Cells

23 pages, 4325 KiB

Open AccessArticle

Transcryptomic Analysis of Human Brain-Microvascular Endothelial Response to -Pericytes: Cell Orientation Defines Barrier Function

by Lisa Kurmann, Michal Okoniewski, Omolara O. Ogunshola, Brigitte Leeners, Bruno Imthurn and Raghvendra K. Dubey

Cells 2021, 10(4), 963; https://doi.org/10.3390/cells10040963 - 20 Apr 2021

Cited by 16 | Viewed by 4289

Abstract

Pericytes facilitate blood–brain barrier (BBB) integrity; however, the mechanisms involved remain unclear. Hence, using co-cultures of human cerebral microvascular endothelial cells (ECs) and vascular pericytes (PCs) in different spatial arrangements, as well as PC conditioned media, we investigated the impact of PC-EC orientation [...] Read more.

Pericytes facilitate blood–brain barrier (BBB) integrity; however, the mechanisms involved remain unclear. Hence, using co-cultures of human cerebral microvascular endothelial cells (ECs) and vascular pericytes (PCs) in different spatial arrangements, as well as PC conditioned media, we investigated the impact of PC-EC orientation and PC-derived soluble factors on EC barrier function. We provide the first evidence that barrier-inducing properties of PCs require basolateral contact with ECs. Gene expression analysis (GEA) in ECs co-cultured with PCs versus ECs alone showed significant upregulation of 38 genes and downregulation of 122 genes. Pathway enrichment analysis of modulated genes showed significant regulation of several pathways, including transforming growth factor-β and interleukin-1 regulated extracellular matrix, interferon and interleukin signaling, immune system signaling, receptor of advanced glycation end products (RAGE), and cytokine–cytokine receptor interaction. Transcriptomic analysis showed a reduction in molecules such as pro-inflammatory cytokines and chemokines, which are known to be induced during BBB disruption. Moreover, cytokine proteome array confirmed the downregulation of key pro-inflammatory cytokines and chemokines on the protein level. Other molecules which influence BBB and were favorably modulated upon EC-PC co-culture include IL-18 binding protein, kallikrein-3, CSF2 CSF3, CXCL10, CXCL11 (downregulated) and IL-1-R4; HGF, PDGF-AB/BB, PECAM, SERPIN E1 (upregulated). In conclusion, we provide the first evidence that (1) basolateral contact between ECs and PCs is essential for EC barrier function and integrity; (2) in ECs co-cultured with PCs, the profile of BBB disrupting pro-inflammatory molecules and cytokines/chemokines is downregulated; (3) PCs significantly modulate EC mechanisms known to improve barrier function, including TGF-β regulated ECM pathway, anti-inflammatory cytokines, growth factors and matrix proteins. This human PC-EC co-culture may serve as a viable in vitro model for investigating BBB function and drug transport. Full article

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12 pages, 2279 KiB

Open AccessCommunication

Salicylic Acid Accumulation Controlled by LSD1 Is Essential in Triggering Cell Death in Response to Abiotic Stress

by Maciej Jerzy Bernacki, Anna Rusaczonek, Weronika Czarnocka and Stanisław Karpiński

Cells 2021, 10(4), 962; https://doi.org/10.3390/cells10040962 - 20 Apr 2021

Cited by 16 | Viewed by 3904

Abstract

Salicylic acid (SA) is well known hormonal molecule involved in cell death regulation. In response to a broad range of environmental factors (e.g., high light, UV, pathogens attack), plants accumulate SA, which participates in cell death induction and spread in some foliar cells. [...] Read more.

Salicylic acid (SA) is well known hormonal molecule involved in cell death regulation. In response to a broad range of environmental factors (e.g., high light, UV, pathogens attack), plants accumulate SA, which participates in cell death induction and spread in some foliar cells. LESION SIMULATING DISEASE 1 (LSD1) is one of the best-known cell death regulators in Arabidopsis thaliana. The lsd1 mutant, lacking functional LSD1 protein, accumulates SA and is conditionally susceptible to many biotic and abiotic stresses. In order to get more insight into the role of LSD1-dependent regulation of SA accumulation during cell death, we crossed the lsd1 with the sid2 mutant, caring mutation in ISOCHORISMATE SYNTHASE 1(ICS1) gene and having deregulated SA synthesis, and with plants expressing the bacterial nahG gene and thus decomposing SA to catechol. In response to UV A+B irradiation, the lsd1 mutant exhibited clear cell death phenotype, which was reversed in lsd1/sid2 and lsd1/NahG plants. The expression of PR-genes and the H₂O₂ content in UV-treated lsd1 were significantly higher when compared with the wild type. In contrast, lsd1/sid2 and lsd1/NahG plants demonstrated comparability with the wild-type level of PR-genes expression and H₂O₂. Our results demonstrate that SA accumulation is crucial for triggering cell death in lsd1, while the reduction of excessive SA accumulation may lead to a greater tolerance toward abiotic stress. Full article

(This article belongs to the Special Issue Programmed Cell Death Regulation in Plants)

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21 pages, 5894 KiB

Open AccessReview

Non-Tumorigenic Pluripotent Reparative Muse Cells Provide a New Therapeutic Approach for Neurologic Diseases

by Toru Yamashita, Yoshihiro Kushida, Koji Abe and Mari Dezawa

Cells 2021, 10(4), 961; https://doi.org/10.3390/cells10040961 - 20 Apr 2021

Cited by 14 | Viewed by 4937

Abstract

Muse cells are non-tumorigenic endogenous reparative pluripotent cells with high therapeutic potential. They are identified as cells positive for the pluripotent surface marker SSEA-3 in the bone marrow, peripheral blood, and connective tissue. Muse cells also express other pluripotent stem cell markers, are [...] Read more.

Muse cells are non-tumorigenic endogenous reparative pluripotent cells with high therapeutic potential. They are identified as cells positive for the pluripotent surface marker SSEA-3 in the bone marrow, peripheral blood, and connective tissue. Muse cells also express other pluripotent stem cell markers, are able to differentiate into cells representative of all three germ layers, self-renew from a single cell, and are stress tolerant. They express receptors for sphingosine-1-phosphate (S1P), which is actively produced by damaged cells, allowing circulating cells to selectively home to damaged tissue. Muse cells spontaneously differentiate on-site into multiple tissue-constituent cells with few errors and replace damaged/apoptotic cells with functional cells, thereby contributing to tissue repair. Intravenous injection of exogenous Muse cells to increase the number of circulating Muse cells enhances their reparative activity. Muse cells also have a specific immunomodulatory system, represented by HLA-G expression, allowing them to be directly administered without HLA-matching or immunosuppressant treatment. Owing to these unique characteristics, clinical trials using intravenously administered donor-Muse cells have been conducted for myocardial infarction, stroke, epidermolysis bullosa, spinal cord injury, perinatal hypoxic ischemic encephalopathy, and amyotrophic lateral sclerosis. Muse cells have the potential to break through the limitations of current cell therapies for neurologic diseases, including amyotrophic lateral sclerosis. Muse cells provide a new therapeutic strategy that requires no HLA-matching or immunosuppressant treatment for administering donor-derived cells, no gene introduction or differentiation induction for cell preparation, and no surgery for delivering the cells to patients. Full article

(This article belongs to the Collection Researches on Normal and Cancer Stem Cells)

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31 pages, 1745 KiB

Open AccessReview

Tissue-Resident and Recruited Macrophages in Primary Tumor and Metastatic Microenvironments: Potential Targets in Cancer Therapy

by Tiziana Cotechini, Aline Atallah and Arielle Grossman

Cells 2021, 10(4), 960; https://doi.org/10.3390/cells10040960 - 20 Apr 2021

Cited by 39 | Viewed by 7301

Abstract

Macrophages within solid tumors and metastatic sites are heterogenous populations with different developmental origins and substantially contribute to tumor progression. A number of tumor-promoting phenotypes associated with both tumor- and metastasis-associated macrophages are similar to innate programs of embryonic-derived tissue-resident macrophages. In contrast [...] Read more.

