Cells

22 pages, 4916 KiB

Open AccessReview

Myeloid-Derived Suppressor Cells in Solid Tumors

by Tianmiao Ma, Bernhard W. Renz, Matthias Ilmer, Dominik Koch, Yuhui Yang, Jens Werner and Alexandr V. Bazhin

Cells 2022, 11(2), 310; https://doi.org/10.3390/cells11020310 - 17 Jan 2022

Cited by 50 | Viewed by 9524

Abstract

Myeloid-derived suppressor cells (MDSCs) are one of the main suppressive cell population of the immune system. They play a pivotal role in the establishment of the tumor microenvironment (TME). In the context of cancers or other pathological conditions, MDSCs can differentiate, expand, and [...] Read more.

Myeloid-derived suppressor cells (MDSCs) are one of the main suppressive cell population of the immune system. They play a pivotal role in the establishment of the tumor microenvironment (TME). In the context of cancers or other pathological conditions, MDSCs can differentiate, expand, and migrate in large quantities during circulation, inhibiting the cytotoxic functions of T cells and NK cells. This process is regulated by ROS, iNOS/NO, arginase-1, and multiple soluble cytokines. The definition of MDSCs and their phenotypes in humans are not as well represented as in other organisms such as mice, owing to the absence of the cognate molecule. However, a comprehensive understanding of the differences between different species and subsets will be beneficial for clarifying the immunosuppressive properties and potential clinical values of these cells during tumor progression. Recently, experimental evidence and clinical investigations have demonstrated that MDSCs have a close relationship with poor prognosis and drug resistance, which is considered to be a leading marker for practical applications and therapeutic methods. In this review, we summarize the remarkable position of MDSCs in solid tumors, explain their classifications in different models, and introduce new treatment approaches to target MDSCs to better understand the advancement of new approaches to cancer treatment. Full article

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

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21 pages, 11104 KiB

Open AccessReview

Fibrosis Is a Basement Membrane-Related Disease in the Cornea: Injury and Defective Regeneration of Basement Membranes May Underlie Fibrosis in Other Organs

by Steven E. Wilson

Cells 2022, 11(2), 309; https://doi.org/10.3390/cells11020309 - 17 Jan 2022

Cited by 18 | Viewed by 4167

Abstract

Every organ develops fibrosis that compromises functions in response to infections, injuries, or diseases. The cornea is a relatively simple, avascular organ that offers an exceptional model to better understand the pathophysiology of the fibrosis response. Injury and defective regeneration of the epithelial [...] Read more.

Every organ develops fibrosis that compromises functions in response to infections, injuries, or diseases. The cornea is a relatively simple, avascular organ that offers an exceptional model to better understand the pathophysiology of the fibrosis response. Injury and defective regeneration of the epithelial basement membrane (EBM) or the endothelial Descemet’s basement membrane (DBM) triggers the development of myofibroblasts from resident corneal fibroblasts and bone marrow-derived blood borne fibrocytes due to the increased entry of TGF beta-1/-2 into the stroma from the epithelium and tears or residual corneal endothelium and aqueous humor. The myofibroblasts, and disordered extracellular matrix these cells produce, persist until the source of injury is removed, the EBM and/or DBM are regenerated, or replaced surgically, resulting in decreased stromal TGF beta requisite for myofibroblast survival. A similar BM injury-related pathophysiology can underly the development of fibrosis in other organs such as skin and lung. The normal liver does not contain traditional BMs but develops sinusoidal endothelial BMs in many fibrotic diseases and models. However, normal hepatic stellate cells produce collagen type IV and perlecan that can modulate TGF beta localization and cognate receptor binding in the space of Dissé. BM-related fibrosis is deserving of more investigation in all organs. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Fibrosis)

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15 pages, 3064 KiB

Open AccessReview

Emerging Role of cAMP/AMPK Signaling

by Muhammad Aslam and Yury Ladilov

Cells 2022, 11(2), 308; https://doi.org/10.3390/cells11020308 - 17 Jan 2022

Cited by 104 | Viewed by 11627

Abstract

The 5′-Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a natural energy sensor in mammalian cells that plays a key role in cellular and systemic energy homeostasis. At the cellular level, AMPK supports numerous processes required for energy and redox homeostasis, including mitochondrial biogenesis, [...] Read more.

