Cells

11 pages, 2631 KiB

Open AccessArticle

The Oocyte-Specific Linker Histone H1FOO Is Not Essential for Mouse Oogenesis and Fertility

by Fernando Sánchez-Sáez, Raquel Sainz-Urruela, Natalia Felipe-Medina, Yazmine B. Condezo, Manuel Sánchez-Martín, Elena Llano and Alberto M. Pendás

Cells 2022, 11(22), 3706; https://doi.org/10.3390/cells11223706 - 21 Nov 2022

Cited by 4 | Viewed by 2417

Abstract

Meiosis is a highly conserved specialized cell division process that generates haploid gametes. Many of its events are associated with dynamically regulated chromosomal structures and chromatin remodeling, which are mainly modulated by histone modifications. Histone H1 is a linker histone essential for packing [...] Read more.

Meiosis is a highly conserved specialized cell division process that generates haploid gametes. Many of its events are associated with dynamically regulated chromosomal structures and chromatin remodeling, which are mainly modulated by histone modifications. Histone H1 is a linker histone essential for packing the nucleosome into higher-order structures, and H1FOO (H1 histone family, member O, oocyte-specific) is a H1 variant whose expression pattern is restricted to growing oocytes and zygotes. To further explore the function of H1FOO, we generated mice lacking the H1foo gene by the CRISPR/Cas9 technique. Herein, we combine mouse genetics and cellular studies to show that H1foo-null mutants have no overt phenotype, with both males and females being fertile and presenting no gross defects in meiosis progression nor in synapsis dynamics. Accordingly, the histological sections show a normal development of gametes in both male and female mice. Considering the important role of oocyte constituents in enhancing mammalian somatic cell reprogramming, we analyzed iPSCs generation in H1foo mutant MEFs and observed no differences in the absence of H1FOO. Taken all together, in this work we present the first in vivo evidence of H1FOO dispensability for mouse fertility, clarifying the debate in the field surrounding its essentiality in meiosis. Full article

(This article belongs to the Section Cell Proliferation and Division)

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21 pages, 1414 KiB

Open AccessReview

In Vitro Veritas: From 2D Cultures to Organ-on-a-Chip Models to Study Immunogenic Cell Death in the Tumor Microenvironment

by Dmitri V. Krysko, Robin Demuynck, Iuliia Efimova, Faye Naessens, Olga Krysko and Elena Catanzaro

Cells 2022, 11(22), 3705; https://doi.org/10.3390/cells11223705 - 21 Nov 2022

Cited by 10 | Viewed by 3411

Abstract

Immunogenic cell death (ICD) is a functionally unique form of cell death that promotes a T-cell-dependent anti-tumor immune response specific to antigens originating from dying cancer cells. Many anticancer agents and strategies induce ICD, but despite their robust effects in vitro and in [...] Read more.

Immunogenic cell death (ICD) is a functionally unique form of cell death that promotes a T-cell-dependent anti-tumor immune response specific to antigens originating from dying cancer cells. Many anticancer agents and strategies induce ICD, but despite their robust effects in vitro and in vivo on mice, translation into the clinic remains challenging. A major hindrance in antitumor research is the poor predictive ability of classic 2D in vitro models, which do not consider tumor biological complexity, such as the contribution of the tumor microenvironment (TME), which plays a crucial role in immunosuppression and cancer evasion. In this review, we describe different tumor models, from 2D cultures to organ-on-a-chip technology, as well as spheroids and perfusion bioreactors, all of which mimic the different degrees of the TME complexity. Next, we discuss how 3D cell cultures can be applied to study ICD and how to increase the translational potential of the ICD inducers. Finally, novel research directions are provided regarding ICD in the 3D cellular context which may lead to novel immunotherapies for cancer. Full article

(This article belongs to the Special Issue Immunogenic Cell Stress and Death)

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20 pages, 1419 KiB

Open AccessReview

The Role of NO/sGC/cGMP/PKG Signaling Pathway in Regulation of Platelet Function

by Stepan Gambaryan

Cells 2022, 11(22), 3704; https://doi.org/10.3390/cells11223704 - 21 Nov 2022

Cited by 19 | Viewed by 4374

Abstract

Circulating blood platelets are controlled by stimulatory and inhibitory factors, and a tightly regulated equilibrium between these two opposing processes is essential for normal platelet and vascular function. NO/cGMP/ Protein Kinase G (PKG) pathways play a highly significant role in platelet inhibition, which [...] Read more.

Circulating blood platelets are controlled by stimulatory and inhibitory factors, and a tightly regulated equilibrium between these two opposing processes is essential for normal platelet and vascular function. NO/cGMP/ Protein Kinase G (PKG) pathways play a highly significant role in platelet inhibition, which is supported by a large body of studies and data. This review focused on inconsistent and controversial data of NO/sGC/cGMP/PKG signaling in platelets including sources of NO that activate sGC in platelets, the role of sGC/PKG in platelet inhibition/activation, and the complexity of the regulation of platelet inhibitory mechanisms by cGMP/PKG pathways. In conclusion, we suggest that the recently developed quantitative phosphoproteomic method will be a powerful tool for the analysis of PKG-mediated effects. Analysis of phosphoproteins in PKG-activated platelets will reveal many new PKG substrates. A future detailed analysis of these substrates and their involvement in different platelet inhibitory pathways could be a basis for the development of new antiplatelet drugs that may target only specific aspects of platelet functions. Full article

(This article belongs to the Special Issue Exclusive Review Papers in "Cell Signaling")

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12 pages, 3721 KiB

Open AccessArticle

Hyperuricemia during Pregnancy Leads to a Preeclampsia-Like Phenotype in Mice

by Benjamin P. Lüscher, Andreina Schoeberlein, Daniel V. Surbek and Marc U. Baumann

Cells 2022, 11(22), 3703; https://doi.org/10.3390/cells11223703 - 21 Nov 2022

Cited by 5 | Viewed by 2396

Abstract

Hyperuricemia is a common feature in pregnancies compromised by pre-eclampsia, a pregnancy disease characterized by hypertension and proteinuria. The role of uric acid in the pathogenesis of pre-eclampsia remains largely unclear. The aim of this study was to investigate the effect of elevated [...] Read more.

Hyperuricemia is a common feature in pregnancies compromised by pre-eclampsia, a pregnancy disease characterized by hypertension and proteinuria. The role of uric acid in the pathogenesis of pre-eclampsia remains largely unclear. The aim of this study was to investigate the effect of elevated uric acid serum levels during pregnancy on maternal blood pressure and neonatal outcome using two different murine knockout models. Non-pregnant liver-specific GLUT9 knockout (LG9KO) mice showed elevated uric acid serum concentrations but no hypertensive blood pressure levels. During pregnancy, however, blood pressure levels of these animals increased in the second and third trimester, and circadian blood pressure dipping was severely altered when compared to non-pregnant LG9KO mice. The impact of hyperuricemia on fetal development was investigated using a systemic GLUT9 knockout (G9KO) mouse model. Fetal hyperuricemia caused distinctive renal tissue injuries and, subsequently an impaired neonatal growth pattern. These findings provide strong evidence that hyperuricemia plays a major role in the pathogenesis of hypertensive pregnancy disorders such as pre-eclampsia. These novel insights may enable the development of preventive and therapeutic strategies for hyperuricemia-related diseases. Full article

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26 pages, 3487 KiB

Open AccessReview

Overlapping Machinery in Lysosome-Related Organelle Trafficking: A Lesson from Rare Multisystem Disorders

by Blerida Banushi and Fiona Simpson

Cells 2022, 11(22), 3702; https://doi.org/10.3390/cells11223702 - 21 Nov 2022

Cited by 9 | Viewed by 4241

Abstract

Lysosome-related organelles (LROs) are a group of functionally diverse, cell type-specific compartments. LROs include melanosomes, alpha and dense granules, lytic granules, lamellar bodies and other compartments with distinct morphologies and functions allowing specialised and unique functions of their host cells. The formation, maturation [...] Read more.

