390/cells11060978 - 12 Mar 2022
Cited by 66 | Viewed by 11664
Abstract
Several bacterial species can generate hydrogen sulfide (H2S). Study evidence favors the view that the microbiome of the colon harbors increased amounts of H2S producing bacteria in Parkinson’s disease. Additionally, H2S can easily penetrate cell membranes and [...] Read more.
Several bacterial species can generate hydrogen sulfide (H2S). Study evidence favors the view that the microbiome of the colon harbors increased amounts of H2S producing bacteria in Parkinson’s disease. Additionally, H2S can easily penetrate cell membranes and enter the cell interior. In the cells, excessive amounts of H2S can potentially release cytochrome c protein from the mitochondria, increase the iron content of the cytosolic iron pool, and increase the amount of reactive oxygen species. These events can lead to the formation of alpha-synuclein oligomers and fibrils in cells containing the alpha-synuclein protein. In addition, bacterially produced H2S can interfere with the body urate metabolism and affect the blood erythrocytes and lymphocytes. Gut bacteria responsible for increased H2S production, especially the mucus-associated species of the bacterial genera belonging to the Desulfovibrionaceae and Enterobacteriaceae families, are likely play a role in the pathogenesis of Parkinson’s disease. Special attention should be devoted to changes not only in the colonic but also in the duodenal microbiome composition with regard to the pathogenesis of Parkinson’s disease. Influenza infections may increase the risk of Parkinson’s disease by causing the overgrowth of H2S-producing bacteria both in the colon and duodenum. Full article
(This article belongs to the Special Issue Focus on Cellular Parkinson’s Disease—from Gut to Brain)
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29 pages, 1908 KB  
Review
Novel Insights into the Therapeutic Potential of Lung-Targeted Gene Transfer in the Most Common Respiratory Diseases
by Malik Bisserier, Xiao-Qing Sun, Shahood Fazal, Irene C. Turnbull, Sébastien Bonnet and Lahouaria Hadri
Cells 2022, 11(6), 984; https://doi.org/10.3390/cells11060984 - 12 Mar 2022
Cited by 22 | Viewed by 12559
Abstract
Over the past decades, a better understanding of the genetic and molecular alterations underlying several respiratory diseases has encouraged the development of new therapeutic strategies. Gene therapy offers new therapeutic alternatives for inherited and acquired diseases by delivering exogenous genetic materials into cells [...] Read more.
Over the past decades, a better understanding of the genetic and molecular alterations underlying several respiratory diseases has encouraged the development of new therapeutic strategies. Gene therapy offers new therapeutic alternatives for inherited and acquired diseases by delivering exogenous genetic materials into cells or tissues to restore physiological protein expression and/or activity. In this review, we review (1) different types of viral and non-viral vectors as well as gene-editing techniques; and (2) the application of gene therapy for the treatment of respiratory diseases and disorders, including pulmonary arterial hypertension, idiopathic pulmonary fibrosis, cystic fibrosis, asthma, alpha-1 antitrypsin deficiency, chronic obstructive pulmonary disease, non-small-cell lung cancer, and COVID-19. Further, we also provide specific examples of lung-targeted therapies and discuss the major limitations of gene therapy. Full article
(This article belongs to the Collection Cellular and Molecular Pathophysiology of Vascular Proliferative Diseases)
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14 pages, 654 KB  
Review
MicroRNA Roles in Cell Reprogramming Mechanisms
by Emilia Pascale, Carmen Caiazza, Martina Paladino, Silvia Parisi, Fabiana Passaro and Massimiliano Caiazzo
Cells 2022, 11(6), 940; https://doi.org/10.3390/cells11060940 - 10 Mar 2022
Cited by 22 | Viewed by 7218
Abstract
Cell reprogramming is a groundbreaking technology that, in few decades, generated a new paradigm in biomedical science. To date we can use cell reprogramming to potentially generate every cell type by converting somatic cells and suitably modulating the expression of key transcription factors. [...] Read more.
Cell reprogramming is a groundbreaking technology that, in few decades, generated a new paradigm in biomedical science. To date we can use cell reprogramming to potentially generate every cell type by converting somatic cells and suitably modulating the expression of key transcription factors. This approach can be used to convert skin fibroblasts into pluripotent stem cells as well as into a variety of differentiated and medically relevant cell types, including cardiomyocytes and neural cells. The molecular mechanisms underlying such striking cell phenotypes are still largely unknown, but in the last decade it has been proven that cell reprogramming approaches are significantly influenced by non-coding RNAs. Specifically, this review will focus on the role of microRNAs in the reprogramming processes that lead to the generation of pluripotent stem cells, neurons, and cardiomyocytes. As highlighted here, non-coding RNA-forced expression can be sufficient to support some cell reprogramming processes, and, therefore, we will also discuss how these molecular determinants could be used in the future for biomedical purposes. Full article
(This article belongs to the Special Issue Role of Non-coding RNA in Health and Disease)
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11 pages, 1007 KB  
Review
Calcium Channels in the Heart: Disease States and Drugs
by Kajol Shah, Sarah Seeley, Castin Schulz, Jacqueline Fisher and Shubha Gururaja Rao
Cells 2022, 11(6), 943; https://doi.org/10.3390/cells11060943 - 10 Mar 2022
Cited by 63 | Viewed by 16820
Abstract
Calcium ions are the major signaling ions in the cells. They regulate muscle contraction, neurotransmitter secretion, cell growth and migration, and the activity of several proteins including enzymes and ion channels and transporters. They participate in various signal transduction pathways, thereby regulating major [...] Read more.
Calcium ions are the major signaling ions in the cells. They regulate muscle contraction, neurotransmitter secretion, cell growth and migration, and the activity of several proteins including enzymes and ion channels and transporters. They participate in various signal transduction pathways, thereby regulating major physiological functions. Calcium ion entry into the cells is regulated by specific calcium channels and transporters. There are mainly six types of calcium channels, of which only two are prominent in the heart. In cardiac tissues, the two types of calcium channels are the L type and the T type. L-type channels are found in all cardiac cells and T-type are expressed in Purkinje cells, pacemaker and atrial cells. Both these types of channels contribute to atrioventricular conduction as well as pacemaker activity. Given the crucial role of calcium channels in the cardiac conduction system, mutations and dysfunctions of these channels are known to cause several diseases and disorders. Drugs targeting calcium channels hence are used in a wide variety of cardiac disorders including but not limited to hypertension, angina, and arrhythmias. This review summarizes the type of cardiac calcium channels, their function, and disorders caused by their mutations and dysfunctions. Finally, this review also focuses on the types of calcium channel blockers and their use in a variety of cardiac disorders. Full article
(This article belongs to the Special Issue Calcium Signaling in Health and Diseases)
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19 pages, 1027 KB  
Review
Biomarkers Associated with Cardiovascular Disease in COVID-19
by Christoph C. Kaufmann, Amro Ahmed, Achim Leo Burger, Marie Muthspiel, Bernhard Jäger, Johann Wojta and Kurt Huber
Cells 2022, 11(6), 922; https://doi.org/10.3390/cells11060922 - 8 Mar 2022
Cited by 19 | Viewed by 6042
Abstract
Coronavirus disease-19 (COVID-19) emerged late December 2019 in the city of Wuhan, China and has since spread rapidly all over the world causing a global pandemic. While the respiratory system is the primary target of disease manifestation, COVID-19 has been shown to also [...] Read more.
Coronavirus disease-19 (COVID-19) emerged late December 2019 in the city of Wuhan, China and has since spread rapidly all over the world causing a global pandemic. While the respiratory system is the primary target of disease manifestation, COVID-19 has been shown to also affect several other organs, making it a rather complex, multi-system disease. As such, cardiovascular involvement has been a topic of discussion since the beginning of the COVID-19 pandemic, primarily due to early reports of excessive myocardial injury in these patients. Treating physicians are faced with multiple challenges in the management and early triage of patients with COVID-19, as disease severity is highly variable ranging from an asymptomatic infection to critical cases rapidly deteriorating to intensive care treatment or even fatality. Laboratory biomarkers provide important prognostic information which can guide decision making in the emergency department, especially in patients with atypical presentations. Several cardiac biomarkers, most notably high-sensitive cardiac troponin (hs-cTn) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), have emerged as valuable predictors of prognosis in patients with COVID-19. The purpose of this review was to offer a concise summary on prognostic cardiac biomarkers in COVID-19 and discuss whether routine measurements of these biomarkers are warranted upon hospital admission. Full article
(This article belongs to the Special Issue Understanding Biomarkers in Cardiology)
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18 pages, 2825 KB  
Article
Viral Interference of Hepatitis C and E Virus Replication in Novel Experimental Co-Infection Systems
by Thomas Burkard, Nora Proske, Kathrin Resner, Laura Collignon, Leonard Knegendorf, Martina Friesland, Lieven Verhoye, Ibrahim M. Sayed, Yannick Brüggemann, Maximilian K. Nocke, Patrick Behrendt, Heiner Wedemeyer, Philip Meuleman, Daniel Todt and Eike Steinmann
Cells 2022, 11(6), 927; https://doi.org/10.3390/cells11060927 - 8 Mar 2022
Cited by 8 | Viewed by 4998
Abstract
Background: Hepatitis C virus (HCV) constitutes a global health problem, while hepatitis E virus (HEV) is the major cause of acute viral hepatitis globally. HCV/HEV co-infections have been poorly characterized, as they are hampered by the lack of robust HEV cell culture systems. [...] Read more.
