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Cells
Volume 11
Issue 7
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Cells, Volume 11, Issue 7 (April-1 2022) – 189 articles

Cover Story (view full-size image): Siglec-6 is an ITIM-bearing glycan-binding receptor previously identified on human mast cells; however, its properties have not been fully elucidated. Herein, Robida et al. assess the expression, endocytosis, and function of Siglec-6. This report demonstrates that Siglec-6 is highly and consistently expressed on all primary mast cells and mast cell lines examined, and that SIGLEC6 mRNA is limited to mast cells in esophageal tissue biopsies. Following the antibody ligation of Siglec-6, mast cell activation in response to stimulation through FcεRI, MRGPRX2, or C5aR is reduced, and Siglec-6 is maintained at the cell surface for prolonged periods. Coaggregating Siglec-6 with FcεRIα enhances its ability to suppress mast cell activation and reduces the activation of the phosphorylation of ERK1/2 and p38. These findings indicate that Siglec-6 is suitable as a therapeutic target on mast cells. View this paper
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19 pages, 2504 KiB  
Article
Proteomic Analysis of the Role of the Adenylyl Cyclase–cAMP Pathway in Red Blood Cell Mechanical Responses
by Elif Ugurel, Evrim Goksel, Neslihan Cilek, Elif Kaga and Ozlem Yalcin
Cells 2022, 11(7), 1250; https://doi.org/10.3390/cells11071250 - 6 Apr 2022
Cited by 10 | Viewed by 3056
Abstract
Red blood cell (RBC) deformability is modulated by the phosphorylation status of the cytoskeletal proteins that regulate the interactions of integral transmembrane complexes. Proteomic studies have revealed that receptor-related signaling molecules and regulatory proteins involved in signaling cascades are present in RBCs. In [...] Read more.
Red blood cell (RBC) deformability is modulated by the phosphorylation status of the cytoskeletal proteins that regulate the interactions of integral transmembrane complexes. Proteomic studies have revealed that receptor-related signaling molecules and regulatory proteins involved in signaling cascades are present in RBCs. In this study, we investigated the roles of the cAMP signaling mechanism in modulating shear-induced RBC deformability and examined changes in the phosphorylation of the RBC proteome. We implemented the inhibitors of adenylyl cyclase (SQ22536), protein kinase A (H89), and phosphodiesterase (PDE) (pentoxifylline) to whole blood samples, applied 5 Pa shear stress (SS) for 300 s with a capillary tubing system, and evaluated RBC deformability using a LORRCA MaxSis. The inhibition of signaling molecules significantly deteriorated shear-induced RBC deformability (p < 0.05). Capillary SS slightly increased the phosphorylation of RBC cytoskeletal proteins. Tyrosine phosphorylation was significantly elevated by the modulation of the cAMP/PKA pathway (p < 0.05), while serine phosphorylation significantly decreased as a result of the inhibition of PDE (p < 0.05). AC is the core element of this signaling pathway, and PDE works as a negative feedback mechanism that could have potential roles in SS-induced RBC deformability. The cAMP/PKA pathway could regulate RBC deformability during capillary transit by triggering significant alterations in the phosphorylation state of RBCs. Full article
(This article belongs to the Collection Advances in Cell Culture and Tissue Engineering)
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26 pages, 2589 KiB  
Review
Early Protective Role of Inflammation in Cardiac Remodeling and Heart Failure: Focus on TNFα and Resident Macrophages
by Sophie Besse, Sophie Nadaud, Elise Balse and Catherine Pavoine
Cells 2022, 11(7), 1249; https://doi.org/10.3390/cells11071249 - 6 Apr 2022
Cited by 28 | Viewed by 5585
Abstract
Cardiac hypertrophy, initiated by a variety of physiological or pathological stimuli (hemodynamic or hormonal stimulation or infarction), is a critical early adaptive compensatory response of the heart. The structural basis of the progression from compensated hypertrophy to pathological hypertrophy and heart failure is [...] Read more.
Cardiac hypertrophy, initiated by a variety of physiological or pathological stimuli (hemodynamic or hormonal stimulation or infarction), is a critical early adaptive compensatory response of the heart. The structural basis of the progression from compensated hypertrophy to pathological hypertrophy and heart failure is still largely unknown. In most cases, early activation of an inflammatory program reflects a reparative or protective response to other primary injurious processes. Later on, regardless of the underlying etiology, heart failure is always associated with both local and systemic activation of inflammatory signaling cascades. Cardiac macrophages are nodal regulators of inflammation. Resident macrophages mostly attenuate cardiac injury by secreting cytoprotective factors (cytokines, chemokines, and growth factors), scavenging damaged cells or mitochondrial debris, and regulating cardiac conduction, angiogenesis, lymphangiogenesis, and fibrosis. In contrast, excessive recruitment of monocyte-derived inflammatory macrophages largely contributes to the transition to heart failure. The current review examines the ambivalent role of inflammation (mainly TNFα-related) and cardiac macrophages (Mφ) in pathophysiologies from non-infarction origin, focusing on the protective signaling processes. Our objective is to illustrate how harnessing this knowledge could pave the way for innovative therapeutics in patients with heart failure. Full article
(This article belongs to the Special Issue Cellular Signaling Leading to Heart Failure)
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13 pages, 2607 KiB  
Article
Morphological and Immunopathological Aspects of Lingual Tissues in COVID-19
by Dolaji Henin, Gaia Pellegrini, Daniela Carmagnola, Giuseppe Carlo Lanza Attisano, Gianluca Lopez, Stefano Ferrero, Antonella Amendola, Danilo De Angelis, Elisabetta Tanzi and Claudia Dellavia
Cells 2022, 11(7), 1248; https://doi.org/10.3390/cells11071248 - 6 Apr 2022
Cited by 13 | Viewed by 4467
Abstract
COVID-19, a recently emerged disease caused by SARS-CoV-2 infection, can present with different degrees of severity and a large variety of signs and symptoms. The oral manifestations of COVID-19 often involve the tongue, with loss of taste being one of the most common [...] Read more.
COVID-19, a recently emerged disease caused by SARS-CoV-2 infection, can present with different degrees of severity and a large variety of signs and symptoms. The oral manifestations of COVID-19 often involve the tongue, with loss of taste being one of the most common symptoms of the disease. This study aimed to detect SARS-CoV-2 RNA and assess possible morphological and immunopathological alterations in the lingual tissue of patients who died with a history of SARS-CoV-2 infection. Sixteen cadavers from 8 SARS-CoV-2 positive (COVID-19+) and 8 negative (COVID-19−) subjects provided 16 tongues, that were biopsied. Samples underwent molecular analysis through Real-Time RT-PCR for the detection of SARS-CoV-2 RNA. Lingual papillae were harvested and processed for histological analysis and for immunohistochemical evaluation for ACE2, IFN-γ and factor VIII. Real-Time RT-PCR revealed the presence of SARS-CoV-2 RNA in filiform, foliate, and circumvallate papillae in 6 out of 8 COVID-19+ subjects while all COVID-19− samples resulted negative. Histology showed a severe inflammation of COVID-19+ papillae with destruction of the taste buds. ACE2 and IFN-γ resulted downregulated in COVID-19+ and no differences were evidenced for factor VIII between the two groups. The virus was detectable in most COVID-19+ tongues. An inflammatory damage to the lingual papillae, putatively mediated by ACE2 and IFN-γ in tongues from COVID-19+ cadavers, was observed. Further investigations are needed to confirm these findings and deepen the association between taste disorders and inflammation in SARS-CoV-2 infection. Full article
(This article belongs to the Section Tissues and Organs)
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9 pages, 919 KiB  
Review
The Cell Biology of Heterochromatin
by Brandt Warecki and William Sullivan
Cells 2022, 11(7), 1247; https://doi.org/10.3390/cells11071247 - 6 Apr 2022
Cited by 1 | Viewed by 3548
Abstract
A conserved feature of virtually all higher eukaryotes is that the centromeres are embedded in heterochromatin. Here we provide evidence that this tight association between pericentric heterochromatin and the centromere is essential for proper metaphase exit and progression into telophase. Analysis of chromosome [...] Read more.