Macrophages within solid tumors and metastatic sites are heterogenous populations with different developmental origins and substantially contribute to tumor progression. A number of tumor-promoting phenotypes associated with both tumor- and metastasis-associated macrophages are similar to innate programs of embryonic-derived tissue-resident macrophages. In contrast to recruited macrophages originating from marrow precursors, tissue-resident macrophages are seeded before birth and function to coordinate tissue remodeling and maintain tissue integrity and homeostasis. Both recruited and tissue-resident macrophage populations contribute to tumor growth and metastasis and are important mediators of resistance to chemotherapy, radiation therapy, and immune checkpoint blockade. Thus, targeting various macrophage populations and their tumor-promoting phenotypes holds therapeutic promise. Here, we discuss various macrophage populations as regulators of tumor progression, immunity, and immunotherapy. We provide an overview of macrophage targeting strategies, including therapeutics designed to induce macrophage depletion, impair recruitment, and induce repolarization. We also provide a perspective on the therapeutic potential for macrophage-specific acquisition of trained immunity as an anti-cancer agent and discuss the therapeutic potential of exploiting macrophages and their traits to reduce tumor burden. Full article

(This article belongs to the Special Issue Targetable Cellular Components of the Immune Microenvironment in Solid Tumors)

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12 pages, 724 KiB

Open AccessStudy Protocol

PROVE—Pre-Eclampsia Obstetric Adverse Events: Establishment of a Biobank and Database for Pre-Eclampsia

by Lina Bergman, Karl Bergman, Eduard Langenegger, Ashley Moodley, Stephanie Griffith-Richards, Johan Wikström, David Hall, Lloyd Joubert, Philip Herbst, Sonja Schell, Teelkien van Veen, Michael Belfort, Stephen Y. C. Tong, Susan Walker, Roxanne Hastie and Catherine Cluver

Cells 2021, 10(4), 959; https://doi.org/10.3390/cells10040959 - 20 Apr 2021

Cited by 13 | Viewed by 4936

Abstract

Pre-eclampsia is a leading cause of maternal and perinatal morbidity and mortality. The burden of disease lies mainly in low-middle income countries. The aim of this project is to establish a pre-eclampsia biobank in South Africa to facilitate research in the field of [...] Read more.

Pre-eclampsia is a leading cause of maternal and perinatal morbidity and mortality. The burden of disease lies mainly in low-middle income countries. The aim of this project is to establish a pre-eclampsia biobank in South Africa to facilitate research in the field of pre-eclampsia with a focus on phenotyping severe disease.The approach of our biobank is to collect biological specimens, detailed clinical data, tests, and biophysical examinations, including magnetic resonance imaging (MRI) of the brain, MRI of the heart, transcranial Doppler, echocardiography, and cognitive function tests.Women diagnosed with pre-eclampsia and normotensive controls are enrolled in the biobank at admission to Tygerberg University Hospital (Cape Town, South Africa). Biological samples and clinical data are collected at inclusion/delivery and during the hospital stay. Special investigations as per above are performed in a subset of women. After two months, women are followed up by telephonic interviews. This project aims to establish a biobank and database for severe organ complications of pre-eclampsia in a low-middle income country where the incidence of pre-eclampsia with organ complications is high. The study integrates different methods to investigate pre-eclampsia, focusing on improved understanding of pathophysiology, prediction of organ complications, and potentially future drug evaluation and discovery. Full article

(This article belongs to the Special Issue The Pathophysiology of Preeclampsia and Eclampsia)

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20 pages, 947 KiB

Open AccessReview

Dysregulation of Multiple Signaling Neurodevelopmental Pathways during Embryogenesis: A Possible Cause of Autism Spectrum Disorder

by Jyoti Upadhyay, Jeevan Patra, Nidhi Tiwari, Nilima Salankar, Mohd Nazam Ansari and Wasim Ahmad

Cells 2021, 10(4), 958; https://doi.org/10.3390/cells10040958 - 20 Apr 2021

Cited by 18 | Viewed by 6190

Abstract

Understanding the autistic brain and the involvement of genetic, non-genetic, and numerous signaling pathways in the etiology and pathophysiology of autism spectrum disorder (ASD) is complex, as is evident from various studies. Apart from multiple developmental disorders of the brain, autistic subjects show [...] Read more.

Understanding the autistic brain and the involvement of genetic, non-genetic, and numerous signaling pathways in the etiology and pathophysiology of autism spectrum disorder (ASD) is complex, as is evident from various studies. Apart from multiple developmental disorders of the brain, autistic subjects show a few characteristics like impairment in social communications related to repetitive, restricted, or stereotypical behavior, which suggests alterations in neuronal circuits caused by defects in various signaling pathways during embryogenesis. Most of the research studies on ASD subjects and genetic models revealed the involvement of mutated genes with alterations of numerous signaling pathways like Wnt, hedgehog, and Retinoic Acid (RA). Despite significant improvement in understanding the pathogenesis and etiology of ASD, there is an increasing awareness related to it as well as a need for more in-depth research because no effective therapy has been developed to address ASD symptoms. Therefore, identifying better therapeutic interventions like “novel drugs for ASD” and biomarkers for early detection and disease condition determination are required. This review article investigated various etiological factors as well as the signaling mechanisms and their alterations to understand ASD pathophysiology. It summarizes the mechanism of signaling pathways, their significance, and implications for ASD. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Cell Signaling and Regulated Cell Death)

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28 pages, 2683 KiB

Open AccessReview

Microglial Function and Regulation during Development, Homeostasis and Alzheimer’s Disease

by Brad T. Casali and Erin G. Reed-Geaghan

Cells 2021, 10(4), 957; https://doi.org/10.3390/cells10040957 - 20 Apr 2021

Cited by 29 | Viewed by 6509

Abstract

Microglia are the resident immune cells of the brain, deriving from yolk sac progenitors that populate the brain parenchyma during development. During development and homeostasis, microglia play critical roles in synaptogenesis and synaptic plasticity, in addition to their primary role as immune sentinels. [...] Read more.

Microglia are the resident immune cells of the brain, deriving from yolk sac progenitors that populate the brain parenchyma during development. During development and homeostasis, microglia play critical roles in synaptogenesis and synaptic plasticity, in addition to their primary role as immune sentinels. In aging and neurodegenerative diseases generally, and Alzheimer’s disease (AD) specifically, microglial function is altered in ways that significantly diverge from their homeostatic state, inducing a more detrimental inflammatory environment. In this review, we discuss the receptors, signaling, regulation and gene expression patterns of microglia that mediate their phenotype and function contributing to the inflammatory milieu of the AD brain, as well as strategies that target microglia to ameliorate the onset, progression and symptoms of AD. Full article

(This article belongs to the Collection Microglia in Aging and Neurodegenerative Diseases)

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20 pages, 6287 KiB

Open AccessArticle

Bone Marrow-Derived IL-1Ra Increases TNF Levels Poststroke

by Christian Ulrich von Linstow, Sofie Mozart Hindkjær, Pernille Vinther Nielsen, Matilda Degn, Kate Lykke Lambertsen, Bente Finsen and Bettina Hjelm Clausen

Cells 2021, 10(4), 956; https://doi.org/10.3390/cells10040956 - 20 Apr 2021

Cited by 3 | Viewed by 3854

Abstract

Tumor necrosis factor (TNF) and interleukin-1 receptor antagonist (IL-1Ra) are key players in stroke, a disease in which cell-based therapies have shown great potential. Having shown an infarct-reducing effect of bone marrow (BM) cells, especially cells with high IL-1Ra expression, we here investigated [...] Read more.