Background: Hepatitis C virus (HCV) constitutes a global health problem, while hepatitis E virus (HEV) is the major cause of acute viral hepatitis globally. HCV/HEV co-infections have been poorly characterized, as they are hampered by the lack of robust HEV cell culture systems. This study developed experimental models to study HCV/HEV co-infections and investigate viral interference in cells and humanized mice. Methods: We used state-of-the art human hepatocytes tissue culture models to assess HEV and HCV replication in co- or super-transfection settings. Findings were confirmed by co- and super-infection experiments in human hepatocytes and in vivo in human liver chimeric mice. Results: HEV was inhibited by concurrent HCV replication in human hepatocytes. This exclusion phenotype was linked to the protease activity of HCV. These findings were corroborated by the fact that in HEV on HCV super-infected mice, HEV viral loads were reduced in individual mice. Similarly, HCV on HEV super-infected mice showed reduced HCV viral loads. Conclusion: Direct interference of both viruses with HCV NS3/4A as the determinant was observed. In vivo, we detected reduced replication of both viruses after super-infection in individual mice. These findings provide new insights into the pathogenesis of HCV-HEV co-infections and should contribute to its clinical management in the future. Full article
(This article belongs to the Special Issue Cells as Viral Hosts)
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15 pages, 3037 KB  
Article
Pathological Relevance of Post-Translationally Modified Alpha-Synuclein (pSer87, pSer129, nTyr39) in Idiopathic Parkinson’s Disease and Multiple System Atrophy
by Berkiye Sonustun, Melek Firat Altay, Catherine Strand, Kirsten Ebanks, Geshanthi Hondhamuni, Thomas T. Warner, Hilal A. Lashuel and Rina Bandopadhyay
Cells 2022, 11(5), 906; https://doi.org/10.3390/cells11050906 - 6 Mar 2022
Cited by 30 | Viewed by 5264
Abstract
Aggregated alpha-synuclein (α-synuclein) is the main component of Lewy bodies (LBs), Lewy neurites (LNs), and glial cytoplasmic inclusions (GCIs), which are pathological hallmarks of idiopathic Parkinson’s disease (IPD) and multiple system atrophy (MSA). Initiating factors that culminate in forming LBs/LNs/GCIs remain elusive. Several [...] Read more.
Aggregated alpha-synuclein (α-synuclein) is the main component of Lewy bodies (LBs), Lewy neurites (LNs), and glial cytoplasmic inclusions (GCIs), which are pathological hallmarks of idiopathic Parkinson’s disease (IPD) and multiple system atrophy (MSA). Initiating factors that culminate in forming LBs/LNs/GCIs remain elusive. Several species of α-synuclein exist, including phosphorylated and nitrated forms. It is unclear which α-synuclein post-translational modifications (PTMs) appear within aggregates throughout disease pathology. Herein we aimed to establish the predominant α-synuclein PTMs in postmortem IPD and MSA pathology using immunohistochemistry. We examined the patterns of three α-synuclein PTMs (pS87, pS129, nY39) simultaneously in pathology-affected regions of 15 IPD cases, 5 MSA cases, and 6 neurologically normal controls. All antibodies recognized LBs, LNs, and GCIs, albeit to a variable extent. pS129 α-synuclein antibody was particularly immunopositive for LNs and synaptic dot-like structures, followed by nY39 α-synuclein antibody. GCIs, neuronal inclusions, and small threads were positive for nY39 α-synuclein in MSA. Quantification of the LB scores revealed that pS129 α-synuclein was the dominant and earliest α-synuclein PTM, followed by nY39 α-synuclein, while lower amounts of pSer87 α-synuclein appeared later in disease progression in PD. These results may have implications for novel biomarker and therapeutic developments. Full article
(This article belongs to the Special Issue Parkinson’s Disease (PD): Molecular Mechanisms and Novel Treatment Strategies)
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14 pages, 2119 KB  
Article
PTH-Induced Bone Regeneration and Vascular Modulation Are Both Dependent on Endothelial Signaling
by Doron Cohn-Schwartz, Yeshai Schary, Eran Yalon, Zoe Krut, Xiaoyu Da, Edward M. Schwarz, Dan Gazit, Gadi Pelled and Zulma Gazit
Cells 2022, 11(5), 897; https://doi.org/10.3390/cells11050897 - 5 Mar 2022
Cited by 11 | Viewed by 3035
Abstract
The use of a bone allograft presents a promising approach for healing nonunion fractures. We have previously reported that parathyroid hormone (PTH) therapy induced allograft integration while modulating angiogenesis at the allograft proximity. Here, we hypothesize that PTH-induced vascular modulation and the osteogenic [...] Read more.
The use of a bone allograft presents a promising approach for healing nonunion fractures. We have previously reported that parathyroid hormone (PTH) therapy induced allograft integration while modulating angiogenesis at the allograft proximity. Here, we hypothesize that PTH-induced vascular modulation and the osteogenic effect of PTH are both dependent on endothelial PTH receptor-1 (PTHR1) signaling. To evaluate our hypothesis, we used multiple transgenic mouse lines, and their wild-type counterparts as a control. In addition to endothelial-specific PTHR1 knock-out mice, we used mice in which PTHR1 was engineered to be constitutively active in collagen-1α+ osteoblasts, to assess the effect of PTH signaling activation exclusively in osteoprogenitors. To characterize resident cell recruitment and osteogenic activity, mice in which the Luciferase reporter gene is expressed under the Osteocalcin promoter (Oc-Luc) were used. Mice were implanted with calvarial allografts and treated with either PTH or PBS. A micro-computed tomography-based structural analysis indicated that the induction of bone formation by PTH, as observed in wild-type animals, was not maintained when PTHR1 was removed from endothelial cells. Furthermore, the induction of PTH signaling exclusively in osteoblasts resulted in significantly less bone formation compared to systemic PTH treatment, and significantly less osteogenic activity was measured by bioluminescence imaging of the Oc-Luc mice. Deletion of the endothelial PTHR1 significantly decreased the PTH-induced formation of narrow blood vessels, formerly demonstrated in wild-type mice. However, the exclusive activation of PTH signaling in osteoblasts was sufficient to re-establish the observed PTH effect. Collectively, our results show that endothelial PTHR1 signaling plays a key role in PTH-induced osteogenesis and has implications in angiogenesis. Full article
(This article belongs to the Special Issue Advances in Bone Metabolism)
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16 pages, 4607 KB  
Article
Transcriptomics Reveals Discordant Lipid Metabolism Effects between In Vitro Models Exposed to Elafibranor and Liver Samples of NAFLD Patients after Bariatric Surgery
by Joost Boeckmans, Alexandra Gatzios, Anja Heymans, Matthias Rombaut, Vera Rogiers, Joery De Kock, Tamara Vanhaecke and Robim M. Rodrigues
Cells 2022, 11(5), 893; https://doi.org/10.3390/cells11050893 - 4 Mar 2022
Cited by 10 | Viewed by 4868
Abstract
Background and aims: Non-alcoholic steatohepatitis (NASH) is a life-threatening stage of non-alcoholic fatty liver disease (NAFLD) for which no drugs have been approved. We have previously shown that human-derived hepatic in vitro models can be used to mimic key cellular mechanisms involved in [...] Read more.
Background and aims: Non-alcoholic steatohepatitis (NASH) is a life-threatening stage of non-alcoholic fatty liver disease (NAFLD) for which no drugs have been approved. We have previously shown that human-derived hepatic in vitro models can be used to mimic key cellular mechanisms involved in the progression of NASH. In the present study, we first characterize the transcriptome of multiple in vitro NASH models. Subsequently, we investigate how elafibranor, which is a peroxisome proliferator-activated receptor (PPAR)-α/δ agonist that has recently failed a phase 3 clinical trial as a potential anti-NASH compound, modulates the transcriptome of these models. Finally, we compare the elafibranor-induced gene expression modulation to transcriptome data of patients with improved/resolved NAFLD/NASH upon bariatric surgery, which is the only proven clinical NASH therapy. Methods: Human whole genome microarrays were used for the transcriptomics evaluation of hepatic in vitro models. Comparison to publicly available clinical datasets was conducted using multiple bioinformatic application tools. Results: Primary human hepatocytes (PHH), HepaRG, and human skin stem cell-derived hepatic progenitors (hSKP-HPC) exposed to NASH-inducing triggers exhibit up to 35% overlap with datasets of liver samples from NASH patients. Exposure of the in vitro NASH models to elafibranor partially reversed the transcriptional modulations, predicting an inhibition of toll-like receptor (TLR)-2/4/9-mediated inflammatory responses, NFκB-signaling, hepatic fibrosis, and leukocyte migration. These transcriptomic changes were also observed in the datasets of liver samples of patients with resolved NASH. Peroxisome Proliferator Activated Receptor Alpha (PPARA), PPARG Coactivator 1 Alpha (PPARGC1A), and Sirtuin 1 (SIRT1) were identified as the major common upstream regulators upon exposure to elafibranor. Analysis of the downstream mechanistic networks further revealed that angiopoietin Like 4 (ANGPTL4), pyruvate dehydrogenase kinase 4 (PDK4), and perilipin 2 (PLIN2), which are involved in the promotion of hepatic lipid accumulation, were also commonly upregulated by elafibranor in all in vitro NASH models. Contrarily, these genes were not upregulated in liver samples of patients with resolved NASH. Conclusion: Transcriptomics comparison between in vitro NASH models exposed to elafibranor and clinical datasets of NAFLD patients after bariatric surgery reveals commonly modulated anti-inflammatory responses, but discordant modulations of key factors in lipid metabolism. This discordant adverse effect of elafibranor deserves further investigation when assessing PPAR-α/δ agonism as a potential anti-NASH therapy. Full article
(This article belongs to the Special Issue The Role of PPARs in Disease II)
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16 pages, 1417 KB  
Review
Metabolic Contribution and Cerebral Blood Flow Regulation by Astrocytes in the Neurovascular Unit
by Shinichi Takahashi
Cells 2022, 11(5), 813; https://doi.org/10.3390/cells11050813 - 25 Feb 2022
Cited by 54 | Viewed by 12445
Abstract
The neurovascular unit (NVU) is a conceptual framework that has been proposed to better explain the relationships between the neural cells and blood vessels in the human brain, focused mainly on the brain gray matter. The major components of the NVU are the [...] Read more.