Lysosome-related organelles (LROs) are a group of functionally diverse, cell type-specific compartments. LROs include melanosomes, alpha and dense granules, lytic granules, lamellar bodies and other compartments with distinct morphologies and functions allowing specialised and unique functions of their host cells. The formation, maturation and secretion of specific LROs are compromised in a number of hereditary rare multisystem disorders, including Hermansky-Pudlak syndromes, Griscelli syndrome and the Arthrogryposis, Renal dysfunction and Cholestasis syndrome. Each of these disorders impacts the function of several LROs, resulting in a variety of clinical features affecting systems such as immunity, neurophysiology and pigmentation. This has demonstrated the close relationship between LROs and led to the identification of conserved components required for LRO biogenesis and function. Here, we discuss aspects of this conserved machinery among LROs in relation to the heritable multisystem disorders they associate with, and present our current understanding of how dysfunctions in the proteins affected in the disease impact the formation, motility and ultimate secretion of LROs. Moreover, we have analysed the expression of the members of the CHEVI complex affected in Arthrogryposis, Renal dysfunction and Cholestasis syndrome, in different cell types, by collecting single cell RNA expression data from the human protein atlas. We propose a hypothesis describing how transcriptional regulation could constitute a mechanism that regulates the pleiotropic functions of proteins and their interacting partners in different LROs. Full article

(This article belongs to the Special Issue Cell Metabolism: Lessons for Common Disease from Rare Metabolic Defects)

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20 pages, 2597 KiB

Open AccessArticle

Melatonin Attenuates Ischemic-like Cell Injury by Promoting Autophagosome Maturation via the Sirt1/FoxO1/Rab7 Axis in Hippocampal HT22 Cells and in Organotypic Cultures

by Francesca Luchetti, Maria G. Nasoni, Sabrina Burattini, Atefeh Mohammadi, Marica Pagliarini, Barbara Canonico, Patrizia Ambrogini, Walter Balduini, Russel J. Reiter and Silvia Carloni

Cells 2022, 11(22), 3701; https://doi.org/10.3390/cells11223701 - 21 Nov 2022

Cited by 6 | Viewed by 2421

Abstract

Dysfunctional autophagy is linked to neuronal damage in ischemia/reperfusion injury. The Ras-related protein 7 (Rab7), a member of the Rab family of small GTPases, appears crucial for the progression of the autophagic flux, and its activity is strictly interconnected with the histone deacetylase [...] Read more.

Dysfunctional autophagy is linked to neuronal damage in ischemia/reperfusion injury. The Ras-related protein 7 (Rab7), a member of the Rab family of small GTPases, appears crucial for the progression of the autophagic flux, and its activity is strictly interconnected with the histone deacetylase Silent information regulator 1 (Sirt1) and transcription factor Forkhead box class O1 (FoxO1). The present study assessed the neuroprotective role of melatonin in the modulation of the Sirt1/FoxO1/Rab7 axis in HT22 cells and organotypic hippocampal cultures exposed to oxygen-glucose deprivation followed by reoxygenation (OGD/R). The results showed that melatonin re-established physiological levels of autophagy and reduced propidium iodide-positive cells, speeding up autophagosome (AP) maturation and increasing lysosomal activity. Our study revealed that melatonin modulates autophagic pathways, increasing the expression of both Rab7 and FoxO1 and restoring the Sirt1 expression affected by OGD/R. In addition, the Sirt1 inhibitor EX-527 significantly reduced Rab7, Sirt1, and FoxO1 expression, as well as autolysosomes formation, and blocked the neuroprotective effect of melatonin. Overall, our findings provide, for the first time, new insights into the neuroprotective role of melatonin against ischemic injury through the activation of the Sirt1/FoxO1/Rab7 axis. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying Organ Damage in Ischemia and Reperfusion Injury)

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12 pages, 721 KiB

Open AccessReview

Targeting PIM Kinases to Improve the Efficacy of Immunotherapy

by Amber N. Clements and Noel A. Warfel

Cells 2022, 11(22), 3700; https://doi.org/10.3390/cells11223700 - 21 Nov 2022

Cited by 8 | Viewed by 2916

Abstract

The Proviral Integration site for Moloney murine leukemia virus (PIM) kinases is a family of serine/threonine kinases that regulates numerous signaling networks that promote cell growth, proliferation, and survival. PIM kinases are commonly upregulated in both solid tumors and hematological malignancies. Recent studies [...] Read more.

The Proviral Integration site for Moloney murine leukemia virus (PIM) kinases is a family of serine/threonine kinases that regulates numerous signaling networks that promote cell growth, proliferation, and survival. PIM kinases are commonly upregulated in both solid tumors and hematological malignancies. Recent studies have demonstrated that PIM facilitates immune evasion in cancer by promoting an immunosuppressive tumor microenvironment that suppresses the innate anti-tumor response. The role of PIM in immune evasion has sparked interest in examining the effect of PIM inhibition in combination with immunotherapy. This review focuses on the role of PIM kinases in regulating immune cell populations, how PIM modulates the immune tumor microenvironment to promote immune evasion, and how PIM inhibitors may be used to enhance the efficacy of immunotherapy. Full article

(This article belongs to the Special Issue Inhibiting Immune Checkpoint-Expressing Cells for Tumor Therapy)

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27 pages, 2440 KiB

Open AccessReview

Cancer Stem Cells—The Insight into Non-Coding RNAs

by Rut Bryl, Oliwia Piwocka, Emilia Kawka, Paul Mozdziak, Bartosz Kempisty and Agnieszka Knopik-Skrocka

Cells 2022, 11(22), 3699; https://doi.org/10.3390/cells11223699 - 21 Nov 2022

Cited by 4 | Viewed by 3168

Abstract

Since their initial identification three decades ago, there has been extensive research regarding cancer stem cells (CSCs). It is important to consider the biology of cancer stem cells with a particular focus on their phenotypic and metabolic plasticity, the most important signaling pathways, [...] Read more.

