Cells

25 pages, 1641 KiB

Open AccessReview

Central Roles of STAT3-Mediated Signals in Onset and Development of Cancers: Tumorigenesis and Immunosurveillance

by Shigeru Hashimoto, Ari Hashimoto, Ryuta Muromoto, Yuichi Kitai, Kenji Oritani and Tadashi Matsuda

Cells 2022, 11(16), 2618; https://doi.org/10.3390/cells11162618 - 22 Aug 2022

Cited by 12 | Viewed by 3174

Abstract

Since the time of Rudolf Virchow in the 19th century, it has been well-known that cancer-associated inflammation contributes to tumor initiation and progression. However, it remains unclear whether a collapse of the balance between the antitumor immune response via the immunological surveillance system [...] Read more.

Since the time of Rudolf Virchow in the 19th century, it has been well-known that cancer-associated inflammation contributes to tumor initiation and progression. However, it remains unclear whether a collapse of the balance between the antitumor immune response via the immunological surveillance system and protumor immunity due to cancer-related inflammation is responsible for cancer malignancy. The majority of inflammatory signals affect tumorigenesis by activating signal transducer and activation of transcription 3 (STAT3) and nuclear factor-κB. Persistent STAT3 activation in malignant cancer cells mediates extremely widespread functions, including cell growth, survival, angiogenesis, and invasion and contributes to an increase in inflammation-associated tumorigenesis. In addition, intracellular STAT3 activation in immune cells causes suppressive effects on antitumor immunity and leads to the differentiation and mobilization of immature myeloid-derived cells and tumor-associated macrophages. In many cancer types, STAT3 does not directly rely on its activation by oncogenic mutations but has important oncogenic and malignant transformation-associated functions in both cancer and stromal cells in the tumor microenvironment (TME). We have reported a series of studies aiming towards understanding the molecular mechanisms underlying the proliferation of various types of tumors involving signal-transducing adaptor protein-2 as an adaptor molecule that modulates STAT3 activity, and we recently found that AT-rich interactive domain-containing protein 5a functions as an mRNA stabilizer that orchestrates an immunosuppressive TME in malignant mesenchymal tumors. In this review, we summarize recent advances in our understanding of the functional role of STAT3 in tumor progression and introduce novel molecular mechanisms of cancer development and malignant transformation involving STAT3 activation that we have identified to date. Finally, we discuss potential therapeutic strategies for cancer that target the signaling pathway to augment STAT3 activity. Full article

(This article belongs to the Special Issue STAT3: Role in Cancer and Stem Cells)

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15 pages, 2191 KiB

Open AccessEditor’s ChoiceArticle

A Multi-Strain Probiotic Formulation Improves Intestinal Barrier Function by the Modulation of Tight and Adherent Junction Proteins

by Raffaella di Vito, Carmela Conte and Giovanna Traina

Cells 2022, 11(16), 2617; https://doi.org/10.3390/cells11162617 - 22 Aug 2022

Cited by 14 | Viewed by 4162

Abstract

In healthy individuals, tight junction proteins (TJPs) maintain the integrity of the intestinal barrier. Dysbiosis and increased intestinal permeability are observed in several diseases, such as inflammatory bowel disease. Many studies highlight the role of probiotics in preventing intestinal barrier dysfunction. The present [...] Read more.

In healthy individuals, tight junction proteins (TJPs) maintain the integrity of the intestinal barrier. Dysbiosis and increased intestinal permeability are observed in several diseases, such as inflammatory bowel disease. Many studies highlight the role of probiotics in preventing intestinal barrier dysfunction. The present study aims to investigate the effects of a commercially available probiotic formulation of L. rhamnosus LR 32, B. lactis BL 04, and B. longum BB 536 (Serobioma, Bromatech s.r.l., Milan, Italy) on TJPs and the integrity of the intestinal epithelial barrier, and the ability of this formulation to prevent lipopolysaccharide-induced, inflammation-associated damage. An in vitro model of the intestinal barrier was developed using a Caco-2 cell monolayer. The mRNA expression levels of the TJ genes were analyzed using real-time PCR. Changes in the amounts of proteins were assessed with Western blotting. The effect of Serobioma on the intestinal epithelial barrier function was assessed using transepithelial electrical resistance (TEER) measurements. The probiotic formulation tested in this study modulates the expression of TJPs and prevents inflammatory damage. Our findings provide new insights into the mechanisms by which probiotics are able to prevent damage to the gut epithelial barrier. Full article

(This article belongs to the Special Issue Gut Microbiota in Nutrition and Health)

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20 pages, 8466 KiB

Open AccessArticle

Açai Berry Mitigates Vascular Dementia-Induced Neuropathological Alterations Modulating Nrf-2/Beclin1 Pathways

by Daniela Impellizzeri, Ramona D’Amico, Roberta Fusco, Tiziana Genovese, Alessio Filippo Peritore, Enrico Gugliandolo, Rosalia Crupi, Livia Interdonato, Davide Di Paola, Rosanna Di Paola, Salvatore Cuzzocrea, Rosalba Siracusa and Marika Cordaro

Cells 2022, 11(16), 2616; https://doi.org/10.3390/cells11162616 - 22 Aug 2022

Cited by 18 | Viewed by 2532

Abstract

The second-most common cause of dementia is vascular dementia (VaD). The majority of VaD patients experience cognitive impairment, which is brought on by oxidative stress and changes in autophagic function, which ultimately result in neuronal impairment and death. In this study, we examine [...] Read more.

The second-most common cause of dementia is vascular dementia (VaD). The majority of VaD patients experience cognitive impairment, which is brought on by oxidative stress and changes in autophagic function, which ultimately result in neuronal impairment and death. In this study, we examine a novel method for reversing VaD-induced changes brought on by açai berry supplementation in a VaD mouse model. The purpose of this study was to examine the impact of açai berries on the molecular mechanisms underlying VaD in a mouse model of the disease that was created by repeated ischemia–reperfusion (IR) of the whole bilateral carotid artery. Here, we found that açai berry was able to reduce VaD-induced behavioral alteration, as well as hippocampal death, in CA1 and CA3 regions. These effects are probably due to the modulation of nuclear factor erythroid 2-related factor 2 (Nrf-2) and Beclin-1, suggesting a possible crosstalk between these molecular pathways. In conclusion, the protective effects of açai berry could be a good supplementation in the future for the management of vascular dementia. Full article

(This article belongs to the Special Issue Oxidative Stress and Antioxidant Strategies: Relationships and Cellular Pathways for Human Health)

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18 pages, 5314 KiB

Open AccessEditor’s ChoiceArticle

Pathogenetic Mechanisms Underlying Spinocerebellar Ataxia Type 3 Are Altered in Primary Oligodendrocyte Culture

by Kristen H. Schuster, Alexandra F. Putka and Hayley S. McLoughlin

Cells 2022, 11(16), 2615; https://doi.org/10.3390/cells11162615 - 22 Aug 2022

Cited by 7 | Viewed by 2426

Abstract

Emerging evidence has implicated non-neuronal cells, particularly oligodendrocytes, in the pathophysiology of many neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease and Spinocerebellar ataxia type 3 (SCA3). We recently demonstrated that cell-autonomous dysfunction of oligodendrocyte maturation is one of [...] Read more.