Tumor necrosis factor (TNF) and interleukin-1 receptor antagonist (IL-1Ra) are key players in stroke, a disease in which cell-based therapies have shown great potential. Having shown an infarct-reducing effect of bone marrow (BM) cells, especially cells with high IL-1Ra expression, we here investigated the effect of BM cells on TNF and other stroke-related mediators in mice after transient middle cerebral artery occlusion (tMCAo) and in vitro using adult microglial cultures. We analyzed stroke-related genes and inflammatory mediators using qPCR stroke Tier panels, electrochemiluminescence, or enzyme-linked immunosorbent assays. We found a significant correlation and cellular colocalization between microglial-derived TNF and IL-1Ra, though IL-1Ra production was TNF independent. BM treatment significantly increased TNF, interleukin (IL)-10, and IL-4 levels, while C-X-C motif ligand 1 (CXCL1), IL-12p70, and Toll-like receptor 2 (TLR2) decreased, suggesting that BM treatment favors an anti-inflammatory environment. Hierarchical clustering identified Tnf and IL-1rn within the same gene cluster, and subsequent STRING analysis identified TLR2 as a shared receptor. Although IL-1Ra producing BM cells specifically modulated TNF levels, this was TLR2 independent. These results demonstrate BM cells as modulators of poststroke inflammation with beneficial effects on poststroke outcomes and place TNF and IL-1Ra as key players of the defense response after tMCAo. Full article

(This article belongs to the Special Issue Tumor Necrosis Factor (TNF) in Neurological Disorders)

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14 pages, 1003 KiB

Open AccessReview

MicroRNAs in Medullary Thyroid Carcinoma: A State of the Art Review of the Regulatory Mechanisms and Future Perspectives

by Francesca Galuppini, Simona Censi, Margherita Moro, Stefano Carraro, Marta Sbaraglia, Maurizio Iacobone, Matteo Fassan, Caterina Mian and Gianmaria Pennelli

Cells 2021, 10(4), 955; https://doi.org/10.3390/cells10040955 - 20 Apr 2021

Cited by 11 | Viewed by 3366

Abstract

Medullary thyroid carcinoma (MTC) is a rare malignant neoplasia with a variable clinical course, with complete remission often difficult to achieve. Genetic alterations lead to fundamental changes not only in hereditary MTC but also in the sporadic form, with close correlations between mutational [...] Read more.

Medullary thyroid carcinoma (MTC) is a rare malignant neoplasia with a variable clinical course, with complete remission often difficult to achieve. Genetic alterations lead to fundamental changes not only in hereditary MTC but also in the sporadic form, with close correlations between mutational status and prognosis. In recent years, microRNAs (miRNAs) have become highly relevant as crucial players in MTC etiology. Current research has focused on their roles in disease carcinogenesis and development, but recent studies have expounded their potential as biomarkers and response predictors to novel biological drugs for advanced MTC. One such element which requires greater investigation is their mechanism of action and the molecular pathways involved in the regulation of gene expression. A more thorough understanding of these mechanisms will help realize the promising potential of miRNAs for MTC therapy and management. Full article

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

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17 pages, 2630 KiB

Open AccessArticle

Proteome Damage Inflicted by Ionizing Radiation: Advancing a Theme in the Research of Miroslav Radman

by Steven T. Bruckbauer, Benjamin B. Minkoff, Michael R. Sussman and Michael M. Cox

Cells 2021, 10(4), 954; https://doi.org/10.3390/cells10040954 - 20 Apr 2021

Cited by 5 | Viewed by 3082

Abstract

Oxidative proteome damage has been implicated as a major contributor to cell death and aging. Protein damage and aging has been a particular theme of the recent research of Miroslav Radman. However, the study of how cellular proteins are damaged by oxidative processes [...] Read more.

Oxidative proteome damage has been implicated as a major contributor to cell death and aging. Protein damage and aging has been a particular theme of the recent research of Miroslav Radman. However, the study of how cellular proteins are damaged by oxidative processes is still in its infancy. Here we examine oxidative changes in the proteomes of four bacterial populations—wild type E. coli, two isolates from E. coli populations evolved for high levels of ionizing radiation (IR) resistance, and D. radiodurans—immediately following exposure to 3000 Gy of ionizing radiation. By a substantial margin, the most prominent intracellular oxidation events involve hydroxylation of methionine residues. Significant but much less frequent are carbonylation events on tyrosine and dioxidation events on tryptophan. A few proteins are exquisitely sensitive to targeted oxidation events, notably the active site of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in E. coli. Extensive experimental evolution of E. coli for IR resistance has decreased overall proteome sensitivity to oxidation but not to the level seen in D. radiodurans. Many observed oxidation events may reflect aspects of protein structure and/or exposure of protein surfaces to water. Proteins such as GAPDH and possibly Ef-Tu may have an evolved sensitivity to oxidation by H₂O₂. Full article

(This article belongs to the Special Issue DNA Repair, Genome Stability/Diversity, and Oxidative Stress and Aging, from Bacteria to Human Cells: A Themed Issue in Honor of Prof. Miroslav Radman)

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18 pages, 3510 KiB

Open AccessArticle

The Impact of Preprocessing Methods for a Successful Prostate Cell Lines Discrimination Using Partial Least Squares Regression and Discriminant Analysis Based on Fourier Transform Infrared Imaging

by Danuta Liberda, Ewa Pięta, Katarzyna Pogoda, Natalia Piergies, Maciej Roman, Paulina Koziol, Tomasz P. Wrobel, Czeslawa Paluszkiewicz and Wojciech M. Kwiatek

Cells 2021, 10(4), 953; https://doi.org/10.3390/cells10040953 - 20 Apr 2021

Cited by 10 | Viewed by 3027

Abstract

Fourier transform infrared spectroscopy (FT-IR) is widely used in the analysis of the chemical composition of biological materials and has the potential to reveal new aspects of the molecular basis of diseases, including different types of cancer. The potential of FT-IR in cancer [...] Read more.

Fourier transform infrared spectroscopy (FT-IR) is widely used in the analysis of the chemical composition of biological materials and has the potential to reveal new aspects of the molecular basis of diseases, including different types of cancer. The potential of FT-IR in cancer research lies in its capability of monitoring the biochemical status of cells, which undergo malignant transformation and further examination of spectral features that differentiate normal and cancerous ones using proper mathematical approaches. Such examination can be performed with the use of chemometric tools, such as partial least squares discriminant analysis (PLS-DA) classification and partial least squares regression (PLSR), and proper application of preprocessing methods and their correct sequence is crucial for success. Here, we performed a comparison of several state-of-the-art methods commonly used in infrared biospectroscopy (denoising, baseline correction, and normalization) with the addition of methods not previously used in infrared biospectroscopy classification problems: Mie extinction extended multiplicative signal correction, Eiler’s smoothing, and probabilistic quotient normalization. We compared all of these approaches and their effect on the data structure, classification, and regression capability on experimental FT-IR spectra collected from five different prostate normal and cancerous cell lines. Additionally, we tested the influence of added spectral noise. Overall, we concluded that in the case of the data analyzed here, the biggest impact on data structure and performance of PLS-DA and PLSR was caused by the baseline correction; therefore, much attention should be given, especially to this step of data preprocessing. Full article