Since their initial identification three decades ago, there has been extensive research regarding cancer stem cells (CSCs). It is important to consider the biology of cancer stem cells with a particular focus on their phenotypic and metabolic plasticity, the most important signaling pathways, and non-coding RNAs (ncRNAs) regulating these cellular entities. Furthermore, the current status of therapeutic approaches against CSCs is an important consideration regarding employing the technology to improve human health. Cancer stem cells have claimed to be one of the most important group of cells for the development of several common cancers as they dictate features, such as resistance to radio- and chemotherapy, metastasis, and secondary tumor formation. Therapies which could target these cells may develop into an effective strategy for tumor eradication and a hope for patients for whom this disease remains uncurable. Full article

(This article belongs to the Special Issue Genetic, Epigenetic, and Transcriptional Control of Cancer Stem Cell)

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23 pages, 4341 KiB

Open AccessReview

The Role of IL-6 in Cancer Cell Invasiveness and Metastasis—Overview and Therapeutic Opportunities

by Magdalena Rašková, Lukáš Lacina, Zdeněk Kejík, Anna Venhauerová, Markéta Skaličková, Michal Kolář, Milan Jakubek, Daniel Rosel, Karel Smetana, Jr. and Jan Brábek

Cells 2022, 11(22), 3698; https://doi.org/10.3390/cells11223698 - 21 Nov 2022

Cited by 79 | Viewed by 7057

Abstract

Interleukin 6 (IL-6) belongs to a broad class of cytokines involved in the regulation of various homeostatic and pathological processes. These activities range from regulating embryonic development, wound healing and ageing, inflammation, and immunity, including COVID-19. In this review, we summarise the role [...] Read more.

Interleukin 6 (IL-6) belongs to a broad class of cytokines involved in the regulation of various homeostatic and pathological processes. These activities range from regulating embryonic development, wound healing and ageing, inflammation, and immunity, including COVID-19. In this review, we summarise the role of IL-6 signalling pathways in cancer biology, with particular emphasis on cancer cell invasiveness and metastasis formation. Targeting principal components of IL-6 signalling (e.g., IL-6Rs, gp130, STAT3, NF-κB) is an intensively studied approach in preclinical cancer research. It is of significant translational potential; numerous studies strongly imply the remarkable potential of IL-6 signalling inhibitors, especially in metastasis suppression. Full article

(This article belongs to the Special Issue Role of Cytokines and Other Soluble Factors in Tumor Development: Rationale for New Therapeutic Strategies)

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19 pages, 2819 KiB

Open AccessReview

Etiopathogenesis, Diagnosis, and Treatment Strategies for Lymphomatoid Papulosis with Particular Emphasis on the Role of the Immune System

by Danuta Nowicka, Paulina Mertowska, Sebastian Mertowski, Anna Hymos, Alicja Forma, Adam Michalski, Izabela Morawska, Rafał Hrynkiewicz, Paulina Niedźwiedzka-Rystwej and Ewelina Grywalska

Cells 2022, 11(22), 3697; https://doi.org/10.3390/cells11223697 - 21 Nov 2022

Cited by 7 | Viewed by 3269

Abstract

Lymphomatoid papulosis (LyP) is a very rare disease that belongs to the group of CD30+ lymphoproliferative skin diseases. LyP is localized or generalized and usually presents as isolated or clustered red/brown-red lesions in the form of nodules and/or papules. The course of the [...] Read more.

Lymphomatoid papulosis (LyP) is a very rare disease that belongs to the group of CD30+ lymphoproliferative skin diseases. LyP is localized or generalized and usually presents as isolated or clustered red/brown-red lesions in the form of nodules and/or papules. The course of the disease is in most cases mild; however, depending on concomitant risk factors and history, it may progress to lymphoma, significantly reducing the survival rate and prognosis. Importantly, the clinical picture of the disease remains somewhat ambiguous, leading to a large number of misdiagnoses that result in inappropriate treatment, which is usually insufficient to alleviate symptoms. In addition to clinical manifestations, the histological characteristics vary widely and usually overlap with other conditions, especially those belonging to the group of lymphoproliferative disorders. Although diagnosis remains a challenge, several recommendations and guidelines have been introduced to standardize and facilitate the diagnostic process. This article reviews the available literature on the most important aspects of etiopathogenesis, clinical and histopathological features, diagnostic criteria, and possible treatment strategies for LyP, with particular emphasis on the role of the immune system. Full article

(This article belongs to the Special Issue Cellular Mechanisms of Skin Diseases)

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18 pages, 1901 KiB

Open AccessReview

The Influence of Interdisciplinary Work towards Advancing Knowledge on Human Liver Physiology

by Blanca Delgado-Coello, Nalu Navarro-Alvarez and Jaime Mas-Oliva

Cells 2022, 11(22), 3696; https://doi.org/10.3390/cells11223696 - 21 Nov 2022

Cited by 2 | Viewed by 2375

Abstract

The knowledge accumulated throughout the years about liver regeneration has allowed a better understanding of normal liver physiology, by reconstructing the sequence of steps that this organ follows when it must rebuild itself after being injured. The scientific community has used several interdisciplinary [...] Read more.

The knowledge accumulated throughout the years about liver regeneration has allowed a better understanding of normal liver physiology, by reconstructing the sequence of steps that this organ follows when it must rebuild itself after being injured. The scientific community has used several interdisciplinary approaches searching to improve liver regeneration and, therefore, human health. Here, we provide a brief history of the milestones that have advanced liver surgery, and review some of the new insights offered by the interdisciplinary work using animals, in vitro models, tissue engineering, or mathematical models to help advance the knowledge on liver regeneration. We also present several of the main approaches currently available aiming at providing liver support and overcoming organ shortage and we conclude with some of the challenges found in clinical practice and the ethical issues that have concomitantly emerged with the use of those approaches. Full article

(This article belongs to the Collection Interdisciplinary Approaches to Studying Human Liver Biology and Promoting Organ Regeneration: Understanding the Curse of Prometheus)

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19 pages, 2755 KiB

Open AccessArticle

Preconditioned Mesenchymal Stromal Cell-Derived Extracellular Vesicles (EVs) Counteract Inflammaging

by Cansu Gorgun, Chiara Africano, Maria Chiara Ciferri, Nadia Bertola, Daniele Reverberi, Rodolfo Quarto, Silvia Ravera and Roberta Tasso

Cells 2022, 11(22), 3695; https://doi.org/10.3390/cells11223695 - 21 Nov 2022

Cited by 3 | Viewed by 2417

Abstract

Inflammaging is one of the evolutionarily conserved mechanisms underlying aging and is defined as the long-term consequence of the chronic stimulation of the innate immune system. As macrophages are intimately involved in initiating and regulating the inflammatory process, their dysregulation plays major roles [...] Read more.