Emerging evidence has implicated non-neuronal cells, particularly oligodendrocytes, in the pathophysiology of many neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease and Spinocerebellar ataxia type 3 (SCA3). We recently demonstrated that cell-autonomous dysfunction of oligodendrocyte maturation is one of the of the earliest and most robust changes in vulnerable regions of the SCA3 mouse brain. However, the cell- and disease-specific mechanisms that underlie oligodendrocyte dysfunction remain poorly understood and are difficult to isolate in vivo. In this study, we used primary oligodendrocyte cultures to determine how known pathogenic SCA3 mechanisms affect this cell type. We isolated oligodendrocyte progenitor cells from 5- to 7-day-old mice that overexpress human mutant ATXN3 or lack mouse ATXN3 and differentiated them for up to 5 days in vitro. Utilizing immunocytochemistry, we characterized the contributions of ATXN3 toxic gain-of-function and loss-of-function in oligodendrocyte maturation, protein quality pathways, DNA damage signaling, and methylation status. We illustrate the utility of primary oligodendrocyte culture for elucidating cell-specific pathway dysregulation relevant to SCA3. Given recent work demonstrating disease-associated oligodendrocyte signatures in other neurodegenerative diseases, this novel model has broad applicability in revealing mechanistic insights of oligodendrocyte contribution to pathogenesis. Full article

(This article belongs to the Collection Spinocerebellar Ataxia (SCA): Molecular Mechanisms and Novel Treatment Strategies)

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13 pages, 8710 KiB

Open AccessArticle

Targeting on Nrf2/Sesn2 Signaling to Rescue Cardiac Dysfunction during High-Fat Diet-Induced Obesity

by Meredith Krause-Hauch, Julia Fedorova, Linda Ines Zoungrana, Hao Wang, Mohammad Kasim Fatmi, Zehui Li, Migdalia Iglesias, Lily Slotabec and Ji Li

Cells 2022, 11(16), 2614; https://doi.org/10.3390/cells11162614 - 22 Aug 2022

Cited by 7 | Viewed by 2014

Abstract

Obesity is of concern to the population because it is known to cause inflammation and oxidative stress throughout the body, leading to patient predisposition for health conditions such as diabetes, hypertension, and some cancers. However, some proteins that are activated in times of [...] Read more.

Obesity is of concern to the population because it is known to cause inflammation and oxidative stress throughout the body, leading to patient predisposition for health conditions such as diabetes, hypertension, and some cancers. However, some proteins that are activated in times of oxidative stress may provide cytoprotective properties. In this study, we aim to gain further understanding of the interconnection between Nrf2 and Sesn2 during obesity-related stress and how this relationship can play a role in cardio-protection. Cardiomyocyte-specific Sesn2 knockout (cSesn2^−/−) and Sesn2 overexpressed (tTa-tet-Sesn2) mice and their wildtype littermates (Sesn2^flox/flox and tet-Sesn2, respectively) were assigned to either a normal chow (NC) or a high-fat (HF) diet to induce obesity. After 16 weeks of dietary intervention, heart function was evaluated via echocardiography and cardiac tissue was collected for analysis. Immunoblotting, histology, and ROS staining were completed. Human heart samples were obtained via the LifeLink Foundation and were also subjected to analysis. Overall, these results indicated that the overexpression of Sesn2 appears to have cardio-protective effects on the obese heart through the reduction of ROS and fibrosis present in the tissues and in cardiac function. These results were consistent for both mouse and human heart samples. In human samples, there was an increase in Sesn2 and Nrf2 expression in the obese patients’ LV tissue. However, there was no observable pattern of Sesn2/Nrf2 expression in mouse LV tissue samples. Further investigation into the link between the Sesn2/Nrf2 pathway and obesity-related oxidative stress is needed. Full article

(This article belongs to the Special Issue Nrf2 Signaling Pathway in Cardiovascular Health and Disease)

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16 pages, 1570 KiB

Open AccessReview

Role of Epigenetic Mechanisms in Chronic Pain

by Daniela Mauceri

Cells 2022, 11(16), 2613; https://doi.org/10.3390/cells11162613 - 22 Aug 2022

Cited by 13 | Viewed by 3421

Abstract

Pain is an unpleasant but essential-to-life sensation, usually resulting from tissue damage. When pain persists long after the injury has resolved, it becomes pathological. The precise molecular and cellular mechanisms causing the transition from acute to chronic pain are not fully understood. A [...] Read more.

Pain is an unpleasant but essential-to-life sensation, usually resulting from tissue damage. When pain persists long after the injury has resolved, it becomes pathological. The precise molecular and cellular mechanisms causing the transition from acute to chronic pain are not fully understood. A key aspect of pain chronicity is that several plasticity events happen along the neural pathways involved in pain. These long-lasting adaptive changes are enabled by alteration in the expression of relevant genes. Among the different modulators of gene transcription in adaptive processes in the nervous system, epigenetic mechanisms play a pivotal role. In this review, I will first outline the main classes of epigenetic mediators and then discuss their implications in chronic pain. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying Pain Chronicity)

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6 pages, 855 KiB

Open AccessCommentary

The Interplay between Telomeres, Mitochondria, and Chronic Stress Exposure in the Aging Egg

by Aksinya Derevyanko, Agnieszka Skowronska, Mariusz T. Skowronski and Paweł Kordowitzki

Cells 2022, 11(16), 2612; https://doi.org/10.3390/cells11162612 - 22 Aug 2022

Cited by 7 | Viewed by 2567

Abstract

While at the organismal level, biological aging can be estimated by telomere length and DNA methylation signatures, reliable biomarkers that can predict reproductive age are much needed to gauge the quality of an oocyte. Reproductive medicine and fertility centers often merely quantitate the [...] Read more.

While at the organismal level, biological aging can be estimated by telomere length and DNA methylation signatures, reliable biomarkers that can predict reproductive age are much needed to gauge the quality of an oocyte. Reproductive medicine and fertility centers often merely quantitate the ovarian reserve to predict the likelihood of fertilization and pregnancy in women of advanced reproductive age. It is highly important to address the level of age-related decline in oocyte quality since it leads to an increased risk of miscarriages and aneuploidy. Conversely, the pathways behind oocyte aging remain, in large part, elusive. Telomere shortening upon chronic stress exposure regulates mitochondria function and biogenesis by various pathways; therefore, establishing a link between these two important players and extrapolating them for the aging of oocytes will be the purpose of our commentary. Full article

(This article belongs to the Special Issue From Development to Death: Molecular Pathways inside the Oocyte)

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13 pages, 10382 KiB

Open AccessArticle

Cyclin-Dependent Kinase Subunit 2 (CKS2) as a Prognostic Marker for Stages I–III Invasive Non-Mucinous Lung Adenocarcinoma and Its Role in Affecting Drug Sensitivity

by Junkai Feng, Menglong Hu, Zongkuo Li, Guiming Hu, Yuting Han, Yan Zhang, Min Zhang and Jingli Ren

Cells 2022, 11(16), 2611; https://doi.org/10.3390/cells11162611 - 22 Aug 2022

Cited by 1 | Viewed by 1966

Abstract

With the aim of improving the prognosis of patients with lung adenocarcinoma (LUAD), we identified the biomarker related to the sensitivity of patients to chemotherapy drugs and explored the potential mechanisms. As a cell cycle-related protein, CKS2 has an essential role to play [...] Read more.