The neurovascular unit (NVU) is a conceptual framework that has been proposed to better explain the relationships between the neural cells and blood vessels in the human brain, focused mainly on the brain gray matter. The major components of the NVU are the neurons, astrocytes (astroglia), microvessels, pericytes, and microglia. In addition, we believe that oligodendrocytes should also be included as an indispensable component of the NVU in the white matter. Of all these components, astrocytes in particular have attracted the interest of researchers because of their unique anatomical location; these cells are interposed between the neurons and the microvessels of the brain. Their location suggests that astrocytes might regulate the cerebral blood flow (CBF) in response to neuronal activity, so as to ensure an adequate supply of glucose and oxygen to meet the metabolic demands of the neurons. In fact, the adult human brain, which accounts for only 2% of the entire body weight, consumes approximately 20–25% of the total amount of glucose and oxygen consumed by the whole body. The brain needs a continuous supply of these essential energy sources through the CBF, because there are practically no stores of glucose or oxygen in the brain; both acute and chronic cessation of CBF can adversely affect brain functions. In addition, another important putative function of the NVU is the elimination of heat and waste materials produced by neuronal activity. Recent evidence suggests that astrocytes play pivotal roles not only in supplying glucose, but also fatty acids and amino acids to neurons. Loss of astrocytic support can be expected to lead to malfunction of the NVU as a whole, which underlies numerous neurological disorders. In this review, we shall focus on historical and recent findings with regard to the metabolic contributions of astrocytes in the NVU. Full article
(This article belongs to the Special Issue Remodeling and Recovery in the Neurovascular Unit)
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18 pages, 2045 KB  
Review
The Role of Mitochondria in Human Fertility and Early Embryo Development: What Can We Learn for Clinical Application of Assessing and Improving Mitochondrial DNA?
by Amira Podolak, Izabela Woclawek-Potocka and Krzysztof Lukaszuk
Cells 2022, 11(5), 797; https://doi.org/10.3390/cells11050797 - 24 Feb 2022
Cited by 43 | Viewed by 9682
Abstract
Mitochondria are well known as ‘the powerhouses of the cell’. Indeed, their major role is cellular energy production driven by both mitochondrial and nuclear DNA. Such a feature makes these organelles essential for successful fertilisation and proper embryo implantation and development. Generally, mitochondrial [...] Read more.
Mitochondria are well known as ‘the powerhouses of the cell’. Indeed, their major role is cellular energy production driven by both mitochondrial and nuclear DNA. Such a feature makes these organelles essential for successful fertilisation and proper embryo implantation and development. Generally, mitochondrial DNA is exclusively maternally inherited; oocyte’s mitochondrial DNA level is crucial to provide sufficient ATP content for the developing embryo until the blastocyst stage of development. Additionally, human fertility and early embryogenesis may be affected by either point mutations or deletions in mitochondrial DNA. It was suggested that their accumulation may be associated with ovarian ageing. If so, is mitochondrial dysfunction the cause or consequence of ovarian ageing? Moreover, such an obvious relationship of mitochondria and mitochondrial genome with human fertility and early embryo development gives the field of mitochondrial research a great potential to be of use in clinical application. However, even now, the area of assessing and improving DNA quantity and function in reproductive medicine drives many questions and uncertainties. This review summarises the role of mitochondria and mitochondrial DNA in human reproduction and gives an insight into the utility of their clinical use. Full article
(This article belongs to the Special Issue Molecular and Clinical Advances in Understanding Early Embryo Development)
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17 pages, 5498 KB  
Article
Response of Astrocyte Subpopulations Following Spinal Cord Injury
by R. Vivian Allahyari, Nicolette M. Heinsinger, Daniel Hwang, David A. Jaffe, Javad Rasouli, Stephanie Shiers, Samantha J. Thomas, Theodore J. Price, Abdolmohamad Rostami and Angelo C. Lepore
Cells 2022, 11(4), 721; https://doi.org/10.3390/cells11040721 - 18 Feb 2022
Cited by 14 | Viewed by 4893
Abstract
There is growing appreciation for astrocyte heterogeneity both across and within central nervous system (CNS) regions, as well as between intact and diseased states. Recent work identified multiple astrocyte subpopulations in mature brain. Interestingly, one subpopulation (Population C) was shown to possess significantly [...] Read more.
There is growing appreciation for astrocyte heterogeneity both across and within central nervous system (CNS) regions, as well as between intact and diseased states. Recent work identified multiple astrocyte subpopulations in mature brain. Interestingly, one subpopulation (Population C) was shown to possess significantly enhanced synaptogenic properties in vitro, as compared with other astrocyte subpopulations of adult cortex and spinal cord. Following spinal cord injury (SCI), damaged neurons lose synaptic connections with neuronal partners, resulting in persistent functional loss. We determined whether SCI induces an enhanced synaptomodulatory astrocyte phenotype by shifting toward a greater proportion of Population C cells and/or increasing expression of relevant synapse formation-associated genes within one or more astrocyte subpopulations. Using flow cytometry and RNAscope in situ hybridization, we found that astrocyte subpopulation distribution in the spinal cord did not change to a selectively synaptogenic phenotype following mouse cervical hemisection-type SCI. We also found that spinal cord astrocytes expressed synapse formation-associated genes to a similar degree across subpopulations, as well as in an unchanged manner between uninjured and SCI conditions. Finally, we confirmed these astrocyte subpopulations are also present in the human spinal cord in a similar distribution as mouse, suggesting possible conservation of spinal cord astrocyte heterogeneity across species. Full article
(This article belongs to the Collection Cell Biology of Spinal Cord Injury and Repair)
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16 pages, 1563 KB  
Article
Epigenetic Dysregulation of the Homeobox A5 (HOXA5) Gene Associates with Subcutaneous Adipocyte Hypertrophy in Human Obesity
by Luca Parrillo, Rosa Spinelli, Mattia Costanzo, Pasqualina Florese, Serena Cabaro, Antonella Desiderio, Immacolata Prevenzano, Gregory Alexander Raciti, Ulf Smith, Claudia Miele, Pietro Formisano, Raffaele Napoli and Francesco Beguinot
Cells 2022, 11(4), 728; https://doi.org/10.3390/cells11040728 - 18 Feb 2022
Cited by 12 | Viewed by 3261
Abstract
Along with insulin resistance and increased risk of type 2 diabetes (T2D), lean first-degree relatives of T2D subjects (FDR) feature impaired adipogenesis in subcutaneous adipose tissue (SAT) and subcutaneous adipocyte hypertrophy well before diabetes onset. The molecular mechanisms linking these events have only [...] Read more.
Along with insulin resistance and increased risk of type 2 diabetes (T2D), lean first-degree relatives of T2D subjects (FDR) feature impaired adipogenesis in subcutaneous adipose tissue (SAT) and subcutaneous adipocyte hypertrophy well before diabetes onset. The molecular mechanisms linking these events have only partially been clarified. In the present report, we show that silencing of the transcription factor Homeobox A5 (HOXA5) in human preadipocytes impaired differentiation in mature adipose cells in vitro. The reduced adipogenesis was accompanied by inappropriate WNT-signaling activation. Importantly, in preadipocytes from FDR individuals, HOXA5 expression was attenuated, with hypermethylation of the HOXA5 promoter region found responsible for its downregulation, as revealed by luciferase assay. Both HOXA5 gene expression and DNA methylation were significantly correlated with SAT adipose cell hypertrophy in FDR, whose increased adipocyte size marks impaired adipogenesis. In preadipocytes from FDR, the low HOXA5 expression negatively correlated with enhanced transcription of the WNT signaling downstream genes NFATC1 and WNT2B. In silico evidence indicated that NFATC1 and WNT2B were directly controlled by HOXA5. The HOXA5 promoter region also was hypermethylated in peripheral blood leukocytes from these same FDR individuals, which was further revealed in peripheral blood leukocytes from an independent group of obese subjects. Thus, HOXA5 controlled adipogenesis in humans by suppressing WNT signaling. Altered DNA methylation of the HOXA5 promoter contributed to restricted adipogenesis in the SAT of lean subjects who were FDR of type 2 diabetics and in obese individuals. Full article
(This article belongs to the Special Issue Transcriptional Factors and Epigenetic Mechanisms in Obesity and Related Metabolic Comorbidities)
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19 pages, 2862 KB  
Article
Aryl Hydrocarbon Receptor (AhR) Limits the Inflammatory Responses in Human Lung Adenocarcinoma A549 Cells via Interference with NF-κB Signaling
by Gerardo Vázquez-Gómez, Martina Karasová, Zuzana Tylichová, Markéta Kabátková, Aleš Hampl, Jason Matthews, Jiří Neča, Miroslav Ciganek, Miroslav Machala and Jan Vondráček
Cells 2022, 11(4), 707; https://doi.org/10.3390/cells11040707 - 17 Feb 2022
Cited by 15 | Viewed by 3702
Abstract
Apart from its role in the metabolism of carcinogens, the aryl hydrocarbon receptor (AhR) has been suggested to be involved in the control of inflammatory responses within the respiratory tract. However, the mechanisms responsible for this are only partially known. In this study, [...] Read more.
Apart from its role in the metabolism of carcinogens, the aryl hydrocarbon receptor (AhR) has been suggested to be involved in the control of inflammatory responses within the respiratory tract. However, the mechanisms responsible for this are only partially known. In this study, we used A549 cell line, as a human model of lung alveolar type II (ATII)-like cells, to study the functional role of the AhR in control of inflammatory responses. Using IL-1β as an inflammation inducer, we found that the induction of cyclooxygenase-2 and secretion of prostaglandins, as well as expression and release of pro-inflammatory cytokines, were significantly higher in the AhR-deficient A549 cells. This was linked with an increased nuclear factor-κB (NF-κB) activity, and significantly enhanced phosphorylation of its regulators, IKKα/β, and their target IκBα, in the AhR-deficient A549 cells. In line with this, when we mimicked the exposure to a complex mixture of airborne pollutants, using an organic extract of reference diesel exhaust particle mixture, an exacerbated inflammatory response was observed in the AhR-deficient cells, as compared with wild-type A549 cells. Together, the present results indicate that the AhR may act as a negative regulator of the inflammatory response in the A549 model, via a direct modulation of NF-κB signaling. Its role(s) in the control of inflammation within the lung alveoli exposed to airborne pollutants, especially those which simultaneously activate the AhR, thus deserve further attention. Full article
(This article belongs to the Special Issue Relationship between Inflammation and Aryl Hydrocarbon Receptor Pathway)
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25 pages, 1312 KB  
Review
Maintenance of NAD+ Homeostasis in Skeletal Muscle during Aging and Exercise
by Li Li Ji and Dongwook Yeo
Cells 2022, 11(4), 710; https://doi.org/10.3390/cells11040710 - 17 Feb 2022
Cited by 28 | Viewed by 12344
Abstract
Nicotinamide adenine dinucleotide (NAD) is a versatile chemical compound serving as a coenzyme in metabolic pathways and as a substrate to support the enzymatic functions of sirtuins (SIRTs), poly (ADP-ribose) polymerase-1 (PARP-1), and cyclic ADP ribose hydrolase (CD38). Under normal physiological conditions, NAD+ [...] Read more.