Inflammaging is one of the evolutionarily conserved mechanisms underlying aging and is defined as the long-term consequence of the chronic stimulation of the innate immune system. As macrophages are intimately involved in initiating and regulating the inflammatory process, their dysregulation plays major roles in inflammaging. The paracrine factors, and in particular extracellular vesicles (EVs), released by mesenchymal stromal cells (MSCs) retain immunoregulatory effects on innate and adaptive immune responses. In this paper, we demonstrate that EVs derived from MSCs preconditioned with hypoxia inflammatory cytokines exerted an anti-inflammatory role in the context of inflammaging. In this study, macrophages isolated from aged mice presented elevated pro-inflammatory factor levels already in basal conditions compared to the young counterpart, and this pre-activation status increased when cells were challenged with IFN-γ. EVs were able to attenuate the age-associated inflammation, inducing a decrease in the expression of TNF-α, iNOS, and the NADase CD38. Moreover, we demonstrate that EVs counteracted the mitochondrial dysfunction that affected the macrophages, reducing lipid peroxidation and hindering the age-associated impairment of mitochondrial complex I activity, oxygen consumption, and ATP synthesis. These results indicate that preconditioned MSC-derived EVs might be exploited as new anti-aging therapies in a variety of age-related diseases. Full article

(This article belongs to the Section Cellular Aging)

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21 pages, 1430 KiB

Open AccessArticle

Increased Lipid Peroxidation and Lowered Antioxidant Defenses Predict Methamphetamine Induced Psychosis

by Hussein Kadhem Al-Hakeim, Mazin Fadhil Altufaili, Abbas F. Almulla, Shatha Rouf Moustafa and Michael Maes

Cells 2022, 11(22), 3694; https://doi.org/10.3390/cells11223694 - 21 Nov 2022

Cited by 6 | Viewed by 2237

Abstract

Background: a significant percentage of methamphetamine (MA) dependent patients develop psychosis. The associations between oxidative pathways and MA-induced psychosis (MIP) are not well delineated. Objective: the aim of this study is to delineate whether acute MA intoxication in MA dependent patients is accompanied [...] Read more.

Background: a significant percentage of methamphetamine (MA) dependent patients develop psychosis. The associations between oxidative pathways and MA-induced psychosis (MIP) are not well delineated. Objective: the aim of this study is to delineate whether acute MA intoxication in MA dependent patients is accompanied by increased nitro-oxidative stress and whether the latter is associated with MIP. Method: we recruited 30 healthy younger males and 60 acutely intoxicated males with MA dependence and assessed severity of MA use and dependence and psychotic symptoms during intoxication, and serum oxidative toxicity (OSTOX) biomarkers including oxidized high (oxHDL) and low (oxLDL)-density lipoprotein, myeloperoxidase (MPO), malondialdehyde (MDA), and nitric oxide (NO), and antioxidant defenses (ANTIOX) including HDL-cholesterol, zinc, glutathione peroxidase (GPx), total antioxidant capacity (TAC), and catalase-1. Results: a large part (50%, n = 30) of patients with MA dependence could be allocated to a cluster characterized by high psychosis ratings including delusions, suspiciousness, conceptual disorganization and difficulties abstract thinking and an increased OSTOX/ANTIOX ratio. Partial Least Squares analysis showed that 29.9% of the variance in MIP severity (a first factor extracted from psychosis, hostility, excitation, mannerism, and formal thought disorder scores) was explained by HDL, TAC and zinc (all inversely) and oxLDL (positively). MA dependence and dosing explained together 44.7% of the variance in the OSTOX/ANTIOX ratio. Conclusions: MA dependence and intoxication are associated with increased oxidative stress and lowered antioxidant defenses, both of which increase risk of MIP during acute intoxication. MA dependence is accompanied by increased atherogenicity due to lowered HDL and increased oxLDL and oxHDL. Full article

(This article belongs to the Special Issue Peripheral and Central Immune-Inflammatory Pathways in Mood Disorders and Schizophrenia)

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14 pages, 2586 KiB

Open AccessArticle

Trypanosoma cruzi DNA Polymerase β Is Phosphorylated In Vivo and In Vitro by Protein Kinase C (PKC) and Casein Kinase 2 (CK2)

by Edio Maldonado, Diego A. Rojas, Fabiola Urbina, Lucía Valenzuela-Pérez, Christian Castillo and Aldo Solari

Cells 2022, 11(22), 3693; https://doi.org/10.3390/cells11223693 - 21 Nov 2022

Cited by 1 | Viewed by 1936

Abstract

DNA polymerase β plays a fundamental role in the life cycle of Trypanosoma cruzi since it participates in the kinetoplast DNA repair and replication. This enzyme can be found in two forms in cell extracts of T. cruzi epimastigotes form. The H form [...] Read more.

DNA polymerase β plays a fundamental role in the life cycle of Trypanosoma cruzi since it participates in the kinetoplast DNA repair and replication. This enzyme can be found in two forms in cell extracts of T. cruzi epimastigotes form. The H form is a phosphorylated form of DNA polymerase β, while the L form is not phosphorylated. The protein kinases which are able to in vivo phosphorylate DNA polymerase β have not been identified yet. In this work, we purified the H form of this DNA polymerase and identified the phosphorylation sites. DNA polymerase β is in vivo phosphorylated at several amino acid residues including Tyr35, Thr123, Thr137 and Ser286. Thr123 is phosphorylated by casein kinase 2 and Thr137 and Ser286 are phosphorylated by protein kinase C-like enzymes. Protein kinase C encoding genes were identified in T. cruzi, and those genes were cloned, expressed in bacteria and the recombinant protein was purified. It was found that T. cruzi possesses three different protein kinase C-like enzymes named TcPKC1, TcPKC2, and TcPKC3. Both TcPKC1 and TcPKC2 were able to in vitro phosphorylate recombinant DNA polymerase β, and in addition, TcPKC1 gets auto phosphorylated. Those proteins contain several regulatory domains at the N-terminus, which are predicted to bind phosphoinositols, and TcPKC1 contains a lipocalin domain at the C-terminus that might be able to bind free fatty acids. Tyr35 is phosphorylated by an unidentified protein kinase and considering that the T. cruzi genome does not contain Tyr kinase encoding genes, it is probable that Tyr35 could be phosphorylated by a dual protein kinase. Wee1 is a eukaryotic dual protein kinase involved in cell cycle regulation. We identified a Wee1 homolog in T. cruzi and the recombinant kinase was assayed using DNA polymerase β as a substrate. T. cruzi Wee1 was able to in vitro phosphorylate recombinant DNA polymerase β, although we were not able to demonstrate specific phosphorylation on Tyr35. Those results indicate that there exists a cell signaling pathway involving PKC-like kinases in T. cruzi. Full article

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14 pages, 2487 KiB

Open AccessCommunication

CAR-Macrophages and CAR-T Cells Synergistically Kill Tumor Cells In Vitro

by Maoxuan Liu, Junchen Liu, Ziwei Liang, Kun Dai, Jiangyu Gan, Qi Wang, Yang Xu, Youhai H. Chen and Xiaochun Wan

Cells 2022, 11(22), 3692; https://doi.org/10.3390/cells11223692 - 21 Nov 2022

Cited by 31 | Viewed by 6136

Abstract

Chimeric antigen receptor (CAR)-expressing macrophages (CAR-M) have a great potential to improve cancer therapy, as shown from several recent preclinical studies. However, unlike CAR-T cell therapy, which has been widely studied, the efficacy and limitations of CAR-M cells remain to be established. To [...] Read more.