(This article belongs to the Special Issue Cellular and Subcellular Analysis Using Vibrational Spectroscopy)

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20 pages, 2697 KiB

Open AccessArticle

Paraburkholderia phymatum Homocitrate Synthase NifV Plays a Key Role for Nitrogenase Activity during Symbiosis with Papilionoids and in Free-Living Growth Conditions

by Paula Bellés-Sancho, Martina Lardi, Yilei Liu, Sebastian Hug, Marta Adriana Pinto-Carbó, Nicola Zamboni and Gabriella Pessi

Cells 2021, 10(4), 952; https://doi.org/10.3390/cells10040952 - 20 Apr 2021

Cited by 12 | Viewed by 3587

Abstract

Homocitrate is an essential component of the iron-molybdenum cofactor of nitrogenase, the bacterial enzyme that catalyzes the reduction of dinitrogen (N₂) to ammonia. In nitrogen-fixing and nodulating alpha-rhizobia, homocitrate is usually provided to bacteroids in root nodules by their plant host. [...] Read more.

Homocitrate is an essential component of the iron-molybdenum cofactor of nitrogenase, the bacterial enzyme that catalyzes the reduction of dinitrogen (N₂) to ammonia. In nitrogen-fixing and nodulating alpha-rhizobia, homocitrate is usually provided to bacteroids in root nodules by their plant host. In contrast, non-nodulating free-living diazotrophs encode the homocitrate synthase (NifV) and reduce N₂ in nitrogen-limiting free-living conditions. Paraburkholderia phymatum STM815 is a beta-rhizobial strain, which can enter symbiosis with a broad range of legumes, including papilionoids and mimosoids. In contrast to most alpha-rhizobia, which lack nifV, P. phymatum harbors a copy of nifV on its symbiotic plasmid. We show here that P. phymatum nifV is essential for nitrogenase activity both in root nodules of papilionoid plants and in free-living growth conditions. Notably, nifV was dispensable in nodules of Mimosa pudica despite the fact that the gene was highly expressed during symbiosis with all tested papilionoid and mimosoid plants. A metabolome analysis of papilionoid and mimosoid root nodules infected with the P. phymatum wild-type strain revealed that among the approximately 400 measured metabolites, homocitrate and other metabolites involved in lysine biosynthesis and degradation have accumulated in all plant nodules compared to uninfected roots, suggesting an important role of these metabolites during symbiosis. Full article

(This article belongs to the Special Issue Metabolomics in Plant Research)

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21 pages, 2389 KiB

Open AccessReview

Targeting Inflammatory Pathways in Cardiovascular Disease: The Inflammasome, Interleukin-1, Interleukin-6 and Beyond

by Peter Libby

Cells 2021, 10(4), 951; https://doi.org/10.3390/cells10040951 - 20 Apr 2021

Cited by 79 | Viewed by 7344

Abstract

Recent clinical trials have now firmly established that inflammation participates causally in human atherosclerosis. These observations point the way toward novel treatments that add to established therapies to help stem the growing global epidemic of cardiovascular disease. Fortunately, we now have a number [...] Read more.

Recent clinical trials have now firmly established that inflammation participates causally in human atherosclerosis. These observations point the way toward novel treatments that add to established therapies to help stem the growing global epidemic of cardiovascular disease. Fortunately, we now have a number of actionable targets whose clinical exploration will help achieve the goal of optimizing beneficial effects while avoiding undue interference with host defenses or other unwanted actions. This review aims to furnish the foundation for this quest by critical evaluation of the current state of anti-inflammatory interventions within close reach of clinical application, with a primary focus on innate immunity. In particular, this paper highlights the pathway from the inflammasome, through interleukin (IL)-1 to IL-6 supported by a promising body of pre-clinical, clinical, and human genetic data. This paper also considers the use of biomarkers to guide allocation of anti-inflammatory therapies as a step toward realizing the promise of precision medicine. The validation of decades of experimental work and association studies in humans by recent clinical investigations provides a strong impetus for further efforts to target inflammation in atherosclerosis to address the considerable risk that remains despite current therapies. Full article

(This article belongs to the Special Issue Inflammation and Atherosclerosis)

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18 pages, 1921 KiB

Open AccessReview

The Role of RhoH in TCR Signalling and Its Involvement in Diseases

by Ana Masara Ahmad Mokhtar, Ilie Fadzilah Hashim, Muaz Mohd Zaini Makhtar, Nor Hawani Salikin and Syafinaz Amin-Nordin

Cells 2021, 10(4), 950; https://doi.org/10.3390/cells10040950 - 20 Apr 2021

Cited by 15 | Viewed by 5073

Abstract

As an atypical member of the Rho family small GTPases, RhoH shares less than 50% sequence similarity with other members, and its expression is commonly observed in the haematopoietic lineage. To date, RhoH function was observed in regulating T cell receptor signalling, and [...] Read more.

As an atypical member of the Rho family small GTPases, RhoH shares less than 50% sequence similarity with other members, and its expression is commonly observed in the haematopoietic lineage. To date, RhoH function was observed in regulating T cell receptor signalling, and less is known in other haematopoietic cells. Its activation may not rely on the standard GDP/GTP cycling of small G proteins and is thought to be constitutively active because critical amino acids involved in GTP hydrolysis are absent. Alternatively, its activation can be regulated by other types of regulation, including lysosomal degradation, somatic mutation and transcriptional repressor, which also results in an altered protein expression. Aberrant protein expression of RhoH has been implicated not only in B cell malignancies but also in immune-related diseases, such as primary immunodeficiencies, systemic lupus erythematosus and psoriasis, wherein its involvement may provide the link between immune-related diseases and cancer. RhoH association with these diseases involves several other players, including its interacting partner, ZAP−70; activation regulators, Vav1 and RhoGDI and other small GTPases, such as RhoA, Rac1 and Cdc42. As such, RhoH and its associated proteins are potential attack points, especially in the treatment of cancer and immune-related diseases. Full article

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11 pages, 2187 KiB

Open AccessArticle

BK_Ca Channel Inhibition by Peripheral Nerve Injury Is Restored by the Xanthine Derivative KMUP-1 in Dorsal Root Ganglia

by Kuang-I Cheng, Kan-Ting Yang, Chien-Lun Kung, Yu-Chi Cheng, Jwu-Lai Yeh, Zen-Kong Dai and Bin-Nan Wu

Cells 2021, 10(4), 949; https://doi.org/10.3390/cells10040949 - 20 Apr 2021

Cited by 1 | Viewed by 2190

Abstract

This study explored whether KMUP-1 improved chronic constriction injury (CCI)-induced BK_Ca current inhibition in dorsal root ganglion (DRG) neurons. Rats were randomly assigned to four groups: sham, sham + KMUP-1, CCI, and CCI + KMUP-1 (5 mg/kg/day, i.p.). DRG neuronal cells (L4–L6) [...] Read more.