A conserved feature of virtually all higher eukaryotes is that the centromeres are embedded in heterochromatin. Here we provide evidence that this tight association between pericentric heterochromatin and the centromere is essential for proper metaphase exit and progression into telophase. Analysis of chromosome rearrangements that separate pericentric heterochromatin and centromeres indicates that they must remain associated in order to balance Cohesin/DNA catenation-based binding forces and centromere-based pulling forces during the metaphase–anaphase transition. In addition, a centromere embedded in heterochromatin facilitates nuclear envelope assembly around the entire complement of segregating chromosomes. Because the nuclear envelope initially forms on pericentric heterochromatin, nuclear envelope formation proceeds from the pole, thus providing time for incorporation of lagging and trailing chromosome arms into the newly formed nucleus. Additional analysis of noncanonical mitoses provides further insights into the functional significance of the tight association between heterochromatin and centromeres. Full article
(This article belongs to the Special Issue Heterochromatin Is No Longer the Dark Side of the Genome: A Themed Issue in Honor of Prof. Sergio Pimpinelli)
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27 pages, 6778 KiB  
Article
Alteration of Mitochondrial Integrity as Upstream Event in the Pathophysiology of SOD1-ALS
by René Günther, Arun Pal, Chloe Williams, Vitaly L. Zimyanin, Maria Liehr, Cläre von Neubeck, Mechthild Krause, Mrudula G. Parab, Susanne Petri, Norman Kalmbach, Stefan L. Marklund, Jared Sterneckert, Peter Munch Andersen, Florian Wegner, Jonathan D. Gilthorpe and Andreas Hermann
Cells 2022, 11(7), 1246; https://doi.org/10.3390/cells11071246 - 6 Apr 2022
Cited by 17 | Viewed by 5095
Abstract
Little is known about the early pathogenic events by which mutant superoxide dismutase 1 (SOD1) causes amyotrophic lateral sclerosis (ALS). This lack of mechanistic understanding is a major barrier to the development and evaluation of efficient therapies. Although protein aggregation is known to [...] Read more.
Little is known about the early pathogenic events by which mutant superoxide dismutase 1 (SOD1) causes amyotrophic lateral sclerosis (ALS). This lack of mechanistic understanding is a major barrier to the development and evaluation of efficient therapies. Although protein aggregation is known to be involved, it is not understood how mutant SOD1 causes degeneration of motoneurons (MNs). Previous research has relied heavily on the overexpression of mutant SOD1, but the clinical relevance of SOD1 overexpression models remains questionable. We used a human induced pluripotent stem cell (iPSC) model of spinal MNs and three different endogenous ALS-associated SOD1 mutations (D90Ahom, R115Ghet or A4Vhet) to investigate early cellular disturbances in MNs. Although enhanced misfolding and aggregation of SOD1 was induced by proteasome inhibition, it was not affected by activation of the stress granule pathway. Interestingly, we identified loss of mitochondrial, but not lysosomal, integrity as the earliest common pathological phenotype, which preceded elevated levels of insoluble, aggregated SOD1. A super-elongated mitochondrial morphology with impaired inner mitochondrial membrane potential was a unifying feature in mutant SOD1 iPSC-derived MNs. Impaired mitochondrial integrity was most prominent in mutant D90Ahom MNs, whereas both soluble disordered and detergent-resistant misfolded SOD1 was more prominent in R115Ghet and A4Vhet mutant lines. Taking advantage of patient-specific models of SOD1-ALS in vitro, our data suggest that mitochondrial dysfunction is one of the first crucial steps in the pathogenic cascade that leads to SOD1-ALS and also highlights the need for individualized medical approaches for SOD1-ALS. Full article
(This article belongs to the Special Issue Neurodegenerative and Neurologic Disease: Genes, Mechanisms, and Therapies)
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21 pages, 2498 KiB  
Article
Urine-Derived Kidney Progenitor Cells in Cystinosis
by Koenraad Veys, Sante Princiero Berlingerio, Dries David, Tjessa Bondue, Katharina Held, Ahmed Reda, Martijn van den Broek, Koen Theunis, Mirian Janssen, Elisabeth Cornelissen, Joris Vriens, Francesca Diomedi-Camassei, Rik Gijsbers, Lambertus van den Heuvel, Fanny O. Arcolino and Elena Levtchenko
Cells 2022, 11(7), 1245; https://doi.org/10.3390/cells11071245 - 6 Apr 2022
Cited by 5 | Viewed by 3078
Abstract
Nephropathic cystinosis is an inherited lysosomal storage disorder caused by pathogenic variants in the cystinosin (CTNS) gene and is characterized by the excessive shedding of proximal tubular epithelial cells (PTECs) and podocytes into urine, development of the renal Fanconi syndrome and [...] Read more.
Nephropathic cystinosis is an inherited lysosomal storage disorder caused by pathogenic variants in the cystinosin (CTNS) gene and is characterized by the excessive shedding of proximal tubular epithelial cells (PTECs) and podocytes into urine, development of the renal Fanconi syndrome and end-stage kidney disease (ESKD). We hypothesized that in compensation for epithelial cell losses, cystinosis kidneys undertake a regenerative effort, and searched for the presence of kidney progenitor cells (KPCs) in the urine of cystinosis patients. Urine was cultured in a specific progenitor medium to isolate undifferentiated cells. Of these, clones were characterized by qPCR, subjected to a differentiation protocol to PTECs and podocytes and assessed by qPCR, Western blot, immunostainings and functional assays. Cystinosis patients voided high numbers of undifferentiated cells in urine, of which various clonal cell lines showed a high capacity for self-renewal and expressed kidney progenitor markers, which therefore were assigned as cystinosis urine-derived KPCs (Cys-uKPCs). Cys-uKPC clones showed the capacity to differentiate between functional PTECs and/or podocytes. Gene addition with wild-type CTNS using lentiviral vector technology resulted in significant reductions in cystine levels. We conclude that KPCs present in the urine of cystinosis patients can be isolated, differentiated and complemented with CTNS in vitro, serving as a novel tool for disease modeling. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Nephropathic Cystinosis)
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12 pages, 1542 KiB  
Article
Cytoplasmic Colocalization of RXRα and PPARγ as an Independent Negative Prognosticator for Breast Cancer Patients
by Wanting Shao, Melitta B. Köpke, Theresa Vilsmaier, Alaleh Zati Zehni, Mirjana Kessler, Sophie Sixou, Mariella Schneider, Nina Ditsch, Vincent Cavaillès and Udo Jeschke
Cells 2022, 11(7), 1244; https://doi.org/10.3390/cells11071244 - 6 Apr 2022
Cited by 4 | Viewed by 1995
Abstract
Retinoid X receptor α (RXRα) is a nuclear receptor (NR) which functions as the primary heterodimeric partner of other NRs including the peroxisome proliferator-activated receptor γ (PPARγ). We previously reported that, in breast cancers (BC), the subcellular localization of these two receptors was [...] Read more.