With the aim of improving the prognosis of patients with lung adenocarcinoma (LUAD), we identified the biomarker related to the sensitivity of patients to chemotherapy drugs and explored the potential mechanisms. As a cell cycle-related protein, CKS2 has an essential role to play in tumor progression and prognosis. CKS2 expression was measured using TCGA RNA-sequencing data and immunohistochemistry. The sensitivity data of tumor cells to chemotherapeutic drugs for lung cancer was acquired from the Cancer Therapeutics Response Portal (CTRP) database. A range of bioinformatics methods was used to explore the mechanisms of CKS2 upregulation. The biological functions of CKS2 were predicted using GO and KEGG enrichment analysis, as well as GSEA. CKS2 expression was up-regulated in stages I–III invasive non-mucinous lung adenocarcinoma and varied significantly between various histological subtypes. High CKS2 expression worsened the prognosis of patients. The CKS2 expression level was linked to the sensitivity of LUAD cells to carboplatin and paclitaxel. CKS2 upregulation was associated with the immune microenvironment, mRNA methylation, and competing endogenous RNAs (ceRNAs). CKS2 can serve as a diagnostic and prognostic biomarker for stages I–III invasive non-mucinous lung adenocarcinoma and modulate the effect of paclitaxel and carboplatin by regulating microtubule binding and influencing carboplatin binding to DNA. Full article

(This article belongs to the Special Issue New Insights into Targeted Therapy for Non-Small-Cell Lung Cancer: From Molecular Biology to Tumor Microenvironment)

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12 pages, 2815 KiB

Open AccessArticle

LPAL2 Suppresses Tumor Growth and Metastasis of Hepatocellular Carcinoma by Modulating MMP9 Expression

by Yang-Hsiang Lin, Yu-Chin Liu, Cheng-Yi Chen, Hsiang-Cheng Chi, Meng-Han Wu, Po-Shuan Huang, Cheng-Chih Chang, Tzu-Kang Lin, Chau-Ting Yeh and Kwang-Huei Lin

Cells 2022, 11(16), 2610; https://doi.org/10.3390/cells11162610 - 22 Aug 2022

Cited by 3 | Viewed by 1698

Abstract

Tumor metastasis is a complex process modulated by both intrinsic and extrinsic factors that ultimately result in poorer patient outcomes, including diminished survival. Pseudogene-derived long non-coding RNAs (lncRNA) play important roles in cancer progression. In the current study, we found that the pseudogene-derived [...] Read more.

Tumor metastasis is a complex process modulated by both intrinsic and extrinsic factors that ultimately result in poorer patient outcomes, including diminished survival. Pseudogene-derived long non-coding RNAs (lncRNA) play important roles in cancer progression. In the current study, we found that the pseudogene-derived lncRNA LPAL2 is downregulated in hepatocellular carcinoma (HCC) tissues, and further showed that elevated LPAL2 expression is positively correlated with survival outcome. The knockdown of LPAL2 in hepatoma cells induced tumor formation, migration, invasion, sphere formation, and drug resistance. Metalloproteinase 9 (MMP9) was identified as an LPAL2-regulated target gene, consistent with clinical findings that LPAL2 expression is significantly associated with MMP9 expression. Furthermore, patients with a higher expression of LPAL2 and lower expression of MMP9 (LPAL2-high/MMP9-low) had a higher survival rate than those with other combinations. Collectively, our findings establish LPAL2 as a novel tumor suppressor in HCC, and suggest targeting LPAL2 and MMP9 as a therapeutic approach for the treatment of HCC. Full article

(This article belongs to the Special Issue Decoding Cancer Transcriptome Non-Coding RNAs and Beyond)

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3 pages, 161 KiB

Open AccessCorrection

Correction: Lee et al. Protein Arginine Methyltransferases in Neuromuscular Function and Diseases. Cells 2022, 11, 364

by Jinwoo Lee, Subin An, Sang-Jin Lee and Jong-Sun Kang

Cells 2022, 11(16), 2609; https://doi.org/10.3390/cells11162609 - 22 Aug 2022

Cited by 2 | Viewed by 886

Abstract

The authors wish to make the following corrections to this paper [...] Full article

40 pages, 1419 KiB

Open AccessReview

Recent Advances in the Modulation of Pain by the Metabotropic Glutamate Receptors

by Mariacristina Mazzitelli, Peyton Presto, Nico Antenucci, Shakira Meltan and Volker Neugebauer

Cells 2022, 11(16), 2608; https://doi.org/10.3390/cells11162608 - 21 Aug 2022

Cited by 5 | Viewed by 3126

Abstract

Metabotropic glutamate receptors (mGluR or mGlu) are G-protein coupled receptors activated by the binding of glutamate, the main classical neurotransmitter of the nervous system. Eight different mGluR subtypes (mGluR1-8) have been cloned and are classified in three groups based on their molecular, pharmacological [...] Read more.

Metabotropic glutamate receptors (mGluR or mGlu) are G-protein coupled receptors activated by the binding of glutamate, the main classical neurotransmitter of the nervous system. Eight different mGluR subtypes (mGluR1-8) have been cloned and are classified in three groups based on their molecular, pharmacological and signaling properties. mGluRs mediate several physiological functions such as neuronal excitability and synaptic plasticity, but they have also been implicated in numerous pathological conditions including pain. The availability of new and more selective allosteric modulators together with the canonical orthosteric ligands and transgenic technologies has led to significant advances in our knowledge about the role of the specific mGluR subtypes in the pathophysiological mechanisms of various diseases. Although development of successful compounds acting on mGluRs for clinical use has been scarce, the subtype-specific-pharmacological manipulation might be a compelling approach for the treatment of several disorders in humans, including pain; this review aims to summarize and update on preclinical evidence for the roles of different mGluRs in the pain system and discusses knowledge gaps regarding mGluR-related sex differences and neuroimmune signaling in pain. Full article

(This article belongs to the Special Issue The Role of Metabotropic Glutamate Receptors in Health and Disease)

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42 pages, 3410 KiB

Open AccessReview

Mitochondrial Impairment: A Common Motif in Neuropsychiatric Presentation? The Link to the Tryptophan–Kynurenine Metabolic System

by Masaru Tanaka, Ágnes Szabó, Eleonóra Spekker, Helga Polyák, Fanni Tóth and László Vécsei

Cells 2022, 11(16), 2607; https://doi.org/10.3390/cells11162607 - 21 Aug 2022

Cited by 105 | Viewed by 9084

Abstract

Nearly half a century has passed since the discovery of cytoplasmic inheritance of human chloramphenicol resistance. The inheritance was then revealed to take place maternally by mitochondrial DNA (mtDNA). Later, a number of mutations in mtDNA were identified as a cause of severe [...] Read more.

