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Cells, Volume 11, Issue 8 (April-2 2022) – 124 articles

Cover Story (view full-size image): Hypoxic stress upregulates genes essential for angiogenesis, such as VEGF-A. Concomitantly with VEGF-A expression, a long isoform called L-VEGF is expressed. Once translated, L-VEGF is proteolytically cleaved to generate N-VEGF and VEGF-A. While VEGF-A is secreted and stimulates angiogenesis in surrounding cells, N-VEGF is mobilized to the nucleus, and its function is unknown. In this study, we found that the mere expression of N-VEGF followed by its hypoxia-independent mobilization to the nucleus was sufficient to induce key angiogenic genes, such as Hif1α and VEGF-A isoforms, as well as genes associated with cell survival under hypoxia. When N-VEGF was genetically depleted, key hypoxia-induced genes were downregulated, and cells were significantly susceptible to hypoxia-mediated apoptosis. View this paper.
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18 pages, 1180 KiB  
Review
Key Signaling in Alcohol-Associated Liver Disease: The Role of Bile Acids
by Grayson W. Way, Kaitlyn G. Jackson, Shreya R. Muscu and Huiping Zhou
Cells 2022, 11(8), 1374; https://doi.org/10.3390/cells11081374 - 18 Apr 2022
Cited by 12 | Viewed by 15593
Abstract
Alcohol-associated liver disease (ALD) is a spectrum of diseases, the onset and progression of which are due to chronic alcohol use. ALD ranges, by increasing severity, from hepatic steatosis to alcoholic hepatitis (AH) and alcohol-associated cirrhosis (AC), and in some cases, can lead [...] Read more.
Alcohol-associated liver disease (ALD) is a spectrum of diseases, the onset and progression of which are due to chronic alcohol use. ALD ranges, by increasing severity, from hepatic steatosis to alcoholic hepatitis (AH) and alcohol-associated cirrhosis (AC), and in some cases, can lead to the development of hepatocellular carcinoma (HCC). ALD continues to be a significant health burden and is now the main cause of liver transplantations in the United States. ALD leads to biological, microbial, physical, metabolic, and inflammatory changes in patients that vary depending on disease severity. ALD deaths have been increasing in recent years and are projected to continue to increase. Current treatment centers focus on abstinence and symptom management, with little in the way of resolving disease progression. Due to the metabolic disruption and gut dysbiosis in ALD, bile acid (BA) signaling and metabolism are also notably affected and play a prominent role in disease progression in ALD, as well as other liver disease states, such as non-alcoholic fatty liver disease (NAFLD). In this review, we summarize the recent advances in the understanding of the mechanisms by which alcohol consumption induces hepatic injury and the role of BA-mediated signaling in the pathogenesis of ALD. Full article
(This article belongs to the Special Issue New Aspects and Mechanisms in Liver Diseases)
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23 pages, 4434 KiB  
Article
Incomplete Recovery of Zebrafish Retina Following Cryoinjury
by Denisa Džulová, Dylan Lawless, Gaëtan G. Pinton, Nicole A. Renner and Daniel F. Schorderet
Cells 2022, 11(8), 1373; https://doi.org/10.3390/cells11081373 - 18 Apr 2022
Cited by 1 | Viewed by 2667
Abstract
Zebrafish show an extraordinary potential for regeneration in several organs from fins to central nervous system. Most impressively, the outcome of an injury results in a near perfect regeneration and a full functional recovery. Indeed, among the various injury paradigms previously tested in [...] Read more.
Zebrafish show an extraordinary potential for regeneration in several organs from fins to central nervous system. Most impressively, the outcome of an injury results in a near perfect regeneration and a full functional recovery. Indeed, among the various injury paradigms previously tested in the field of zebrafish retina regeneration, a perfect layered structure is observed after one month of recovery in most of the reported cases. In this study, we applied cryoinjury to the zebrafish eye. We show that retina exposed to this treatment for one second undergoes an acute damage affecting all retinal cell types, followed by a phase of limited tissue remodeling and regrowth. Surprisingly, zebrafish developed a persistent retinal dysplasia observable through 300 days post-injury. There is no indication of fibrosis during the regeneration period, contrary to the regeneration process after cryoinjury to the zebrafish cardiac ventricle. RNA sequencing analysis of injured retinas at different time points has uncovered enriched processes and a number of potential candidate genes. By means of this simple, time and cost-effective technique, we propose a zebrafish injury model that displays a unique inability to completely recover following focal retinal damage; an outcome that is unreported to our knowledge. Furthermore, RNA sequencing proved to be useful in identifying pathways, which may play a crucial role not only in the regeneration of the retina, but in the first initial step of regeneration, degeneration. We propose that this model may prove useful in comparative and translational studies to examine critical pathways for successful regeneration. Full article
(This article belongs to the Special Issue Neurogenesis and Regeneration in Teleost Central Nervous System)
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27 pages, 886 KiB  
Review
The Role of Amino Acids in Endothelial Biology and Function
by Meng Li, Yanqing Wu and Lei Ye
Cells 2022, 11(8), 1372; https://doi.org/10.3390/cells11081372 - 18 Apr 2022
Cited by 17 | Viewed by 4254
Abstract
The vascular endothelium acts as an important component of the vascular system. It is a barrier between the blood and vessel wall. It plays an important role in regulating blood vessel tone, permeability, angiogenesis, and platelet functions. Several studies have shown that amino [...] Read more.
The vascular endothelium acts as an important component of the vascular system. It is a barrier between the blood and vessel wall. It plays an important role in regulating blood vessel tone, permeability, angiogenesis, and platelet functions. Several studies have shown that amino acids (AA) are key regulators in maintaining vascular homeostasis by modulating endothelial cell (EC) proliferation, migration, survival, and function. This review summarizes the metabolic and signaling pathways of AAs in ECs and discusses the importance of AA homeostasis in the functioning of ECs and vascular homeostasis. It also discusses the challenges in understanding the role of AA in the development of cardiovascular pathophysiology and possible directions for future research. Full article
(This article belongs to the Special Issue Cell-Based Therapy of Cardiovascular Diseases)
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12 pages, 1408 KiB  
Article
Genetic Variations and mRNA Expression of Goat DNAH1 and Their Associations with Litter Size
by Zhen Wang, Ruolan Wang, Chuanying Pan, Hong Chen, Lei Qu, Lian Wu, Zhengang Guo, Haijing Zhu and Xianyong Lan
Cells 2022, 11(8), 1371; https://doi.org/10.3390/cells11081371 - 18 Apr 2022
Cited by 7 | Viewed by 2242
Abstract
Dynein Axonemal Heavy Chain 1 (DNAH1) encodes proteins which provide structural support for the physiological function and motor structure of spermatozoa (hereafter referred to as sperm) and ova. This study found that three single nucleotide polymorphisms (SNPs), the 27-bp insertion/deletion (InDel) [...] Read more.