Retinoid X receptor α (RXRα) is a nuclear receptor (NR) which functions as the primary heterodimeric partner of other NRs including the peroxisome proliferator-activated receptor γ (PPARγ). We previously reported that, in breast cancers (BC), the subcellular localization of these two receptors was strongly associated with patient prognosis. In the present work, we investigated the prognosis value of the combined cytoplasmic expression of RXRα and PPARγ using a retrospective cohort of 250 BC samples. Patients with tumors expressing both NRs in tumor cell cytoplasm exhibited a significant shorter overall (OS) and disease-free survival (DFS). This was also observed for patients with stage 1 tumors. Cox univariate analysis indicated that patients with tumors coexpressing RXRα and PPARγ in the cytoplasm of tumor cells have a decreased 5 y OS rate. Cytoplasmic co-expression of the two NRs significantly correlated with HER2 positivity and with NCAD and CD133, two markers of tumor aggressiveness. Finally, in Cox multivariate analysis, the co-expression of RXRα and PPARγ in the cytoplasm appeared as an independent OS prognosticator. Altogether, this study demonstrates that the cytoplasmic co-expression of RXRα and PPARγ could be of relevance for clinicians by identifying high-risk BC patients, especially amongst those with early and node-negative disease. Full article
(This article belongs to the Special Issue Retinoic Acid and Retinoid X Receptors)
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22 pages, 396 KiB  
Review
CFTR Modulator Therapies: Potential Impact on Airway Infections in Cystic Fibrosis
by Francesca Saluzzo, Luca Riberi, Barbara Messore, Nicola Ivan Loré, Irene Esposito, Elisabetta Bignamini and Virginia De Rose
Cells 2022, 11(7), 1243; https://doi.org/10.3390/cells11071243 - 6 Apr 2022
Cited by 22 | Viewed by 4085
Abstract
Cystic Fibrosis (CF) is an autosomal recessive disease caused by mutations in the gene encoding for the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein, expressed on the apical surface of epithelial cells. CFTR absence/dysfunction results in ion imbalance and airway surface dehydration that [...] Read more.
Cystic Fibrosis (CF) is an autosomal recessive disease caused by mutations in the gene encoding for the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein, expressed on the apical surface of epithelial cells. CFTR absence/dysfunction results in ion imbalance and airway surface dehydration that severely compromise the CF airway microenvironment, increasing infection susceptibility. Recently, novel therapies aimed at correcting the basic CFTR defect have become available, leading to substantial clinical improvement of CF patients. The restoration or increase of CFTR function affects the airway microenvironment, improving local defence mechanisms. CFTR modulator drugs might therefore affect the development of chronic airway infections and/or improve the status of existing infections in CF. Thus far, however, the full extent of these effects of CFTR-modulators, especially in the long-term remains still unknown. This review aims to provide an overview of current evidence on the potential impact of CFTR modulators on airway infections in CF. Their role in affecting CF microbiology, the susceptibility to infections as well as the potential efficacy of their use in preventing/decreasing the development of chronic lung infections and the recurrent acute exacerbations in CF will be critically analysed. Full article
(This article belongs to the Collection Cystic Fibrosis: Cells, Physiopathology and Emerging Therapies)
16 pages, 6494 KiB  
Article
The Role of N-Glycosylation in the Intracellular Trafficking and Functionality of Neuronal Growth Regulator 1
by Gyuri Sim, Moonkyung Jeong, Hyunseok Seo, Jangrae Kim and Soojin Lee
Cells 2022, 11(7), 1242; https://doi.org/10.3390/cells11071242 - 6 Apr 2022
Cited by 4 | Viewed by 3119
Abstract
Neuronal growth regulator 1 (NEGR1) is a brain-enriched membrane protein that is involved in neural cell communication and synapse formation. Accumulating evidence indicates that NEGR1 is a generic risk factor for various psychiatric diseases including autism and depression. Endoglycosidase digestion of single NEGR1 [...] Read more.
Neuronal growth regulator 1 (NEGR1) is a brain-enriched membrane protein that is involved in neural cell communication and synapse formation. Accumulating evidence indicates that NEGR1 is a generic risk factor for various psychiatric diseases including autism and depression. Endoglycosidase digestion of single NEGR1 mutants revealed that the wild type NEGR1 has six putative N-glycosylation sites partly organized in a Golgi-dependent manner. To understand the role of each putative N-glycan residue, we generated a series of multi-site mutants (2MT–6MT) with additive mutations. Cell surface staining and biotinylation revealed that NEGR1 mutants 1MT to 4MT were localized on the cell surface at different levels, whereas 5MT and 6MT were retained in the endoplasmic reticulum to form highly stable multimer complexes. This indicated 5MT and 6MT are less likely to fold correctly. Furthermore, the removal of two N-terminal sites N75 and N155 was sufficient to completely abrogate membrane targeting. An in vivo binding assay using the soluble NEGR1 protein demonstrated that glycans N286, N294 and N307 on the C-terminal immunoglobulin-like domain play important roles in homophilic interactions. Taken together, these results suggest that the N-glycan moieties of NEGR1 are closely involved in the folding, trafficking, and homodimer formation of NEGR1 protein in a site-specific manner. Full article
(This article belongs to the Topic Proteins in Health and Diseases: New Knowledge and Practical Applications)
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21 pages, 3670 KiB  
Article
Plasma Metabolomic Alterations Induced by COVID-19 Vaccination Reveal Putative Biomarkers Reflecting the Immune Response
by Ioanna Dagla, Aikaterini Iliou, Dimitra Benaki, Evagelos Gikas, Emmanuel Mikros, Tina Bagratuni, Efstathios Kastritis, Meletios A. Dimopoulos, Evangelos Terpos and Anthony Tsarbopoulos
Cells 2022, 11(7), 1241; https://doi.org/10.3390/cells11071241 - 6 Apr 2022
Cited by 17 | Viewed by 4065
Abstract
Vaccination is currently the most effective strategy for the mitigation of the COVID-19 pandemic. mRNA vaccines trigger the immune system to produce neutralizing antibodies (NAbs) against SARS-CoV-2 spike proteins. However, the underlying molecular processes affecting immune response after vaccination remain poorly understood, while [...] Read more.
Vaccination is currently the most effective strategy for the mitigation of the COVID-19 pandemic. mRNA vaccines trigger the immune system to produce neutralizing antibodies (NAbs) against SARS-CoV-2 spike proteins. However, the underlying molecular processes affecting immune response after vaccination remain poorly understood, while there is significant heterogeneity in the immune response among individuals. Metabolomics have often been used to provide a deeper understanding of immune cell responses, but in the context of COVID-19 vaccination such data are scarce. Mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR)-based metabolomics were used to provide insights based on the baseline metabolic profile and metabolic alterations induced after mRNA vaccination in paired blood plasma samples collected and analysed before the first and second vaccination and at 3 months post first dose. Based on the level of NAbs just before the second dose, two groups, “low” and “high” responders, were defined. Distinct plasma metabolic profiles were observed in relation to the level of immune response, highlighting the role of amino acid metabolism and the lipid profile as predictive markers of response to vaccination. Furthermore, levels of plasma ceramides along with certain amino acids could emerge as predictive biomarkers of response and severity of inflammation. Full article
(This article belongs to the Collection Cellular Immunology and COVID-19)
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23 pages, 42816 KiB  
Article
Total and Mitochondrial Transcriptomic and Proteomic Insights into Regulation of Bioenergetic Processes for Shoot Fast-Growth Initiation in Moso Bamboo
by Xiaojing Wang, Xin Geng, Lilin Yang, Yuzhen Chen, Zhiheng Zhao, Weijia Shi, Lan Kang, Ruihua Wu, Cunfu Lu and Jian Gao
Cells 2022, 11(7), 1240; https://doi.org/10.3390/cells11071240 - 6 Apr 2022
Cited by 10 | Viewed by 2548
Abstract
As a fast-growing, woody grass plant, Moso bamboo (Phyllostachys edulis) can supply edible shoots, building materials, fibrous raw material, raw materials for crafts and furniture and so on within a relatively short time. Rapid growth of Moso bamboo occurs after the [...] Read more.