Chimeric antigen receptor (CAR)-expressing macrophages (CAR-M) have a great potential to improve cancer therapy, as shown from several recent preclinical studies. However, unlike CAR-T cell therapy, which has been widely studied, the efficacy and limitations of CAR-M cells remain to be established. To address this issue, in the present study, we compared three intracellular signaling domains (derived from common γ subunit of Fc receptors (FcRγ), multiple EGF-like-domains protein 10 (Megf10), and the CD19 cytoplasmic domain that recruits the p85 subunit of phosphoinositide-3 kinase (PI3K), respectively) for their ability to promote primary CAR-M functions, and investigated the potential synergistic effect between CAR-M and CAR-T cells in their ability to kill tumor cells. We found that CAR-M^FcRγ exerted more potent phagocytic and tumor-killing capacity than CAR-M^Megf10 and CAR-M^PI3K. CAR-M and CAR-T demonstrated synergistic cytotoxicity against tumor cells in vitro. Mechanistically, the inflammatory factors secreted by CAR-T increased the expression of costimulatory ligands (CD86 and CD80) on CAR-M and augmented the cytotoxicity of CAR-M by inducing macrophage M1 polarization. The upregulated costimulatory ligands may promote the fitness and activation of CAR-T cells in turn, achieving significantly enhanced cytotoxicity. Taken together, our study demonstrated for the first time that CAR-M could synergize with CAR-T cells to kill tumor cells, which provides proof-of-concept for a novel combinational immunotherapy. Full article

(This article belongs to the Section Cell and Gene Therapy)

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10 pages, 1102 KiB

Open AccessArticle

Inactivation of Autophagy in Keratinocytes Reduces Tumor Growth in Mouse Models of Epithelial Skin Cancer

by Caterina Barresi, Heidemarie Rossiter, Maria Buchberger, Johannes Pammer, Supawadee Sukseree, Maria Sibilia, Erwin Tschachler and Leopold Eckhart

Cells 2022, 11(22), 3691; https://doi.org/10.3390/cells11223691 - 21 Nov 2022

Cited by 6 | Viewed by 1783

Abstract

Autophagy is a ubiquitous degradation mechanism, which plays a critical role in cellular homeostasis. To test whether autophagy suppresses or supports the growth of tumors in the epidermis of the skin, we inactivated the essential autophagy gene Atg7 specifically in the epidermal keratinocytes [...] Read more.

Autophagy is a ubiquitous degradation mechanism, which plays a critical role in cellular homeostasis. To test whether autophagy suppresses or supports the growth of tumors in the epidermis of the skin, we inactivated the essential autophagy gene Atg7 specifically in the epidermal keratinocytes of mice (Atg7^∆ep) and subjected such mutant mice and fully autophagy-competent mice to tumorigenesis. The lack of epithelial Atg7 did not prevent tumor formation in response to 7, 12-dimethylbenz(a)anthracene (DMBA) as the initiator and 12-O tetradecanoylphorbol-13-acetate (TPA) as the promoter of tumor growth. However, the number of tumors per mouse was reduced in mice with epithelial Atg7 deficiency. In the K5-SOS EGFR^wa2/wa2 mouse model, epithelial tumors were initiated by Son of sevenless (SOS) in response to wounding. Within 12 weeks after tumor initiation, 60% of the autophagy-competent K5-SOS EGFR^wa2/wa2 mice had tumors of 1 cm diameter and had to be sacrificed, whereas none of the Atg7^∆ep K5-SOS EGFR^wa2/wa2 mice formed tumors of this size. In summary, the deletion of Atg7 reduced the growth of epithelial tumors in these two mouse models of skin cancer. Thus, our data show that the inhibition of autophagy limits the growth of epithelial skin tumors. Full article

(This article belongs to the Special Issue Autophagy and Inflammation in Chronic Disease)

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25 pages, 866 KiB

Open AccessReview

Signaling Pathways Regulating Human Cervical Ripening in Preterm and Term Delivery

by Maciej W. Socha, Wojciech Flis, Miłosz Pietrus, Mateusz Wartęga and Martyna Stankiewicz

Cells 2022, 11(22), 3690; https://doi.org/10.3390/cells11223690 - 21 Nov 2022

Cited by 12 | Viewed by 6747

Abstract

At the end of gestation, the cervical tissue changes profoundly. As a result of these changes, the uterine cervix becomes soft and vulnerable to dilation. The process occurring in the cervical tissue can be described as cervical ripening. The ripening is a process [...] Read more.

At the end of gestation, the cervical tissue changes profoundly. As a result of these changes, the uterine cervix becomes soft and vulnerable to dilation. The process occurring in the cervical tissue can be described as cervical ripening. The ripening is a process derivative of enzymatic breakdown and inflammatory response. Therefore, it is apparent that cervical remodeling is a derivative of the reactions mediated by multiple factors such as hormones, prostaglandins, nitric oxide, and inflammatory cytokines. However, despite the research carried out over the years, the cellular pathways responsible for regulating this process are still poorly understood. A comprehensive understanding of the entire process of cervical ripening seems crucial in the context of labor induction. Greater knowledge could provide us with the means to help women who suffer from dysfunctional labor. The overall objective of this review is to present the current understanding of cervical ripening in terms of molecular regulation and cell signaling. Full article

(This article belongs to the Special Issue Signaling Pathways in Pregnancy)

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17 pages, 13752 KiB

Open AccessEssay

Involvement of DAAO Overexpression in Delayed Hippocampal Neuronal Death

by Hao Liu, Jun-Tao Zhang, Chen-Ye Mou, Yue Hao and Wei Cui

Cells 2022, 11(22), 3689; https://doi.org/10.3390/cells11223689 - 21 Nov 2022

Cited by 3 | Viewed by 2186

Abstract

Background: D-amino acid oxidase (DAAO) is a flavoenzyme that specifically catalyzes the deamination of many neutral and basic D-amino acids. This study aims to explore the pathological increment of hippocampal DAAO and its potential relationship with delayed hippocampal neuronal death. Methods: Ischemia–reperfusion was [...] Read more.

Background: D-amino acid oxidase (DAAO) is a flavoenzyme that specifically catalyzes the deamination of many neutral and basic D-amino acids. This study aims to explore the pathological increment of hippocampal DAAO and its potential relationship with delayed hippocampal neuronal death. Methods: Ischemia–reperfusion was induced in mice through middle cerebral artery occlusion (MCAO). Neurological deficit scores and hippocampal neuronal death were assessed in MCAO mice. Immunofluorescent staining was applied to identify activated astrocytes and evaluate DAAO expression. TUNEL and Nissl staining were utilized to identify cell apoptosis of hippocampal neurons. Results: Hippocampal astrocytic DAAO was strikingly increased following ischemic stroke, with the greatest increase on day 5 after surgery, followed by the manifestation of neurobehavioral deficits. Astrocytic DAAO was found to be mainly expressed in the hippocampal CA2 region and linked with subsequent specific neural apoptosis. Thus, it is supposed that the activation of astrocytic DAAO in ischemic stroke might contribute to neuronal death. An intravenous, twice-daily administration of 4H-furo[3,2-b]pyrrole-5-carboxylic acid (SUN, 10 mg/kg) markedly relieved behavioral status and delayed hippocampal neuronal death by 38.0% and 41.5%, respectively, compared to the model group treated with saline. In transfected primary astrocytes, DAAO overexpression inhibits cell activity, induces cytotoxicity, and promotes hippocampal neuronal death at least partly by enhancing H₂O₂ levels with subsequent activation of TRP calcium channels in neurons. Conclusions: Our findings suggest that increased hippocampal DAAO is causally associated with the development of delayed neuronal death after MCAO onset via astrocyte–neuron interactions. Hence, targeting DAAO is a promising therapeutic strategy for the management of neurological disorders. Full article

(This article belongs to the Special Issue Advance in Neuron-Glia Interaction: From Brain-Physiology To-Pathology)

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14 pages, 638 KiB

Open AccessReview

Sex-Dependent Differences in Colorectal Cancer: With a Focus on Obesity

by Prachi Wele, Xian Wu and Haifei Shi

Cells 2022, 11(22), 3688; https://doi.org/10.3390/cells11223688 - 20 Nov 2022

Cited by 15 | Viewed by 3366

Abstract

Colorectal cancer (CRC) is the third most common cancer and has the second highest cancer-related mortality in the world. The incident rates of CRC vary country-wise; however, population studies and data from different countries show a general increase in the CRC rate in [...] Read more.