Dynein Axonemal Heavy Chain 1 (DNAH1) encodes proteins which provide structural support for the physiological function and motor structure of spermatozoa (hereafter referred to as sperm) and ova. This study found that three single nucleotide polymorphisms (SNPs), the 27-bp insertion/deletion (InDel) mutations and three exonic copy number variations (CNVs) within DNAH1 were significantly associated with litter size of Shaanbei white cashmere goats (n = 1101). Goats with the wildtypes of these three SNPs had higher litter sizes than other carriers (p < 0.05). II genotype of the 27-bp InDel had the highest litter size compared with ID carriers (p = 0.000022). The gain genotype had the largest litter sizes compared with the loss or medium carriers for the three CNV mutations (p < 0.01). Individuals with the AA-TT-CC-II-M1-M2-M3 and AA-TT-CC-II-G1-G2-M3 combination genotypes had larger litter sizes compared with the other genotypes. This study also showed the DNAH1 expression in mothers of multiple kids was higher than mothers of single kids. These three SNPs, the 27-bp InDel and three CNVs in DNAH1 could be used as molecular markers for the selection of goat reproductive traits. Full article
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21 pages, 1811 KiB  
Review
Genomic Hippo Pathway Alterations and Persistent YAP/TAZ Activation: New Hallmarks in Head and Neck Cancer
by Farhoud Faraji, Sydney I. Ramirez, Paola Y. Anguiano Quiroz, Amaya N. Mendez-Molina and J. Silvio Gutkind
Cells 2022, 11(8), 1370; https://doi.org/10.3390/cells11081370 - 18 Apr 2022
Cited by 15 | Viewed by 4905
Abstract
Head and neck squamous cell carcinoma (HNSCC) represents a highly prevalent and deadly malignancy worldwide. The prognosis for locoregionally advanced HNSCC has not appreciably improved over the past 30 years despite advances in surgical, radiation, and targeted therapies and less than 20% of [...] Read more.
Head and neck squamous cell carcinoma (HNSCC) represents a highly prevalent and deadly malignancy worldwide. The prognosis for locoregionally advanced HNSCC has not appreciably improved over the past 30 years despite advances in surgical, radiation, and targeted therapies and less than 20% of HNSCC patients respond to recently approved immune checkpoint inhibitors. The Hippo signaling pathway, originally discovered as a mechanism regulating tissue growth and organ size, transduces intracellular and extracellular signals to regulate the transcriptional co-activators YAP and TAZ. Alterations in the Hippo pathway resulting in persistent YAP and TAZ activation have emerged as major oncogenic drivers. Our analysis of the human HNSCC oncogenome revealed multiple genomic alterations impairing Hippo signaling and activating YAP and TAZ, which in turn contribute to HNSCC development. This includes mutations and deletions of the FAT1 gene (29%) and amplification of the WWTR1 (encoding TAZ, 14%) and YAP1 genes (8%), together representing one of the most genetically altered signaling mechanisms in this malignancy. Here, we discuss key elements of the mammalian Hippo pathway, detail mechanisms by which perturbations in Hippo signaling promote HNSCC initiation and progression and outline emerging strategies to target Hippo signaling vulnerabilities as part of novel multimodal precision therapies for HNSCC. Full article
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19 pages, 3603 KiB  
Article
Taste Cells of the Type III Employ CASR to Maintain Steady Serotonin Exocytosis at Variable Ca2+ in the Extracellular Medium
by Aleksandr P. Cherkashin, Olga A. Rogachevskaja, Natalia V. Kabanova, Polina D. Kotova, Marina F. Bystrova and Stanislav S. Kolesnikov
Cells 2022, 11(8), 1369; https://doi.org/10.3390/cells11081369 - 18 Apr 2022
Cited by 4 | Viewed by 2198
Abstract
Type III taste cells are the only taste bud cells which express voltage-gated (VG) Ca2+ channels and employ Ca2+-dependent exocytosis to release neurotransmitters, particularly serotonin. The taste bud is a tightly packed cell population, wherein extracellular Ca2+ is expected [...] Read more.
Type III taste cells are the only taste bud cells which express voltage-gated (VG) Ca2+ channels and employ Ca2+-dependent exocytosis to release neurotransmitters, particularly serotonin. The taste bud is a tightly packed cell population, wherein extracellular Ca2+ is expected to fluctuate markedly due to the electrical activity of taste cells. It is currently unclear whether the Ca2+ entry-driven synapse in type III cells could be reliable enough at unsteady extracellular Ca2. Here we assayed depolarization-induced Ca2+ signals and associated serotonin release in isolated type III cells at varied extracellular Ca2+. It turned out that the same depolarizing stimulus elicited invariant Ca2+ signals in type III cells irrespective of bath Ca2+ varied within 0.5–5 mM. The serotonin release from type III cells was assayed with the biosensor approach by using HEK-293 cells co-expressing the recombinant 5-HT4 receptor and genetically encoded cAMP sensor Pink Flamindo. Consistently with the weak Ca2+ dependence of intracellular Ca2+ transients produced by VG Ca2+ entry, depolarization-triggered serotonin secretion varied negligibly with bath Ca2+. The evidence implicated the extracellular Ca2+-sensing receptor in mediating the negative feedback mechanism that regulates VG Ca2+ entry and levels off serotonin release in type III cells at deviating Ca2+ in the extracellular medium. Full article
(This article belongs to the Special Issue Advances in Calcium Signaling)
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19 pages, 1811 KiB  
Review
Chromosome Territories in Hematological Malignancies
by Matheus Fabiao de Lima, Mateus de Oliveira Lisboa, Lucas E. L. Terceiro, Aline Rangel-Pozzo and Sabine Mai
Cells 2022, 11(8), 1368; https://doi.org/10.3390/cells11081368 - 17 Apr 2022
Cited by 2 | Viewed by 2987
Abstract
Chromosomes are organized in distinct nuclear areas designated as chromosome territories (CT). The structural formation of CT is a consequence of chromatin packaging and organization that ultimately affects cell function. Chromosome positioning can identify structural signatures of genomic organization, especially for diseases where [...] Read more.
Chromosomes are organized in distinct nuclear areas designated as chromosome territories (CT). The structural formation of CT is a consequence of chromatin packaging and organization that ultimately affects cell function. Chromosome positioning can identify structural signatures of genomic organization, especially for diseases where changes in gene expression contribute to a given phenotype. The study of CT in hematological diseases revealed chromosome position as an important factor for specific chromosome translocations. In this review, we highlight the history of CT theory, current knowledge on possible clinical applications of CT analysis, and the impact of CT in the development of hematological neoplasia such as multiple myeloma, leukemia, and lymphomas. Accumulating data on nuclear architecture in cancer allow one to propose the three-dimensional nuclear genomic landscape as a novel cancer biomarker for the future. Full article
(This article belongs to the Special Issue Regulation of Nuclear Organization and Function)
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42 pages, 1307 KiB  
Review
Blood-Based Biomarkers for Alzheimer’s Disease Diagnosis and Progression: An Overview
by Angelica Varesi, Adelaide Carrara, Vitor Gomes Pires, Valentina Floris, Elisa Pierella, Gabriele Savioli, Sakshi Prasad, Ciro Esposito, Giovanni Ricevuti, Salvatore Chirumbolo and Alessia Pascale
Cells 2022, 11(8), 1367; https://doi.org/10.3390/cells11081367 - 17 Apr 2022
Cited by 36 | Viewed by 9299
Abstract
Alzheimer’s Disease (AD) is a progressive neurodegenerative disease characterized by amyloid-β (Aβ) plaque deposition and neurofibrillary tangle accumulation in the brain. Although several studies have been conducted to unravel the complex and interconnected pathophysiology of AD, clinical trial failure rates have been high, [...] Read more.