Nearly half a century has passed since the discovery of cytoplasmic inheritance of human chloramphenicol resistance. The inheritance was then revealed to take place maternally by mitochondrial DNA (mtDNA). Later, a number of mutations in mtDNA were identified as a cause of severe inheritable metabolic diseases with neurological manifestation, and the impairment of mitochondrial functions has been probed in the pathogenesis of a wide range of illnesses including neurodegenerative diseases. Recently, a growing number of preclinical studies have revealed that animal behaviors are influenced by the impairment of mitochondrial functions and possibly by the loss of mitochondrial stress resilience. Indeed, as high as 54% of patients with one of the most common primary mitochondrial diseases, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome, present psychiatric symptoms including cognitive impairment, mood disorder, anxiety, and psychosis. Mitochondria are multifunctional organelles which produce cellular energy and play a major role in other cellular functions including homeostasis, cellular signaling, and gene expression, among others. Mitochondrial functions are observed to be compromised and to become less resilient under continuous stress. Meanwhile, stress and inflammation have been linked to the activation of the tryptophan (Trp)–kynurenine (KYN) metabolic system, which observably contributes to the development of pathological conditions including neurological and psychiatric disorders. This review discusses the functions of mitochondria and the Trp-KYN system, the interaction of the Trp-KYN system with mitochondria, and the current understanding of the involvement of mitochondria and the Trp-KYN system in preclinical and clinical studies of major neurological and psychiatric diseases. Full article

(This article belongs to the Special Issue Advances in Mitochondrial Dynamics and Neurodegeneration)

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17 pages, 2896 KiB

Open AccessArticle

Sympathetic Innervation Modulates Mucosal Immune Homeostasis and Epithelial Host Defense

by Shilpashree Mallesh, Anne S. Ten Hove, Reiner Schneider, Bianca Schneiker, Patrik Efferz, Jörg C. Kalff, Wouter J. de Jonge and Sven Wehner

Cells 2022, 11(16), 2606; https://doi.org/10.3390/cells11162606 - 21 Aug 2022

Cited by 5 | Viewed by 2248

Abstract

Intestinal mucosal cells, such as resident macrophages and epithelial cells, express adrenergic receptors and are receptive to norepinephrine, the primary neurotransmitter of the sympathetic nervous system (SNS). It has been suggested that the SNS affects intestinal immune activity in conditions, such as inflammatory [...] Read more.

Intestinal mucosal cells, such as resident macrophages and epithelial cells, express adrenergic receptors and are receptive to norepinephrine, the primary neurotransmitter of the sympathetic nervous system (SNS). It has been suggested that the SNS affects intestinal immune activity in conditions, such as inflammatory bowel disease; however, the underlying mechanisms remain ambiguous. Here, we investigated the effect of SNS on mucosal immune and epithelial cell functions. We employed 6-OHDA-induced sympathetic denervation (cSTX) to characterize muscularis-free mucosal transcriptomes by RNA-seq and qPCR, and quantified mucosal immune cells by flow cytometry. The role of norepinephrine and cytokines on epithelial functions was studied using small intestinal organoids. cSTX increased the presence of activated CD68⁺CD86⁺ macrophages and monocytes in the mucosa. In addition, through transcriptional profiling, the proinflammatory cytokines IL-1β, TNF-α, and IFN-γ were induced, while Arg-1 and CD163 expression was reduced. Further, cSTX increased intestinal permeability in vivo and induced genes involved in barrier integrity and antimicrobial defense. In intestinal organoids, similar alterations were observed after treatment with proinflammatory cytokines, but not norepinephrine. We conclude that a loss in sympathetic input induces a proinflammatory mucosal state, leading to reduced epithelial barrier functioning and enhanced antimicrobial defense. This implies that the SNS might be required to maintain intestinal immune functions during homeostasis. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Chronic Intestinal Diseases in Response to Microbiota)

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20 pages, 3410 KiB

Open AccessArticle

Elicitation of Roots and AC-DC with PEP-13 Peptide Shows Differential Defense Responses in Multi-Omics

by Marie Chambard, Mohamed Amine Ben Mlouka, Lun Jing, Carole Plasson, Pascal Cosette, Jérôme Leprince, Marie-Laure Follet-Gueye, Azeddine Driouich, Eric Nguema-Ona and Isabelle Boulogne

Cells 2022, 11(16), 2605; https://doi.org/10.3390/cells11162605 - 21 Aug 2022

Cited by 3 | Viewed by 2105

Abstract

The root extracellular trap (RET) has emerged as a specialized compartment consisting of root AC-DC and mucilage. However, the RET’s contribution to plant defense is still poorly understood. While the roles of polysaccharides and glycoproteins secreted by root AC-DC have started to be [...] Read more.

The root extracellular trap (RET) has emerged as a specialized compartment consisting of root AC-DC and mucilage. However, the RET’s contribution to plant defense is still poorly understood. While the roles of polysaccharides and glycoproteins secreted by root AC-DC have started to be elucidated, how the low-molecular-weight exudates of the RET contribute to root defense is poorly known. In order to better understand the RET and its defense response, the transcriptomes, proteomes and metabolomes of roots, root AC-DC and mucilage of soybean (Glycine max (L.) Merr, var. Castetis) upon elicitation with the peptide PEP-13 were investigated. This peptide is derived from the pathogenic oomycete Phytophthora sojae. In this study, the root and the RET responses to elicitation were dissected and sequenced using transcriptional, proteomic and metabolomic approaches. The major finding is increased synthesis and secretion of specialized metabolites upon induced defense activation following PEP-13 peptide elicitation. This study provides novel findings related to the pivotal role of the root extracellular trap in root defense. Full article

(This article belongs to the Special Issue Research on Plant Functional Genomics and Stress Response)

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26 pages, 1631 KiB

Open AccessFeature PaperReview

Kynurenine Pathway—An Underestimated Factor Modulating Innate Immunity in Sepsis-Induced Acute Kidney Injury?

by Anna Krupa, Mikolaj M. Krupa and Krystyna Pawlak

Cells 2022, 11(16), 2604; https://doi.org/10.3390/cells11162604 - 21 Aug 2022

Cited by 3 | Viewed by 2819

Abstract

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, and it accounts for about half of the cases of acute kidney injury (AKI). Although sepsis is the most frequent cause of AKI in critically ill patients, its pathophysiological [...] Read more.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, and it accounts for about half of the cases of acute kidney injury (AKI). Although sepsis is the most frequent cause of AKI in critically ill patients, its pathophysiological mechanisms are not well understood. Sepsis has the ability to modulate the function of cells belonging to the innate immune system. Increased activity of indoleamine 2,3-dioxygenase 1 (IDO1) and production of kynurenines are the major metabolic pathways utilized by innate immunity cells to maintain immunological tolerance. The activation of the kynurenine pathway (KP) plays a dual role in sepsis—in the early stage, the induction of IDO1 elicits strong proinflammatory effects that may lead to tissue damage and septic shock. Afterwards, depletion of tryptophan and production of kynurenines contribute to the development of immunosuppression that may cause the inability to overpower opportunistic infections. The presented review provides available data on the various interdependencies between elements of innate immunity and sepsis-induced AKI (SAKI) with particular emphasis on the immunomodulatory significance of KP in the above processes. We believe that KP activation may be one of the crucial, though underestimated, components of a deregulated host response to infection during SAKI. Full article

(This article belongs to the Special Issue Kynurenine Pathway in Health and Disease)

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17 pages, 2248 KiB

Open AccessArticle

Cognitive Decline and BPSD Are Concomitant with Autophagic and Synaptic Deficits Associated with G9a Alterations in Aged SAMP8 Mice

by Foteini Vasilopoulou, Aina Bellver-Sanchis, Júlia Companys-Alemany, Júlia Jarne-Ferrer, Alba Irisarri, Verónica Palomera-Ávalos, Celia Gonzalez-Castillo, Daniel Ortuño-Sahagún, Coral Sanfeliu, Mercè Pallàs and Christian Griñán-Ferré

Cells 2022, 11(16), 2603; https://doi.org/10.3390/cells11162603 - 21 Aug 2022

Cited by 12 | Viewed by 2817

Abstract

Behavioural and psychological symptoms of dementia (BPSD) are presented in 95% of Alzheimer’s Disease (AD) patients and are also associated with neurotrophin deficits. The molecular mechanisms leading to age-related diseases are still unclear; however, emerging evidence has suggested that epigenetic modulation is a [...] Read more.