Nicotinamide adenine dinucleotide (NAD) is a versatile chemical compound serving as a coenzyme in metabolic pathways and as a substrate to support the enzymatic functions of sirtuins (SIRTs), poly (ADP-ribose) polymerase-1 (PARP-1), and cyclic ADP ribose hydrolase (CD38). Under normal physiological conditions, NAD+ consumption is matched by its synthesis primarily via the salvage pathway catalyzed by nicotinamide phosphoribosyltransferase (NAMPT). However, aging and muscular contraction enhance NAD+ utilization, whereas NAD+ replenishment is limited by cellular sources of NAD+ precursors and/or enzyme expression. This paper will briefly review NAD+ metabolic functions, its roles in regulating cell signaling, mechanisms of its degradation and biosynthesis, and major challenges to maintaining its cellular level in skeletal muscle. The effects of aging, physical exercise, and dietary supplementation on NAD+ homeostasis will be highlighted based on recent literature. Full article
(This article belongs to the Special Issue Redox Control of Cell Signaling in Cardiac and Skeletal Muscle)
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22 pages, 1085 KB  
Review
Detection of Hypoxia in Cancer Models: Significance, Challenges, and Advances
by Inês Godet, Steven Doctorman, Fan Wu and Daniele M. Gilkes
Cells 2022, 11(4), 686; https://doi.org/10.3390/cells11040686 - 16 Feb 2022
Cited by 84 | Viewed by 12507
Abstract
The rapid proliferation of cancer cells combined with deficient vessels cause regions of nutrient and O2 deprivation in solid tumors. Some cancer cells can adapt to these extreme hypoxic conditions and persist to promote cancer progression. Intratumoral hypoxia has been consistently associated [...] Read more.
The rapid proliferation of cancer cells combined with deficient vessels cause regions of nutrient and O2 deprivation in solid tumors. Some cancer cells can adapt to these extreme hypoxic conditions and persist to promote cancer progression. Intratumoral hypoxia has been consistently associated with a worse patient prognosis. In vitro, 3D models of spheroids or organoids can recapitulate spontaneous O2 gradients in solid tumors. Likewise, in vivo murine models of cancer reproduce the physiological levels of hypoxia that have been measured in human tumors. Given the potential clinical importance of hypoxia in cancer progression, there is an increasing need to design methods to measure O2 concentrations. O2 levels can be directly measured with needle-type probes, both optical and electrochemical. Alternatively, indirect, noninvasive approaches have been optimized, and include immunolabeling endogenous or exogenous markers. Fluorescent, phosphorescent, and luminescent reporters have also been employed experimentally to provide dynamic measurements of O2 in live cells or tumors. In medical imaging, modalities such as MRI and PET are often the method of choice. This review provides a comparative overview of the main methods utilized to detect hypoxia in cell culture and preclinical models of cancer. Full article
(This article belongs to the Special Issue Hypoxia and Cancer: Mechanisms of Resistance and Metastasis)
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20 pages, 1260 KB  
Review
Implications of Poly(A) Tail Processing in Repeat Expansion Diseases
by Paweł Joachimiak, Adam Ciesiołka, Grzegorz Figura and Agnieszka Fiszer
Cells 2022, 11(4), 677; https://doi.org/10.3390/cells11040677 - 15 Feb 2022
Cited by 5 | Viewed by 4757
Abstract
Repeat expansion diseases are a group of more than 40 disorders that affect mainly the nervous and/or muscular system and include myotonic dystrophies, Huntington’s disease, and fragile X syndrome. The mutation-driven expanded repeat tract occurs in specific genes and is composed of tri- [...] Read more.
Repeat expansion diseases are a group of more than 40 disorders that affect mainly the nervous and/or muscular system and include myotonic dystrophies, Huntington’s disease, and fragile X syndrome. The mutation-driven expanded repeat tract occurs in specific genes and is composed of tri- to dodeca-nucleotide-long units. Mutant mRNA is a pathogenic factor or important contributor to the disease and has great potential as a therapeutic target. Although repeat expansion diseases are quite well known, there are limited studies concerning polyadenylation events for implicated transcripts that could have profound effects on transcript stability, localization, and translation efficiency. In this review, we briefly present polyadenylation and alternative polyadenylation (APA) mechanisms and discuss their role in the pathogenesis of selected diseases. We also discuss several methods for poly(A) tail measurement (both transcript-specific and transcriptome-wide analyses) and APA site identification—the further development and use of which may contribute to a better understanding of the correlation between APA events and repeat expansion diseases. Finally, we point out some future perspectives on the research into repeat expansion diseases, as well as APA studies. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Neurodegenerative Diseases)
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18 pages, 590 KB  
Systematic Review
Ketamine and Lamotrigine Combination in Psychopharmacology: Systematic Review
by Alina Wilkowska, Mariusz S. Wiglusz, Katarzyna Jakuszkowiak-Wojten and Wiesław J. Cubała
Cells 2022, 11(4), 645; https://doi.org/10.3390/cells11040645 - 12 Feb 2022
Cited by 14 | Viewed by 12399
Abstract
Background and Objectives: Ketamine is a rapid-acting antidepressant with proven efficacy as an add-on agent in unipolar and bipolar treatment-resistant depression. Although many studies have been published, there is still not enough data on the effect of ketamine in combination with other medications. [...] Read more.
Background and Objectives: Ketamine is a rapid-acting antidepressant with proven efficacy as an add-on agent in unipolar and bipolar treatment-resistant depression. Although many studies have been published, there is still not enough data on the effect of ketamine in combination with other medications. Particularly interesting is the combination of ketamine and lamotrigine, and its potential role in bipolar depression. The aim of this review was to identify animal and human studies in which ketamine and lamotrigine were used together in order to find out if there is scientific ground for combining ketamine and lamotrigine in the treatment of mood disorders. Directions for future studies are presented. Materials and Methods: PubMed and Web of Science were searched. Preferred Reporting Items for Systematic Reviews and Meta-Analyses PRISMA 2020 methodology was applied. Results: Seventeen studies were included for review. Animal studies using models of depression suggested a synergistic effect of ketamine and lamotrigine in combination. Studies on healthy humans showed a reduction in ketamine-induced dissociative symptoms with lamotrigine pretreatment. In a study on patients with depression, ketamine and lamotrigine did not have a stronger antidepressant effect than ketamine alone, but in this study only one ketamine infusion was administered. One case series described the antidepressant and anti-suicidal effect of the combination in two bipolar patients. Available clinical studies on patients with mood disorders did not support the hypothesis that lamotrigine reduces ketamine-induced dissociative symptoms. Conclusions: The results of the analyzed studies were not sufficient to answer any of the stated questions; however, they allowed us to delineate future research directions. The identified animal studies suggested a possible synergistic antidepressant effect of ketamine and lamotrigine. The available clinical studies were not conclusive. No controlled studies on large groups of bipolar patients with multiple ketamine infusions combined with lamotrigine treatment have been published so far. There is some evidence for the reduction of ketamine’s side effects by lamotrigine, and there are reports suggesting that lamotrigine can reduce ketamine craving. More studies with follow-up are needed in order to investigate the ketamine–lamotrigine combination in bipolar patients. Full article
(This article belongs to the Special Issue New Molecular Targets for Antipsychotic and Antidepressant Pharmacotherapies)
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19 pages, 2266 KB  
Review
Drug Resistance and Endoplasmic Reticulum Stress in Hepatocellular Carcinoma
by Jaafar Khaled, Maria Kopsida, Hans Lennernäs and Femke Heindryckx
Cells 2022, 11(4), 632; https://doi.org/10.3390/cells11040632 - 11 Feb 2022
Cited by 63 | Viewed by 7501
Abstract
Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide. It is usually diagnosed in an advanced stage and is characterized by a high intrinsic drug resistance, leading to limited chemotherapeutic efficacy and relapse after treatment. There is therefore a [...] Read more.
Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide. It is usually diagnosed in an advanced stage and is characterized by a high intrinsic drug resistance, leading to limited chemotherapeutic efficacy and relapse after treatment. There is therefore a vast need for understanding underlying mechanisms that contribute to drug resistance and for developing therapeutic strategies that would overcome this. The rapid proliferation of tumor cells, in combination with a highly inflammatory microenvironment, causes a chronic increase of protein synthesis in different hepatic cell populations. This leads to an intensified demand of protein folding, which inevitably causes an accumulation of misfolded or unfolded proteins in the lumen of the endoplasmic reticulum (ER). This process is called ER stress and triggers the unfolded protein response (UPR) in order to restore protein synthesis or—in the case of severe or prolonged ER stress—to induce cell death. Interestingly, the three different arms of the ER stress signaling pathways have been shown to drive chemoresistance in several tumors and could therefore form a promising therapeutic target. This review provides an overview of how ER stress and activation of the UPR contributes to drug resistance in HCC. Full article
(This article belongs to the Special Issue Unfolded Protein Response in Inflammation and Cancer)
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16 pages, 4470 KB  
Article
Discordant Genome Assemblies Drastically Alter the Interpretation of Single-Cell RNA Sequencing Data Which Can Be Mitigated by a Novel Integration Method
by Helen G. Potts, Madeleine E. Lemieux, Edward S. Rice, Wesley Warren, Robin P. Choudhury and Mathilda T. M. Mommersteeg
Cells 2022, 11(4), 608; https://doi.org/10.3390/cells11040608 - 10 Feb 2022
Cited by 4 | Viewed by 3578
Abstract
Advances in sequencing and assembly technology have led to the creation of genome assemblies for a wide variety of non-model organisms. The rapid production and proliferation of updated, novel assembly versions can create vexing problems for researchers when multiple-genome assembly versions are available [...] Read more.