Alzheimer’s Disease (AD) is a progressive neurodegenerative disease characterized by amyloid-β (Aβ) plaque deposition and neurofibrillary tangle accumulation in the brain. Although several studies have been conducted to unravel the complex and interconnected pathophysiology of AD, clinical trial failure rates have been high, and no disease-modifying therapies are presently available. Fluid biomarker discovery for AD is a rapidly expanding field of research aimed at anticipating disease diagnosis and following disease progression over time. Currently, Aβ1–42, phosphorylated tau, and total tau levels in the cerebrospinal fluid are the best-studied fluid biomarkers for AD, but the need for novel, cheap, less-invasive, easily detectable, and more-accessible markers has recently led to the search for new blood-based molecules. However, despite considerable research activity, a comprehensive and up-to-date overview of the main blood-based biomarker candidates is still lacking. In this narrative review, we discuss the role of proteins, lipids, metabolites, oxidative-stress-related molecules, and cytokines as possible disease biomarkers. Furthermore, we highlight the potential of the emerging miRNAs and long non-coding RNAs (lncRNAs) as diagnostic tools, and we briefly present the role of vitamins and gut-microbiome-related molecules as novel candidates for AD detection and monitoring, thus offering new insights into the diagnosis and progression of this devastating disease. Full article
(This article belongs to the Special Issue Biomarkers of Alzheimer’s Disease: New Insights)
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13 pages, 2053 KiB  
Article
Tet1 Suppresses p21 to Ensure Proper Cell Cycle Progression in Embryonic Stem Cells
by Stephanie Chrysanthou, Julio C. Flores and Meelad M. Dawlaty
Cells 2022, 11(8), 1366; https://doi.org/10.3390/cells11081366 - 17 Apr 2022
Cited by 10 | Viewed by 2778
Abstract
Ten eleven translocation 1 (Tet1) is a DNA dioxygenase that promotes DNA demethylation by oxidizing 5-methylcytosine. It can also partner with chromatin-activating and repressive complexes to regulate gene expressions independent of its enzymatic activity. Tet1 is highly expressed in embryonic stem cells (ESCs) [...] Read more.
Ten eleven translocation 1 (Tet1) is a DNA dioxygenase that promotes DNA demethylation by oxidizing 5-methylcytosine. It can also partner with chromatin-activating and repressive complexes to regulate gene expressions independent of its enzymatic activity. Tet1 is highly expressed in embryonic stem cells (ESCs) and regulates pluripotency and differentiation. However, its roles in ESC cell cycle progression and proliferation have not been investigated. Using a series of Tet1 catalytic mutant (Tet1m/m), knockout (Tet1−/−) and wild type (Tet1+/+) mouse ESCs (mESCs), we identified a non-catalytic role of Tet1 in the proper cell cycle progression and proliferation of mESCs. Tet1−/−, but not Tet1m/m, mESCs exhibited a significant reduction in proliferation and delayed progression through G1. We found that the cyclin-dependent kinase inhibitor p21/Cdkn1a was uniquely upregulated in Tet1−/− mESCs and its knockdown corrected the slow proliferation and delayed G1 progression. Mechanistically, we found that p21 was a direct target of Tet1. Tet1 occupancy at the p21 promoter overlapped with the repressive histone mark H3K27me3 as well as with the H3K27 trimethyl transferase PRC2 component Ezh2. A loss of Tet1, but not loss of its catalytic activity, significantly reduced the enrichment of Ezh2 and H3K27 trimethylation at the p21 promoter without affecting the DNA methylation levels. We also found that the proliferation defects of Tet1−/− mESCs were independent of their differentiation defects. Together, these findings established a non-catalytic role for Tet1 in suppressing p21 in mESCs to ensure a rapid G1-to-S progression, which is a key hallmark of ESC proliferation. It also established Tet1 as an epigenetic regulator of ESC proliferation in addition to its previously defined roles in ESC pluripotency and differentiation. Full article
(This article belongs to the Special Issue Feature Papers in Stem Cells)
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11 pages, 279 KiB  
Review
Squamous Cell Carcinoma in Patients with Inherited Epidermolysis Bullosa: Review of Current Literature
by Domenico Bonamonte, Angela Filoni, Aurora De Marco, Lucia Lospalluti, Eleonora Nacchiero, Valentina Ronghi, Anna Colagrande, Giuseppe Giudice and Gerardo Cazzato
Cells 2022, 11(8), 1365; https://doi.org/10.3390/cells11081365 - 17 Apr 2022
Cited by 10 | Viewed by 2642
Abstract
Epidermolysis bullosa (EB) is a group of rare congenital diseases caused by mutations in structural proteins of the dermal/epidermal junction that are characterized by extreme epithelial fragility, which determines the formation of bullae and erosions either spontaneously or after local mechanical traumas. In [...] Read more.
Epidermolysis bullosa (EB) is a group of rare congenital diseases caused by mutations in structural proteins of the dermal/epidermal junction that are characterized by extreme epithelial fragility, which determines the formation of bullae and erosions either spontaneously or after local mechanical traumas. In EB patients, skin fragility leads to many possible complications and comorbidities. One of the most feared complications is the development of cutaneous squamous cell carcinomas (SCCs) that particularly in the dystrophic recessive EB subtype can be extremely aggressive and often metastatic. SCCs in EB patients generally arise more often in the extremities, where chronic blisters and scars are generally located. SCCs represent a big therapeutic challenge in the EB population. No standard of care exists for the treatment of SCC in these patients, and therapy is based on small case studies. Moreover, the pathogenesis of cSCC in EB patients is still unclear. Many theories have been indeed postulated in order to explain why cSCC behaves so much more aggressively in EB patients compared to the general population. cSCC in EB seems to be the result of many complex interactions among cancer cells, skin microenvironment, susceptibility to DNA mutations and host immune response. In this review, we analyze the different pathogenetic mechanisms of cSCC in EB patients, as well as new therapies for this condition. Full article
(This article belongs to the Special Issue Molecular and Cell Basis of Skin Diseases and Aging)
24 pages, 5603 KiB  
Article
Cysteine-Rich LIM-Only Protein 4 (CRP4) Promotes Atherogenesis in the ApoE−/− Mouse Model
by Natalie Längst, Julia Adler, Anna Kuret, Andreas Peter, Peter Ruth, Karsten Boldt and Robert Lukowski
Cells 2022, 11(8), 1364; https://doi.org/10.3390/cells11081364 - 17 Apr 2022
Cited by 4 | Viewed by 2773
Abstract
Vascular smooth muscle cells (VSMCs) can switch from their contractile state to a synthetic phenotype resulting in high migratory and proliferative capacity and driving atherosclerotic lesion formation. The cysteine-rich LIM-only protein 4 (CRP4) reportedly modulates VSM-like transcriptional signatures, which are perturbed in VSMCs [...] Read more.
Vascular smooth muscle cells (VSMCs) can switch from their contractile state to a synthetic phenotype resulting in high migratory and proliferative capacity and driving atherosclerotic lesion formation. The cysteine-rich LIM-only protein 4 (CRP4) reportedly modulates VSM-like transcriptional signatures, which are perturbed in VSMCs undergoing phenotypic switching. Thus, we hypothesized that CRP4 contributes to adverse VSMC behaviours and thereby to atherogenesis in vivo. The atherogenic properties of CRP4 were investigated in plaque-prone apolipoprotein E (ApoE) and CRP4 double-knockout (dKO) as well as ApoE-deficient CRP4 wildtype mice. dKO mice exhibited lower plaque numbers and lesion areas as well as a reduced content of α-smooth muscle actin positive cells in the lesion area, while lesion-associated cell proliferation was elevated in vessels lacking CRP4. Reduced plaque volumes in dKO correlated with significantly less intra-plaque oxidized low-density lipoprotein (oxLDL), presumably due to upregulation of the antioxidant factor peroxiredoxin-4 (PRDX4). This study identifies CRP4 as a novel pro-atherogenic factor that facilitates plaque oxLDL deposition and identifies the invasion of atherosclerotic lesions by VSMCs as important determinants of plaque vulnerability. Thus, targeting of VSMC CRP4 should be considered in plaque-stabilizing pharmacological strategies. Full article
(This article belongs to the Special Issue Altered Cellular Communication in Cardiac Diseases)
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27 pages, 5456 KiB  
Article
Organismal and Cellular Stress Responses upon Disruption of Mitochondrial Lonp1 Protease
by Eirini Taouktsi, Eleni Kyriakou, Stefanos Smyrniotis, Fivos Borbolis, Labrina Bondi, Socratis Avgeris, Efstathios Trigazis, Stamatis Rigas, Gerassimos E. Voutsinas and Popi Syntichaki
Cells 2022, 11(8), 1363; https://doi.org/10.3390/cells11081363 - 16 Apr 2022
Cited by 8 | Viewed by 3844
Abstract
Cells engage complex surveillance mechanisms to maintain mitochondrial function and protein homeostasis. LonP1 protease is a key component of mitochondrial quality control and has been implicated in human malignancies and other pathological disorders. Here, we employed two experimental systems, the worm Caenorhabditis elegans [...] Read more.