As a fast-growing, woody grass plant, Moso bamboo (Phyllostachys edulis) can supply edible shoots, building materials, fibrous raw material, raw materials for crafts and furniture and so on within a relatively short time. Rapid growth of Moso bamboo occurs after the young bamboo shoots are covered with a shell and emerge from the ground. However, the molecular reactions of bioenergetic processes essential for fast growth remain undefined. Herein, total and mitochondrial transcriptomes and proteomes were compared between spring and winter shoots. Numerous key genes and proteins responsible for energy metabolism were significantly upregulated in spring shoots, including those involved in starch and sucrose catabolism, glycolysis, the pentose phosphate pathway, the tricarboxylic acid cycle and oxidative phosphorylation. Accordingly, significant decreases in starch and soluble sugar, higher ATP content and higher rates of respiration and glycolysis were identified in spring shoots. Further, the upregulated genes and proteins related to mitochondrial fission significantly increased the number of mitochondria, indirectly promoting intracellular energy metabolism. Moreover, enhanced alternate-oxidase and uncoupled-protein pathways in winter shoots showed that an efficient energy-dissipating system was important for winter shoots to adapt to the low-temperature environment. Heterologous expression of PeAOX1b in Arabidopsis significantly affected seedling growth and enhanced cold-stress tolerance. Overall, this study highlights the power of comparing total and mitochondrial omics and integrating physiochemical data to understand how bamboo initiates fast growth through modulating bioenergetic processes. Full article
(This article belongs to the Special Issue New Insight in Molecular and Cellular Mechanism of Plant Growth)
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28 pages, 4089 KiB  
Review
The Influence of Gut Dysbiosis in the Pathogenesis and Management of Ischemic Stroke
by Saravana Babu Chidambaram, Annan Gopinath Rathipriya, Arehally M. Mahalakshmi, Sonali Sharma, Tousif Ahmed Hediyal, Bipul Ray, Tuladhar Sunanda, Wiramon Rungratanawanich, Rajpal Singh Kashyap, M. Walid Qoronfleh, Musthafa Mohamed Essa, Byoung-Joon Song and Tanya M. Monaghan
Cells 2022, 11(7), 1239; https://doi.org/10.3390/cells11071239 - 6 Apr 2022
Cited by 77 | Viewed by 9811
Abstract
Recent research on the gut microbiome has revealed the influence of gut microbiota (GM) on ischemic stroke pathogenesis and treatment outcomes. Alterations in the diversity, abundance, and functions of the gut microbiome, termed gut dysbiosis, results in dysregulated gut–brain signaling, which induces intestinal [...] Read more.
Recent research on the gut microbiome has revealed the influence of gut microbiota (GM) on ischemic stroke pathogenesis and treatment outcomes. Alterations in the diversity, abundance, and functions of the gut microbiome, termed gut dysbiosis, results in dysregulated gut–brain signaling, which induces intestinal barrier changes, endotoxemia, systemic inflammation, and infection, affecting post-stroke outcomes. Gut–brain interactions are bidirectional, and the signals from the gut to the brain are mediated by microbially derived metabolites, such as trimethylamine N-oxide (TMAO) and short-chain fatty acids (SCFAs); bacterial components, such as lipopolysaccharide (LPS); immune cells, such as T helper cells; and bacterial translocation via hormonal, immune, and neural pathways. Ischemic stroke affects gut microbial composition via neural and hypothalamic–pituitary–adrenal (HPA) pathways, which can contribute to post-stroke outcomes. Experimental and clinical studies have demonstrated that the restoration of the gut microbiome usually improves stroke treatment outcomes by regulating metabolic, immune, and inflammatory responses via the gut–brain axis (GBA). Therefore, restoring healthy microbial ecology in the gut may be a key therapeutic target for the effective management and treatment of ischemic stroke. Full article
(This article belongs to the Collection Feature Papers in 'Cells of the Nervous System' Section)
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33 pages, 3273 KiB  
Review
Molecular Markers of Pediatric Solid Tumors—Diagnosis, Optimizing Treatments, and Determining Susceptibility: Current State and Future Directions
by Joanna Trubicka, Wiesława Grajkowska and Bożenna Dembowska-Bagińska
Cells 2022, 11(7), 1238; https://doi.org/10.3390/cells11071238 - 6 Apr 2022
Cited by 13 | Viewed by 3185
Abstract
Advances in molecular technologies, from genomics and transcriptomics to epigenetics, are providing unprecedented insight into the molecular landscape of pediatric tumors. Multi-omics approaches provide an opportunity to identify a wide spectrum of molecular alterations that account for the initiation of the neoplastic process [...] Read more.
Advances in molecular technologies, from genomics and transcriptomics to epigenetics, are providing unprecedented insight into the molecular landscape of pediatric tumors. Multi-omics approaches provide an opportunity to identify a wide spectrum of molecular alterations that account for the initiation of the neoplastic process in children, response to treatment and disease progression. The detection of molecular markers is crucial to assist clinicians in accurate tumor diagnosis, risk stratification, disease subtyping, prediction of treatment response, and surveillance, allowing also for personalized cancer management. This review summarizes the most recent developments in genomics research and their relevance to the field of pediatric oncology with the aim of generating an overview of the most important, from the clinical perspective, molecular markers for pediatric solid tumors. We present an overview of the molecular markers selected based on therapeutic protocols, guidelines from international committees and scientific societies, and published data. Full article
(This article belongs to the Special Issue Harnessing the Immune System to Fight Pediatric Cancer)
22 pages, 943 KiB  
Review
Microglial Endocannabinoid Signalling in AD
by Lucia Scipioni, Francesca Ciaramellano, Veronica Carnicelli, Alessandro Leuti, Anna Rita Lizzi, Noemi De Dominicis, Sergio Oddi and Mauro Maccarrone
Cells 2022, 11(7), 1237; https://doi.org/10.3390/cells11071237 - 6 Apr 2022
Cited by 13 | Viewed by 3211
Abstract
Chronic inflammation in Alzheimer’s disease (AD) has been recently identified as a major contributor to disease pathogenesis. Once activated, microglial cells, which are brain-resident immune cells, exert several key actions, including phagocytosis, chemotaxis, and the release of pro- or anti-inflammatory mediators, which could [...] Read more.
Chronic inflammation in Alzheimer’s disease (AD) has been recently identified as a major contributor to disease pathogenesis. Once activated, microglial cells, which are brain-resident immune cells, exert several key actions, including phagocytosis, chemotaxis, and the release of pro- or anti-inflammatory mediators, which could have opposite effects on brain homeostasis, depending on the stage of disease and the particular phenotype of microglial cells. The endocannabinoids (eCBs) are pleiotropic bioactive lipids increasingly recognized for their essential roles in regulating microglial activity both under normal and AD-driven pathological conditions. Here, we review the current literature regarding the involvement of this signalling system in modulating microglial phenotypes and activity in the context of homeostasis and AD-related neurodegeneration. Full article
(This article belongs to the Collection Novel Insights into Cannabinoid Receptors, Molecular Targets, and Therapeutic Potentials)
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17 pages, 4446 KiB  
Article
Distinct Dominant Lineage from In Vitro Expanded Adipose-Derived Stem Cells (ASCs) Exhibits Enhanced Wound Healing Properties
by Qiuyue Peng, Guoqiang Ren, Zongzhe Xuan, Martyna Duda, Cristian Pablo Pennisi, Simone Riis Porsborg, Trine Fink and Vladimir Zachar
Cells 2022, 11(7), 1236; https://doi.org/10.3390/cells11071236 - 6 Apr 2022
Cited by 3 | Viewed by 2787 | Correction
Abstract
It has been suggested that immunophenotypically defined lineages within the in vitro expanded adipose-derived stem cell (ASC) may play a beneficial role from the perspective of a personalized intervention. Therefore, to better understand the implications of different surface marker profiles for the functionality, [...] Read more.