This study explored whether KMUP-1 improved chronic constriction injury (CCI)-induced BK_Ca current inhibition in dorsal root ganglion (DRG) neurons. Rats were randomly assigned to four groups: sham, sham + KMUP-1, CCI, and CCI + KMUP-1 (5 mg/kg/day, i.p.). DRG neuronal cells (L4–L6) were isolated on day 7 after CCI surgery. Perforated patch-clamp and inside-out recordings were used to monitor BK_Ca currents and channel activities, respectively, in the DRG neurons. Additionally, DRG neurons were immunostained with anti-NeuN, anti-NF200 and anti-BK_Ca. Real-time PCR was used to measure BK_Ca mRNA levels. In perforated patch-clamp recordings, CCI-mediated nerve injury inhibited BK_Ca currents in DRG neurons compared with the sham group, whereas KMUP-1 prevented this effect. CCI also decreased BK_Ca channel activity, which was recovered by KMUP-1 administration. Immunofluorescent staining further demonstrated that CCI reduced BK_Ca-channel proteins, and KMUP-1 reversed this. KMUP-1 also changed CCI-reduced BK_Ca mRNA levels. KMUP-1 prevented CCI-induced neuropathic pain and BK_Ca current inhibition in a peripheral nerve injury model, suggesting that KMUP-1 could be a potential agent for controlling neuropathic pain. Full article

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17 pages, 3003 KiB

Open AccessEditor’s ChoiceReview

Coordinated and Independent Roles for MLH Subunits in DNA Repair

by Gianno Pannafino and Eric Alani

Cells 2021, 10(4), 948; https://doi.org/10.3390/cells10040948 - 20 Apr 2021

Cited by 13 | Viewed by 5435

Abstract

The MutL family of DNA mismatch repair proteins (MMR) acts to maintain genomic integrity in somatic and meiotic cells. In baker’s yeast, the MutL homolog (MLH) MMR proteins form three heterodimeric complexes, MLH1-PMS1, MLH1-MLH2, and MLH1-MLH3. The recent discovery of human PMS2 (homolog [...] Read more.

The MutL family of DNA mismatch repair proteins (MMR) acts to maintain genomic integrity in somatic and meiotic cells. In baker’s yeast, the MutL homolog (MLH) MMR proteins form three heterodimeric complexes, MLH1-PMS1, MLH1-MLH2, and MLH1-MLH3. The recent discovery of human PMS2 (homolog of baker’s yeast PMS1) and MLH3 acting independently of human MLH1 in the repair of somatic double-strand breaks questions the assumption that MLH1 is an obligate subunit for MLH function. Here we provide a summary of the canonical roles for MLH factors in DNA genomic maintenance and in meiotic crossover. We then present the phenotypes of cells lacking specific MLH subunits, particularly in meiotic recombination, and based on this analysis, propose a model for an independent early role for MLH3 in meiosis to promote the accurate segregation of homologous chromosomes in the meiosis I division. Full article

(This article belongs to the Special Issue DNA Repair, Genome Stability/Diversity, and Oxidative Stress and Aging, from Bacteria to Human Cells: A Themed Issue in Honor of Prof. Miroslav Radman)

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15 pages, 12185 KiB

Open AccessArticle

The Role of Galectin-9 as Mediator of Atopic Dermatitis: Effect on Keratinocytes

by Mab P. Corrêa, Libnah L. Areias, Rebeca D. Correia-Silva, Solange C. G. P. D’Ávila, Andréia M. Leopoldino, Karin V. Greco and Cristiane D. Gil

Cells 2021, 10(4), 947; https://doi.org/10.3390/cells10040947 - 20 Apr 2021

Cited by 4 | Viewed by 3292

Abstract

Galectin-9 (Gal-9) is a beta-galactoside-binding protein with a variety of biological functions related to immune response. However, in allergic diseases, its mechanism of action is not fully understood. This study evaluates the expression pattern of Gal-9 in patients with atopic dermatitis (AD), in [...] Read more.

Galectin-9 (Gal-9) is a beta-galactoside-binding protein with a variety of biological functions related to immune response. However, in allergic diseases, its mechanism of action is not fully understood. This study evaluates the expression pattern of Gal-9 in patients with atopic dermatitis (AD), in ovalbumin (OVA)-induced experimental atopic dermatitis (AD) in mice, as well as its effect on human keratinocytes. The skin of OVA-immunized BALB/c mice was challenged with drops containing OVA on days 11, 14–18, and 21–24. HaCaT cells were cultured in the following experimental conditions: control (growth medium only) or stimulated with TNF-α/IFN-γ, or IL-4, or IL-17 with or without Gal-9 treatment. AD was characterized by increased levels of Gal-9 in mouse and human skin, especially in the epidermis, and with a marked influx of Gal-9 positive eosinophils and mast cells compared to the control group. Gal-9 showed an immunomodulatory effect on keratinocytes by decreasing the release of IL-6 by IL-4-stimulated keratinocytes or increasing the IL-6 and RANTES levels by IL-17- or TNF-α/IFN-γ-stimulated cells, respectively. Under IL-17, Gal-9 treatment also altered the proliferation rate of cells. Overall, increased levels of Gal-9 in AD skin contribute to the control of inflammatory response and the proliferative process of keratinocytes, suggesting this lectin as a relevant therapeutic target. Full article

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16 pages, 2207 KiB

Open AccessArticle

Proline Concentration and Its Metabolism Are Regulated in a Leaf Age Dependent Manner But Not by Abscisic Acid in Pea Plants Exposed to Cadmium Stress

by Edyta Zdunek-Zastocka, Agnieszka Grabowska, Beata Michniewska and Sławomir Orzechowski

Cells 2021, 10(4), 946; https://doi.org/10.3390/cells10040946 - 20 Apr 2021

Cited by 26 | Viewed by 3458

Abstract

The accumulation of proline is one of the defense mechanisms of plants against the harmful effects of adverse environmental conditions; however, when pea plants were treated for 12 h with CdCl₂, the proline concentration decreased in the youngest A (not expanded) [...] Read more.

The accumulation of proline is one of the defense mechanisms of plants against the harmful effects of adverse environmental conditions; however, when pea plants were treated for 12 h with CdCl₂, the proline concentration decreased in the youngest A (not expanded) and B1 (expanded) leaves, and did not change significantly in the B2 (mature, expanded) or C (the oldest) leaves. After 24 h of cadmium (Cd) stress, the proline concentration remained low in A and B1 leaves, while in B2 and C leaves, it increased, and after 48 h, an increase in the proline concentration in the leaves at each stage of development was observed. The role of proline in the different phases of plant response to the Cd treatment is discussed. Changes in proline accumulation corresponded closely with changes in the transcript levels of PsP5CS2, a gene encoding D1-pyrroline-5-carboxylate synthetase involved in proline synthesis, and PsPDH1, a gene encoding proline dehydrogenase engaged in proline degradation. CdCl₂ application induced the expression of PsProT1 and PsProT2, genes encoding proline transporters, especially during the first 12 h of treatment in A and B1 leaves. When the time courses of abscisic acid (ABA) and proline accumulation were compared, it was concluded that an increase in the proline concentration in the leaves of Cd-treated pea plants was more related to a decrease in chlorophyll concentration (leaves B2 and C) and an increase in the malondialdehyde level (A and B1 leaves) than with an increase in ABA concentration alone. Exogenous application of ABA (0.5, 5, 50 µM) significantly increased the proline concentration in the A leaves of pea plants only, and was accompanied by an elevated and repressed expression of PsP5CS2 and PsPDH1 in these leaves, respectively. The presented results suggest that under Cd stress, the accumulation of proline in leaves of pea plants may take place independently of the ABA signaling. Full article

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

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8 pages, 445 KiB

Open AccessReview

Learning Yeast Genetics from Miro Radman

by James E. Haber

Cells 2021, 10(4), 945; https://doi.org/10.3390/cells10040945 - 20 Apr 2021

Cited by 1 | Viewed by 2447

Abstract

Miroslav Radman’s far-sighted ideas have penetrated many aspects of our study of the repair of broken eukaryotic chromosomes. For over 35 years my lab has studied different aspects of the repair of chromosomal breaks in the budding yeast, Saccharomyces cerevisiae. From the [...] Read more.