Behavioural and psychological symptoms of dementia (BPSD) are presented in 95% of Alzheimer’s Disease (AD) patients and are also associated with neurotrophin deficits. The molecular mechanisms leading to age-related diseases are still unclear; however, emerging evidence has suggested that epigenetic modulation is a key pathophysiological basis of ageing and neurodegeneration. In particular, it has been suggested that G9a methyltransferase and its repressive histone mark (H3K9me2) are important in shaping learning and memory by modulating autophagic activity and synaptic plasticity. This work deepens our understanding of the epigenetic mechanisms underlying the loss of cognitive function and BPSD in AD. For this purpose, several tasks were performed to evaluate the parameters of sociability (three-chamber test), aggressiveness (resident intruder), anxiety (elevated plus maze and open field) and memory (novel object recognition test) in mice, followed by the evaluation of epigenetic, autophagy and synaptic plasticity markers at the molecular level. The behavioural alterations presented by senescence-accelerated mice prone 8 (SAMP8) of 12 months of age compared with their senescence-accelerated mouse resistant mice (SAMR1), the healthy control strain was accompanied by age-related cognitive deficits and alterations in epigenetic markers. Increased levels of G9a are concomitant to the dysregulation of the JNK pathway in aged SAMP8, driving a failure in autophagosome formation. Furthermore, lower expression of the genes involved in the memory-consolidation process modulated by ERK was observed in the aged male SAMP8 model, suggesting the implication of G9a. In any case, two of the most important neurotrophins, namely brain-derived neurotrophic factor (Bdnf) and neurotrophin-3 (NT3), were found to be reduced, along with a decrease in the levels of dendritic branching and spine density presented by SAMP8 mice. Thus, the present study characterizes and provides information regarding the non-cognitive and cognitive states, as well as molecular alterations, in aged SAMP8, demonstrating the AD-like symptoms presented by this model. In any case, our results indicate that higher levels of G9a are associated with autophagic deficits and alterations in synaptic plasticity, which could further explain the BPSD and cognitive decline exhibited by the model. Full article

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25 pages, 1599 KiB

Open AccessSystematic Review

Optical Monitoring in Neonatal Seizures

by Rachel Howard, Runci Li, Kelly Harvey-Jones, Vinita Verma, Frédéric Lange, Geraldine Boylan, Ilias Tachtsidis and Subhabrata Mitra

Cells 2022, 11(16), 2602; https://doi.org/10.3390/cells11162602 - 21 Aug 2022

Cited by 3 | Viewed by 2340

Abstract

Background: Neonatal seizures remain a significant cause of morbidity and mortality worldwide. The past decade has resulted in substantial progress in seizure detection and understanding the impact seizures have on the developing brain. Optical monitoring such as cerebral near-infrared spectroscopy (NIRS) and broadband [...] Read more.

Background: Neonatal seizures remain a significant cause of morbidity and mortality worldwide. The past decade has resulted in substantial progress in seizure detection and understanding the impact seizures have on the developing brain. Optical monitoring such as cerebral near-infrared spectroscopy (NIRS) and broadband NIRS can provide non-invasive continuous real-time monitoring of the changes in brain metabolism and haemodynamics. Aim: To perform a systematic review of optical biomarkers to identify changes in cerebral haemodynamics and metabolism during the pre-ictal, ictal, and post-ictal phases of neonatal seizures. Method: A systematic search was performed in eight databases. The search combined the three broad categories: (neonates) AND (NIRS) AND (seizures) using the stepwise approach following PRISMA guidance. Results: Fifteen papers described the haemodynamic and/or metabolic changes observed with NIRS during neonatal seizures. No randomised controlled trials were identified during the search. Studies reported various changes occurring in the pre-ictal, ictal, and post-ictal phases of seizures. Conclusion: Clear changes in cerebral haemodynamics and metabolism were noted during the pre-ictal, ictal, and post-ictal phases of seizures in neonates. Further studies are necessary to determine whether NIRS-based methods can be used at the cot-side to provide clear pathophysiological data in real-time during neonatal seizures. Full article

(This article belongs to the Special Issue Brain Injury, Microcirculation and Tissue Perfusion)

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15 pages, 1199 KiB

Open AccessFeature PaperReview

SALL4: An Intriguing Therapeutic Target in Cancer Treatment

by Shiva Moein, Daniel G. Tenen, Giovanni Amabile and Li Chai

Cells 2022, 11(16), 2601; https://doi.org/10.3390/cells11162601 - 20 Aug 2022

Cited by 11 | Viewed by 3458

Abstract

Spalt-Like Transcription Factor 4 (SALL4) is a critical factor for self-renewal ability and pluripotency of stem cells. On the other hand, various reports show tight relation of SALL4 to cancer occurrence and metastasis. SALL4 exerts its effects not only by inducing gene expression [...] Read more.

Spalt-Like Transcription Factor 4 (SALL4) is a critical factor for self-renewal ability and pluripotency of stem cells. On the other hand, various reports show tight relation of SALL4 to cancer occurrence and metastasis. SALL4 exerts its effects not only by inducing gene expression but also repressing a large cluster of genes through interaction with various epigenetic modifiers. Due to high expression of SALL4 in cancer cells and its silence in almost all adult tissues, it is an ideal target for cancer therapy. However, targeting SALL4 meets various challenges. SALL4 is a transcription factor and designing appropriate drug to inhibit this intra-nucleus component is challenging. On the other hand, due to lack of our knowledge on structure of the protein and the suitable active sites, it becomes more difficult to reach the appropriate drugs against SALL4. In this review, we have focused on approaches applied yet to target this oncogene and discuss the potential of degrader systems as new therapeutics to target oncogenes. Full article

(This article belongs to the Collection Emerging Cancer Target Genes)

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15 pages, 2468 KiB

Open AccessArticle

Mechanical Stretch Induced Osteogenesis on Human Annulus Fibrosus Cells through Upregulation of BMP-2/6 Heterodimer and Activation of P38 and SMAD1/5/8 Signaling Pathways

by Cheng-Nan Chen, Hsin-I Chang, Chia-Kung Yen, Wen-Lung Liu and Kuo-Yuan Huang

Cells 2022, 11(16), 2600; https://doi.org/10.3390/cells11162600 - 20 Aug 2022

Cited by 6 | Viewed by 1981

Abstract

Degenerative disc disease (DDD) is an important cause of low back pain. Repetitive tensile stress from the daily motion of the spine predisposes it to injury of the annulus fibrosus (AF) which causes IVD degeneration. This study aims to determine the causal relationship [...] Read more.