It has been suggested that immunophenotypically defined lineages within the in vitro expanded adipose-derived stem cell (ASC) may play a beneficial role from the perspective of a personalized intervention. Therefore, to better understand the implications of different surface marker profiles for the functionality, we set out to examine the evolution of ASC-variants based on the co-expression of five bright or eight dim epitopes. At passages P1, P4, and P8, the co-localization of five bright markers (CD73, CD90, CD105, CD166, and CD201), or eight dim markers (CD34, CD36, CD200, CD248, CD271, CD274, CD146, and the Stro-1), was investigated by flow cytometry. Selected subpopulations were isolated using the fluorescence-activated cells sorting from the cryopreserved P4 and analyzed in terms of proliferative and clonogenic properties, trilineage differentiation, and wound healing potential. Only two of the dim epitopes were found in representative subpopulations (SP), and from the P4 onwards, two major combinations featuring the CD274+ (SP1) or the CD274+ CD146+ (SP2) emerged. Upon sorting and growth, both subpopulations assumed new but highly similar clonal profiles, consisting of the CD274+ CD146+ and the CD274+ CD146+ CD248+ phenotypes. The functional analysis revealed that the SP2 surpassed SP1 and the unfractionated cells regarding the growth rate, clonogenic activity, and the wound closure and endothelial tube formation potential. The surface epitopes may be considered a tool to enrich specific functionality and thus improve therapeutic outcomes in dedicated circumstances. Full article
(This article belongs to the Section Stem Cells)
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18 pages, 16451 KiB  
Article
Two Different Therapeutic Approaches for SARS-CoV-2 in hiPSCs-Derived Lung Organoids
by Paola Spitalieri, Federica Centofanti, Michela Murdocca, Maria Giovanna Scioli, Andrea Latini, Silvia Di Cesare, Gennaro Citro, Antonio Rossi, Augusto Orlandi, Shane Miersch, Sachdev S. Sidhu, Pier Paolo Pandolfi, Annalisa Botta, Federica Sangiuolo and Giuseppe Novelli
Cells 2022, 11(7), 1235; https://doi.org/10.3390/cells11071235 - 5 Apr 2022
Cited by 23 | Viewed by 4770
Abstract
The global health emergency for SARS-CoV-2 (COVID-19) created an urgent need to develop new treatments and therapeutic drugs. In this study, we tested, for the first time on human cells, a new tetravalent neutralizing antibody (15033-7) targeting Spike protein and a synthetic peptide [...] Read more.
The global health emergency for SARS-CoV-2 (COVID-19) created an urgent need to develop new treatments and therapeutic drugs. In this study, we tested, for the first time on human cells, a new tetravalent neutralizing antibody (15033-7) targeting Spike protein and a synthetic peptide homologous to dipeptidyl peptidase-4 (DPP4) receptor on host cells. Both could represent powerful immunotherapeutic candidates for COVID-19 treatment. The infection begins in the proximal airways, namely the alveolar type 2 (AT2) cells of the distal lung, which express both ACE2 and DPP4 receptors. Thus, to evaluate the efficacy of both approaches, we developed three-dimensional (3D) complex lung organoid structures (hLORGs) derived from human-induced pluripotent stem cells (iPSCs) and resembling the in vivo organ. Afterward, hLORGs were infected by different SARS-CoV-2 S pseudovirus variants and treated by the Ab15033-7 or DPP4 peptide. Using both approaches, we observed a significant reduction of viral entry and a modulation of the expression of genes implicated in innate immunity and inflammatory response. These data demonstrate the efficacy of such approaches in strongly reducing the infection efficiency in vitro and, importantly, provide proof-of-principle evidence that hiPSC-derived hLORGs represent an ideal in vitro system for testing both therapeutic and preventive modalities against COVID-19. Full article
(This article belongs to the Special Issue Advances in iPSC-Based Disease Modeling: From Two Dimensional Monolayers to Organoids)
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20 pages, 8051 KiB  
Article
Trophectoderm Transcriptome Analysis in LIN28 Knockdown Ovine Conceptuses Suggests Diverse Roles of the LIN28-let-7 Axis in Placental and Fetal Development
by Asghar Ali, Muhammad A. Iqbal, Muhammad W. Abbas, Gerrit J. Bouma, Russell V. Anthony, Thomas E. Spencer and Quinton A. Winger
Cells 2022, 11(7), 1234; https://doi.org/10.3390/cells11071234 - 5 Apr 2022
Cited by 2 | Viewed by 2551
Abstract
The proper conceptus elongation in ruminants is critical for the successful placentation and establishment of pregnancy. We have previously shown that the trophectoderm-specific knockdown of LIN28A/B in day 9 ovine blastocysts resulted in increased let-7 miRNAs and reduced conceptus elongation at day 16 [...] Read more.
The proper conceptus elongation in ruminants is critical for the successful placentation and establishment of pregnancy. We have previously shown that the trophectoderm-specific knockdown of LIN28A/B in day 9 ovine blastocysts resulted in increased let-7 miRNAs and reduced conceptus elongation at day 16 of gestation. In this current study, by transcriptome analysis of LIN28A knockdown (AKD) or LIN28B knockdown (BKD) trophectoderm (TE), we explored the downstream target genes of the LIN28-let-7 axis and their roles in the placental and fetal development. We identified 449 differentially expressed genes (DEGs) in AKD TE and 1214 DEGs in BKD TE compared to non-targeting control (NTC). Our analysis further revealed that 210 downregulated genes in AKD TE and 562 downregulated genes in BKD TE were the potential targets of let-7 miRNAs. Moreover, 16 downregulated genes in AKD TE and 57 downregulated and 7 upregulated genes in BKD TE were transcription factors. The DEGs in AKD and BKD TE showed enrichment in the biological processes and pathways critical for placental development and function, and fetal development and growth. The results of this study suggest the potential roles of the LIN28-let-7 axis in placental and fetal development beyond its involvement in trophoblast proliferation and conceptus elongation. Full article
(This article belongs to the Special Issue Role of Non-coding RNA in Health and Disease)
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31 pages, 950 KiB  
Review
The Evolution of Complex Muscle Cell In Vitro Models to Study Pathomechanisms and Drug Development of Neuromuscular Disease
by Jana Zschüntzsch, Stefanie Meyer, Mina Shahriyari, Karsten Kummer, Matthias Schmidt, Susann Kummer and Malte Tiburcy
Cells 2022, 11(7), 1233; https://doi.org/10.3390/cells11071233 - 5 Apr 2022
Cited by 8 | Viewed by 4438
Abstract
Many neuromuscular disease entities possess a significant disease burden and therapeutic options remain limited. Innovative human preclinical models may help to uncover relevant disease mechanisms and enhance the translation of therapeutic findings to strengthen neuromuscular disease precision medicine. By concentrating on idiopathic inflammatory [...] Read more.
Many neuromuscular disease entities possess a significant disease burden and therapeutic options remain limited. Innovative human preclinical models may help to uncover relevant disease mechanisms and enhance the translation of therapeutic findings to strengthen neuromuscular disease precision medicine. By concentrating on idiopathic inflammatory muscle disorders, we summarize the recent evolution of the novel in vitro models to study disease mechanisms and therapeutic strategies. A particular focus is laid on the integration and simulation of multicellular interactions of muscle tissue in disease phenotypes in vitro. Finally, the requirements of a neuromuscular disease drug development workflow are discussed with a particular emphasis on cell sources, co-culture systems (including organoids), functionality, and throughput. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Neuromuscular Diseases: From Basic Research to Clinical Approach)
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18 pages, 2066 KiB  
Article
Identification of Transcription Factors Responsible for a Transforming Growth Factor-β-Driven Hypertrophy-like Phenotype in Human Osteoarthritic Chondrocytes
by Nathalie G. M. Thielen, Margot Neefjes, Elly L. Vitters, Henk M. van Beuningen, Arjen B. Blom, Marije I. Koenders, Peter L. E. M. van Lent, Fons A. J. van de Loo, Esmeralda N. Blaney Davidson, Arjan P. M. van Caam and Peter M. van der Kraan
Cells 2022, 11(7), 1232; https://doi.org/10.3390/cells11071232 - 5 Apr 2022
Cited by 11 | Viewed by 3084
Abstract
During osteoarthritis (OA), hypertrophy-like chondrocytes contribute to the disease process. TGF-β’s signaling pathways can contribute to a hypertrophy(-like) phenotype in chondrocytes, especially at high doses of TGF-β. In this study, we examine which transcription factors (TFs) are activated and involved in TGF-β-dependent induction [...] Read more.