The 5′-Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a natural energy sensor in mammalian cells that plays a key role in cellular and systemic energy homeostasis. At the cellular level, AMPK supports numerous processes required for energy and redox homeostasis, including mitochondrial biogenesis, autophagy, and glucose and lipid metabolism. Thus, understanding the pathways regulating AMPK activity is crucial for developing strategies to treat metabolic disorders. Mounting evidence suggests the presence of a link between cyclic AMP (cAMP) and AMPK signaling. cAMP signaling is known to be activated in circumstances of physiological and metabolic stress due to the release of stress hormones, such as adrenaline and glucagon, which is followed by activation of membrane-bound adenylyl cyclase and elevation of cellular cAMP. Because the majority of physiological stresses are associated with elevated energy consumption, it is not surprising that activation of cAMP signaling may promote AMPK activity. Aside from the physiological role of the cAMP/AMPK axis, numerous reports have suggested its role in several pathologies, including inflammation, ischemia, diabetes, obesity, and aging. Furthermore, novel reports have provided more mechanistic insight into the regulation of the cAMP/AMPK axis. In particular, the role of distinct cAMP microdomains generated by soluble adenylyl cyclase in regulating basal and induced AMPK activity has recently been demonstrated. In the present review, we discuss current advances in the understanding of the regulation of the cAMP/AMPK axis and its role in cellular homeostasis and explore some translational aspects. Full article

(This article belongs to the Special Issue Advances in AMPK Research: Basic and Translational Aspects)

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16 pages, 1055 KiB

Open AccessReview

A Special Network Comprised of Macrophages, Epithelial Cells, and Gut Microbiota for Gut Homeostasis

by Wei Chen, Dan Liu, Changhao Ren, Xiaomin Su, Chun-Kwok Wong and Rongcun Yang

Cells 2022, 11(2), 307; https://doi.org/10.3390/cells11020307 - 17 Jan 2022

Cited by 9 | Viewed by 3989

Abstract

A number of gut epithelial cells derived immunological factors such as cytokines and chemokines, which are stimulated by the gut microbiota, can regulate host immune responses to maintain a well-balance between gut microbes and host immune system. Multiple specialized immune cell populations, such [...] Read more.

A number of gut epithelial cells derived immunological factors such as cytokines and chemokines, which are stimulated by the gut microbiota, can regulate host immune responses to maintain a well-balance between gut microbes and host immune system. Multiple specialized immune cell populations, such as macrophages, dendritic cells (DCs), innate lymphoid cells, and T regulatory (Treg) cells, can communicate with intestinal epithelial cells (IEC) and/or the gut microbiota bi-directionally. The gut microbiota contributes to the differentiation and function of resident macrophages. Situated at the interface between the gut commensals and macrophages, the gut epithelium is crucial for gut homeostasis in microbial recognition, signaling transformation, and immune interactions, apart from being a physical barrier. Thus, three distinct but interactive components—macrophages, microbiota, and IEC—can form a network for the delicate and dynamic regulation of intestinal homeostasis. In this review, we will discuss the crucial features of gut microbiota, macrophages, and IEC. We will also summarize recent advances in understanding the cooperative and dynamic interactions among the gut microbiota, gut macrophages, and IEC, which constitute a special network for gut homeostasis. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Cell Microenvironment)

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11 pages, 3978 KiB

Open AccessReview

Janus Kinase Signaling Pathway and Its Role in COVID-19 Inflammatory, Vascular, and Thrombotic Manifestations

by Jonathan D. Ravid, Orly Leiva and Vipul C. Chitalia

Cells 2022, 11(2), 306; https://doi.org/10.3390/cells11020306 - 17 Jan 2022

Cited by 21 | Viewed by 2760

Abstract

Acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection continues to be a worldwide public health crisis. Among the several severe manifestations of this disease, thrombotic processes drive the catastrophic organ failure and mortality in these patients. In addition to a well-established cytokine storm associated with the [...] Read more.

Acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection continues to be a worldwide public health crisis. Among the several severe manifestations of this disease, thrombotic processes drive the catastrophic organ failure and mortality in these patients. In addition to a well-established cytokine storm associated with the disease, perturbations in platelets, endothelial cells, and the coagulation system are key in triggering systemic coagulopathy, involving both the macro- and microvasculatures of different organs. Of the several mechanisms that might contribute to dysregulation of these cells following SARS-CoV-2 infection, the current review focuses on the role of activated Janus kinase (JAK) signaling in augmenting thrombotic processes and organ dysfunction. The review concludes with presenting the current understanding and emerging controversies concerning the potential therapeutic applications of JAK inhibitors for ameliorating the inflammation-thrombosis phenotype in COVID-19 patients. Full article

(This article belongs to the Special Issue COVID19, Renin-Angiotensin System and Endothelial Dysfunction)

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17 pages, 3222 KiB

Open AccessArticle

Rhenium Perrhenate (¹⁸⁸ReO₄) Induced Apoptosis and Reduced Cancerous Phenotype in Liver Cancer Cells

by Samieh Asadian, Abbas Piryaei, Nematollah Gheibi, Bagher Aziz Kalantari, Mohamad Reza Davarpanah, Mehdi Azad, Valentina Kapustina, Mehdi Alikhani, Sahar Moghbeli Nejad, Hani Keshavarz Alikhani, Morteza Mohamadi, Anastasia Shpichka, Peter Timashev, Moustapha Hassan and Massoud Vosough

Cells 2022, 11(2), 305; https://doi.org/10.3390/cells11020305 - 17 Jan 2022

Cited by 18 | Viewed by 3251 | Correction

Abstract

Recurrence in hepatocellular carcinoma (HCC) after conventional treatments is a crucial challenge. Despite the promising progress in advanced targeted therapies, HCC is the fourth leading cause of cancer death worldwide. Radionuclide therapy can potentially be a practical targeted approach to address this concern. [...] Read more.

Recurrence in hepatocellular carcinoma (HCC) after conventional treatments is a crucial challenge. Despite the promising progress in advanced targeted therapies, HCC is the fourth leading cause of cancer death worldwide. Radionuclide therapy can potentially be a practical targeted approach to address this concern. Rhenium-188 (¹⁸⁸Re) is a β-emitting radionuclide used in the clinic to induce apoptosis and inhibit cell proliferation. Although adherent cell cultures are efficient and reliable, appropriate cell-cell and cell-extracellular matrix (ECM) contact is still lacking. Thus, we herein aimed to assess ¹⁸⁸Re as a potential therapeutic component for HCC in 2D and 3D models. The death rate in treated Huh7 and HepG2 lines was significantly higher than in untreated control groups using viability assay. After treatment with ¹⁸⁸ReO₄, Annexin/PI data indicated considerable apoptosis induction in HepG2 cells after 48 h but not Huh7 cells. Quantitative RT-PCR and western blotting data also showed increased apoptosis in response to ¹⁸⁸ReO₄ treatment. In Huh7 cells, exposure to an effective dose of ¹⁸⁸ReO₄ led to cell cycle arrest in the G2 phase. Moreover, colony formation assay confirmed post-exposure growth suppression in Huh7 and HepG2 cells. Then, the immunostaining displayed proliferation inhibition in the ¹⁸⁸ReO₄-treated cells on 3D scaffolds of liver ECM. The PI3-AKT signaling pathway was activated in 3D culture but not in 2D culture. In nude mice, Huh7 cells treated with an effective dose of ¹⁸⁸ReO₄ lost their tumor formation ability compared to the control group. These findings suggest that ¹⁸⁸ReO₄ can be a potential new therapeutic agent against HCC through induction of apoptosis and cell cycle arrest and inhibition of tumor formation. This approach can be effectively combined with antibodies and peptides for more selective and personalized therapy. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Cellular Pathology)