Advances in sequencing and assembly technology have led to the creation of genome assemblies for a wide variety of non-model organisms. The rapid production and proliferation of updated, novel assembly versions can create vexing problems for researchers when multiple-genome assembly versions are available at once, requiring researchers to work with more than one reference genome. Multiple-genome assemblies are especially problematic for researchers studying the genetic makeup of individual cells, as single-cell RNA sequencing (scRNAseq) requires sequenced reads to be mapped and aligned to a single reference genome. Using the Astyanax mexicanus, this study highlights how the interpretation of a single-cell dataset from the same sample changes when aligned to its two different available genome assemblies. We found that the number of cells and expressed genes detected were drastically different when aligning to the different assemblies. When the genome assemblies were used in isolation with their respective annotations, cell-type identification was confounded, as some classic cell-type markers were assembly-specific, whilst other genes showed differential patterns of expression between the two assemblies. To overcome the problems posed by multiple-genome assemblies, we propose that researchers align to each available assembly and then integrate the resultant datasets to produce a final dataset in which all genome alignments can be used simultaneously. We found that this approach increased the accuracy of cell-type identification and maximised the amount of data that could be extracted from our single-cell sample by capturing all possible cells and transcripts. As scRNAseq becomes more widely available, it is imperative that the single-cell community is aware of how genome assembly alignment can alter single-cell data and their interpretation, especially when reviewing studies on non-model organisms. Full article
(This article belongs to the Special Issue Single Cell Analysis 2.0)
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27 pages, 2888 KB  
Article
MSK-Mediated Phosphorylation of Histone H3 Ser28 Couples MAPK Signalling with Early Gene Induction and Cardiac Hypertrophy
by Emma L. Robinson, Faye M. Drawnel, Saher Mehdi, Caroline R. Archer, Wei Liu, Hanneke Okkenhaug, Kanar Alkass, Jan Magnus Aronsen, Chandan K. Nagaraju, Ivar Sjaastad, Karin R. Sipido, Olaf Bergmann, J. Simon C. Arthur, Xin Wang and H. Llewelyn Roderick
Cells 2022, 11(4), 604; https://doi.org/10.3390/cells11040604 - 9 Feb 2022
Cited by 16 | Viewed by 4617
Abstract
Heart failure is a leading cause of death that develops subsequent to deleterious hypertrophic cardiac remodelling. MAPK pathways play a key role in coordinating the induction of gene expression during hypertrophy. Induction of the immediate early gene (IEG) response including activator protein 1 [...] Read more.
Heart failure is a leading cause of death that develops subsequent to deleterious hypertrophic cardiac remodelling. MAPK pathways play a key role in coordinating the induction of gene expression during hypertrophy. Induction of the immediate early gene (IEG) response including activator protein 1 (AP-1) complex factors is a necessary and early event in this process. How MAPK and IEG expression are coupled during cardiac hypertrophy is not resolved. Here, in vitro, in rodent models and in human samples, we demonstrate that MAPK-stimulated IEG induction depends on the mitogen and stress-activated protein kinase (MSK) and its phosphorylation of histone H3 at serine 28 (pH3S28). pH3S28 in IEG promoters in turn recruits Brg1, a BAF60 ATP-dependent chromatin remodelling complex component, initiating gene expression. Without MSK activity and IEG induction, the hypertrophic response is suppressed. These studies provide new mechanistic insights into the role of MAPK pathways in signalling to the epigenome and regulation of gene expression during cardiac hypertrophy. Full article
(This article belongs to the Special Issue Cellular Signaling Leading to Heart Failure)
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27 pages, 1228 KB  
Review
Biomarker Development in Cardiology: Reviewing the Past to Inform the Future
by Katharine A. Kott, Michael Bishop, Christina H. J. Yang, Toby M. Plasto, Daniel C. Cheng, Adam I. Kaplan, Louise Cullen, David S. Celermajer, Peter J. Meikle, Stephen T. Vernon and Gemma A. Figtree
Cells 2022, 11(3), 588; https://doi.org/10.3390/cells11030588 - 8 Feb 2022
Cited by 9 | Viewed by 6211
Abstract
Cardiac biomarkers have become pivotal to the clinical practice of cardiology, but there remains much to discover that could benefit cardiology patients. We review the discovery of key protein biomarkers in the fields of acute coronary syndrome, heart failure, and atherosclerosis, giving an [...] Read more.
Cardiac biomarkers have become pivotal to the clinical practice of cardiology, but there remains much to discover that could benefit cardiology patients. We review the discovery of key protein biomarkers in the fields of acute coronary syndrome, heart failure, and atherosclerosis, giving an overview of the populations they were studied in and the statistics that were used to validate them. We review statistical approaches that are currently in use to assess new biomarkers and overview a framework for biomarker discovery and evaluation that could be incorporated into clinical trials to evaluate cardiovascular outcomes in the future. Full article
(This article belongs to the Special Issue Understanding Biomarkers in Cardiology)
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15 pages, 2208 KB  
Review
Regulation of Nucleolar Activity by MYC
by Isabella N. Brown, M. Carmen Lafita-Navarro and Maralice Conacci-Sorrell
Cells 2022, 11(3), 574; https://doi.org/10.3390/cells11030574 - 7 Feb 2022
Cited by 13 | Viewed by 4587
Abstract
The nucleolus harbors the machinery necessary to produce new ribosomes which are critical for protein synthesis. Nucleolar size, shape, and density are highly dynamic and can be adjusted to accommodate ribosome biogenesis according to the needs for protein synthesis. In cancer, cells undergo [...] Read more.
The nucleolus harbors the machinery necessary to produce new ribosomes which are critical for protein synthesis. Nucleolar size, shape, and density are highly dynamic and can be adjusted to accommodate ribosome biogenesis according to the needs for protein synthesis. In cancer, cells undergo continuous proliferation; therefore, nucleolar activity is elevated due to their high demand for protein synthesis. The transcription factor and universal oncogene MYC promotes nucleolar activity by enhancing the transcription of ribosomal DNA (rDNA) and ribosomal proteins. This review summarizes the importance of nucleolar activity in mammalian cells, MYC’s role in nucleolar regulation in cancer, and discusses how a better understanding (and the potential inhibition) of aberrant nucleolar activity in cancer cells could lead to novel therapeutics. Full article
(This article belongs to the Special Issue Nucleolar Organization and Functions in Health and Disease II)
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19 pages, 11682 KB  
Article
Brite Adipocyte FGF21 Attenuates Cardiac Ischemia/Reperfusion Injury in Rat Hearts by Modulating NRF2
by Hanbyeol Moon, Jung-Won Choi, Byeong-Wook Song, Il-Kwon Kim, Soyeon Lim, Seahyoung Lee, Gyoonhee Han, Ki-Chul Hwang and Sang Woo Kim
Cells 2022, 11(3), 567; https://doi.org/10.3390/cells11030567 - 6 Feb 2022
Cited by 14 | Viewed by 4009
Abstract
Although the optimal therapy for myocardial infarction includes reperfusion to restore blood flow to the ischemic area, myocardial injury after ischemia/reperfusion usually leads to an inflammatory response, oxidative stress, and cardiomyocyte apoptosis. In this study, rat adipose-derived stem cells were differentiated into low-thermogenic [...] Read more.
Although the optimal therapy for myocardial infarction includes reperfusion to restore blood flow to the ischemic area, myocardial injury after ischemia/reperfusion usually leads to an inflammatory response, oxidative stress, and cardiomyocyte apoptosis. In this study, rat adipose-derived stem cells were differentiated into low-thermogenic beige adipocytes (LBACs) and high-thermogenic beige adipocytes (HBACs) to study the different cardioprotective effects of heterogeneous expression of brown adipocytes. We found that antioxidant and antiapoptotic factors in H9c2 cardiomyocytes were upregulated by high levels of secreted FGF21 in HBAC conditioned medium (HBAC-CM), whereas FGF21 in HBAC-CM did not affect antioxidative or antiapoptotic cell death in H9c2 cardiomyocytes with Nrf2 knockdown. These results show that NRF2 mediates antioxidative and antiapoptotic effects through the HBAC-secreted factor FGF21. Consistent with this finding, the expression of antioxidant and antiapoptotic genes was upregulated by highly secreted FGF21 after HBAC-CM treatment compared to LBAC-CM treatment in H9c2 cardiomyocytes via NRF2 activation. Furthermore, HBAC-CM significantly attenuated ischemic rat heart tissue injury via NRF2 activation. Based on these findings, we propose that HBAC-CM exerts beneficial effects in rat cardiac ischemia/reperfusion injury by modulating NRF2 and has potential as a promising therapeutic agent for myocardial infarction. Full article
(This article belongs to the Special Issue Fat Is a Matter? The Implication of Adipose Tissue in Cardiovascular Health and Disease)
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26 pages, 1216 KB  
Review
ISG15 and ISGylation in Human Diseases
by Oygul Mirzalieva, Meredith Juncker, Joshua Schwartzenburg and Shyamal Desai
Cells 2022, 11(3), 538; https://doi.org/10.3390/cells11030538 - 4 Feb 2022
Cited by 67 | Viewed by 15164
Abstract
Type I Interferons (IFNs) induce the expression of >500 genes, which are collectively called ISGs (IFN-stimulated genes). One of the earliest ISGs induced by IFNs is ISG15 (Interferon-Stimulated Gene 15). Free ISG15 protein synthesized from the ISG15 gene is post-translationally conjugated to cellular [...] Read more.