During osteoarthritis (OA), hypertrophy-like chondrocytes contribute to the disease process. TGF-β’s signaling pathways can contribute to a hypertrophy(-like) phenotype in chondrocytes, especially at high doses of TGF-β. In this study, we examine which transcription factors (TFs) are activated and involved in TGF-β-dependent induction of a hypertrophy-like phenotype in human OA chondrocytes. We found that TGF-β, at levels found in synovial fluid in OA patients, induces hypertrophic differentiation, as characterized by increased expression of RUNX2, COL10A1, COL1A1, VEGFA and IHH. Using luciferase-based TF activity assays, we observed that the expression of these hypertrophy genes positively correlated to SMAD3:4, STAT3 and AP1 activity. Blocking these TFs using specific inhibitors for ALK-5-induced SMAD signaling (5 µM SB-505124), JAK-STAT signaling (1 µM Tofacitinib) and JNK signaling (10 µM SP-600125) led to the striking observation that only SB-505124 repressed the expression of hypertrophy factors in TGF-β-stimulated chondrocytes. Therefore, we conclude that ALK5 kinase activity is essential for TGF-β-induced expression of crucial hypertrophy factors in chondrocytes. Full article
(This article belongs to the Special Issue Frontiers in Chondrocyte Biology)
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23 pages, 7346 KiB  
Article
RNA Editing in Glioma as a Sexually Dimorphic Prognostic Factor That Affects mRNA Abundance in Fatty Acid Metabolism and Inflammation Pathways
by Sheng-Hau Lin and Sean Chun-Chang Chen
Cells 2022, 11(7), 1231; https://doi.org/10.3390/cells11071231 - 5 Apr 2022
Viewed by 3215
Abstract
RNA editing alters the nucleotide sequence and has been associated with cancer progression. However, little is known about its prognostic and regulatory roles in glioma, one of the most common types of primary brain tumors. We characterized and analyzed RNA editomes of glioblastoma [...] Read more.
RNA editing alters the nucleotide sequence and has been associated with cancer progression. However, little is known about its prognostic and regulatory roles in glioma, one of the most common types of primary brain tumors. We characterized and analyzed RNA editomes of glioblastoma and isocitrate dehydrogenase mutated (IDH-MUT) gliomas from The Cancer Genome Atlas and the Chinese Glioma Genome Atlas (CGGA). We showed that editing change during glioma progression was another layer of molecular alterations and that editing profiles predicted the prognosis of glioblastoma and IDH-MUT gliomas in a sex-dependent manner. Hyper-editing was associated with poor survival in females but better survival in males. Moreover, noncoding editing events impacted mRNA abundance of the host genes. Genes associated with inflammatory response (e.g., EIF2AK2, a key mediator of innate immunity) and fatty acid oxidation (e.g., acyl-CoA oxidase 1, the rate-limiting enzyme in fatty acid β-oxidation) were editing-regulated and associated with glioma progression. The above findings were further validated in CGGA samples. Establishment of the prognostic and regulatory roles of RNA editing in glioma holds promise for developing editing-based therapeutic strategies against glioma progression. Furthermore, sexual dimorphism at the epitranscriptional level highlights the importance of developing sex-specific treatments for glioma. Full article
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16 pages, 6289 KiB  
Article
D-Cysteine Activates Chaperone-Mediated Autophagy in Cerebellar Purkinje Cells via the Generation of Hydrogen Sulfide and Nrf2 Activation
by Erika Ueda, Tomoko Ohta, Ayumu Konno, Hirokazu Hirai, Yuki Kurauchi, Hiroshi Katsuki and Takahiro Seki
Cells 2022, 11(7), 1230; https://doi.org/10.3390/cells11071230 - 5 Apr 2022
Cited by 2 | Viewed by 3029
Abstract
Chaperone-mediated autophagy (CMA) is a pathway in the autophagy-lysosome protein degradation system. CMA impairment has been implicated to play a role in spinocerebellar ataxia (SCA) pathogenesis. D-cysteine is metabolized by D-amino acid oxidase (DAO), leading to hydrogen sulfide generation in the cerebellum. Although [...] Read more.
Chaperone-mediated autophagy (CMA) is a pathway in the autophagy-lysosome protein degradation system. CMA impairment has been implicated to play a role in spinocerebellar ataxia (SCA) pathogenesis. D-cysteine is metabolized by D-amino acid oxidase (DAO), leading to hydrogen sulfide generation in the cerebellum. Although D-cysteine alleviates the disease phenotypes in SCA-model mice, it remains unknown how hydrogen sulfide derived from D-cysteine exerts this effect. In the present study, we investigated the effects of D-cysteine and hydrogen sulfide on CMA activity using a CMA activity marker that we have established. D-cysteine activated CMA in Purkinje cells (PCs) of primary cerebellar cultures where DAO was expressed, while it failed to activate CMA in DAO-deficient AD293 cells. In contrast, Na2S, a hydrogen sulfide donor, activated CMA in both PCs and AD293 cells. Nuclear factor erythroid 2-related factor 2 (Nrf2) is known to be activated by hydrogen sulfide and regulate CMA activity. An Nrf2 inhibitor, ML385, prevented CMA activation triggered by D-cysteine and Na2S. Additionally, long-term treatment with D-cysteine increased the amounts of Nrf2 and LAMP2A, a CMA-related protein, in the mouse cerebellum. These findings suggest that hydrogen sulfide derived from D-cysteine enhances CMA activity via Nrf2 activation. Full article
(This article belongs to the Special Issue New Advance in Chaperone-Mediated Autophagy)
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19 pages, 4535 KiB  
Article
Therapeutic Efficacy of Pharmacological Ascorbate on Braf Inhibitor Resistant Melanoma Cells In Vitro and In Vivo
by Heike Niessner, Markus Burkard, Christian Leischner, Olga Renner, Sarah Plöger, Francisco Meraz-Torres, Matti Böcker, Constanze Hirn, Ulrich M. Lauer, Sascha Venturelli, Christian Busch and Tobias Sinnberg
Cells 2022, 11(7), 1229; https://doi.org/10.3390/cells11071229 - 5 Apr 2022
Cited by 4 | Viewed by 2852
Abstract
High-dose ascorbate paradoxically acts as a pro-oxidant causing the formation of hydrogen peroxide in an oxygen dependent manner. Tumor cells (in particular melanoma cells) show an increased vulnerability to ascorbate induced reactive oxygen species (ROS). Therefore, high-dose ascorbate is a promising pharmacological approach [...] Read more.
High-dose ascorbate paradoxically acts as a pro-oxidant causing the formation of hydrogen peroxide in an oxygen dependent manner. Tumor cells (in particular melanoma cells) show an increased vulnerability to ascorbate induced reactive oxygen species (ROS). Therefore, high-dose ascorbate is a promising pharmacological approach to treating refractory melanomas, e.g., with secondary resistance to targeted BRAF inhibitor therapy. BRAF mutated melanoma cells were treated with ascorbate alone or in combination with the BRAF inhibitor vemurafenib. Viability, cell cycle, ROS production, and the protein levels of phospho-ERK1/2, GLUT-1 and HIF-1α were analyzed. To investigate the treatment in vivo, C57BL/6NCrl mice were subcutaneously injected with D4M.3A (BrafV600E) melanoma cells and treated with intraperitoneal injections of ascorbate with or without vemurafenib. BRAF mutated melanoma cell lines either sensitive or resistant to vemurafenib were susceptible to the induction of cell death by pharmacological ascorbate. Treatment of BrafV600E melanoma bearing mice with ascorbate resulted in plasma levels in the pharmacologically active range and significantly improved the therapeutic effect of vemurafenib. We conclude that intravenous high-dose ascorbate will be beneficial for melanoma patients by interfering with the tumor’s energy metabolism and can be safely combined with standard melanoma therapies such as BRAF inhibitors without pharmacological interference. Full article
(This article belongs to the Topic Cancer Cell Metabolism)
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17 pages, 1053 KiB  
Review
Insulin-Degrading Enzyme, an Under-Estimated Potential Target to Treat Cancer?
by Laetitia Lesire, Florence Leroux, Rebecca Deprez-Poulain and Benoit Deprez
Cells 2022, 11(7), 1228; https://doi.org/10.3390/cells11071228 - 5 Apr 2022
Cited by 9 | Viewed by 4659
Abstract
Insulin-degrading enzyme (IDE) is a multifunctional protease due to the variety of its substrates, its various cellular locations, its conservation between species and its many non-proteolytic functions. Numerous studies have successfully demonstrated its implication in two main therapeutic areas: metabolic and neuronal diseases. [...] Read more.