Cells engage complex surveillance mechanisms to maintain mitochondrial function and protein homeostasis. LonP1 protease is a key component of mitochondrial quality control and has been implicated in human malignancies and other pathological disorders. Here, we employed two experimental systems, the worm Caenorhabditis elegans and human cancer cells, to investigate and compare the effects of LONP-1/LonP1 deficiency at the molecular, cellular, and organismal levels. Deletion of the lonp-1 gene in worms disturbed mitochondrial function, provoked reactive oxygen species accumulation, and impaired normal processes, such as growth, behavior, and lifespan. The viability of lonp-1 mutants was dependent on the activity of the ATFS-1 transcription factor, and loss of LONP-1 evoked retrograde signaling that involved both the mitochondrial and cytoplasmic unfolded protein response (UPRmt and UPRcyt) pathways and ensuing diverse organismal stress responses. Exposure of worms to triterpenoid CDDO-Me, an inhibitor of human LonP1, stimulated only UPRcyt responses. In cancer cells, CDDO-Me induced key components of the integrated stress response (ISR), the UPRmt and UPRcyt pathways, and the redox machinery. However, genetic knockdown of LonP1 revealed a genotype-specific cellular response and induced apoptosis similar to CDDO-Me treatment. Overall, the mitochondrial dysfunction ensued by disruption of LonP1 elicits adaptive cytoprotective mechanisms that can inhibit cancer cell survival but diversely modulate organismal stress response and aging. Full article
(This article belongs to the Section Mitochondria)
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27 pages, 2056 KiB  
Review
Mechanistic Insights into the Link between Gut Dysbiosis and Major Depression: An Extensive Review
by Sharma Sonali, Bipul Ray, Hediyal Ahmed Tousif, Annan Gopinath Rathipriya, Tuladhar Sunanda, Arehally M. Mahalakshmi, Wiramon Rungratanawanich, Musthafa Mohamed Essa, M. Walid Qoronfleh, Saravana Babu Chidambaram and Byoung-Joon Song
Cells 2022, 11(8), 1362; https://doi.org/10.3390/cells11081362 - 16 Apr 2022
Cited by 46 | Viewed by 9561
Abstract
Depression is a highly common mental disorder, which is often multifactorial with sex, genetic, environmental, and/or psychological causes. Recent advancements in biomedical research have demonstrated a clear correlation between gut dysbiosis (GD) or gut microbial dysbiosis and the development of anxiety or depressive [...] Read more.
Depression is a highly common mental disorder, which is often multifactorial with sex, genetic, environmental, and/or psychological causes. Recent advancements in biomedical research have demonstrated a clear correlation between gut dysbiosis (GD) or gut microbial dysbiosis and the development of anxiety or depressive behaviors. The gut microbiome communicates with the brain through the neural, immune, and metabolic pathways, either directly (via vagal nerves) or indirectly (via gut- and microbial-derived metabolites as well as gut hormones and endocrine peptides, including peptide YY, pancreatic polypeptide, neuropeptide Y, cholecystokinin, corticotropin-releasing factor, glucagon-like peptide, oxytocin, and ghrelin). Maintaining healthy gut microbiota (GM) is now being recognized as important for brain health through the use of probiotics, prebiotics, synbiotics, fecal microbial transplantation (FMT), etc. A few approaches exert antidepressant effects via restoring GM and hypothalamus–pituitary–adrenal (HPA) axis functions. In this review, we have summarized the etiopathogenic link between gut dysbiosis and depression with preclinical and clinical evidence. In addition, we have collated information on the recent therapies and supplements, such as probiotics, prebiotics, short-chain fatty acids, and vitamin B12, omega-3 fatty acids, etc., which target the gut–brain axis (GBA) for the effective management of depressive behavior and anxiety. Full article
(This article belongs to the Special Issue Gut Microbiota in Nutrition and Health)
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12 pages, 3593 KiB  
Article
Verteporfin Inhibits the Progression of Spontaneous Osteosarcoma Caused by Trp53 and Rb1 Deficiency in Ctsk-Expressing Cells via Impeding Hippo Pathway
by Yang Li, Shuting Yang and Shuying Yang
Cells 2022, 11(8), 1361; https://doi.org/10.3390/cells11081361 - 16 Apr 2022
Cited by 11 | Viewed by 2720
Abstract
Osteosarcoma is the most common primary malignancy of bone in children and adolescents. Others and our previous studies have shown that Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) as core components of the Hippo pathway are crucial regulators of osteosarcoma formation and [...] Read more.
Osteosarcoma is the most common primary malignancy of bone in children and adolescents. Others and our previous studies have shown that Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) as core components of the Hippo pathway are crucial regulators of osteosarcoma formation and progression. Recent studies demonstrated that verteporfin (VP) is an inhibitor of YAP/TAZ signaling in xenograft osteosarcoma. However, whether VP can inhibit primary osteosarcoma in mice is unknown. Mutations of Trp53 and Rb1 occur in approximately 50~70% of human osteosarcoma. In this study, we successfully generated the Ctsk-Cre;Trp53f/f/Rb1f/f mice in which Trp53/Rb1 was ablated in Ctsk-expressing cells and found that Ctsk-Cre;Trp53f/f/Rb1f/f mice spontaneously developed osteosarcoma with increased expansive osteoid lesions in the cortical bone with aging. Loss of Trp53/Rb1 in Ctsk-expressing cells significantly promoted the expression and nuclear translocation of YAP/TAZ. Micro-CT results showed that inhibition of YAP/TAZ by VP delays osteosarcoma progression and protected against bone erosion in Ctsk-Cre;Trp53f/f/Rb1f/f mice. Importantly, the Kaplan–Meier survival curves displayed a significantly longer survival rate after VP treatment in Ctsk-Cre;Trp53f/f/Rb1f/f mice compared to non-injected groups. In vitro studies further showed that VP inhibited the proliferation, migration and invasion in Trp53/Rb1-mutant Ctsk-expressing cells. Moreover, the results from promoter luciferase activity analysis showed that the transcriptional activity of YAP/TAZ was significantly increased in osteosarcoma tissue from Ctsk-Cre;Trp53f/f/Rb1f/f mice, which was attenuated by VP treatment. Overall, these findings suggest that targeting Hippo pathway by VP may be a potential therapeutic strategy for osteosarcoma. Full article
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16 pages, 4369 KiB  
Article
Integrin-Mediated Adhesion Promotes Centrosome Separation in Early Mitosis
by Siamak A. Kamranvar, Deepesh Kumar Gupta, Anishia Wasberg, Liangwen Liu, Joan Roig and Staffan Johansson
Cells 2022, 11(8), 1360; https://doi.org/10.3390/cells11081360 - 16 Apr 2022
Cited by 7 | Viewed by 3040
Abstract
Integrin-mediated adhesion to the extracellular matrix is a key regulator of the cell cycle, as demonstrated for the passage of the G1/S checkpoint and the completion of cytokinetic abscission. Here, integrin-dependent regulation of the cell cycle in G2 and early M phases was [...] Read more.