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12 pages, 7788 KiB

Open AccessFeature PaperReview

Endolysosomal Cation Channels and Lung Disease

by Barbara Spix, Aicha Jeridi, Meshal Ansari, Ali Önder Yildirim, Herbert B. Schiller and Christian Grimm

Cells 2022, 11(2), 304; https://doi.org/10.3390/cells11020304 - 17 Jan 2022

Cited by 4 | Viewed by 3846

Abstract

Endolysosomal cation channels are emerging as key players of endolysosomal function such as endolysosomal trafficking, fusion/fission, lysosomal pH regulation, autophagy, lysosomal exocytosis, and endocytosis. Diseases comprise lysosomal storage disorders (LSDs) and neurodegenerative diseases, metabolic diseases, pigmentation defects, cancer, immune disorders, autophagy related diseases, [...] Read more.

Endolysosomal cation channels are emerging as key players of endolysosomal function such as endolysosomal trafficking, fusion/fission, lysosomal pH regulation, autophagy, lysosomal exocytosis, and endocytosis. Diseases comprise lysosomal storage disorders (LSDs) and neurodegenerative diseases, metabolic diseases, pigmentation defects, cancer, immune disorders, autophagy related diseases, infectious diseases and many more. Involvement in lung diseases has not been a focus of attention so far but recent developments in the field suggest critical functions in lung physiology and pathophysiology. Thus, loss of TRPML3 was discovered to exacerbate emphysema formation and cigarette smoke induced COPD due to dysregulated matrix metalloproteinase 12 (MMP-12) levels in the extracellular matrix of the lung, a known risk factor for emphysema/COPD. While direct lung function measurements with the exception of TRPML3 are missing for other endolysosomal cation channels or channels expressed in lysosome related organelles (LRO) in the lung, links between those channels and important roles in lung physiology have been established such as the role of P2X4 in surfactant release from alveolar epithelial Type II cells. Other channels with demonstrated functions and disease relevance in the lung such as TRPM2, TRPV2, or TRPA1 may mediate their effects due to plasma membrane expression but evidence accumulates that these channels might also be expressed in endolysosomes, suggesting additional and/or dual roles of these channels in cell and intracellular membranes. We will discuss here the current knowledge on cation channels residing in endolysosomes or LROs with respect to their emerging roles in lung disease. Full article

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

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13 pages, 940 KiB

Open AccessFeature PaperReview

Functions of CNKSR2 and Its Association with Neurodevelopmental Disorders

by Hidenori Ito and Koh-ichi Nagata

Cells 2022, 11(2), 303; https://doi.org/10.3390/cells11020303 - 17 Jan 2022

Cited by 5 | Viewed by 3411

Abstract

The Connector Enhancer of Kinase Suppressor of Ras-2 (CNKSR2), also known as CNK2 or MAGUIN, is a scaffolding molecule that contains functional protein binding domains: Sterile Alpha Motif (SAM) domain, Conserved Region in CNK (CRIC) domain, PSD-95/Dlg-A/ZO-1 (PDZ) domain, Pleckstrin Homology (PH) domain, [...] Read more.