Miroslav Radman’s far-sighted ideas have penetrated many aspects of our study of the repair of broken eukaryotic chromosomes. For over 35 years my lab has studied different aspects of the repair of chromosomal breaks in the budding yeast, Saccharomyces cerevisiae. From the start, we have made what we thought were novel observations that turned out to have been predicted by Miro’s extraordinary work in the bacterium Escherichia coli and then later in the radiation-resistant Dienococcus radiodurans. In some cases, we have been able to extend some of his ideas a bit further. Full article

(This article belongs to the Special Issue DNA Repair, Genome Stability/Diversity, and Oxidative Stress and Aging, from Bacteria to Human Cells: A Themed Issue in Honor of Prof. Miroslav Radman)

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14 pages, 2698 KiB

Open AccessArticle

Clusterin Deficiency Exacerbates Hyperoxia-Induced Acute Lung Injury

by Jung Yeon Hong, Mi Na Kim, Eun Gyul Kim, Jae Woo Lee, Hye Rin Kim, Soo Yeon Kim, Soon Min Lee, Yoon Hee Kim, Kyung Won Kim and Myung Hyun Sohn

Cells 2021, 10(4), 944; https://doi.org/10.3390/cells10040944 - 19 Apr 2021

Cited by 10 | Viewed by 2899

Abstract

Exposure to high oxygen concentrations leads to generation of excessive reactive oxygen species, causing cellular injury and multiple organ dysfunctions and is associated with a high mortality rate. Clusterin (CLU) is a heterodimeric glycoprotein that mediates several intracellular signaling pathways, including cell death [...] Read more.

Exposure to high oxygen concentrations leads to generation of excessive reactive oxygen species, causing cellular injury and multiple organ dysfunctions and is associated with a high mortality rate. Clusterin (CLU) is a heterodimeric glycoprotein that mediates several intracellular signaling pathways, including cell death and inflammation. However, the role of CLU in the pathogenesis of hyperoxic acute lung injury (HALI) is unknown. Wild-type (WT) and CLU-deficient mice and cultured human airway epithelial cells were used. Changes in cell death- and inflammation-related molecules with or without hyperoxia exposure in cells and animals were determined. Hyperoxia induced an increase in CLU expression in mouse lungs and human airway epithelial cells. Mice lacking CLU had increased HALI and mortality rate compared with WT mice. In vitro, CLU-disrupted cells showed enhanced release of cytochrome c, Bax translocation, cell death and inflammatory cytokine expression. However, treatment with recombinant CLU attenuated hyperoxia-induced apoptosis. Moreover, the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses revealed metabolic pathways, hematopoietic cell lineage, response to stress and localization and regulation of immune system that were differentially regulated between WT and CLU^−/− mice. These results demonstrate that prolonged hyperoxia-induced lung injury is associated with CLU expression and that CLU replenishment may alleviate hyperoxia-induced cell death. Full article

(This article belongs to the Section Cell Signaling)

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17 pages, 34153 KiB

Open AccessArticle

Genome-Wide Identification and Expression Analysis of SOS Response Genes in Salmonella enterica Serovar Typhimurium

by Angela Mérida-Floriano, Will P. M. Rowe and Josep Casadesús

Cells 2021, 10(4), 943; https://doi.org/10.3390/cells10040943 - 19 Apr 2021

Cited by 10 | Viewed by 3497

Abstract

A bioinformatic search for LexA boxes, combined with transcriptomic detection of loci responsive to DNA damage, identified 48 members of the SOS regulon in the genome of Salmonella enterica serovar Typhimurium. Single cell analysis using fluorescent fusions revealed that heterogeneous expression is a [...] Read more.

A bioinformatic search for LexA boxes, combined with transcriptomic detection of loci responsive to DNA damage, identified 48 members of the SOS regulon in the genome of Salmonella enterica serovar Typhimurium. Single cell analysis using fluorescent fusions revealed that heterogeneous expression is a common trait of SOS response genes, with formation of SOS^OFF and SOS^ON subpopulations. Phenotypic cell variants formed in the absence of external DNA damage show gene expression patterns that are mainly determined by the position and the heterology index of the LexA box. SOS induction upon DNA damage produces SOS^OFF and SOS^ON subpopulations that contain live and dead cells. The nature and concentration of the DNA damaging agent and the time of exposure are major factors that influence the population structure upon SOS induction. An analogy can thus be drawn between the SOS response and other bacterial stress responses that produce phenotypic cell variants. Full article

(This article belongs to the Special Issue DNA Repair, Genome Stability/Diversity, and Oxidative Stress and Aging, from Bacteria to Human Cells: A Themed Issue in Honor of Prof. Miroslav Radman)

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18 pages, 7102 KiB

Open AccessArticle

MRCKα Is Dispensable for Breast Cancer Development in the MMTV-PyMT Model

by Mei Qi Kwa, Rafael Brandao, Trong H. Phung, Jianfeng Ge, Giuseppe Scieri and Cord Brakebusch

Cells 2021, 10(4), 942; https://doi.org/10.3390/cells10040942 - 19 Apr 2021

Cited by 2 | Viewed by 3410

Abstract

MRCKα is a ubiquitously expressed serine/threonine kinase involved in cell contraction and F-actin turnover, which is highly amplified in human breast cancer and part of a gene expression signature for bad prognosis. Nothing is known about the in vivo function of MRCKα. To [...] Read more.

MRCKα is a ubiquitously expressed serine/threonine kinase involved in cell contraction and F-actin turnover, which is highly amplified in human breast cancer and part of a gene expression signature for bad prognosis. Nothing is known about the in vivo function of MRCKα. To explore MRCKα function in development and in breast cancer, we generated mice lacking a functional MRCKα gene. Mice were born close to the Mendelian ratio and showed no obvious phenotype including a normal mammary gland formation. Assessing breast cancer development using the transgenic MMTV-PyMT mouse model, loss of MRCKα did not affect tumor onset, tumor growth and metastasis formation. Deleting MRCKα and its related family member MRCKβ in two triple-negative breast cancer cell lines resulted in reduced invasion of MDA-MB-231 cells, but did not affect migration of 4T1 cells. Further genomic analysis of human breast cancers revealed that MRCKα is frequently co-amplified with the oncogenes ARID4B and AKT3 which might contribute to the prognostic value of MRCKα expression. Collectively, these data suggest that MRCKα might be a prognostic marker for breast cancer, but probably of limited functional importance. Full article

(This article belongs to the Section Cell Signaling)

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28 pages, 1370 KiB

Open AccessReview

Dendritic Cells: Neglected Modulators of Peripheral Immune Responses and Neuroinflammation in Mood Disorders?

by Rafael Leite Dantas, Jana Freff, Oliver Ambrée, Eva C. Beins, Andreas J. Forstner, Udo Dannlowski, Bernhard T. Baune, Stefanie Scheu and Judith Alferink

Cells 2021, 10(4), 941; https://doi.org/10.3390/cells10040941 - 19 Apr 2021

Cited by 12 | Viewed by 5887

Abstract

Affective disorders (AD) including major depressive disorder (MDD) and bipolar disorder (BD) are common mood disorders associated with increased disability and poor health outcomes. Altered immune responses characterized by increased serum levels of pro-inflammatory cytokines and neuroinflammation are common findings in patients with [...] Read more.