Type I Interferons (IFNs) induce the expression of >500 genes, which are collectively called ISGs (IFN-stimulated genes). One of the earliest ISGs induced by IFNs is ISG15 (Interferon-Stimulated Gene 15). Free ISG15 protein synthesized from the ISG15 gene is post-translationally conjugated to cellular proteins and is also secreted by cells into the extracellular milieu. ISG15 comprises two ubiquitin-like domains (UBL1 and UBL2), each of which bears a striking similarity to ubiquitin, accounting for its earlier name ubiquitin cross-reactive protein (UCRP). Like ubiquitin, ISG15 harbors a characteristic β-grasp fold in both UBL domains. UBL2 domain has a conserved C-terminal Gly-Gly motif through which cellular proteins are appended via an enzymatic cascade similar to ubiquitylation called ISGylation. ISG15 protein is minimally expressed under physiological conditions. However, its IFN-dependent expression is aberrantly elevated or compromised in various human diseases, including multiple types of cancer, neurodegenerative disorders (Ataxia Telangiectasia and Amyotrophic Lateral Sclerosis), inflammatory diseases (Mendelian Susceptibility to Mycobacterial Disease (MSMD), bacteriopathy and viropathy), and in the lumbar spinal cords of veterans exposed to Traumatic Brain Injury (TBI). ISG15 and ISGylation have both inhibitory and/or stimulatory roles in the etiology and pathogenesis of human diseases. Thus, ISG15 is considered a “double-edged sword” for human diseases in which its expression is elevated. Because of the roles of ISG15 and ISGylation in cancer cell proliferation, migration, and metastasis, conferring anti-cancer drug sensitivity to tumor cells, and its elevated expression in cancer, neurodegenerative disorders, and veterans exposed to TBI, both ISG15 and ISGylation are now considered diagnostic/prognostic biomarkers and therapeutic targets for these ailments. In the current review, we shall cover the exciting journey of ISG15, spanning three decades from the bench to the bedside. Full article
(This article belongs to the Special Issue Ubiquitin and Ubiquitin-Like Pathways in Development and Disease)
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20 pages, 2131 KB  
Review
Endomembrane-Based Signaling by GPCRs and G-Proteins
by Federica Liccardo, Alberto Luini and Rosaria Di Martino
Cells 2022, 11(3), 528; https://doi.org/10.3390/cells11030528 - 3 Feb 2022
Cited by 25 | Viewed by 10672
Abstract
G-protein-coupled receptors (GPCRs) and G-proteins have a range of roles in many physiological and pathological processes and are among the most studied signaling proteins. A plethora of extracellular stimuli can activate the GPCR and can elicit distinct intracellular responses through the activation of [...] Read more.
G-protein-coupled receptors (GPCRs) and G-proteins have a range of roles in many physiological and pathological processes and are among the most studied signaling proteins. A plethora of extracellular stimuli can activate the GPCR and can elicit distinct intracellular responses through the activation of specific transduction pathways. For many years, biologists thought that GPCR signaling occurred entirely on the plasma membrane. However, in recent decades, many lines of evidence have proved that the GPCRs and G-proteins may reside on endomembranes and can start or propagate signaling pathways through the organelles that form the secretory route. How these alternative intracellular signaling pathways of the GPCR and G-proteins influence the physiological and pathological function of the endomembranes is still under investigation. Here, we review the general role and classification of GPCRs and G-proteins with a focus on their signaling pathways in the membrane transport apparatus. Full article
(This article belongs to the Section Intracellular and Plasma Membranes)
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19 pages, 2198 KB  
Article
Mitochondria-Endoplasmic Reticulum Interplay Regulates Exo-Cytosis in Human Neuroblastoma Cells
by Giacomo Dentoni, Luana Naia and Maria Ankarcrona
Cells 2022, 11(3), 514; https://doi.org/10.3390/cells11030514 - 2 Feb 2022
Cited by 8 | Viewed by 4158
Abstract
Mitochondria–endoplasmic reticulum (ER) contact sites (MERCS) have been emerging as a multifaceted subcellular region of the cell which affects several physiological and pathological mechanisms. A thus far underexplored aspect of MERCS is their contribution to exocytosis. Here, we set out to understand the [...] Read more.
Mitochondria–endoplasmic reticulum (ER) contact sites (MERCS) have been emerging as a multifaceted subcellular region of the cell which affects several physiological and pathological mechanisms. A thus far underexplored aspect of MERCS is their contribution to exocytosis. Here, we set out to understand the role of these contacts in exocytosis and find potential mechanisms linking these structures to vesicle release in human neuroblastoma SH-SY5Y cells. We show that increased mitochondria to ER juxtaposition through Mitofusin 2 (Mfn2) knock-down resulted in a substantial upregulation of the number of MERCS, confirming the role of Mfn2 as a negative regulator of these structures. Furthermore, we report that both vesicle numbers and vesicle protein levels were decreased, while a considerable upregulation in exocytotic events upon cellular depolarization was detected. Interestingly, in Mfn2 knock-down cells, the inhibition of the inositol 1,4,5-trisphosphate receptor (IP3R) and the mitochondrial calcium (Ca2+) uniporter (MCU) restored vesicle protein content and attenuated exocytosis. We thus suggest that MERCS could be targeted to prevent increased exocytosis in conditions in which ER to mitochondria proximity is upregulated. Full article
(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Organelle Function)
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13 pages, 1382 KB  
Review
Common Themes and Future Challenges in Understanding Gene Regulatory Network Evolution
by Isabella Schember and Marc S. Halfon
Cells 2022, 11(3), 510; https://doi.org/10.3390/cells11030510 - 1 Feb 2022
Cited by 6 | Viewed by 3938
Abstract
A major driving force behind the evolution of species-specific traits and novel structures is alterations in gene regulatory networks (GRNs). Comprehending evolution therefore requires an understanding of the nature of changes in GRN structure and the responsible mechanisms. Here, we review two insect [...] Read more.
A major driving force behind the evolution of species-specific traits and novel structures is alterations in gene regulatory networks (GRNs). Comprehending evolution therefore requires an understanding of the nature of changes in GRN structure and the responsible mechanisms. Here, we review two insect pigmentation GRNs in order to examine common themes in GRN evolution and to reveal some of the challenges associated with investigating changes in GRNs across different evolutionary distances at the molecular level. The pigmentation GRN in Drosophila melanogaster and other drosophilids is a well-defined network for which studies from closely related species illuminate the different ways co-option of regulators can occur. The pigmentation GRN for butterflies of the Heliconius species group is less fully detailed but it is emerging as a useful model for exploring important questions about redundancy and modularity in cis-regulatory systems. Both GRNs serve to highlight the ways in which redeployment of trans-acting factors can lead to GRN rewiring and network co-option. To gain insight into GRN evolution, we discuss the importance of defining GRN architecture at multiple levels both within and between species and of utilizing a range of complementary approaches. Full article
(This article belongs to the Special Issue Crossroads between Gene Regulatory Networks and Evolution)
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22 pages, 6039 KB  
Article
Extracellular Vesicles Derived from Primed Mesenchymal Stromal Cells Loaded on Biphasic Calcium Phosphate Biomaterial Exhibit Enhanced Macrophage Polarization
by Neha Rana, Salwa Suliman, Niyaz Al-Sharabi and Kamal Mustafa
Cells 2022, 11(3), 470; https://doi.org/10.3390/cells11030470 - 29 Jan 2022
Cited by 14 | Viewed by 4983
Abstract
Mesenchymal stromal cells (MSC) loaded on biphasic calcium phosphate biomaterial (MSC + BCP) have been used as an advanced therapy medicinal product to treat complex maxillofacial bone defects in patients. Further, MSC-derived extracellular vesicles (EVs) are established vehicles of paracrine factors, supporting inter-cellular [...] Read more.
Mesenchymal stromal cells (MSC) loaded on biphasic calcium phosphate biomaterial (MSC + BCP) have been used as an advanced therapy medicinal product to treat complex maxillofacial bone defects in patients. Further, MSC-derived extracellular vesicles (EVs) are established vehicles of paracrine factors, supporting inter-cellular communication between MSC and other interacting cell types, such as monocytes/macrophages. However, the information about the immunomodulatory potential of EVs derived from MSC and biomaterial constructs (MSC + BCP:EV) and inflammatory primed constructs (MSCp + BCP:EV) are scarce. Hence, we isolated and characterized EVs from these different systems, and compared their cytokine contents with plastic-adherent MSC-derived EVs (MSC:EV). When EVs from all three MSC systems were added to the primary blood-derived macrophages in vitro, significantly higher numbers of M0 (naive) macrophages shifted to M2-like (anti-inflammatory) by MSCp + BCP:EV treatment. Further, this treatment led to enhanced switching of M1 polarized macrophages to M2 polarized, and conversely, M2 to M1, as evaluated by determining the M1/M2 ratios after treatment. The enhanced macrophage modulation by MSCp + BCP:EV was attributed to their higher immunomodulatory (TNFα, IL1β, IL5), angiogenic (VEGF), and chemokine-rich (RANTES, MCP1, MIP1β) cytokine cargo. In conclusion, we successfully isolated and characterized EVs from MSC + BCP constructs and demonstrated that, depending upon the tissue microenvironment, these EVs contribute towards modulating the macrophage-mediated inflammation and healing responses. The study offers new insights into the use of biomaterial-induced EVs for MSC secretome delivery, as a step towards future ‘cell-free’ bone regenerative therapies. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cell-Derived Extracellular Vesicles)
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21 pages, 3477 KB  
Article
Hypoxia-Mimetic CoCl2 Agent Enhances Pro-Angiogenic Activities in Ovine Amniotic Epithelial Cells-Derived Conditioned Medium
by Miriam Di Mattia, Annunziata Mauro, Simona Delle Monache, Fanny Pulcini, Valentina Russo, Paolo Berardinelli, Maria Rita Citeroni, Maura Turriani, Alessia Peserico and Barbara Barboni
Cells 2022, 11(3), 461; https://doi.org/10.3390/cells11030461 - 28 Jan 2022
Cited by 16 | Viewed by 5862
Abstract
Amniotic epithelial stem cells (AECs) are largely studied for their pro-regenerative properties. However, it remains undetermined if low oxygen (O2) levels that AECs experience in vivo can be of value in maintaining their biological properties after isolation. To this aim, the [...] Read more.