The Connector Enhancer of Kinase Suppressor of Ras-2 (CNKSR2), also known as CNK2 or MAGUIN, is a scaffolding molecule that contains functional protein binding domains: Sterile Alpha Motif (SAM) domain, Conserved Region in CNK (CRIC) domain, PSD-95/Dlg-A/ZO-1 (PDZ) domain, Pleckstrin Homology (PH) domain, and C-terminal PDZ binding motif. CNKSR2 interacts with different molecules, including RAF1, ARHGAP39, and CYTH2, and regulates the Mitogen-Activated Protein Kinase (MAPK) cascade and small GTPase signaling. CNKSR2 has been reported to control the development of dendrite and dendritic spines in primary neurons. CNKSR2 is encoded by the CNKSR2 gene located in the X chromosome. CNKSR2 is now considered as a causative gene of the Houge type of X-linked syndromic mental retardation (MRXHG), an X-linked Intellectual Disability (XLID) that exhibits delayed development, intellectual disability, early-onset seizures, language delay, attention deficit, and hyperactivity. In this review, we summarized molecular features, neuronal function, and neurodevelopmental disorder-related variations of CNKSR2. Full article

(This article belongs to the Special Issue Pathophysiological Mechanism of Neurodevelopmental Disorders)

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22 pages, 974 KiB

Open AccessReview

A Defective Viral Particle Approach to COVID-19

by Maria Kalamvoki and Vic Norris

Cells 2022, 11(2), 302; https://doi.org/10.3390/cells11020302 - 17 Jan 2022

Cited by 9 | Viewed by 3638

Abstract

The novel coronavirus SARS-CoV-2 has caused a pandemic resulting in millions of deaths worldwide. While multiple vaccines have been developed, insufficient vaccination combined with adaptive mutations create uncertainty for the future. Here, we discuss novel strategies to control COVID-19 relying on Defective Interfering [...] Read more.

The novel coronavirus SARS-CoV-2 has caused a pandemic resulting in millions of deaths worldwide. While multiple vaccines have been developed, insufficient vaccination combined with adaptive mutations create uncertainty for the future. Here, we discuss novel strategies to control COVID-19 relying on Defective Interfering Particles (DIPs) and related particles that arise naturally during an infection. Our intention is to encourage and to provide the basis for the implementation of such strategies by multi-disciplinary teams. We therefore provide an overview of SARS-CoV-2 for a multi-disciplinary readership that is specifically tailored to these strategies, we identify potential targets based on the current knowledge of the properties and functions of coronaviruses, and we propose specific strategies to engineer DIPs and other interfering or therapeutic nanoparticles. Full article

(This article belongs to the Special Issue Multifunctional Cytoskeleton Network in Human Diseases: Mutual Risk of Dementia, Cancer and COVID-19)

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22 pages, 4714 KiB

Open AccessArticle

[(WR)₈WKβA]-Doxorubicin Conjugate: A Delivery System to Overcome Multi-Drug Resistance against Doxorubicin

by Khalid Zoghebi, Hamidreza Montazeri Aliabadi, Rakesh Kumar Tiwari and Keykavous Parang

Cells 2022, 11(2), 301; https://doi.org/10.3390/cells11020301 - 16 Jan 2022

Cited by 12 | Viewed by 3637

Abstract

Doxorubicin (Dox) is an anthracycline chemotherapeutic agent used to treat breast, leukemia, and lymphoma malignancies. However, cardiotoxicity and inherent acquired resistance are major drawbacks, limiting its clinical application. We have previously shown that cyclic peptide [WR]₉ containing alternate tryptophan (W) and arginine [...] Read more.