Integrin-mediated adhesion to the extracellular matrix is a key regulator of the cell cycle, as demonstrated for the passage of the G1/S checkpoint and the completion of cytokinetic abscission. Here, integrin-dependent regulation of the cell cycle in G2 and early M phases was investigated. The progression through the G2 and M phases was monitored by live-cell imaging and immunofluorescence staining in adherent and non-adherent fibroblast cells. Non-adherent cells, as well as adherent cells lacking FAK activity due to suppressed expression or pharmacological inhibition, exhibited a prolonged G2 phase and severely defect centrosome separation, resulting in delayed progress through the early mitotic stages. The activation of the critical mitotic regulator PLK1 and its indirect target Eg5, a kinesin-family motor protein driving the centrosome separation, were reduced in the cells lacking FAK activity. Furthermore, the absence of integrin adhesion or FAK activity destabilized the structural integrity of centrosomes and often caused detachment of pericentriolar material from the centrioles. These data identify a novel adhesion-dependent mechanism by which integrins via FAK and PLK1 contribute to the regulation of the cell cycle in the G2 and early M phases, and to the maintenance of genome integrity. Full article
(This article belongs to the Section Cell Motility and Adhesion)
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9 pages, 1202 KiB  
Review
Autophagy in Rheumatic Diseases: Role in the Pathogenesis and Therapeutic Approaches
by Alessandra Ida Celia, Serena Colafrancesco, Cristiana Barbati, Cristiano Alessandri and Fabrizio Conti
Cells 2022, 11(8), 1359; https://doi.org/10.3390/cells11081359 - 15 Apr 2022
Cited by 13 | Viewed by 2999
Abstract
Autophagy is a lysosomal pathway for the degradation of damaged proteins and intracellular components that promotes cell survival under specific conditions. Apoptosis is, in contrast, a critical programmed cell death mechanism, and the relationship between these two processes influences cell fate. Recent evidence [...] Read more.
Autophagy is a lysosomal pathway for the degradation of damaged proteins and intracellular components that promotes cell survival under specific conditions. Apoptosis is, in contrast, a critical programmed cell death mechanism, and the relationship between these two processes influences cell fate. Recent evidence suggests that autophagy and apoptosis are involved in the self-tolerance promotion and in the regulatory mechanisms contributing to disease susceptibility and immune regulation in rheumatic diseases. The aim of this review is to discuss how the balance between autophagy and apoptosis may be dysregulated in multiple rheumatic diseases and to dissect the role of autophagy in the pathogenesis of rheumatoid arthritis, systemic lupus erythematosus, and Sjögren’s syndrome. Furthermore, to discuss the potential capacity of currently used disease-modifying antirheumatic drugs (DMARDs) to target and modulate autophagic processes. Full article
(This article belongs to the Special Issue Crosstalk of Autophagy and Apoptosis)
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14 pages, 1848 KiB  
Review
Ubiquitin Proteasome System and Microtubules Are Master Regulators of Central and Peripheral Nervous System Axon Degeneration
by Daniele Cartelli, Guido Cavaletti, Giuseppe Lauria and Cristina Meregalli
Cells 2022, 11(8), 1358; https://doi.org/10.3390/cells11081358 - 15 Apr 2022
Cited by 4 | Viewed by 2938
Abstract
Axonal degeneration is an active process that differs from neuronal death, and it is the hallmark of many disorders affecting the central and peripheral nervous system. Starting from the analyses of Wallerian degeneration, the simplest experimental model, here we describe how the long [...] Read more.
Axonal degeneration is an active process that differs from neuronal death, and it is the hallmark of many disorders affecting the central and peripheral nervous system. Starting from the analyses of Wallerian degeneration, the simplest experimental model, here we describe how the long projecting neuronal populations affected in Parkinson’s disease and chemotherapy-induced peripheral neuropathies share commonalities in the mechanisms and molecular players driving the earliest phase of axon degeneration. Indeed, both dopaminergic and sensory neurons are particularly susceptible to alterations of microtubules and axonal transport as well as to dysfunctions of the ubiquitin proteasome system and protein quality control. Finally, we report an updated review on current knowledge of key molecules able to modulate these targets, blocking the on-going axonal degeneration and inducing neuronal regeneration. These molecules might represent good candidates for disease-modifying treatment, which might expand the window of intervention improving patients’ quality of life. Full article
(This article belongs to the Special Issue The Cytoskeleton: Structural, Functional, and Pathological Aspects)
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17 pages, 2381 KiB  
Article
Rank-Rankl-Opg Axis in Multiple Sclerosis: The Contribution of Placenta
by Sofia Passaponti, Leonardo Ermini, Giulia Acconci, Filiberto Maria Severi, Roberta Romagnoli, Santina Cutrupi, Marinella Clerico, Gisella Guerrera and Francesca Ietta
Cells 2022, 11(8), 1357; https://doi.org/10.3390/cells11081357 - 15 Apr 2022
Cited by 3 | Viewed by 2129
Abstract
Women with multiple sclerosis (MS) can safely become pregnant and give birth, with no side effects or impediments. Pregnancy is generally accepted as a period of well-being in which relapses have a softer evolution, particularly in the third trimester. Herein, we hypothesized that [...] Read more.
Women with multiple sclerosis (MS) can safely become pregnant and give birth, with no side effects or impediments. Pregnancy is generally accepted as a period of well-being in which relapses have a softer evolution, particularly in the third trimester. Herein, we hypothesized that the placenta, via its “secretome”, could contribute to the recognized beneficial effects of pregnancy on MS activity. We focused on a well-known receptor/ligand/decoy receptor system, such as the one composed by the receptor activator of nuclear factor-kB (RANK), its ligand (RANKL), and the decoy receptor osteoprotegerin (OPG), which have never been investigated in an integrated way in MS, pregnancy, and placenta. We reported that pregnancy at the term of gestation influences the balance between circulating RANKL and its endogenous inhibitor OPG in MS women. We demonstrated that the placenta at term is an invaluable source of homodimeric OPG. By functional studies on astrocytes, we showed that placental OPG suppresses the mRNA expression of the CCL20, a chemokine responsible for Th17 cell recruitment. We propose placental OPG as a crucial molecule for the recognized beneficial effect of late pregnancy on MS and its potential utility for the development of new and more effective therapeutic approaches. Full article
(This article belongs to the Special Issue Immunology of Multiple Sclerosis)
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19 pages, 2411 KiB  
Article
GABAA and Glycine Receptor-Mediated Inhibitory Synaptic Transmission onto Adult Rat Lamina IIi PKCγ-Interneurons: Pharmacological but Not Anatomical Specialization
by Corinne El Khoueiry, Cristina Alba-Delgado, Myriam Antri, Maria Gutierrez-Mecinas, Andrew J. Todd, Alain Artola and Radhouane Dallel
Cells 2022, 11(8), 1356; https://doi.org/10.3390/cells11081356 - 15 Apr 2022
Cited by 2 | Viewed by 2672
Abstract
Mechanical allodynia (pain to normally innocuous tactile stimuli) is a widespread symptom of inflammatory and neuropathic pain. Spinal or medullary dorsal horn (SDH or MDH) circuits mediating tactile sensation and pain need to interact in order to evoke mechanical allodynia. PKCγ-expressing (PKCγ+ [...] Read more.