Colorectal cancer (CRC) is the third most common cancer and has the second highest cancer-related mortality in the world. The incident rates of CRC vary country-wise; however, population studies and data from different countries show a general increase in the CRC rate in young adults, males, and females ≥65 years. CRC incidence is affected by age, sex, environmental, dietary, hormonal, and lifestyle factors. Obesity is a known disease that is spreading rapidly throughout the world. A large body of literature indicates that, among many conditions, obesity is the increasing cause of CRC. Even though obesity is one of the known factors for CRC development, limited studies are available that explain the mechanistic link between obesity, sex hormones, and CRC development. Thus, this review summarizes the literature and aims to understand sex-dependent differences in CRC, especially in the context of obesity. Full article

(This article belongs to the Special Issue Effects of Sex Hormones in the Regulation of Energy Metabolism in Health and Diseases)

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14 pages, 1125 KiB

Open AccessReview

RUNX Proteins as Epigenetic Modulators in Cancer

by Hongyang Yi, Yuhao He, Qionghua Zhu and Liang Fang

Cells 2022, 11(22), 3687; https://doi.org/10.3390/cells11223687 - 20 Nov 2022

Cited by 6 | Viewed by 2840

Abstract

RUNX proteins are highly conserved in metazoans and perform critical functions during development. Dysregulation of RUNX proteins through various molecular mechanisms facilitates the development and progression of various cancers, where different RUNX proteins show tumor type-specific functions and regulate different aspects of tumorigenesis [...] Read more.

RUNX proteins are highly conserved in metazoans and perform critical functions during development. Dysregulation of RUNX proteins through various molecular mechanisms facilitates the development and progression of various cancers, where different RUNX proteins show tumor type-specific functions and regulate different aspects of tumorigenesis by cross-talking with different signaling pathways such as Wnt, TGF-β, and Hippo. Molecularly, they could serve as transcription factors (TFs) to activate their direct target genes or interact with many other TFs to modulate chromatin architecture globally. Here, we review the current knowledge on the functions and regulations of RUNX proteins in different cancer types and highlight their potential role as epigenetic modulators in cancer. Full article

(This article belongs to the Special Issue Roles of RUNX Family in Cancer)

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14 pages, 4086 KiB

Open AccessArticle

Natural Cross-Kingdom Spread of Apple Scar Skin Viroid from Apple Trees to Fungi

by Mengyuan Tian, Shuang Wei, Ruiling Bian, Jingxian Luo, Haris Ahmed Khan, Huanhuan Tai, Hideki Kondo, Ahmed Hadidi, Ida Bagus Andika and Liying Sun

Cells 2022, 11(22), 3686; https://doi.org/10.3390/cells11223686 - 20 Nov 2022

Cited by 13 | Viewed by 2375

Abstract

Viroids are the smallest known infectious agents that are thought to only infect plants. Here, we reveal that several species of plant pathogenic fungi that were isolated from apple trees infected with apple scar skin viroid (ASSVd) carried ASSVd naturally. This finding indicates [...] Read more.

Viroids are the smallest known infectious agents that are thought to only infect plants. Here, we reveal that several species of plant pathogenic fungi that were isolated from apple trees infected with apple scar skin viroid (ASSVd) carried ASSVd naturally. This finding indicates the spread of viroids to fungi under natural conditions and further suggests the possible existence of mycoviroids in nature. A total of 117 fungal isolates were isolated from ASSVd-infected apple trees, with the majority (85.5%) being an ascomycete Alternaria alternata and the remaining isolates being other plant-pathogenic or -endophytic fungi. Out of the examined samples, viroids were detected in 81 isolates (69.2%) including A. alternata as well as other fungal species. The phenotypic comparison of ASSVd-free specimens developed by single-spore isolation and ASSVd-infected fungal isogenic lines showed that ASSVd affected the growth and pathogenicity of certain fungal species. ASSVd confers hypovirulence on ascomycete Epicoccum nigrum. The mycobiome analysis of apple tree-associated fungi showed that ASSVd infection did not generally affect the diversity and structure of fungal communities but specifically increased the abundance of Alternaria species. Taken together, these data reveal the occurrence of the natural spread of viroids to plants; additionally, as an integral component of the ecosystem, viroids may affect the abundance of certain fungal species in plants. Moreover, this study provides further evidence that viroid infection could induce symptoms in certain filamentous fungi. Full article

(This article belongs to the Special Issue Celebrating 50 Years of Viroid Discovery)

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22 pages, 4746 KiB

Open AccessArticle

The Molecular Signature of Human Testicular Peritubular Cells Revealed by Single-Cell Analysis

by Annika Liebich, Nina Schmid, Christina Koupourtidou, Carola Herrmann, Kim-Gwendolyn Dietrich, Harald Welter, Jovica Ninkovic and Artur Mayerhofer

Cells 2022, 11(22), 3685; https://doi.org/10.3390/cells11223685 - 19 Nov 2022

Cited by 6 | Viewed by 2715

Abstract

Peritubular cells of the human testis form a small compartment surrounding the seminiferous tubules. They are crucial for sperm transport, and they emerge as contributors to the spermatogonial stem cell niche. They are among the least known cell types of the human body. [...] Read more.

Peritubular cells of the human testis form a small compartment surrounding the seminiferous tubules. They are crucial for sperm transport, and they emerge as contributors to the spermatogonial stem cell niche. They are among the least known cell types of the human body. We employed single-cell RNA sequencing of cultured human testicular peritubular cells (HTPCs), which had been isolated from testicular samples of donors with normal spermatogenesis. The significant overlap between our results and recently published ex vivo data indicates that HTPCs are a highly adequate cellular model to define and study these cells. Thus, based on the expression of several markers, HTPCs can be classified as testicular smooth muscle cells. Small differences between the in vivo/in vitro expressed genes may be due to cellular plasticity. Plasticity was also shown upon addition of FCS to the culture medium. Based on transcriptome similarities, four cellular states were identified. Further analyses confirmed the presence of known stem cell niche-relevant factors (e.g., GDNF) and identified unknown functions, e.g., the ability to produce retinoic acid. Therefore, HTPCs allow us to define the signature(s) and delineate the functions of human testicular peritubular cells. The data may also serve as a resource for future studies to better understand male (in)fertility. Full article

(This article belongs to the Section Reproductive Cells and Development)

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17 pages, 358 KiB

Open AccessReview

The Species of Gut Bacteria Associated with Antitumor Immunity in Cancer Therapy

by Xiaoqiang Qi, Yajun Liu, Samira Hussein, Grace Choi, Eric T. Kimchi, Kevin F. Staveley-O’Carroll and Guangfu Li

Cells 2022, 11(22), 3684; https://doi.org/10.3390/cells11223684 - 19 Nov 2022

Cited by 4 | Viewed by 3177

Abstract

Both preclinical and clinical studies have demonstrated that the modulation of gut microbiota could be a promising strategy for enhancing antitumor immune responses and reducing resistance to immunotherapy in cancer. Various mechanisms, including activation of pattern recognition receptors, gut commensals-produced metabolites and antigen [...] Read more.