Doxorubicin (Dox) is an anthracycline chemotherapeutic agent used to treat breast, leukemia, and lymphoma malignancies. However, cardiotoxicity and inherent acquired resistance are major drawbacks, limiting its clinical application. We have previously shown that cyclic peptide [WR]₉ containing alternate tryptophan (W) and arginine (R) residues acts as an efficient molecular transporter. An amphiphilic cyclic peptide containing a lysine (K) residue and alternative W and R was conjugated through a free side chain amino group with Dox via a glutarate linker to afford [(WR)₈WKβA]-Dox conjugate. Antiproliferative assays were performed in different cancer cell lines using the conjugate and the corresponding physical mixture of the peptide and Dox to evaluate the effectiveness of synthesized conjugate compared to the parent drug alone. [(WR)₈WKβA]-Dox conjugate showed higher antiproliferative activity at 10 µM and 5 µM than Dox alone at 5 μM. The conjugate inhibited the cell viability of ovarian adenocarcinoma (SK-OV-3) by 59% and the triple-negative breast cancer cells MDA-MB-231 and MCF-7 by 71% and 77%, respectively, at a concentration of 5 μM after 72 h of incubation. In contrast, Dox inhibited the proliferation of SK-OV-3, MDA-MB-231, and MCF-7 by 35%, 63%, and 57%, respectively. Furthermore, [(WR)₈WKβA]-Dox conjugate (5 µM) inhibited the cell viability of Dox-resistant cells (MES-SA/MX2) by 92%, while the viability of cells incubated with free Dox was only 15% at 5 μM. Confocal microscopy images confirmed the ability of both Dox conjugate and the physical mixture of the peptide with the drug to deliver Dox through an endocytosis-independent pathway, as the uptake was not inhibited in the presence of endocytosis inhibitors. The stability of Dox conjugate was observed at different time intervals using analytical HPLC when the conjugate was incubated with 25% human serum. Half-life (t_1/2) for [(WR)₈WKβA]-Dox conjugate was (∼6 h), and more than 80% of the conjugate was degraded at 12 h. The release of free Dox was assessed intracellularly using the CCRF-CEM cell line. The experiment demonstrated that approximately 100% of free Dox was released from the conjugate intracellularly within 72 h. These data confirm the ability of the cyclic cell-penetrating peptide containing tryptophan and arginine residues as an efficient tool for delivery of Dox and for overcoming resistance to it. Full article

(This article belongs to the Special Issue Cell-Penetrating Peptides: From Basic Research to Application in Human Therapies)

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Graphical abstract

15 pages, 5018 KiB

Open AccessArticle

STAT3 Is the Master Regulator for the Forming of 3D Spheroids of 3T3-L1 Preadipocytes

by Hiroshi Ohguro, Yosuke Ida, Fumihito Hikage, Araya Umetsu, Hanae Ichioka, Megumi Watanabe and Masato Furuhashi

Cells 2022, 11(2), 300; https://doi.org/10.3390/cells11020300 - 16 Jan 2022

Cited by 25 | Viewed by 4609

Abstract

To elucidate the currently unknown mechanisms responsible for the diverse biological aspects between two-dimensional (2D) and three-dimensional (3D) cultured 3T3-L1 preadipocytes, RNA-sequencing analyses were performed. During a 7-day culture period, 2D- and 3D-cultured 3T3-L1 cells were subjected to lipid staining by BODIPY, qPCR [...] Read more.