Amniotic epithelial stem cells (AECs) are largely studied for their pro-regenerative properties. However, it remains undetermined if low oxygen (O2) levels that AECs experience in vivo can be of value in maintaining their biological properties after isolation. To this aim, the present study has been designed to evaluate the effects of a hypoxia-mimetic agent, cobalt chloride (CoCl2), on AECs’ stemness and angiogenic activities. First, a CoCl2 dose-effect was performed to select the concentration able to induce hypoxia, through HIF-1α stabilization, without promoting any cytotoxicity effect assessed through the analysis of cell vitality, proliferation, and apoptotic-related events. Then, the identified CoCl2 dose was evaluated on the expression and angiogenic properties of AECs’ stemness markers (OCT-4, NANOG, SOX-2) by analysing VEGF expression, angiogenic chemokines’ profiles, and AEC-derived conditioned media activity through an in vitro angiogenic xeno-assay. Results demonstrated that AECs are sensitive to the cytotoxicity effects of CoCl2. The unique concentration leading to HIF-1α stabilization and nuclear translocation was 10 µM, preserving cell viability and proliferation up to 48 h. CoCl2 exposure did not modulate stemness markers in AECs while progressively decreasing VEGF expression. On the contrary, CoCl2 treatment promoted a significant short-term release of angiogenic chemokines in culture media (CM). The enrichment in bio-active factors was confirmed by the ability of CoCl2-derived CM to induce HUVEC growth and the cells’ organization in tubule-like structures. These findings demonstrate that an appropriate dose of CoCl2 can be adopted as a hypoxia-mimetic agent in AECs. The short-term, chemical-induced hypoxic condition can be targeted to enhance AECs’ pro-angiogenic properties by providing a novel approach for stem cell-free therapy protocols. Full article
(This article belongs to the Special Issue 3D Cultures, Organoids, Organ-on-Chip: New Research and Innovation Challenges in Reproduction)
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19 pages, 3255 KB  
Article
Epiregulin as an Alternative Ligand for Leptin Receptor Alleviates Glucose Intolerance without Change in Obesity
by No-Joon Song, Aejin Lee, Rumana Yasmeen, Qiwen Shen, Kefeng Yang, Shashi Bhushan Kumar, Danah Muhanna, Shanvanth Arnipalli, Sabrena F. Noria, Bradley J. Needleman, Jeffrey W. Hazey, Dean J. Mikami, Joana Ortega-Anaya, Rafael Jiménez-Flores, Jeremy Prokop and Ouliana Ziouzenkova
Cells 2022, 11(3), 425; https://doi.org/10.3390/cells11030425 - 26 Jan 2022
Cited by 8 | Viewed by 3844
Abstract
The leptin receptor (LepR) acts as a signaling nexus for the regulation of glucose uptake and obesity, among other metabolic responses. The functional role of LepR under leptin-deficient conditions remains unclear. This study reports that epiregulin (EREG) governed glucose uptake in vitro and [...] Read more.
The leptin receptor (LepR) acts as a signaling nexus for the regulation of glucose uptake and obesity, among other metabolic responses. The functional role of LepR under leptin-deficient conditions remains unclear. This study reports that epiregulin (EREG) governed glucose uptake in vitro and in vivo in Lepob mice by activating LepR under leptin-deficient conditions. Single and long-term treatment with EREG effectively rescued glucose intolerance in comparative insulin and EREG tolerance tests in Lepob mice. The immunoprecipitation study revealed binding between EREG and LepR in adipose tissue of Lepob mice. EREG/LepR regulated glucose uptake without changes in obesity in Lepob mice via mechanisms, including ERK activation and translocation of GLUT4 to the cell surface. EREG-dependent glucose uptake was abolished in Leprdb mice which supports a key role of LepR in this process. In contrast, inhibition of the canonical epidermal growth factor receptor (EGFR) pathway implicated in other EREG responses, increased glucose uptake. Our data provide a basis for understanding glycemic responses of EREG that are dependent on LepR unlike functions mediated by EGFR, including leptin secretion, thermogenesis, pain, growth, and other responses. The computational analysis identified a conserved amino acid sequence, supporting an evolutionary role of EREG as an alternative LepR ligand. Full article
(This article belongs to the Special Issue Molecular Mechanisms in Metabolic Disease 2022)
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22 pages, 7662 KB  
Article
Single-Cell RNA-Seq Reveals a Crosstalk between Hyaluronan Receptor LYVE-1-Expressing Macrophages and Vascular Smooth Muscle Cells
by Fabienne Burger, Daniela Baptista, Aline Roth, Karim J. Brandt, Rafaela Fernandes da Silva, Fabrizio Montecucco, François Mach and Kapka Miteva
Cells 2022, 11(3), 411; https://doi.org/10.3390/cells11030411 - 25 Jan 2022
Cited by 26 | Viewed by 7668
Abstract
Background: Atherosclerosis is a chronic inflammatory disease where macrophages participate in the progression of the disease. However, the role of resident-like macrophages (res-like) in the atherosclerotic aorta is not completely understood. Methods: A single-cell RNA sequencing analysis of CD45+ leukocytes in [...] Read more.
Background: Atherosclerosis is a chronic inflammatory disease where macrophages participate in the progression of the disease. However, the role of resident-like macrophages (res-like) in the atherosclerotic aorta is not completely understood. Methods: A single-cell RNA sequencing analysis of CD45+ leukocytes in the atherosclerotic aorta of apolipoprotein E–deficient (Apoe−/−) mice on a normal cholesterol diet (NCD) or a high cholesterol diet (HCD), respecting the side-to-specific predisposition to atherosclerosis, was performed. A population of res-like macrophages expressing hyaluronan receptor LYVE-1 was investigated via flow cytometry, co-culture experiments, and immunofluorescence in human atherosclerotic plaques from carotid artery disease patients (CAD). Results: We identified 12 principal leukocyte clusters with distinct atherosclerosis disease-relevant gene expression signatures. LYVE-1+ res-like macrophages, expressing a high level of CC motif chemokine ligand 24 (CCL24, eotaxin-2), expanded under hypercholesteremia in Apoe−/− mice and promoted VSMC phenotypic modulation to osteoblast/chondrocyte-like cells, ex vivo, in a CCL24-dependent manner. Moreover, the abundance of LYVE-1+CCL24+ macrophages and elevated systemic levels of CCL24 were associated with vascular calcification and CAD events. Conclusions: LYVE-1 res-like macrophages, via the secretion of CCL24, promote the transdifferentiation of VSMC to osteogenic-like cells with a possible role in vascular calcification and likely a detrimental role in atherosclerotic plaque destabilization. Full article
(This article belongs to the Collection Cardiovascular Disease: From Molecular and Cellular Mechanisms to Therapeutic Opportunities)
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36 pages, 7267 KB  
Review
Physiological Function during Exercise and Environmental Stress in Humans—An Integrative View of Body Systems and Homeostasis
by Gavin Travers, Pascale Kippelen, Steven J. Trangmar and José González-Alonso
Cells 2022, 11(3), 383; https://doi.org/10.3390/cells11030383 - 24 Jan 2022
Cited by 43 | Viewed by 33880
Abstract
Claude Bernard’s milieu intérieur (internal environment) and the associated concept of homeostasis are fundamental to the understanding of the physiological responses to exercise and environmental stress. Maintenance of cellular homeostasis is thought to happen during exercise through the precise matching of cellular energetic [...] Read more.
Claude Bernard’s milieu intérieur (internal environment) and the associated concept of homeostasis are fundamental to the understanding of the physiological responses to exercise and environmental stress. Maintenance of cellular homeostasis is thought to happen during exercise through the precise matching of cellular energetic demand and supply, and the production and clearance of metabolic by-products. The mind-boggling number of molecular and cellular pathways and the host of tissues and organ systems involved in the processes sustaining locomotion, however, necessitate an integrative examination of the body’s physiological systems. This integrative approach can be used to identify whether function and cellular homeostasis are maintained or compromised during exercise. In this review, we discuss the responses of the human brain, the lungs, the heart, and the skeletal muscles to the varying physiological demands of exercise and environmental stress. Multiple alterations in physiological function and differential homeostatic adjustments occur when people undertake strenuous exercise with and without thermal stress. These adjustments can include: hyperthermia; hyperventilation; cardiovascular strain with restrictions in brain, muscle, skin and visceral organs blood flow; greater reliance on muscle glycogen and cellular metabolism; alterations in neural activity; and, in some conditions, compromised muscle metabolism and aerobic capacity. Oxygen supply to the human brain is also blunted during intense exercise, but global cerebral metabolism and central neural drive are preserved or enhanced. In contrast to the strain seen during severe exercise and environmental stress, a steady state is maintained when humans exercise at intensities and in environmental conditions that require a small fraction of the functional capacity. The impact of exercise and environmental stress upon whole-body functions and homeostasis therefore depends on the functional needs and differs across organ systems. Full article
(This article belongs to the Collection Brain-Body Interactions in the Maintenance of Homeostasis: An Honorary Issue in Memory of Prof. Claude Bernard)
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15 pages, 4588 KB  
Article
Beta-Amyloid Instigates Dysfunction of Mitochondria in Cardiac Cells
by Sehwan Jang, Xavier R. Chapa-Dubocq, Rebecca M. Parodi-Rullán, Silvia Fossati and Sabzali Javadov
Cells 2022, 11(3), 373; https://doi.org/10.3390/cells11030373 - 22 Jan 2022
Cited by 24 | Viewed by 5134
Abstract
Alzheimer’s disease (AD) includes the formation of extracellular deposits comprising aggregated β-amyloid (Aβ) fibers associated with oxidative stress, inflammation, mitochondrial abnormalities, and neuronal loss. There is an associative link between AD and cardiac diseases; however, the mechanisms underlying the potential role of AD, [...] Read more.
Alzheimer’s disease (AD) includes the formation of extracellular deposits comprising aggregated β-amyloid (Aβ) fibers associated with oxidative stress, inflammation, mitochondrial abnormalities, and neuronal loss. There is an associative link between AD and cardiac diseases; however, the mechanisms underlying the potential role of AD, particularly Aβ in cardiac cells, remain unknown. Here, we investigated the role of mitochondria in mediating the effects of Aβ1-40 and Aβ1-42 in cultured cardiomyocytes and primary coronary endothelial cells. Our results demonstrated that Aβ1-40 and Aβ1-42 are differently accumulated in cardiomyocytes and coronary endothelial cells. Aβ1-42 had more adverse effects than Aβ1-40 on cell viability and mitochondrial function in both types of cells. Mitochondrial and cellular ROS were significantly increased, whereas mitochondrial membrane potential and calcium retention capacity decreased in both types of cells in response to Aβ1-42. Mitochondrial dysfunction induced by Aβ was associated with apoptosis of the cells. The effects of Aβ1-42 on mitochondria and cell death were more evident in coronary endothelial cells. In addition, Aβ1-40 and Aβ1-42 significantly increased Ca2+ -induced swelling in mitochondria isolated from the intact rat hearts. In conclusion, this study demonstrates the toxic effects of Aβ on cell survival and mitochondria function in cardiac cells. Full article
(This article belongs to the Special Issue Molecular and Cellular Basis of Alzheimer's Disease)
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12 pages, 14778 KB  
Article
Tumor-Derived Extracellular Vesicles Induce CCL18 Production by Mast Cells: A Possible Link to Angiogenesis
by Irit Shefler, Pazit Salamon, Tali Zitman-Gal and Yoseph A. Mekori
Cells 2022, 11(3), 353; https://doi.org/10.3390/cells11030353 - 21 Jan 2022
Cited by 8 | Viewed by 3636
Abstract
Mast cells (MCs) function as a component of the tumor microenvironment (TME) and have both pro- and anti-tumorigenic roles depending on the tumor type and its developmental stage. Several reports indicate the involvement of MCs in angiogenesis in the TME by releasing angiogenic [...] Read more.