Mechanical allodynia (pain to normally innocuous tactile stimuli) is a widespread symptom of inflammatory and neuropathic pain. Spinal or medullary dorsal horn (SDH or MDH) circuits mediating tactile sensation and pain need to interact in order to evoke mechanical allodynia. PKCγ-expressing (PKCγ+) interneurons and inhibitory controls within SDH/MDH inner lamina II (IIi) are pivotal in connecting touch and pain circuits. However, the relative contribution of GABA and glycine to PKCγ+ interneuron inhibition remains unknown. We characterized inhibitory inputs onto PKCγ+ interneurons by combining electrophysiology to record spontaneous and miniature IPSCs (sIPSCs, mIPSCs) and immunohistochemical detection of GABAARα2 and GlyRα1 subunits in adult rat MDH. While GlyR-only- and GABAAR-only-mediated mIPSCs/sIPSCs are predominantly recorded from PKCγ+ interneurons, immunohistochemistry reveals that ~80% of their inhibitory synapses possess both GABAARα2 and GlyRα1. Moreover, nearly all inhibitory boutons at gephyrin-expressing synapses on these cells contain glutamate decarboxylase and are therefore GABAergic, with around half possessing the neuronal glycine transporter (GlyT2) and therefore being glycinergic. Thus, while GABA and glycine are presumably co-released and GABAARs and GlyRs are present at most inhibitory synapses on PKCγ+ interneurons, these interneurons exhibit almost exclusively GABAAR-only and GlyR-only quantal postsynaptic inhibitory currents, suggesting a pharmacological specialization of their inhibitory synapses. Full article
(This article belongs to the Section Cells of the Nervous System)
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25 pages, 1245 KiB  
Review
Role of Estrogens in Menstrual Migraine
by Rossella E. Nappi, Lara Tiranini, Simona Sacco, Eleonora De Matteis, Roberto De Icco and Cristina Tassorelli
Cells 2022, 11(8), 1355; https://doi.org/10.3390/cells11081355 - 15 Apr 2022
Cited by 30 | Viewed by 9853
Abstract
Migraine is a major neurological disorder affecting one in nine adults worldwide with a significant impact on health care and socioeconomic systems. Migraine is more prevalent in women than in men, with 17% of all women meeting the diagnostic criteria for migraine. In [...] Read more.
Migraine is a major neurological disorder affecting one in nine adults worldwide with a significant impact on health care and socioeconomic systems. Migraine is more prevalent in women than in men, with 17% of all women meeting the diagnostic criteria for migraine. In women, the frequency of migraine attacks shows variations over the menstrual cycle and pregnancy, and the use of combined hormonal contraception (CHC) or hormone replacement therapy (HRT) can unveil or modify migraine disease. In the general population, 18–25% of female migraineurs display a menstrual association of their headache. Here we present an overview on the evidence supporting the role of reproductive hormones, in particular estrogens, in the pathophysiology of migraine. We also analyze the efficacy and safety of prescribing exogenous estrogens as a potential treatment for menstrual-related migraine. Finally, we point to controversial issues and future research areas in the field of reproductive hormones and migraine. Full article
(This article belongs to the Special Issue Ovary and Brain)
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26 pages, 9282 KiB  
Article
Smarcb1 Loss Results in a Deregulation of esBAF Binding and Impacts the Expression of Neurodevelopmental Genes
by Amelie Alfert, Carolin Walter, Natalia Moreno, Viktoria Melcher, Monika Graf, Marc Hotfilder, Martin Dugas, Thomas Albert and Kornelius Kerl
Cells 2022, 11(8), 1354; https://doi.org/10.3390/cells11081354 - 15 Apr 2022
Cited by 2 | Viewed by 2645
Abstract
The murine esBAF complex plays a major role in the regulation of gene expression during stem cell development and differentiation. As one of its core subunits, Smarcb1 is indispensable for its function and its loss is connected to neurodevelopmental disorders and participates in [...] Read more.
The murine esBAF complex plays a major role in the regulation of gene expression during stem cell development and differentiation. As one of its core subunits, Smarcb1 is indispensable for its function and its loss is connected to neurodevelopmental disorders and participates in the carcinogenesis of entities such as rhabdoid tumours. We explored how Smarcb1 regulates gene programs in murine embryonic stem cells (mESC) and in this way orchestrates differentiation. Our data underline the importance of Smarcb1 expression and function for the development of the nervous system along with basic cellular functions, such as cell adhesion and cell organisation. Using ChIP-seq, we were able to portray the consequences of Smarcb1 knockdown (kd) for the binding of esBAF and PRC2 as well as its influence on histone marks H3K27me3, H3K4me3 and H3K27ac. Their signals are changed in gene and enhancer regions of genes connected to nervous system development and offers a plausible explanation for changes in gene expression. Further, we describe a group of genes that are, despite increased BAF binding, suppressed after Smarcb1 kd by mechanisms independent of PRC2 function. Full article
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16 pages, 1672 KiB  
Review
Clinical Sphingolipids Pathway in Parkinson’s Disease: From GCase to Integrated-Biomarker Discovery
by Ali Esfandiary, David Isaac Finkelstein, Nicolas Hans Voelcker and David Rudd
Cells 2022, 11(8), 1353; https://doi.org/10.3390/cells11081353 - 15 Apr 2022
Cited by 8 | Viewed by 3400
Abstract
Alterations in the sphingolipid metabolism of Parkinson’s Disease (PD) could be a potential diagnostic feature. Only around 10–15% of PD cases can be diagnosed through genetic alterations, while the remaining population, idiopathic PD (iPD), manifest without validated and specific biomarkers either before or [...] Read more.
Alterations in the sphingolipid metabolism of Parkinson’s Disease (PD) could be a potential diagnostic feature. Only around 10–15% of PD cases can be diagnosed through genetic alterations, while the remaining population, idiopathic PD (iPD), manifest without validated and specific biomarkers either before or after motor symptoms appear. Therefore, clinical diagnosis is reliant on the skills of the clinician, which can lead to misdiagnosis. IPD cases present with a spectrum of non-specific symptoms (e.g., constipation and loss of the sense of smell) that can occur up to 20 years before motor function loss (prodromal stage) and formal clinical diagnosis. Prodromal alterations in metabolites and proteins from the pathways underlying these symptoms could act as biomarkers if they could be differentiated from the broad values seen in a healthy age-matched control population. Additionally, these shifts in metabolites could be integrated with other emerging biomarkers/diagnostic tests to give a PD-specific signature. Here we provide an up-to-date review of the diagnostic value of the alterations in sphingolipids pathway in PD by focusing on the changes in definitive PD (postmortem confirmed brain data) and their representation in “probable PD” cerebrospinal fluid (CSF) and blood. We conclude that the trend of holistic changes in the sphingolipid pathway in the PD brain seems partly consistent in CSF and blood, and could be one of the most promising pathways in differentiating PD cases from healthy controls, with the potential to improve early-stage iPD diagnosis and distinguish iPD from other Parkinsonism when combined with other pathological markers. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Parkinson’s Disease 2021)
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21 pages, 2452 KiB  
Review
PYR/PYL/RCAR Receptors Play a Vital Role in the Abscisic-Acid-Dependent Responses of Plants to External or Internal Stimuli
by Justyna Fidler, Jakub Graska, Marta Gietler, Małgorzata Nykiel, Beata Prabucka, Anna Rybarczyk-Płońska, Ewa Muszyńska, Iwona Morkunas and Mateusz Labudda
Cells 2022, 11(8), 1352; https://doi.org/10.3390/cells11081352 - 15 Apr 2022
Cited by 28 | Viewed by 4209
Abstract
Abscisic acid (ABA) is a phytohormone that plays a key role in regulating several developmental processes as well as in response to stressful conditions such as drought. Activation of the ABA signaling cascade allows the induction of an appropriate physiological response. The basic [...] Read more.