To elucidate the currently unknown mechanisms responsible for the diverse biological aspects between two-dimensional (2D) and three-dimensional (3D) cultured 3T3-L1 preadipocytes, RNA-sequencing analyses were performed. During a 7-day culture period, 2D- and 3D-cultured 3T3-L1 cells were subjected to lipid staining by BODIPY, qPCR for adipogenesis related genes, including peroxisome proliferator-activated receptor γ (Pparγ), CCAAT/enhancer-binding protein alpha (Cebpa), Ap2 (fatty acid-binding protein 4; Fabp4), leptin, and AdipoQ (adiponectin), and RNA-sequencing analysis. Differentially expressed genes (DEGs) were detected by next-generation RNA sequencing (RNA-seq) and validated by a quantitative reverse transcription–polymerase chain reaction (qRT–PCR). Bioinformatic analyses were performed on DEGs using a Gene Ontology (GO) enrichment analysis and an Ingenuity Pathway Analysis (IPA). Significant spontaneous adipogenesis was observed in 3D 3T3-L1 spheroids, but not in 2D-cultured cells. The mRNA expression of Pparγ, Cebpa, and Ap2 among the five genes tested were significantly higher in 3D spheroids than in 2D-cultured cells, thus providing support for this conclusion. RNA analysis demonstrated that a total of 826 upregulated and 725 downregulated genes were identified as DEGs. GO enrichment analysis and IPA found 50 possible upstream regulators, and among these, 6 regulators—transforming growth factor β1 (TGFβ1), signal transducer and activator of transcription 3 (STAT3), interleukin 6 (IL6), angiotensinogen (AGT), FOS, and MYC—were, in fact, significantly upregulated. Further analyses of these regulators by causal networks of the top 14 predicted diseases and functions networks (IPA network score indicated more than 30), suggesting that STAT3 was the most critical upstream regulator. The findings presented herein suggest that STAT3 has a critical role in regulating the unique biological properties of 3D spheroids that are produced from 3T3-L1 preadipocytes. Full article

(This article belongs to the Section Cell Methods)

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15 pages, 2177 KiB

Open AccessArticle

Sacsin Deletion Induces Aggregation of Glial Intermediate Filaments

by Fernanda Murtinheira, Mafalda Migueis, Ricardo Letra-Vilela, Mickael Diallo, Andrea Quezada, Cláudia A. Valente, Abel Oliva, Carmen Rodriguez, Vanesa Martin and Federico Herrera

Cells 2022, 11(2), 299; https://doi.org/10.3390/cells11020299 - 16 Jan 2022

Cited by 8 | Viewed by 3652

Abstract

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disorder commonly diagnosed in infants and characterized by progressive cerebellar ataxia, spasticity, motor sensory neuropathy and axonal demyelination. ARSACS is caused by mutations in the SACS gene that lead to truncated or defective [...] Read more.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disorder commonly diagnosed in infants and characterized by progressive cerebellar ataxia, spasticity, motor sensory neuropathy and axonal demyelination. ARSACS is caused by mutations in the SACS gene that lead to truncated or defective forms of the 520 kDa multidomain protein, sacsin. Sacsin function is exclusively studied on neuronal cells, where it regulates mitochondrial network organization and facilitates the normal polymerization of neuronal intermediate filaments (i.e., neurofilaments and vimentin). Here, we show that sacsin is also highly expressed in astrocytes, C6 rat glioma cells and N9 mouse microglia. Sacsin knockout in C6 cells (C6^Sacs−/−) induced the accumulation of the glial intermediate filaments glial fibrillary acidic protein (GFAP), nestin and vimentin in the juxtanuclear area, and a concomitant depletion of mitochondria. C6^Sacs−/− cells showed impaired responses to oxidative challenges (Rotenone) and inflammatory stimuli (Interleukin-6). GFAP aggregation is also associated with other neurodegenerative conditions diagnosed in infants, such as Alexander disease or Giant Axonal Neuropathy. Our results, and the similarities between these disorders, reinforce the possible connection between ARSACS and intermediate filament-associated diseases and point to a potential role of glia in ARSACS pathology. Full article

(This article belongs to the Topic Cellular Redox Homeostasis)

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13 pages, 5545 KiB

Open AccessArticle

Endogenous pH 6.0 β-Galactosidase Activity Is Linked to Neuronal Differentiation in the Olfactory Epithelium

by José Antonio de Mera-Rodríguez, Guadalupe Álvarez-Hernán, Yolanda Gañán, Ana Santos-Almeida, Gervasio Martín-Partido, Joaquín Rodríguez-León and Javier Francisco-Morcillo

Cells 2022, 11(2), 298; https://doi.org/10.3390/cells11020298 - 16 Jan 2022

Cited by 7 | Viewed by 2980

Abstract

The histochemical detection of β-galactosidase enzymatic activity at pH 6.0 (β-gal-pH6) is a widely used biomarker of cellular senescence in aging tissues. This histochemical assay also detects the presence of programmed cell senescence during specific time windows in degenerating structures of vertebrate embryos. [...] Read more.