Insulin-degrading enzyme (IDE) is a multifunctional protease due to the variety of its substrates, its various cellular locations, its conservation between species and its many non-proteolytic functions. Numerous studies have successfully demonstrated its implication in two main therapeutic areas: metabolic and neuronal diseases. In recent years, several reports have underlined the overexpression of this enzyme in different cancers. Still, the exact role of IDE in the physiopathology of cancer remains to be elucidated. Known as the main enzyme responsible for the degradation of insulin, an essential growth factor for healthy cells and cancer cells, IDE has also been shown to behave like a chaperone and interact with the proteasome. The pharmacological modulation of IDE (siRNA, chemical compounds, etc.) has demonstrated interesting results in cancer models. All these results point towards IDE as a potential target in cancer. In this review, we will discuss evidence of links between IDE and cancer development or resistance, IDE’s functions, catalytic or non-catalytic, in the context of cell proliferation, cancer development and the impact of the pharmacomodulation of IDE via cancer therapeutics. Full article
(This article belongs to the Special Issue Insulin-Degrading Enzyme in Health and Disease)
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22 pages, 1484 KiB  
Systematic Review
Raman Spectroscopy as a Neuromonitoring Tool in Traumatic Brain Injury: A Systematic Review and Clinical Perspectives
by Andrew R. Stevens, Clarissa A. Stickland, Georgia Harris, Zubair Ahmed, Pola Goldberg Oppenheimer, Antonio Belli and David J. Davies
Cells 2022, 11(7), 1227; https://doi.org/10.3390/cells11071227 - 5 Apr 2022
Cited by 13 | Viewed by 3852
Abstract
Traumatic brain injury (TBI) is a significant global health problem, for which no disease-modifying therapeutics are currently available to improve survival and outcomes. Current neuromonitoring modalities are unable to reflect the complex and changing pathophysiological processes of the acute changes that occur after [...] Read more.
Traumatic brain injury (TBI) is a significant global health problem, for which no disease-modifying therapeutics are currently available to improve survival and outcomes. Current neuromonitoring modalities are unable to reflect the complex and changing pathophysiological processes of the acute changes that occur after TBI. Raman spectroscopy (RS) is a powerful, label-free, optical tool which can provide detailed biochemical data in vivo. A systematic review of the literature is presented of available evidence for the use of RS in TBI. Seven research studies met the inclusion/exclusion criteria with all studies being performed in pre-clinical models. None of the studies reported the in vivo application of RS, with spectral acquisition performed ex vivo and one performed in vitro. Four further studies were included that related to the use of RS in analogous brain injury models, and a further five utilised RS in ex vivo biofluid studies for diagnosis or monitoring of TBI. RS is identified as a potential means to identify injury severity and metabolic dysfunction which may hold translational value. In relation to the available evidence, the translational potentials and barriers are discussed. This systematic review supports the further translational development of RS in TBI to fully ascertain its potential for enhancing patient care. Full article
(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases)
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16 pages, 1340 KiB  
Review
Involvement of Oxidative Stress in Protective Cardiac Functions of Calprotectin
by Luc Rochette, Geoffrey Dogon, Eve Rigal, Marianne Zeller, Yves Cottin and Catherine Vergely
Cells 2022, 11(7), 1226; https://doi.org/10.3390/cells11071226 - 5 Apr 2022
Cited by 6 | Viewed by 3223
Abstract
Calprotectin (CLP) belonging to the S-100 protein family is a heterodimeric complex (S100A8/S100A9) formed by two binding proteins. Upon cell activation, CLP stored in neutrophils is released extracellularly in response to inflammatory stimuli and acts as damage-associated molecular patterns (DAMPs). S100A8 and S100A9 [...] Read more.
Calprotectin (CLP) belonging to the S-100 protein family is a heterodimeric complex (S100A8/S100A9) formed by two binding proteins. Upon cell activation, CLP stored in neutrophils is released extracellularly in response to inflammatory stimuli and acts as damage-associated molecular patterns (DAMPs). S100A8 and S100A9 possess both anti-inflammatory and anti-bacterial properties. The complex is a ligand of the toll-like receptor 4 (TLR4) and receptor for advanced glycation end (RAGE). At sites of infection and inflammation, CLP is a target for oxidation due to its co-localization with neutrophil-derived oxidants. In the heart, oxidative stress (OS) responses and S100 proteins are closely related and intimately linked through pathophysiological processes. Our review summarizes the roles of S100A8, S100A9 and CLP in the inflammation in relationship with vascular OS, and we examine the importance of CLP for the mechanisms driving in the protection of myocardium. Recent evidence interpreting CLP as a critical modulator during the inflammatory response has identified this alarmin as an interesting drug target. Full article
(This article belongs to the Topic Cellular Redox Homeostasis)
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15 pages, 1235 KiB  
Article
Functional Voltage-Gated Sodium Channels Are Present in the Human B Cell Membrane
by Adam Feher, Marianna Pócsi, Ferenc Papp, Tibor G. Szanto, Agota Csoti, Zsolt Fejes, Béla Nagy, Jr., Balázs Nemes and Zoltan Varga
Cells 2022, 11(7), 1225; https://doi.org/10.3390/cells11071225 - 5 Apr 2022
Viewed by 3075
Abstract
B cells express various ion channels, but the presence of voltage-gated sodium (NaV) channels has not been confirmed in the plasma membrane yet. In this study, we have identified several NaV channels, which are expressed in the human B cell [...] Read more.
B cells express various ion channels, but the presence of voltage-gated sodium (NaV) channels has not been confirmed in the plasma membrane yet. In this study, we have identified several NaV channels, which are expressed in the human B cell membrane, by electrophysiological and molecular biology methods. The sensitivity of the detected sodium current to tetrodotoxin was between the values published for TTX-sensitive and TTX-insensitive channels, which suggests the co-existence of multiple NaV1 subtypes in the B cell membrane. This was confirmed by RT-qPCR results, which showed high expression of TTX-sensitive channels along with the lower expression of TTX-insensitive NaV1 channels. The biophysical characteristics of the currents also supported the expression of multiple NaV channels. In addition, we investigated the potential functional role of NaV channels by membrane potential measurements. Removal of Na+ from the extracellular solution caused a reversible hyperpolarization, supporting the role of NaV channels in shaping and maintaining the resting membrane potential. As this study was mainly limited to electrophysiological properties, we cannot exclude the possible non-canonical functions of these channels. This work concludes that the presence of voltage-gated sodium channels in the plasma membrane of human B cells should be recognized and accounted for in the future. Full article
(This article belongs to the Section Cell Signaling)
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13 pages, 5103 KiB  
Article
Altered Spinal Homeostasis and Maladaptive Plasticity in GFAP Null Mice Following Peripheral Nerve Injury
by Ciro De Luca, Assunta Virtuoso, Sohaib Ali Korai, Raffaella Cirillo, Francesca Gargano, Michele Papa and Giovanni Cirillo
Cells 2022, 11(7), 1224; https://doi.org/10.3390/cells11071224 - 5 Apr 2022
Cited by 9 | Viewed by 2943
Abstract
The maladaptive response of the central nervous system (CNS) following nerve injury is primarily linked to the activation of glial cells (reactive gliosis) that produce an inflammatory reaction and a wide cellular morpho-structural and functional/metabolic remodeling. Glial acidic fibrillary protein (GFAP), a major [...] Read more.