Affective disorders (AD) including major depressive disorder (MDD) and bipolar disorder (BD) are common mood disorders associated with increased disability and poor health outcomes. Altered immune responses characterized by increased serum levels of pro-inflammatory cytokines and neuroinflammation are common findings in patients with AD and in corresponding animal models. Dendritic cells (DCs) represent a heterogeneous population of myeloid cells that orchestrate innate and adaptive immune responses and self-tolerance. Upon sensing exogenous and endogenous danger signals, mature DCs secrete proinflammatory factors, acquire migratory and antigen presenting capacities and thus contribute to neuroinflammation in trauma, autoimmunity, and neurodegenerative diseases. However, little is known about the involvement of DCs in the pathogenesis of AD. In this review, we summarize the current knowledge on DCs in peripheral immune responses and neuroinflammation in MDD and BD. In addition, we consider the impact of DCs on neuroinflammation and behavior in animal models of AD. Finally, we will discuss therapeutic perspectives targeting DCs and their effector molecules in mood disorders. Full article

(This article belongs to the Special Issue Studies around Neuroinflammation - Series 2)

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14 pages, 1665 KiB

Open AccessArticle

Placenta-Expanded Stromal Cell Therapy in a Rodent Model of Simulated Weightlessness

by Linda Rubinstein, Amber M. Paul, Charles Houseman, Metadel Abegaz, Steffy Tabares Ruiz, Nathan O’Neil, Gilad Kunis, Racheli Ofir, Jacob Cohen, April E. Ronca, Ruth K. Globus and Candice G. T. Tahimic

Cells 2021, 10(4), 940; https://doi.org/10.3390/cells10040940 - 19 Apr 2021

Cited by 4 | Viewed by 4149

Abstract

Long duration spaceflight poses potential health risks to astronauts during flight and re-adaptation after return to Earth. There is an emerging need for NASA to provide successful and reliable therapeutics for long duration missions when capability for medical intervention will be limited. Clinically [...] Read more.

Long duration spaceflight poses potential health risks to astronauts during flight and re-adaptation after return to Earth. There is an emerging need for NASA to provide successful and reliable therapeutics for long duration missions when capability for medical intervention will be limited. Clinically relevant, human placenta-derived therapeutic stromal cells (PLX-PAD) are a promising therapeutic alternative. We found that treatment of adult female mice with PLX-PAD near the onset of simulated weightlessness by hindlimb unloading (HU, 30 d) was well-tolerated and partially mitigated decrements caused by HU. Specifically, PLX-PAD treatment rescued HU-induced thymic atrophy, and mitigated HU-induced changes in percentages of circulating neutrophils, but did not rescue changes in the percentages of lymphocytes, monocytes, natural killer (NK) cells, T-cells and splenic atrophy. Further, PLX-PAD partially mitigated HU effects on the expression of select cytokines in the hippocampus. In contrast, PLX-PAD failed to protect bone and muscle from HU-induced effects, suggesting that the mechanisms which regulate the structure of these mechanosensitive tissues in response to disuse are discrete from those that regulate the immune- and central nervous system (CNS). These findings support the therapeutic potential of placenta-derived stromal cells for select physiological deficits during simulated spaceflight. Multiple countermeasures are likely needed for comprehensive protection from the deleterious effects of prolonged spaceflight. Full article

(This article belongs to the Section Stem Cells)

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13 pages, 1204 KiB

Open AccessReview

The Expression Regulation and Biological Function of Autotaxin

by Xiaotian Zhang, Mengmiao Li, Nan Yin and Junjie Zhang

Cells 2021, 10(4), 939; https://doi.org/10.3390/cells10040939 - 19 Apr 2021

Cited by 49 | Viewed by 5698

Abstract

Autotaxin (ATX) is a secreted glycoprotein and functions as a key enzyme to produce extracellular lysophosphatidic acid (LPA). LPA interacts with at least six G protein-coupled receptors, LPAR1-6, on the cell membrane to activate various signal transduction pathways through distinct G proteins, such [...] Read more.

Autotaxin (ATX) is a secreted glycoprotein and functions as a key enzyme to produce extracellular lysophosphatidic acid (LPA). LPA interacts with at least six G protein-coupled receptors, LPAR1-6, on the cell membrane to activate various signal transduction pathways through distinct G proteins, such as Gi/0, G12/13, Gq/11, and Gs. The ATX-LPA axis plays an important role in physiological and pathological processes, including embryogenesis, obesity, and inflammation. ATX is one of the top 40 most unregulated genes in metastatic cancer, and the ATX-LPA axis is involved in the development of different types of cancers, such as colorectal cancer, ovarian cancer, breast cancer, and glioblastoma. ATX expression is under multifaceted controls at the transcription, post-transcription, and secretion levels. ATX and LPA in the tumor microenvironment not only promote cell proliferation, migration, and survival, but also increase the expression of inflammation-related circuits, which results in poor outcomes for patients with cancer. Currently, ATX is regarded as a potential cancer therapeutic target, and an increasing number of ATX inhibitors have been developed. In this review, we focus on the mechanism of ATX expression regulation and the functions of ATX in cancer development. Full article

(This article belongs to the Special Issue Role and Signaling Mechanisms of LPA in Cancer Development)

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19 pages, 1757 KiB

Open AccessReview

Neurobiological Processes Induced by Aerobic Exercise through the Endocannabinoidome

by Fabiola Forteza, Giada Giorgini and Frédéric Raymond

Cells 2021, 10(4), 938; https://doi.org/10.3390/cells10040938 - 17 Apr 2021

Cited by 14 | Viewed by 4849

Abstract

Evidence suggesting the triangulation of the endocannabinoid system, exercise, and neurological health is emerging. In addition to the endocannabinoids N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG), the expanded endocannabinoid system, known as the endocannabinoidome (eCBome), appears to be an important player in this [...] Read more.

Evidence suggesting the triangulation of the endocannabinoid system, exercise, and neurological health is emerging. In addition to the endocannabinoids N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG), the expanded endocannabinoid system, known as the endocannabinoidome (eCBome), appears to be an important player in this relationship. The eCBome includes several endocannabinoid-like mediators such as N-acylethanolamines and 2-monoacylglycerols, the enzymes involved in their biosynthesis and degradation, and the receptors they affect. This review aims to relate the functional interactions between aerobic exercise, and the molecular and cellular pathways related to endocannabinoids, in the hypothalamus, hippocampus, and the periphery, with special attention given to associations with emotional state, cognition, and mental health. Given the well-documented roles of many eCBome members in regulating stress and neurological processes, we posit that the eCBome is an important effector of exercise-induced central and peripheral adaptive mechanisms that benefit mental health. Gut microbiota imbalance, affecting the gut-brain axis and metabolism, also influences certain eCBome-modulated inflammation pathways. The integrity of the gut microbiota could thus be crucial in the onset of neuroinflammation and mental conditions. Further studies on how the modulation by exercise of the peripheral eCBome affects brain functions could reveal to be key elements in the prevention and treatment of neuropsychological disorders. Full article

(This article belongs to the Special Issue The Endocannabinoidome: A Pleiotropic Expanded Endocannabinoid System Controlling Cell Function)

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23 pages, 6754 KiB

Open AccessArticle

Polyunsaturated Phospholipids Increase Cell Resilience to Mechanical Constraints

by Linette Kadri, Amélie Bacle, Spiro Khoury, Clarisse Vandebrouck, Jocelyn Bescond, Jean-François Faivre, Thierry Ferreira and Stéphane Sebille

Cells 2021, 10(4), 937; https://doi.org/10.3390/cells10040937 - 17 Apr 2021

Cited by 5 | Viewed by 2615

Abstract

If polyunsaturated fatty acids (PUFAs) are generally accepted to be good for health, the mechanisms of their bona fide benefits still remain elusive. Membrane phospholipids (PLs) of the cardiovascular system and skeletal muscles are particularly enriched in PUFAs. The fatty acid composition of [...] Read more.