Both preclinical and clinical studies have demonstrated that the modulation of gut microbiota could be a promising strategy for enhancing antitumor immune responses and reducing resistance to immunotherapy in cancer. Various mechanisms, including activation of pattern recognition receptors, gut commensals-produced metabolites and antigen mimicry, have been revealed. Different gut microbiota modulation strategies have been raised, such as fecal microbiota transplantation, probiotics, and dietary selection. However, the identification of gut bacteria species that are either favorable or unfavorable for cancer therapy remains a major challenge. Herein, we summarized the findings related to gut microbiota species observed in the modulation of antitumor immunity. We also discussed the different mechanisms underlying different gut bacteria’s functions and the potential applications of these bacteria to cancer immunotherapy in the future. Full article

(This article belongs to the Section Cellular Immunology)

16 pages, 674 KiB

Open AccessReview

Cell Dissemination in Pancreatic Cancer

by Jungsun Kim

Cells 2022, 11(22), 3683; https://doi.org/10.3390/cells11223683 - 19 Nov 2022

Cited by 8 | Viewed by 3255

Abstract

Pancreatic cancer is a disease notorious for its high frequency of recurrence and low survival rate. Surgery is the most effective treatment for localized pancreatic cancer, but most cancer recurs after surgery, and patients die within ten years of diagnosis. The question persists: [...] Read more.

Pancreatic cancer is a disease notorious for its high frequency of recurrence and low survival rate. Surgery is the most effective treatment for localized pancreatic cancer, but most cancer recurs after surgery, and patients die within ten years of diagnosis. The question persists: what makes pancreatic cancer recur and metastasize with such a high frequency? Herein, we review evidence that subclinical dormant pancreatic cancer cells disseminate before developing metastatic or recurring cancer. We then discuss several routes by which pancreatic cancer migrates and the mechanisms by which pancreatic cancer cells adapt. Lastly, we discuss unanswered questions in pancreatic cancer cell migration and our perspectives. Full article

(This article belongs to the Special Issue Pancreatic Cancer: From Molecular Mechanisms to Therapeutic Opportunities)

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20 pages, 4805 KiB

Open AccessArticle

S-nitrosylated PARIS Leads to the Sequestration of PGC-1α into Insoluble Deposits in Parkinson’s Disease Model

by Hanna Kim, Ji-Yeong Lee, Soo Jeong Park, Eunsang Kwag, Jihye Kim and Joo-Ho Shin

Cells 2022, 11(22), 3682; https://doi.org/10.3390/cells11223682 - 19 Nov 2022

Cited by 6 | Viewed by 2541

Abstract

Neuronal accumulation of parkin-interacting substrate (PARIS), a transcriptional repressor of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), has been observed in Parkinson’s disease (PD). Herein, we showed that PARIS can be S-nitrosylated at cysteine 265 (C265), and S-nitrosylated PARIS (SNO-PARIS) translocates to the [...] Read more.

Neuronal accumulation of parkin-interacting substrate (PARIS), a transcriptional repressor of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), has been observed in Parkinson’s disease (PD). Herein, we showed that PARIS can be S-nitrosylated at cysteine 265 (C265), and S-nitrosylated PARIS (SNO-PARIS) translocates to the insoluble fraction, leading to the sequestration of PGC-1α into insoluble deposits. The mislocalization of PGC-1α in the insoluble fraction was observed in S-nitrosocysteine-treated PARIS knockout (KO) cells overexpressing PARIS WT but not S-nitrosylation deficient C265S mutant, indicating that insolubility of PGC-1α is SNO-PARIS-dependent. In the sporadic PD model, α-synuclein preformed fibrils (α-syn PFFs)-injected mice, we found an increase in PARIS, SNO-PARIS, and insoluble sequestration of PGC-1α in substantia nigra (SN), resulting in the reduction of mitochondrial DNA copy number and ATP concentration that were restored by N(ω)-nitro-L-arginine methyl ester, a nitric oxide synthase (NOS) inhibitor. To assess the dopaminergic (DA) neuronal toxicity by SNO-PARIS, lentiviral PARIS WT, C265S, and S-nitrosylation mimic C265W was injected into the SN of either PBS- or α-syn PFFs-injected mice. PARIS WT and C265S caused DA neuronal death to a comparable extent, whereas C265W caused more severe DA neuronal loss in PBS-injected mice. Interestingly, there was synergistic DA loss in both lenti-PARIS WT and α-syn PFFs-injected mice, indicating that SNO-PARIS by α-syn PFFs contributes to the DA toxicity in vivo. Moreover, α-syn PFFs-mediated increment of PARIS, SNO-PARIS, DA toxicity, and behavioral deficits were completely nullified in neuronal NOS KO mice, suggesting that modulation of NO can be a therapeutic for α-syn PFFs-mediated neurodegeneration. Full article

(This article belongs to the Special Issue The Cell Biology of Parkinson’s Disease)

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13 pages, 2915 KiB

Open AccessArticle

Evaluation of Tissue Ischemia/Reperfusion Injury in Lung Recipients Supported by Intraoperative Extracorporeal Membrane Oxygenation: A Single-Center Pilot Study

by Fiorella Calabrese, Federica Pezzuto, Francesco Fortarezza, Francesca Lunardi, Eleonora Faccioli, Giulia Lorenzoni, Annalisa Boscolo, Nicolò Sella, Dario Gregori, Marco Schiavon, Paolo Navalesi, Andrea Dell’Amore and Federico Rea

Cells 2022, 11(22), 3681; https://doi.org/10.3390/cells11223681 - 19 Nov 2022

Cited by 4 | Viewed by 1742

Abstract

Intraoperative veno-arterial (VA) extracorporeal membrane oxygenation (ECMO) as intraoperative hemodynamic support during lung transplantation is becoming a standard practice due to promising clinical results. Nevertheless, studies on tissue/molecular pathways investigating ischemia/reperfusion injury are still lacking. Patients receiving a bilateral lung transplantation between January [...] Read more.