The maladaptive response of the central nervous system (CNS) following nerve injury is primarily linked to the activation of glial cells (reactive gliosis) that produce an inflammatory reaction and a wide cellular morpho-structural and functional/metabolic remodeling. Glial acidic fibrillary protein (GFAP), a major protein constituent of astrocyte intermediate filaments (IFs), is the hallmark of the reactive astrocytes, has pleiotropic functions and is significantly upregulated in the spinal cord after nerve injury. Here, we investigated the specific role of GFAP in glial reaction and maladaptive spinal cord plasticity following sciatic nerve spared nerve injury (SNI) in GFAP KO and wild-type (WT) animals. We evaluated the neuropathic behavior (thermal hyperalgesia, allodynia) and the expression of glial (vimentin, Iba1) and glutamate/GABA system markers (GLAST, GLT1, EAAC1, vGLUT, vGAT, GAD) in lumbar spinal cord sections of KO/WT animals. SNI induced neuropathic behavior in both GFAP KO and WT mice, paralleled by intense microglial reaction (Iba1 expression more pronounced in KO mice), reactive astrocytosis (vimentin increase) and expression remodeling of glial/neuronal glutamate/GABA transporters. In conclusion, it is conceivable that the lack of GFAP could be detrimental to the CNS as it lacks a critical sensor for neuroinflammation and morpho-functional–metabolic rewiring after nerve injury. Understanding the maladaptive morpho-functional changes of glial cells could represent the first step for a new glial-based targeted approach for mechanisms of disease in the CNS. Full article
(This article belongs to the Special Issue Neuroplasticity of Central Nervous System in Health and Disease)
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18 pages, 5548 KiB  
Article
Drosophila as a Model of Unconventional Translation in Spinocerebellar Ataxia Type 3
by Sean L. Johnson, Matthew V. Prifti, Alyson Sujkowski, Kozeta Libohova, Jessica R. Blount, Luke Hong, Wei-Ling Tsou and Sokol V. Todi
Cells 2022, 11(7), 1223; https://doi.org/10.3390/cells11071223 - 4 Apr 2022
Cited by 11 | Viewed by 2967
Abstract
RNA toxicity contributes to diseases caused by anomalous nucleotide repeat expansions. Recent work demonstrated RNA-based toxicity from repeat-associated, non-AUG-initiated translation (RAN translation). RAN translation occurs around long nucleotide repeats that form hairpin loops, allowing for translation initiation in the absence of a start [...] Read more.
RNA toxicity contributes to diseases caused by anomalous nucleotide repeat expansions. Recent work demonstrated RNA-based toxicity from repeat-associated, non-AUG-initiated translation (RAN translation). RAN translation occurs around long nucleotide repeats that form hairpin loops, allowing for translation initiation in the absence of a start codon that results in potentially toxic, poly-amino acid repeat-containing proteins. Discovered in Spinocerebellar Ataxia Type (SCA) 8, RAN translation has been documented in several repeat-expansion diseases, including in the CAG repeat-dependent polyglutamine (polyQ) disorders. The ATXN3 gene, which causes SCA3, also known as Machado–Joseph Disease (MJD), contains a CAG repeat that is expanded in disease. ATXN3 mRNA possesses features linked to RAN translation. In this paper, we examined the potential contribution of RAN translation to SCA3/MJD in Drosophila by using isogenic lines that contain homomeric or interrupted CAG repeats. We did not observe unconventional translation in fly neurons or glia. However, our investigations indicate differential toxicity from ATXN3 protein-encoding mRNA that contains pure versus interrupted CAG repeats. Additional work suggests that this difference may be due in part to toxicity from homomeric CAG mRNA. We conclude that Drosophila is not suitable to model RAN translation for SCA3/MJD, but offers clues into the potential pathogenesis stemming from CAG repeat-containing mRNA in this disorder. Full article
(This article belongs to the Collection Spinocerebellar Ataxia (SCA): Molecular Mechanisms and Novel Treatment Strategies)
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21 pages, 2016 KiB  
Review
Senotherapeutics in Cancer and HIV
by Laura Sánchez-Díaz, Asunción Espinosa-Sánchez, José-Ramón Blanco and Amancio Carnero
Cells 2022, 11(7), 1222; https://doi.org/10.3390/cells11071222 - 4 Apr 2022
Cited by 10 | Viewed by 5240
Abstract
Cellular senescence is a stress-response mechanism that contributes to homeostasis maintenance, playing a beneficial role during embryogenesis and in normal adult organisms. In contrast, chronic senescence activation may be responsible for other events such as age-related disorders, HIV and cancer development. Cellular senescence [...] Read more.
Cellular senescence is a stress-response mechanism that contributes to homeostasis maintenance, playing a beneficial role during embryogenesis and in normal adult organisms. In contrast, chronic senescence activation may be responsible for other events such as age-related disorders, HIV and cancer development. Cellular senescence activation can be triggered by different insults. Regardless of the inducer, there are several phenotypes generally shared among senescent cells: cell division arrest, an aberrant shape, increased size, high granularity because of increased numbers of lysosomes and vacuoles, apoptosis resistance, defective metabolism and some chromatin alterations. Senescent cells constitute an important area for research due to their contributions to the pathogenesis of different diseases such as frailty, sarcopenia and aging-related diseases, including cancer and HIV infection, which show an accelerated aging. Hence, a new pharmacological category of treatments called senotherapeutics is under development. This group includes senolytic drugs that selectively attack senescent cells and senostatic drugs that suppress SASP factor delivery, inhibiting senescent cell development. These new drugs can have positive therapeutic effects on aging-related disorders and act in cancer as antitumor drugs, avoiding the undesired effects of senescent cells such as those from SASP. Here, we review senotherapeutics and how they might affect cancer and HIV disease, two very different aging-related diseases, and review some compounds acting as senolytics in clinical trials. Full article
(This article belongs to the Special Issue HIV and Host Interactions)
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15 pages, 1450 KiB  
Review
Necroptosis and Prostate Cancer: Molecular Mechanisms and Therapeutic Potential
by Giovanni Luca Beretta and Nadia Zaffaroni
Cells 2022, 11(7), 1221; https://doi.org/10.3390/cells11071221 - 4 Apr 2022
Cited by 20 | Viewed by 3910
Abstract
Necroptosis is a programmed form of necrosis characterized by mitochondrial alterations and plasma membrane permeabilization resulting in the release of cytoplasmic content into extracellular space, and leading to inflammatory reactions. Besides its critical role in viral defense mechanisms and inflammatory diseases, necroptosis plays [...] Read more.
Necroptosis is a programmed form of necrosis characterized by mitochondrial alterations and plasma membrane permeabilization resulting in the release of cytoplasmic content into extracellular space, and leading to inflammatory reactions. Besides its critical role in viral defense mechanisms and inflammatory diseases, necroptosis plays pivotal functions in the drug response of tumors, including prostate cancer. Necroptosis is mainly governed by kinase enzymes, including RIP1, RIP3, and MLKL, and conversely to apoptosis, is a caspase-independent mechanism of cell death. Numerous compounds induce necroptosis in prostate cancer models, including (i) compounds of natural origin, (ii) synthetic and semisynthetic small molecules, and (iii) selenium and selenium-based nanoparticles. Here, we overview the molecular mechanisms underlying necroptosis and discuss the possible implications of drugs inducing necroptosis for prostate cancer therapy. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Prostate Cancer)
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