Mast cells (MCs) function as a component of the tumor microenvironment (TME) and have both pro- and anti-tumorigenic roles depending on the tumor type and its developmental stage. Several reports indicate the involvement of MCs in angiogenesis in the TME by releasing angiogenic mediators. Tumor cells and other cells in the TME may interact by releasing extracellular vesicles (EVs) that affect the cells in the region. We have previously shown that tumor-derived microvesicles (TMVs) from non-small-cell lung cancer (NSCLC) cells interact with human MCs and activate them to release several cytokines and chemokines. In the present study, we characterized the MC expression of other mediators after exposure to TMVs derived from NSCLC. Whole-genome expression profiling disclosed the production of several chemokines, including CC chemokine ligand 18 (CCL18). This chemokine is expressed in various types of cancer, and was found to be associated with extensive angiogenesis, both in vitro and in vivo. We now show that CCL18 secreted from MCs activated by NSCLC-TMVs increased the migration of human umbilical cord endothelial cells (HUVECs), tube formation and endothelial- to-mesenchymal transition (EndMT), thus promoting angiogenesis. Our findings support the conclusion that TMVs have the potential to influence MC activity and may affect angiogenesis in the TME. Full article
(This article belongs to the Collection Mast Cells in Health and Diseases)
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17 pages, 22065 KB  
Article
Neuron–Microglia Contact-Dependent Mechanisms Attenuate Methamphetamine-Induced Microglia Reactivity and Enhance Neuronal Plasticity
by Joana Bravo, Inês Ribeiro, Ana Filipa Terceiro, Elva B. Andrade, Camila Cabral Portugal, Igor M. Lopes, Maria M. Azevedo, Mafalda Sousa, Cátia D. F. Lopes, Andrea C. Lobo, Teresa Canedo, João Bettencourt Relvas and Teresa Summavielle
Cells 2022, 11(3), 355; https://doi.org/10.3390/cells11030355 - 21 Jan 2022
Cited by 14 | Viewed by 6289
Abstract
Exposure to methamphetamine (Meth) has been classically associated with damage to neuronal terminals. However, it is now becoming clear that addiction may also result from the interplay between glial cells and neurons. Recently, we demonstrated that binge Meth administration promotes microgliosis and microglia [...] Read more.
Exposure to methamphetamine (Meth) has been classically associated with damage to neuronal terminals. However, it is now becoming clear that addiction may also result from the interplay between glial cells and neurons. Recently, we demonstrated that binge Meth administration promotes microgliosis and microglia pro-inflammation via astrocytic glutamate release in a TNF/IP3R2-Ca2+-dependent manner. Here, we investigated the contribution of neuronal cells to this process. As the crosstalk between microglia and neurons may occur by contact-dependent and/or contact-independent mechanisms, we developed co-cultures of primary neurons and microglia in microfluidic devices to investigate how their interaction affects Meth-induced microglia activation. Our results show that neurons exposed to Meth do not activate microglia in a cell-autonomous way but require astrocyte mediation. Importantly, we found that neurons can partially prevent Meth-induced microglia activation via astrocytes, which seems to be achieved by increasing arginase 1 expression and strengthening the CD200/CD200r pathway. We also observed an increase in synaptic individual area, as determined by co-localization of pre- and post-synaptic markers. The present study provides evidence that contact-dependent mechanisms between neurons and microglia can attenuate pro-inflammatory events such as Meth-induced microglia activation. Full article
(This article belongs to the Special Issue Frontiers in Neurogenesis)
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48 pages, 2385 KB  
Review
Interconnections between Inflammageing and Immunosenescence during Ageing
by Thibault Teissier, Eric Boulanger and Lynne S. Cox
Cells 2022, 11(3), 359; https://doi.org/10.3390/cells11030359 - 21 Jan 2022
Cited by 174 | Viewed by 29106
Abstract
Acute inflammation is a physiological response to injury or infection, with a cascade of steps that ultimately lead to the recruitment of immune cells to clear invading pathogens and heal wounds. However, chronic inflammation arising from the continued presence of the initial trigger, [...] Read more.
Acute inflammation is a physiological response to injury or infection, with a cascade of steps that ultimately lead to the recruitment of immune cells to clear invading pathogens and heal wounds. However, chronic inflammation arising from the continued presence of the initial trigger, or the dysfunction of signalling and/or effector pathways, is harmful to health. While successful ageing in older adults, including centenarians, is associated with low levels of inflammation, elevated inflammation increases the risk of poor health and death. Hence inflammation has been described as one of seven pillars of ageing. Age-associated sterile, chronic, and low-grade inflammation is commonly termed inflammageing—it is not simply a consequence of increasing chronological age, but is also a marker of biological ageing, multimorbidity, and mortality risk. While inflammageing was initially thought to be caused by “continuous antigenic load and stress”, reports from the last two decades describe a much more complex phenomenon also involving cellular senescence and the ageing of the immune system. In this review, we explore some of the main sources and consequences of inflammageing in the context of immunosenescence and highlight potential interventions. In particular, we assess the contribution of cellular senescence to age-associated inflammation, identify patterns of pro- and anti-inflammatory markers characteristic of inflammageing, describe alterations in the ageing immune system that lead to elevated inflammation, and finally assess the ways that diet, exercise, and pharmacological interventions can reduce inflammageing and thus, improve later life health. Full article
(This article belongs to the Special Issue Inflammaging: The Immunology of Aging)
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25 pages, 9360 KB  
Article
Assessment of FDA-Approved Drugs as a Therapeutic Approach for Niemann-Pick Disease Type C1 Using Patient-Specific iPSC-Based Model Systems
by Christin Völkner, Supansa Pantoom, Maik Liedtke, Jan Lukas, Andreas Hermann and Moritz J. Frech
Cells 2022, 11(3), 319; https://doi.org/10.3390/cells11030319 - 18 Jan 2022
Cited by 7 | Viewed by 4134
Abstract
Niemann-Pick type C1 (NP-C1) is a fatal, progressive neurodegenerative disease caused by mutations in the NPC1 gene. Mutations of NPC1 can result in a misfolded protein that is subsequently marked for proteasomal degradation. Such loss-of-function mutations lead to cholesterol accumulation in late endosomes [...] Read more.
Niemann-Pick type C1 (NP-C1) is a fatal, progressive neurodegenerative disease caused by mutations in the NPC1 gene. Mutations of NPC1 can result in a misfolded protein that is subsequently marked for proteasomal degradation. Such loss-of-function mutations lead to cholesterol accumulation in late endosomes and lysosomes. Pharmacological chaperones (PCs) are described to protect misfolded proteins from proteasomal degradation and are being discussed as a treatment strategy for NP-C1. Here, we used a combinatorial approach of high-throughput in silico screening of FDA-approved drugs and in vitro biochemical assays to identify potential PCs. The effects of the hit compounds identified by molecular docking were compared in vitro with 25-hydroxycholesterol (25-HC), which is known to act as a PC for NP-C1. We analyzed cholesterol accumulation, NPC1 protein content, and lysosomal localization in patient-specific fibroblasts, as well as in neural differentiated and hepatocyte-like cells derived from patient-specific induced pluripotent stem cells (iPSCs). One compound, namely abiraterone acetate, showed comparable results to 25-HC and restored NPC1 protein level, corrected the intracellular localization of NPC1, and consequently decreased cholesterol accumulation in NPC1-mutated fibroblasts and iPSC-derived neural differentiated and hepatocyte-like cells. The discovered PC altered not only the pathophysiological phenotype of cells carrying the I1061T mutation— known to be responsive to treatment with PCs—but an effect was also observed in cells carrying other NPC1 missense mutations. Therefore, we hypothesize that the PCs studied here may serve as an effective treatment strategy for a large group of NP-C1 patients. Full article
(This article belongs to the Special Issue Induced Pluripotent Stem Cells (IPSC) as a Disease Modeling and Drug Development Platform)
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25 pages, 4231 KB  
Article
Generation of a NES-mScarlet Red Fluorescent Reporter Human iPSC Line for Live Cell Imaging and Flow Cytometric Analysis and Sorting Using CRISPR-Cas9-Mediated Gene Editing
by Parivash Nouri, Anja Zimmer, Stefanie Brüggemann, Robin Friedrich, Ralf Kühn and Nilima Prakash
Cells 2022, 11(2), 268; https://doi.org/10.3390/cells11020268 - 13 Jan 2022
Cited by 4 | Viewed by 5675
Abstract
Advances in the regenerative stem cell field have propelled the generation of tissue-specific cells in the culture dish for subsequent transplantation, drug screening purposes, or the elucidation of disease mechanisms. One major obstacle is the heterogeneity of these cultures, in which the tissue-specific [...] Read more.
Advances in the regenerative stem cell field have propelled the generation of tissue-specific cells in the culture dish for subsequent transplantation, drug screening purposes, or the elucidation of disease mechanisms. One major obstacle is the heterogeneity of these cultures, in which the tissue-specific cells of interest usually represent only a fraction of all generated cells. Direct identification of the cells of interest and the ability to specifically isolate these cells in vitro is, thus, highly desirable for these applications. The type VI intermediate filament protein NESTIN is widely used as a marker for neural stem/progenitor cells (NSCs/NPCs) in the developing and adult central and peripheral nervous systems. Applying CRISPR-Cas9 technology, we have introduced a red fluorescent reporter (mScarlet) into the NESTIN (NES) locus of a human induced pluripotent stem cell (hiPSC) line. We describe the generation and characterization of NES-mScarlet reporter hiPSCs and demonstrate that this line is an accurate reporter of NSCs/NPCs during their directed differentiation into human midbrain dopaminergic (mDA) neurons. Furthermore, NES-mScarlet hiPSCs can be used for direct identification during live cell imaging and for flow cytometric analysis and sorting of red fluorescent NSCs/NPCs in this paradigm. Full article
(This article belongs to the Special Issue iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases)
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