If polyunsaturated fatty acids (PUFAs) are generally accepted to be good for health, the mechanisms of their bona fide benefits still remain elusive. Membrane phospholipids (PLs) of the cardiovascular system and skeletal muscles are particularly enriched in PUFAs. The fatty acid composition of PLs is known to regulate crucial membrane properties, including elasticity and plasticity. Since muscle cells undergo repeated cycles of elongation and relaxation, we postulated in the present study that PUFA-containing PLs could be central players for muscle cell adaptation to mechanical constraints. By a combination of in cellulo and in silico approaches, we show that PUFAs, and particularly the ω-3 docosahexaenoic acid (DHA), regulate important properties of the plasma membrane that improve muscle cell resilience to mechanical constraints. Thanks to their unique property to contortionate within the bilayer plane, they facilitate the formation of vacuole-like dilation (VLD), which, in turn, avoid cell breakage under mechanical constraints. Full article

(This article belongs to the Section Intracellular and Plasma Membranes)

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15 pages, 3395 KiB

Open AccessArticle

The Effect of the Clenbuterol—β2-Adrenergic Receptor Agonist on the Peripheral Blood Mononuclear Cells Proliferation, Phenotype, Functions, and Reactive Oxygen Species Production in Race Horses In Vitro

by Olga Witkowska-Piłaszewicz, Rafał Pingwara, Jarosław Szczepaniak and Anna Winnicka

Cells 2021, 10(4), 936; https://doi.org/10.3390/cells10040936 - 17 Apr 2021

Cited by 3 | Viewed by 4912

Abstract

Clenbuterol, the β2-adrenoceptor agonist, is gaining growing popularity because of its effects on weight loss (i.e., chemical liposuction). It is also popular in bodybuilding and professional sports, due to its effects that are similar to anabolic steroids. However, it is prohibited by anti-doping [...] Read more.

Clenbuterol, the β2-adrenoceptor agonist, is gaining growing popularity because of its effects on weight loss (i.e., chemical liposuction). It is also popular in bodybuilding and professional sports, due to its effects that are similar to anabolic steroids. However, it is prohibited by anti-doping control. On the other hand, it is suggested that clenbuterol can inhibit the inflammatory process. The cells from 14 untrained and 14 well-trained race horses were collected after acute exercise and cultured with clenbuterol. The expressions of CD4, CD8, FoxP3, CD14, MHCII, and CD5 in PBMC, and reactive oxygen species (ROS) production, as well as cell proliferation, were evaluated by flow cytometry. In addition, IL-1β, IL-4, IL-6, IL-10, IL-17, INF-γ and TNF-α concentrations were evaluated by ELISA. β2-adrenoceptor stimulation leads to enhanced anti-inflammatory properties in well-trained horses, as do low doses in untrained animals. In contrast, higher clenbuterol doses create a pro-inflammatory environment in inexperienced horses. In conclusion, β2-adrenoceptor stimulation leads to a biphasic response. In addition, the immune cells are more sensitive to drug abuse in inexperienced individuals under physical training. Full article

(This article belongs to the Special Issue Novel Insight into Cell Cycle and Proliferation: Impact on Pathophysiology and Translational Medicine)

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24 pages, 4233 KiB

Open AccessArticle

Bacillus subtilis PcrA Helicase Removes Trafficking Barriers

by María Moreno-del Álamo, Begoña Carrasco, Rubén Torres and Juan Carlos Alonso

Cells 2021, 10(4), 935; https://doi.org/10.3390/cells10040935 - 17 Apr 2021

Cited by 11 | Viewed by 2792

Abstract

Bacillus subtilis PcrA interacts with the RNA polymerase and might contribute to mitigate replication–transcription conflicts (RTCs). We show that PcrA depletion lethality is partially suppressed by rnhB inactivation, but cell viability is significantly reduced by rnhC or dinG inactivation. Following PcrA depletion, cells [...] Read more.

Bacillus subtilis PcrA interacts with the RNA polymerase and might contribute to mitigate replication–transcription conflicts (RTCs). We show that PcrA depletion lethality is partially suppressed by rnhB inactivation, but cell viability is significantly reduced by rnhC or dinG inactivation. Following PcrA depletion, cells lacking RnhC or DinG are extremely sensitive to DNA damage. Chromosome segregation is not further impaired by rnhB or dinG inactivation but is blocked by rnhC or recA inactivation upon PcrA depletion. Despite our efforts, we could not construct a ΔrnhC ΔrecA strain. These observations support the idea that PcrA dismantles RTCs. Purified PcrA, which binds single-stranded (ss) DNA over RNA, is a ssDNA-dependent ATPase and preferentially unwinds DNA in a 3′→5′direction. PcrA unwinds a 3′-tailed RNA of an RNA-DNA hybrid significantly faster than that of a DNA substrate. Our results suggest that a replicative stress, caused by mis-incorporated rNMPs, indirectly increases cell viability upon PcrA depletion. We propose that PcrA, in concert with RnhC or DinG, contributes to removing spontaneous or enzyme-driven R-loops, to counteract deleterious trafficking conflicts and preserve to genomic integrity. Full article

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14 pages, 2915 KiB

Open AccessArticle

The p23 of Citrus Tristeza Virus Interacts with Host FKBP-Type Peptidyl-Prolylcis-Trans Isomerase 17-2 and Is Involved in the Intracellular Movement of the Viral Coat Protein

by Zuokun Yang, Yongle Zhang, Guoping Wang, Shaohua Wen, Yanxiang Wang, Liu Li, Feng Xiao and Ni Hong

Cells 2021, 10(4), 934; https://doi.org/10.3390/cells10040934 - 17 Apr 2021

Cited by 9 | Viewed by 3240

Abstract

Citrus tristeza virus is a member of the genus Closterovirus in the family Closteroviridae. The p23 of citrus tristeza virus (CTV) is a multifunctional protein and RNA silencing suppressor. In this study, we identified a p23 interacting partner, FK506-binding protein (FKBP) 17-2, [...] Read more.

Citrus tristeza virus is a member of the genus Closterovirus in the family Closteroviridae. The p23 of citrus tristeza virus (CTV) is a multifunctional protein and RNA silencing suppressor. In this study, we identified a p23 interacting partner, FK506-binding protein (FKBP) 17-2, from Citrus aurantifolia (CaFKBP17-2), a susceptible host, and Nicotiana benthamiana (NbFKBP17-2), an experimental host for CTV. The interaction of p23 with CaFKBP17-2 and NbFKBP17-2 were individually confirmed by yeast two-hybrid (Y2H) and bimolecular fluorescence complementation (BiFC) assays. Subcellular localization tests showed that the viral p23 translocated FKBP17-2 from chloroplasts to the plasmodesmata of epidermal cells of N. benthamiana leaves. The knocked-down expression level of NbFKBP17-2 mRNA resulted in a decreased CTV titer in N. benthamiana plants. Further, BiFC and Y2H assays showed that NbFKBP17-2 also interacted with the coat protein (CP) of CTV, and the complexes of CP/NbFKBP17-2 rapidly moved in the cytoplasm. Moreover, p23 guided the CP/NbFKBP17-2 complexes to move along the cell wall. To the best of our knowledge, this is the first report of viral proteins interacting with FKBP17-2 encoded by plants. Our results provide insights for further revealing the mechanism of the CTV CP protein movement. Full article

(This article belongs to the Collection Plant-Virus/Viroid-Vector Interactions)

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