Degenerative disc disease (DDD) is an important cause of low back pain. Repetitive tensile stress from the daily motion of the spine predisposes it to injury of the annulus fibrosus (AF) which causes IVD degeneration. This study aims to determine the causal relationship between mechanical stretch and osteogenesis in the AF cells of IVD as affected by bone morphogenic proteins (BMPs), specifically BMP-2/6 heterodimers. Our results found that 15% tensile stress (high cyclic stretching, HCS) may induce the expression of osteogenesis-related markers (Runx2, osterix) by upregulating BMP-2/6 heterodimeric ligands and their receptors on the human AF cell line. HCS also induced transient phosphorylation of p38 mitogen-activated protein (MAP) kinase and SMAD1/5/8. Neutralizing antibodies to the BMP-2/6 receptor (ALK3) blocked the expression of Runx2 and osterix, as well as the phosphorylation of p38 and SMAD1/5/8. In addition, treatment with a p38 MAPK inhibitor (SB203580) or siRNA to neutralize the effects of SMAD1/5/8 suppressed tensile stress-induced Runx2 and osterix expression. Mechanical stretching induces activation of p38 MAP kinase and SMAD1/5/8 signaling pathways, followed by the upregulation of BMP-2/6 heterodimer expression, thereby stimulating osteogenic Runx2 and osterix expression on AF cells. HCS may accelerate the progression of IVD degeneration by promoting an osteogenic response. Full article

(This article belongs to the Special Issue Molecular Mechanism of Stress, Stress Response, and Adaptation)

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12 pages, 853 KiB

Open AccessArticle

Transcriptome Profiling Reveals Differential Expression of Circadian Behavior Genes in Peripheral Blood of Monozygotic Twins Discordant for Parkinson’s Disease

by Ekaterina I. Semenova, Ivan N. Vlasov, Suzanna A. Partevian, Anna V. Rosinskaya, Ivan N. Rybolovlev, Petr A. Slominsky, Maria I. Shadrina and Anelya Kh. Alieva

Cells 2022, 11(16), 2599; https://doi.org/10.3390/cells11162599 - 20 Aug 2022

Cited by 1 | Viewed by 1868

Abstract

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. Investigating individuals with the most identical genetic background is optimal for minimizing the genetic contribution to gene expression. These individuals include monozygotic twins discordant for PD. Monozygotic twins have the same genetic [...] Read more.

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. Investigating individuals with the most identical genetic background is optimal for minimizing the genetic contribution to gene expression. These individuals include monozygotic twins discordant for PD. Monozygotic twins have the same genetic background, age, sex, and often similar environmental conditions. The aim of this study was to carry out a transcriptome analysis of the peripheral blood of three pairs of monozygotic twins discordant for PD. We identified the metabolic process “circadian behavior” as a priority process for further study. Different expression of genes included in the term “circadian behavior” confirms that this process is involved in PD pathogenesis. We found increased expression of three genes associated with circadian behavior, i.e., PTGDS, ADORA2A, and MTA1, in twins with PD. These genes can be considered as potential candidate genes for this disease. Full article

(This article belongs to the Collection Advances in Neurodegenerative Disease)

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19 pages, 2159 KiB

Open AccessReview

Glycosylation in Renal Cell Carcinoma: Mechanisms and Clinical Implications

by Xinqing Zhu, Abdullah Al-Danakh, Lin Zhang, Xiaoxin Sun, Yuli Jian, Haotian Wu, Dan Feng, Shujing Wang and Deyong Yang

Cells 2022, 11(16), 2598; https://doi.org/10.3390/cells11162598 - 20 Aug 2022

Cited by 3 | Viewed by 2622

Abstract

Renal cell carcinoma (RCC) is one of the most prevalent malignant tumors of the urinary system, accounting for around 2% of all cancer diagnoses and deaths worldwide. Clear cell RCC (ccRCC) is the most prevalent and aggressive histology with an unfavorable prognosis and [...] Read more.

Renal cell carcinoma (RCC) is one of the most prevalent malignant tumors of the urinary system, accounting for around 2% of all cancer diagnoses and deaths worldwide. Clear cell RCC (ccRCC) is the most prevalent and aggressive histology with an unfavorable prognosis and inadequate treatment. Patients’ progression-free survival is considerably improved by surgery; however, 30% of patients develop metastases following surgery. Identifying novel targets and molecular markers for RCC prognostic detection is crucial for more accurate clinical diagnosis and therapy. Glycosylation is a critical post-translational modification (PMT) for cancer cell growth, migration, and invasion, involving the transfer of glycosyl moieties to specific amino acid residues in proteins to form glycosidic bonds through the activity of glycosyltransferases. Most cancers, including RCC, undergo glycosylation changes such as branching, sialylation, and fucosylation. In this review, we discuss the latest findings on the significance of aberrant glycans in the initiation, development, and progression of RCC. The potential biomarkers of altered glycans for the diagnosis and their implications in RCC have been further highlighted. Full article

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

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13 pages, 3412 KiB

Open AccessArticle

GPT2 Is Induced by Hypoxia-Inducible Factor (HIF)-2 and Promotes Glioblastoma Growth

by Bo Zhang, Yan Chen, Lei Bao and Weibo Luo

Cells 2022, 11(16), 2597; https://doi.org/10.3390/cells11162597 - 20 Aug 2022

Cited by 7 | Viewed by 3468

Abstract

Hypoxia-inducible factor (HIF) directly activates the transcription of metabolic enzymes in response to hypoxia to reprogram cellular metabolism required for tumor cell proliferation. Through analyzing glutamate-linked aminotransferases, we here identified glutamate pyruvate transaminase 2 (GPT2) as a direct HIF-2 target gene [...] Read more.

Hypoxia-inducible factor (HIF) directly activates the transcription of metabolic enzymes in response to hypoxia to reprogram cellular metabolism required for tumor cell proliferation. Through analyzing glutamate-linked aminotransferases, we here identified glutamate pyruvate transaminase 2 (GPT2) as a direct HIF-2 target gene in human glioblastoma (GBM). Hypoxia upregulated GPT2 mRNA and protein levels in GBM cells, which required HIF-2 but not HIF-1. HIF-2 directly bound to the hypoxia response element of the human GPT2 gene, leading to its transcription in hypoxic GBM cells. GPT2 located at the nucleus and mitochondria and reduced α-ketoglutarate levels in GBM cells. Genetic or pharmacological inhibition of GPT2 decreased GBM cell growth and migration under normoxia and hypoxia. Knockout of GPT2 inhibited GBM tumor growth in mice. Collectively, these findings uncover a hypoxia-inducible aminotransferase GPT2 required for GBM progression. Full article

(This article belongs to the Special Issue Hypoxia Signaling and Hormonal Signaling in Cancer Progression)

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21 pages, 882 KiB

Open AccessReview

The Role of SIRT3 in Exercise and Aging

by Lei Zhou, Ricardo Pinho, Yaodong Gu and Zsolt Radak

Cells 2022, 11(16), 2596; https://doi.org/10.3390/cells11162596 - 20 Aug 2022

Cited by 33 | Viewed by 4016

Abstract

The health benefits of regular exercise are well established. Nonetheless, the molecular mechanism(s) responsible for exercise-induced health benefits remain a topic of debate. One of the key cell-signaling candidates proposed to provide exercise-induced benefits is sirtuin 3 (SIRT3). SIRT3, an NAD+ dependent mitochondrial [...] Read more.