Intraoperative veno-arterial (VA) extracorporeal membrane oxygenation (ECMO) as intraoperative hemodynamic support during lung transplantation is becoming a standard practice due to promising clinical results. Nevertheless, studies on tissue/molecular pathways investigating ischemia/reperfusion injury are still lacking. Patients receiving a bilateral lung transplantation between January 2012 and December 2018 at the University Hospital of Padova were included in this retrospective single-center observational study. The present study aimed to investigate ischemia/reperfusion injury in 51 tissue specimens obtained from 13 recipients supported by intraoperative VA-ECMO and 38 who were not. Several tissue analyses, including apoptosis evaluation and inducible nitric oxide synthase expression, were performed on the biopsies at the time of transplantation. Lung samples from the ECMO group (both pre- and post-reperfusion) were comparable, or for some parameters better, than samples from the non-ECMO group. Leukocyte margination was significantly lower in the ECMO group than in the non-ECMO group. Primary graft dysfunction, mainly at 24 and 48 h, was correlated with the tissue injury score of the post-reperfusion biopsy. The interquartile ranges for all morphological parameters showed high grade variability between pre- and post-reperfusion in the non-ECMO group. These preliminary data support the use of intraoperative ECMO based on lower lung tissue ischemia/reperfusion injury. Larger case series are mandatory to confirm our findings. Full article

(This article belongs to the Special Issue Advances in Lung Transplantation—Series 2)

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17 pages, 3735 KiB

Open AccessArticle

Antibody Mediated Intercommunication of Germinal Centers

by Theinmozhi Arulraj, Sebastian C. Binder and Michael Meyer-Hermann

Cells 2022, 11(22), 3680; https://doi.org/10.3390/cells11223680 - 19 Nov 2022

Cited by 1 | Viewed by 1764

Abstract

Antibody diversification and selection of B cells occur in dynamic structures called germinal centers (GCs). Passively administered soluble antibodies regulate the GC response by masking the antigen displayed on follicular dendritic cells (FDCs). This suggests that GCs might intercommunicate via naturally produced soluble [...] Read more.

Antibody diversification and selection of B cells occur in dynamic structures called germinal centers (GCs). Passively administered soluble antibodies regulate the GC response by masking the antigen displayed on follicular dendritic cells (FDCs). This suggests that GCs might intercommunicate via naturally produced soluble antibodies, but the role of such GC–GC interactions is unknown. In this study, we performed in silico simulations of interacting GCs and predicted that intense interactions by soluble antibodies limit the magnitude and lifetime of GC responses. With asynchronous GC onset, we observed a higher inhibition of late formed GCs compared to early ones. We also predicted that GC–GC interactions can lead to a bias in the epitope recognition even in the presence of equally dominant epitopes due to differences in founder cell composition or initiation timing of GCs. We show that there exists an optimal range for GC–GC interaction strength that facilitates the affinity maturation towards an incoming antigenic variant during an ongoing GC reaction. These findings suggest that GC–GC interactions might be a contributing factor to the unexplained variability seen among individual GCs and a critical factor in the modulation of GC response to antigenic variants during viral infections. Full article

(This article belongs to the Special Issue Emerging Mechanisms in B Cell Activation)

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19 pages, 6815 KiB

Open AccessArticle

Thymosin Beta 15 Alters the Spatial Development of Thymic Epithelial Cells

by Xie Xu, Kai He, Robert D. Hoffman, Yuyuan Ying, Nana Tao, Wenqin Guo, Jiaman Shen, Xi Liu, Meiya Li, Meiqiu Yan, Guiyuan Lv and Jianli Gao

Cells 2022, 11(22), 3679; https://doi.org/10.3390/cells11223679 - 19 Nov 2022

Cited by 6 | Viewed by 2162

Abstract

The thymus is the most sensitive organ under various pathophysiological conditions, such as aging, starvation, and infection. As a key stromal cell for T cell development, it is well-known that thymic epithelial cells (TECs) play an important role in the thymus response to [...] Read more.

The thymus is the most sensitive organ under various pathophysiological conditions, such as aging, starvation, and infection. As a key stromal cell for T cell development, it is well-known that thymic epithelial cells (TECs) play an important role in the thymus response to the external environment. Thymosin beta 15 (Tβ15) is a G-actin binding protein secreted by TECs, it plays an important role in maintaining the dynamic balance of actin, angiogenesis, axonal formation, and wound healing, but the relationship between Tβ15 and TECs is not clear yet. Here, we show the impact of Tβ15 on the TEC’s spatial development, as well as the T-cell differentiation and thymic output. As a result, TEC is the main effector cell of Tβ15 in the thymus. Tβ15 OX inhibits the chemotaxis of TECs to the medulla and subsequently blocks the positive selection of thymocytes from CD3⁺TCRβ⁺CD4⁺CD8⁺ double positive cells to CD3⁺TCRβ⁺CD4⁺CD8⁻ single-positive (CD4SP) cells. Tβ15-knockdown accelerates the reticular differentiation of astral TECs and medullary TECs. Importantly, mice implanted with Tβ15-knockdown iTECs show high thymic output but low peripheral T cell maturity and activity. In a word, our results explain the role of Tβ15 on the differentiation and function of TECs and provide a new perspective for understanding the process of thymus development and degeneration. Full article

(This article belongs to the Special Issue Cell Biology: State-of-the-Art and Perspectives in China)

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14 pages, 3665 KiB

Open AccessArticle

6-Shogaol Exhibits a Promoting Effect with Tax via Binding HSP60 in Non-Small-Cell Lung Cancer

by Shulipan Mulati, Rongsong Jiang, Jinfeng Wang, Yicun Tao and Weiyi Zhang

Cells 2022, 11(22), 3678; https://doi.org/10.3390/cells11223678 - 19 Nov 2022

Cited by 5 | Viewed by 1984

Abstract

Non-small-cell lung cancer (NSCLC) is a prevalent malignant tumor with high morbidity and mortality rates worldwide. Although surgical resection, adjuvant radiotherapy/chemotherapy, and targeted molecular therapy are the cornerstones of NSCLC treatment, NSCLC is associated with high recurrence rates and drug resistance. This study [...] Read more.

Non-small-cell lung cancer (NSCLC) is a prevalent malignant tumor with high morbidity and mortality rates worldwide. Although surgical resection, adjuvant radiotherapy/chemotherapy, and targeted molecular therapy are the cornerstones of NSCLC treatment, NSCLC is associated with high recurrence rates and drug resistance. This study analyzed the potential targets and pathways of 6-Shogaol (6-SH) in NSCLC, showing that 6-SH binds to heat-shock 60 kDa protein (HSP60) in A549 cells, induces cell apoptosis, and arrests the cell cycle possibly by disrupting the mitochondrial function. HSP60 was identified as the target of 6-SH and 6-SH-induced HSP60 degradation which was mediated by the proteasome. The binding of 6-SH with HSP60 altered its stability, inhibited the ERK, Stat3, PI3K, Akt, and mTOR signaling pathways, and Tax acted synergistically with 6-SH, indicating that 6-SH could be developed as a potential therapeutic agent for an NSCLC treatment. Full article

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2 pages, 196 KiB

Open AccessEditorial

microRNA Bioinformatics

by Y-h. Taguchi

Cells 2022, 11(22), 3677; https://doi.org/10.3390/cells11223677 - 18 Nov 2022

Cited by 1 | Viewed by 1564

Abstract

Firstly, I apologize for the delayed publication of this Special Issue in the form of a book title [...] Full article

(This article belongs to the Special Issue microRNA Bioinformatics)

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Cells, Volume 11, Issue 22 (November-2 2022) – 180 articles

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