Abscisic acid (ABA) is a phytohormone that plays a key role in regulating several developmental processes as well as in response to stressful conditions such as drought. Activation of the ABA signaling cascade allows the induction of an appropriate physiological response. The basic components of the ABA signaling pathway have been recognized and characterized in recent years. Pyrabactin resistance, pyrabactin resistance-like, and the regulatory component of ABA receptors (PYR/PYL/RCAR) are the major components responsible for the regulation of the ABA signaling pathway. Here, we review recent findings concerning the PYR/PYL/RCAR receptor structure, function, and interaction with other components of the ABA signaling pathway as well as the termination mechanism of ABA signals in plant cells. Since ABA is one of the basic elements related to abiotic stress, which is increasingly common in the era of climate changes, understanding the perception and transduction of the signal related to this phytohormone is of paramount importance in further increasing crop tolerance to various stress factors. Full article
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15 pages, 1714 KiB  
Article
Interspecies Diversity of Osmotic Gradient Deformability of Red Blood Cells in Human and Seven Vertebrate Animal Species
by Adam Varga, Adam Attila Matrai, Barbara Barath, Adam Deak, Laszlo Horvath and Norbert Nemeth
Cells 2022, 11(8), 1351; https://doi.org/10.3390/cells11081351 - 15 Apr 2022
Cited by 8 | Viewed by 2262
Abstract
Plasma and blood osmolality values show interspecies differences and are strictly regulated. The effect of these factors also has an influence on microrheological parameters, such as red blood cell (RBC) deformability and aggregation. However, little is known about the interspecies differences in RBC [...] Read more.
Plasma and blood osmolality values show interspecies differences and are strictly regulated. The effect of these factors also has an influence on microrheological parameters, such as red blood cell (RBC) deformability and aggregation. However, little is known about the interspecies differences in RBC deformability at various blood osmolality levels (osmotic gradient RBC deformability). Our aim was to conduct a descriptive–comparative study on RBC osmotic gradient deformability in several vertebrate species and human blood. Blood samples were taken from healthy volunteers, dogs, cats, pigs, sheep, rabbits, rats, and mice, to measure hematological parameters, as well as conventional and osmotic gradient RBC deformability. Analyzing the elongation index (EI)–osmolality curves, we found the highest maximal EI values (EI max) in human, dog, and rabbit samples. The lowest EI max values were seen in sheep and cat samples, in addition to a characteristic leftward shift of the elongation index–osmolality curves. We found significant differences in the hyperosmolar region. A correlation of mean corpuscular volume and mean corpuscular hemoglobin concentration with osmoscan parameters was found. Osmotic gradient deformability provides further information for better exploration of microrheological diversity between species and may help to better understand the alterations caused by osmolality changes in various disorders. Full article
(This article belongs to the Collection Advances in Red Blood Cells Research)
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22 pages, 1600 KiB  
Article
Effects of Soy-Based Infant Formula on Weight Gain and Neurodevelopment in an Autism Mouse Model
by Cara J. Westmark, Mikolaj J. Filon, Patricia Maina, Lauren I. Steinberg, Chrysanthy Ikonomidou and Pamela R. Westmark
Cells 2022, 11(8), 1350; https://doi.org/10.3390/cells11081350 - 15 Apr 2022
Cited by 6 | Viewed by 2490
Abstract
Mice fed soy-based diets exhibit increased weight gain compared to mice fed casein-based diets, and the effects are more pronounced in a model of fragile X syndrome (FXS; Fmr1KO). FXS is a neurodevelopmental disability characterized by intellectual impairment, seizures, autistic behavior, [...] Read more.
Mice fed soy-based diets exhibit increased weight gain compared to mice fed casein-based diets, and the effects are more pronounced in a model of fragile X syndrome (FXS; Fmr1KO). FXS is a neurodevelopmental disability characterized by intellectual impairment, seizures, autistic behavior, anxiety, and obesity. Here, we analyzed body weight as a function of mouse age, diet, and genotype to determine the effect of diet (soy, casein, and grain-based) on weight gain. We also assessed plasma protein biomarker expression and behavior in response to diet. Juvenile Fmr1KO mice fed a soy protein-based rodent chow throughout gestation and postnatal development exhibit increased weight gain compared to mice fed a casein-based purified ingredient diet or grain-based, low phytoestrogen chow. Adolescent and adult Fmr1KO mice fed a soy-based infant formula diet exhibited increased weight gain compared to reference diets. Increased body mass was due to increased lean mass. Wild-type male mice fed soy-based infant formula exhibited increased learning in a passive avoidance paradigm, and Fmr1KO male mice had a deficit in nest building. Thus, at the systems level, consumption of soy-based diets increases weight gain and affects behavior. At the molecular level, a soy-based infant formula diet was associated with altered expression of numerous plasma proteins, including the adipose hormone leptin and the β-amyloid degrading enzyme neprilysin. In conclusion, single-source, soy-based diets may contribute to the development of obesity and the exacerbation of neurological phenotypes in developmental disabilities, such as FXS. Full article
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16 pages, 7942 KiB  
Review
Regional Development of Glioblastoma: The Anatomical Conundrum of Cancer Biology and Its Surgical Implication
by Ciro De Luca, Assunta Virtuoso, Michele Papa, Francesco Certo, Giuseppe Maria Vincenzo Barbagallo and Roberto Altieri
Cells 2022, 11(8), 1349; https://doi.org/10.3390/cells11081349 - 15 Apr 2022
Cited by 10 | Viewed by 2582
Abstract
Glioblastoma (GBM) are among the most common malignant central nervous system (CNS) cancers, they are relatively rare. This evidence suggests that the CNS microenvironment is naturally equipped to control proliferative cells, although, rarely, failure of this system can lead to cancer development. Moreover, [...] Read more.
Glioblastoma (GBM) are among the most common malignant central nervous system (CNS) cancers, they are relatively rare. This evidence suggests that the CNS microenvironment is naturally equipped to control proliferative cells, although, rarely, failure of this system can lead to cancer development. Moreover, the adult CNS is innately non-permissive to glioma cell invasion. Thus, glioma etiology remains largely unknown. In this review, we analyze the anatomical and biological basis of gliomagenesis considering neural stem cells, the spatiotemporal diversity of astrocytes, microglia, neurons and glutamate transporters, extracellular matrix and the peritumoral environment. The precise understanding of subpopulations constituting GBM, particularly astrocytes, is not limited to glioma stem cells (GSC) and could help in the understanding of tumor pathophysiology. The anatomical fingerprint is essential for non-invasive assessment of patients’ prognosis and correct surgical/radiotherapy planning. Full article
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16 pages, 3699 KiB  
Article
Intranasal Administration of Agomir-let-7i Improves Cognitive Function in Mice with Traumatic Brain Injury
by Xuan-Cheng He, Jian Wang, Hong-Zhen Du, Chang-Mei Liu and Zhao-Qian Teng
Cells 2022, 11(8), 1348; https://doi.org/10.3390/cells11081348 - 15 Apr 2022
Cited by 10 | Viewed by 2752 | Correction
Abstract
Overcoming the lack of drugs for the treatment of traumatic brain injury (TBI) has long been a major challenge for the pharmaceutical industry. MiRNAs have emerged as potential targets for progress assessment and intervention against TBI. The brain-enriched miRNA let-7i has been proposed [...] Read more.