The health benefits of regular exercise are well established. Nonetheless, the molecular mechanism(s) responsible for exercise-induced health benefits remain a topic of debate. One of the key cell-signaling candidates proposed to provide exercise-induced benefits is sirtuin 3 (SIRT3). SIRT3, an NAD+ dependent mitochondrial deacetylase, positively modulates many cellular processes, including energy metabolism, mitochondrial biogenesis, and protection against oxidative stress. Although the exercise-induced change in SIRT3 signaling is a potential mechanism contributing to the health advantages of exercise on aging, studies investigating the impact of exercise on SIRT3 abundance in cells provide conflicting results. To resolve this conundrum, this narrative review provides a detailed analysis of the role that exercise-induced changes in SIRT3 play in providing the health and aging benefits associated with regular physical activity. We begin with an overview of SIRT3 function in cells followed by a comprehensive review of the impact of exercise on SIRT3 expression in humans and other mammalians. We then discuss the impact of SIRT3 on aging, followed by a thorough analysis of the cell-signaling links between SIRT3 and exercise-induced adaptation. Notably, to stimulate future research, we conclude with a discussion of key unanswered questions related to exercise, aging, and SIRT3 expression. Full article

(This article belongs to the Topic Skeletal Muscle Structure and Function in Health and Disease)

29 pages, 2370 KiB

Open AccessReview

Promises and Challenges of Cell-Based Therapies to Promote Lung Regeneration in Idiopathic Pulmonary Fibrosis

by Alejandro Egea-Zorrilla, Laura Vera, Borja Saez and Ana Pardo-Saganta

Cells 2022, 11(16), 2595; https://doi.org/10.3390/cells11162595 - 20 Aug 2022

Cited by 8 | Viewed by 4130

Abstract

The lung epithelium is constantly exposed to harmful agents present in the air that we breathe making it highly susceptible to damage. However, in instances of injury to the lung, it exhibits a remarkable capacity to regenerate injured tissue thanks to the presence [...] Read more.

The lung epithelium is constantly exposed to harmful agents present in the air that we breathe making it highly susceptible to damage. However, in instances of injury to the lung, it exhibits a remarkable capacity to regenerate injured tissue thanks to the presence of distinct stem and progenitor cell populations along the airway and alveolar epithelium. Mechanisms of repair are affected in chronic lung diseases such as idiopathic pulmonary fibrosis (IPF), a progressive life-threatening disorder characterized by the loss of alveolar structures, wherein excessive deposition of extracellular matrix components cause the distortion of tissue architecture that limits lung function and impairs tissue repair. Here, we review the most recent findings of a study of epithelial cells with progenitor behavior that contribute to tissue repair as well as the mechanisms involved in mouse and human lung regeneration. In addition, we describe therapeutic strategies to promote or induce lung regeneration and the cell-based strategies tested in clinical trials for the treatment of IPF. Finally, we discuss the challenges, concerns and limitations of applying these therapies of cell transplantation in IPF patients. Further research is still required to develop successful strategies focused on cell-based therapies to promote lung regeneration to restore lung architecture and function. Full article

(This article belongs to the Collection Pulmonary Fibrosis and Cell Therapy)

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13 pages, 2190 KiB

Open AccessArticle

How to Verify Non-Presence—The Challenge of Axenic Algae Cultivation

by Leo Pokorny, Bela Hausmann, Petra Pjevac and Michael Schagerl

Cells 2022, 11(16), 2594; https://doi.org/10.3390/cells11162594 - 20 Aug 2022

Cited by 5 | Viewed by 2656

Abstract

Many phycological applications require the growth and maintenance of pure algae cultures. In some research areas, such as biochemistry and physiology, axenic growth is essential to avoid misinterpretations caused by contaminants. Nonetheless, axenicity—defined as the state of only a single strain being present, [...] Read more.

Many phycological applications require the growth and maintenance of pure algae cultures. In some research areas, such as biochemistry and physiology, axenic growth is essential to avoid misinterpretations caused by contaminants. Nonetheless, axenicity—defined as the state of only a single strain being present, free of any other organism—needs to be verified. We compare the available methods to assess axenicity. We first purified unialgal Limnospira fusiformis cultures with an established series of axenicity treatments, and by including two additional treatment steps. The presumable axenic cultures were then tested for their axenic state by applying conventional tests on LB (lysogeny broth) agar-plates, 16S rRNA gene amplicon sequencing, flow-cytometry and epifluorescence microscopy. Only the plate tests indicated axenic conditions. We found a linear relationship between total cell counts of contaminants achieved by flow cytometry and epifluorescence microscopy, with flow cytometry counts being consistently higher. In addition, 16S rRNA gene amplicon sequencing demonstrated its superiority by not only being an efficient tool for axenicity testing, but also for identification of persistent contaminants. Although classic plate tests are still commonly used to verify axenicity, we found the LB-agar-plate technique to be inappropriate. Cultivation-independent methods are highly recommended to test for axenic conditions. A combination of flow-cytometry and 16S rRNA gene amplicon sequencing complement each other and will yield the most reliable result. Full article

(This article belongs to the Special Issue Growth and Division in Algae)

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20 pages, 3171 KiB

Open AccessArticle

Varied Responses to a High m.3243A>G Mutation Load and Respiratory Chain Dysfunction in Patient-Derived Cardiomyocytes

by Sanna Ryytty, Shalem R. Modi, Nikolay Naumenko, Anastasia Shakirzyanova, Muhammad Obaidur Rahman, Miia Vaara, Anu Suomalainen, Pasi Tavi and Riikka H. Hämäläinen

Cells 2022, 11(16), 2593; https://doi.org/10.3390/cells11162593 - 19 Aug 2022

Cited by 5 | Viewed by 2279

Abstract

The m.3243A>G mutation in mitochondrial tRNA-Leu(UUR) is one of the most common pathogenic mitochondrial DNA mutations in humans. The clinical manifestations are highly heterogenous and the causes for the drastic clinical variability are unknown. Approximately one third of patients suffer from cardiac disease, [...] Read more.

The m.3243A>G mutation in mitochondrial tRNA-Leu(UUR) is one of the most common pathogenic mitochondrial DNA mutations in humans. The clinical manifestations are highly heterogenous and the causes for the drastic clinical variability are unknown. Approximately one third of patients suffer from cardiac disease, which often increases mortality. Why only some patients develop cardiomyopathy is unknown. Here, we studied the molecular effects of a high m.3243A>G mutation load on cardiomyocyte functionality, using cells derived from induced pluripotent stem cells (iPSC-CM) of two different m.3243A>G patients, only one of them suffering from severe cardiomyopathy. While high mutation load impaired mitochondrial respiration in both patients’ iPSC-CMs, the downstream consequences varied. mtDNA mutant cells from a patient with no clinical heart disease showed increased glucose metabolism and retained cellular ATP levels, whereas cells from the cardiac disease patient showed reduced ATP levels. In this patient, the mutations also affected intracellular calcium signaling, while this was not true in the other patient’s cells. Our results reflect the clinical variability in mitochondrial disease patients and show that iPSC-CMs retain tissue specific features seen in patients. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction in Cardiovascular Disease)

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16 pages, 1526 KiB

Open AccessArticle

Cytosine Methylation in Genomic DNA and Characterization of DNA Methylases and Demethylases and Their Expression Profiles in Viroid-Infected Hop Plants (Humulus lupulus Var. ‘Celeia’)

by Andrej Sečnik, Nataša Štajner, Sebastjan Radišek, Urban Kunej, Mitja Križman and Jernej Jakše

Cells 2022, 11(16), 2592; https://doi.org/10.3390/cells11162592 - 19 Aug 2022

Cited by 3 | Viewed by 1723

Abstract

Abiotic and biotic stresses can lead to changes in host DNA methylation, which in plants is also mediated by an RNA-directed DNA methylation mechanism. Infections with viroids have been shown to affect DNA methylation dynamics in different plant hosts. The aim of our [...] Read more.