Overcoming the lack of drugs for the treatment of traumatic brain injury (TBI) has long been a major challenge for the pharmaceutical industry. MiRNAs have emerged as potential targets for progress assessment and intervention against TBI. The brain-enriched miRNA let-7i has been proposed as an ideal candidate biomarker for TBI, but its regulatory roles in brain injury remain largely unknown. Here, we find that the expression of let-7i is significantly downregulated in the early stages of a hippocampal stab wound injury. The noninvasive intranasal administration of let-7i agomir significantly improves cognitive function and suppresses neuroinflammation, glial scar formation, and neuronal apoptosis in TBI mice. Mechanically, STING is a direct downstream target of let-7i after brain injury. Furthermore, the intranasal delivery of let-7i agomir can also effectively inhibit STING and is beneficial for inflammation resolution and neuronal survival in a mouse model of pial vessel disruption stroke. Consequently, let-7i agomir is a promising candidate for clinical application as a chemically engineered oligonucleotides-based therapeutic for brain injury. Full article
(This article belongs to the Special Issue Non-coding RNAs: Epigenetic Players Implicated in Human Diseases)
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17 pages, 4241 KiB  
Article
CFTR Modulation Reduces SARS-CoV-2 Infection in Human Bronchial Epithelial Cells
by Virginia Lotti, Flavia Merigo, Anna Lagni, Andrea Di Clemente, Marco Ligozzi, Paolo Bernardi, Giada Rossini, Ercole Concia, Roberto Plebani, Mario Romano, Andrea Sbarbati, Claudio Sorio and Davide Gibellini
Cells 2022, 11(8), 1347; https://doi.org/10.3390/cells11081347 - 15 Apr 2022
Cited by 15 | Viewed by 3576
Abstract
People with cystic fibrosis should be considered at increased risk of developing severe symptoms of COVID-19. Strikingly, a broad array of evidence shows reduced spread of SARS-CoV-2 in these subjects, suggesting a potential role for CFTR in the regulation of SARS-CoV-2 infection/replication. Here, [...] Read more.
People with cystic fibrosis should be considered at increased risk of developing severe symptoms of COVID-19. Strikingly, a broad array of evidence shows reduced spread of SARS-CoV-2 in these subjects, suggesting a potential role for CFTR in the regulation of SARS-CoV-2 infection/replication. Here, we analyzed SARS-CoV-2 replication in wild-type and CFTR-modified human bronchial epithelial cell lines and primary cells to investigate SARS-CoV-2 infection in people with cystic fibrosis. Both immortalized and primary human bronchial epithelial cells expressing wt or F508del-CFTR along with CRISPR/Cas9 CFTR-ablated clones were infected with SARS-CoV-2 and samples were harvested before and from 24 to 72 h post-infection. CFTR function was also inhibited in wt-CFTR cells with the CFTR-specific inhibitor IOWH-032 and partially restored in F508del-CFTR cells with a combination of CFTR modulators (VX-661+VX-445). Viral load was evaluated by real-time RT-PCR in both supernatant and cell extracts, and ACE-2 expression was analyzed by both western blotting and flow cytometry. SARS-CoV-2 replication was reduced in CFTR-modified bronchial cells compared with wild-type cell lines. No major difference in ACE-2 expression was detected before infection between wild-type and CFTR-modified cells, while a higher expression in wild-type compared to CFTR-modified cells was detectable at 72 h post-infection. Furthermore, inhibition of CFTR channel function elicited significant inhibition of viral replication in cells with wt-CFTR, and correction of CFTR function in F508del-CFTR cells increased the release of SARS-CoV-2 viral particles. Our study provides evidence that CFTR expression/function is involved in the regulation of SARS-CoV-2 replication, thus providing novel insights into the role of CFTR in SARS-CoV-2 infection and the development of therapeutic strategies for COVID-19. Full article
(This article belongs to the Topic Cystic Fibrosis)
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39 pages, 1787 KiB  
Review
An Unanticipated Modulation of Cyclin-Dependent Kinase Inhibitors: The Role of Long Non-Coding RNAs
by Debora Bencivenga, Emanuela Stampone, Angela Vastante, Myassar Barahmeh, Fulvio Della Ragione and Adriana Borriello
Cells 2022, 11(8), 1346; https://doi.org/10.3390/cells11081346 - 14 Apr 2022
Cited by 6 | Viewed by 3090
Abstract
It is now definitively established that a large part of the human genome is transcribed. However, only a scarce percentage of the transcriptome (about 1.2%) consists of RNAs that are translated into proteins, while the large majority of transcripts include a variety of [...] Read more.
It is now definitively established that a large part of the human genome is transcribed. However, only a scarce percentage of the transcriptome (about 1.2%) consists of RNAs that are translated into proteins, while the large majority of transcripts include a variety of RNA families with different dimensions and functions. Within this heterogeneous RNA world, a significant fraction consists of sequences with a length of more than 200 bases that form the so-called long non-coding RNA family. The functions of long non-coding RNAs range from the regulation of gene transcription to the changes in DNA topology and nucleosome modification and structural organization, to paraspeckle formation and cellular organelles maturation. This review is focused on the role of long non-coding RNAs as regulators of cyclin-dependent kinase inhibitors’ (CDKIs) levels and activities. Cyclin-dependent kinases are enzymes necessary for the tuned progression of the cell division cycle. The control of their activity takes place at various levels. Among these, interaction with CDKIs is a vital mechanism. Through CDKI modulation, long non-coding RNAs implement control over cellular physiology and are associated with numerous pathologies. However, although there are robust data in the literature, the role of long non-coding RNAs in the modulation of CDKIs appears to still be underestimated, as well as their importance in cell proliferation control. Full article
(This article belongs to the Section Cell Proliferation and Division)
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10 pages, 1109 KiB  
Article
Skeletal Muscle Pathological Fat Infiltration (Myosteatosis) Is Associated with Higher Mortality in Patients with Cirrhosis
by Maryam Ebadi, Cynthia Tsien, Rahima A. Bhanji, Abha R. Dunichand-Hoedl, Elora Rider, Maryam Motamedrad, Vera C. Mazurak, Vickie Baracos and Aldo J. Montano-Loza
Cells 2022, 11(8), 1345; https://doi.org/10.3390/cells11081345 - 14 Apr 2022
Cited by 23 | Viewed by 3260
Abstract
Myosteatosis (pathological fat accumulation in muscle) is defined by lower mean skeletal muscle radiodensity in CT. We aimed to determine the optimal cut-offs for myosteatosis in a cohort of 855 patients with cirrhosis. CT images were used to determine the skeletal muscle radiodensity [...] Read more.
Myosteatosis (pathological fat accumulation in muscle) is defined by lower mean skeletal muscle radiodensity in CT. We aimed to determine the optimal cut-offs for myosteatosis in a cohort of 855 patients with cirrhosis. CT images were used to determine the skeletal muscle radiodensity expressed as Hounsfield Unit (HU). Patients with muscle radiodensity values below the lowest tertile were considered to have myosteatosis. Competing-risk analysis was performed to determine associations between muscle radiodensity and pre-transplant mortality. Muscle radiodensity less than 33 and 28 HU in males and females, respectively, were used as cut-offs to identify myosteatosis. In the univariate analysis, cirrhosis etiology, MELD score, refractory ascites, variceal bleeding, hepatic encephalopathy, sarcopenia and myosteatosis were predictors of mortality. Myosteatosis association with mortality remained significant after adjusting for confounding factors (sHR 1.47, 95% CI 1.17–1.84, p = 0.001). Patients with concurrent presence of myosteatosis and sarcopenia constituted 17% of the patient population. The cumulative incidence of mortality was the highest in patients with concomitant sarcopenia and myosteatosis (sHR 2.22, 95% CI 1.64–3.00, p < 0.001). In conclusion, myosteatosis is common in patients with cirrhosis and is associated with increased mortality. The concomitant presence of myosteatosis and sarcopenia is associated with worse outcomes. Full article
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