Abiotic and biotic stresses can lead to changes in host DNA methylation, which in plants is also mediated by an RNA-directed DNA methylation mechanism. Infections with viroids have been shown to affect DNA methylation dynamics in different plant hosts. The aim of our research was to determine the content of 5-methylcytosine (5-mC) in genomic DNA at the whole genome level of hop plants (Humulus lupulus Var. ‘Celeia’) infected with different viroids and their combinations and to analyse the expression of the selected genes to improve our understanding of DNA methylation dynamics in plant-viroid systems. The adapted HPLC-UV method used proved to be suitable for this purpose, and thus we were able to estimate for the first time that the cytosine methylation level in viroid-free hop plants was 26.7%. Interestingly, the observed 5-mC level was the lowest in hop plants infected simultaneously with CBCVd, HLVd and HSVd (23.7%), whereas the highest level was observed in plants infected with HLVd (31.4%). In addition, we identified three DNA methylases and one DNA demethylase gene in the hop’s draft genome. The RT-qPCR revealed upregulation of all newly identified genes in hop plants infected with all three viroids, while no altered expression was observed in any of the other hop plants tested, except for CBCVd-infected hop plants, in which one DNA methylase was also upregulated. Full article

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

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17 pages, 9835 KiB

Open AccessArticle

Developing a Reliable Holographic Flow Cyto-Tomography Apparatus by Optimizing the Experimental Layout and Computational Processing

by Jaromír Běhal, Francesca Borrelli, Martina Mugnano, Vittorio Bianco, Amedeo Capozzoli, Claudio Curcio, Angelo Liseno, Lisa Miccio, Pasquale Memmolo and Pietro Ferraro

Cells 2022, 11(16), 2591; https://doi.org/10.3390/cells11162591 - 19 Aug 2022

Cited by 4 | Viewed by 1755

Abstract

Digital Holographic Tomography (DHT) has recently been established as a means of retrieving the 3D refractive index mapping of single cells. To make DHT a viable system, it is necessary to develop a reliable and robust holographic apparatus in order that such technology [...] Read more.

Digital Holographic Tomography (DHT) has recently been established as a means of retrieving the 3D refractive index mapping of single cells. To make DHT a viable system, it is necessary to develop a reliable and robust holographic apparatus in order that such technology can be utilized outside of specialized optics laboratories and operated in the in-flow modality. In this paper, we propose a quasi-common-path lateral-shearing holographic optical set-up to be used, for the first time, for DHT in a flow-cytometer modality. The proposed solution is able to withstand environmental vibrations that can severely affect the interference process. Furthermore, we have scaled down the system while ensuring that a full 360° rotation of the cells occurs in the field-of-view, in order to retrieve 3D phase-contrast tomograms of single cells flowing along a microfluidic channel. This was achieved by setting the camera sensor at 45° with respect to the microfluidic direction. Additional optimizations were made to the computational elements to ensure the reliable retrieval of 3D refractive index distributions by demonstrating an effective method of tomographic reconstruction, based on high-order total variation. The results were first demonstrated using realistic 3D numerical phantom cells to assess the performance of the proposed high-order total variation method in comparison with the gold-standard algorithm for tomographic reconstructions: namely, filtered back projection. Then, the proposed DHT system and the processing pipeline were experimentally validated for monocytes and mouse embryonic fibroblast NIH-3T3 cells lines. Moreover, the repeatability of these tomographic measurements was also investigated by recording the same cell multiple times and quantifying the ability to provide reliable and comparable tomographic reconstructions, as confirmed by a correlation coefficient greater than 95%. The reported results represent various steps forward in several key aspects of in-flow DHT, thus paving the way for its use in real-world applications. Full article

(This article belongs to the Special Issue Super-Resolution Microscopy in Cells)

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24 pages, 14012 KiB

Open AccessReview

Proteostasis Deregulation in Neurodegeneration and Its Link with Stress Granules: Focus on the Scaffold and Ribosomal Protein RACK1

by Mirco Masi, Alessandro Attanzio, Marco Racchi, Benjamin Wolozin, Sofia Borella, Fabrizio Biundo and Erica Buoso

Cells 2022, 11(16), 2590; https://doi.org/10.3390/cells11162590 - 19 Aug 2022

Cited by 4 | Viewed by 3052

Abstract

The role of protein misfolding, deposition, and clearance has been the dominant topic in the last decades of investigation in the field of neurodegeneration. The impairment of protein synthesis, along with RNA metabolism and RNA granules, however, are significantly emerging as novel potential [...] Read more.

The role of protein misfolding, deposition, and clearance has been the dominant topic in the last decades of investigation in the field of neurodegeneration. The impairment of protein synthesis, along with RNA metabolism and RNA granules, however, are significantly emerging as novel potential targets for the comprehension of the molecular events leading to neuronal deficits. Indeed, defects in ribosome activity, ribosome stalling, and PQC—all ribosome-related processes required for proteostasis regulation—can contribute to triggering stress conditions and promoting the formation of stress granules (SGs) that could evolve in the formation of pathological granules, usually occurring during neurodegenerating effects. In this review, the interplay between proteostasis, mRNA metabolism, and SGs has been explored in a neurodegenerative context with a focus on Alzheimer’s disease (AD), although some defects in these same mechanisms can also be found in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which are discussed here. Finally, we highlight the role of the receptor for activated C kinase 1 (RACK1) in these pathologies and note that, besides its well characterized function as a scaffold protein, it has an important role in translation and can associate to stress granules (SGs) determining cell fate in response to diverse stress stimuli. Full article

(This article belongs to the Special Issue Cellular Senescence in Age-Related Diseases: Molecular Bases and Therapeutic Interventions II)

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15 pages, 1387 KiB

Open AccessReview

How Azanucleosides Affect Myeloid Cell Fate

by Anna Stein, Uwe Platzbecker and Michael Cross

Cells 2022, 11(16), 2589; https://doi.org/10.3390/cells11162589 - 19 Aug 2022

Cited by 2 | Viewed by 1647

Abstract

The azanucleosides decitabine and azacytidine are used widely in the treatment of myeloid neoplasia and increasingly in the context of combination therapies. Although they were long regarded as being largely interchangeable in their function as hypomethylating agents, the azanucleosides actually have different mechanisms [...] Read more.

The azanucleosides decitabine and azacytidine are used widely in the treatment of myeloid neoplasia and increasingly in the context of combination therapies. Although they were long regarded as being largely interchangeable in their function as hypomethylating agents, the azanucleosides actually have different mechanisms of action; decitabine interferes primarily with the methylation of DNA and azacytidine with that of RNA. Here, we examine the role of DNA methylation in the lineage commitment of stem cells during normal hematopoiesis and consider how mutations in epigenetic regulators such as DNMT3A and TET2 can lead to clonal expansion and subsequent neoplastic progression. We also consider why the efficacy of azanucleoside treatment is not limited to neoplasias carrying mutations in epigenetic regulators. Finally, we summarise recent data describing a role for azacytidine-sensitive RNA methylation in lineage commitment and in the cellular response to stress. By summarising and interpreting evidence for azanucleoside involvement in a range of cellular processes, our review is intended to illustrate the need to consider multiple modes of action in the design and stratification of future combination therapies. Full article

(This article belongs to the Collection Epigenetics in Myeloproliferative Neoplasms and Acute Myeloid Leukemia)

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