The histochemical detection of β-galactosidase enzymatic activity at pH 6.0 (β-gal-pH6) is a widely used biomarker of cellular senescence in aging tissues. This histochemical assay also detects the presence of programmed cell senescence during specific time windows in degenerating structures of vertebrate embryos. However, it has recently been shown that this enzymatic activity is also enhanced in subpopulations of differentiating neurons in the developing central nervous system in vertebrates. The present study addressed the histochemical detection of β-gal-pH6 enzymatic activity in the developing postnatal olfactory epithelium in the mouse. This activity was detected in the intermediate layer of the olfactory epithelium. As development progressed, the band of β-gal-pH6 labeling in this layer increased in width. Immunohistochemistry and lectin histochemistry showed the β-gal-pH6 staining to be strongly correlated with the immunolabeling of the olfactory marker protein (OMP) that identifies mature olfactory sensory neurons. The cell somata of a subpopulation of differentiated olfactory neurons that were recognized with the Dolichos biflorus agglutinin (DBA) were always located inside this band of β-gal-pH6 staining. However, the β-gal-pH6 histochemical signal was always absent from the apical region where the cytokeratin-8 positive supporting cells were located. Furthermore, no β-gal-pH6 staining was found in the basal region of the olfactory epithelium where PCNA/pHisH3 immunoreactive proliferating progenitor cells, GAP43 positive immature neurons, and cytokeratin-5 positive horizontal basal cells were located. Therefore, β-gal-pH6 seems to be linked to neuronal differentiation and cannot be regarded as a biomarker of cellular senescence during olfactory epithelium development in mice. Full article

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

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18 pages, 4535 KiB

Open AccessArticle

Changes in the Mitochondria-Related Nuclear Gene Expression Profile during Human Oocyte Maturation by the IVM Technique

by Zhi-Yong Yang, Min Ye, Ya-Xin Xing, Qi-Gui Xie, Jian-Hong Zhou, Xin-Rui Qi, Kehkooi Kee and Ri-Cheng Chian

Cells 2022, 11(2), 297; https://doi.org/10.3390/cells11020297 - 16 Jan 2022

Cited by 7 | Viewed by 3010

Abstract

To address which mitochondria-related nuclear differentially expressed genes (DEGs) and related pathways are altered during human oocyte maturation, single-cell analysis was performed in three oocyte states: in vivo matured (M-IVO), in vitro matured (M-IVT), and failed to mature in vitro (IM-IVT). There were [...] Read more.

To address which mitochondria-related nuclear differentially expressed genes (DEGs) and related pathways are altered during human oocyte maturation, single-cell analysis was performed in three oocyte states: in vivo matured (M-IVO), in vitro matured (M-IVT), and failed to mature in vitro (IM-IVT). There were 691 DEGs and 16 mitochondria-related DEGs in the comparison of M-IVT vs. IM-IVT oocytes, and 2281 DEGs and 160 mitochondria-related DEGs in the comparison of M-IVT vs. M-IVO oocytes, respectively. The GO and KEGG analyses showed that most of them were involved in pathways such as oxidative phosphorylation, pyruvate metabolism, peroxisome, and amino acid metabolism, i.e., valine, leucine, isoleucine, glycine, serine, and threonine metabolism or degradation. During the progress of oocyte maturation, the metabolic pathway, which derives the main source of ATP, shifted from glucose metabolism to pyruvate and fatty acid oxidation in order to maintain a low level of damaging reactive oxygen species (ROS) production. Although the immature oocytes could be cultured to a mature stage by an in vitro technique (IVM), there were still some differences in mitochondria-related regulations, which showed that the mitochondria were regulated by nuclear genes to compensate for their developmental needs. Meanwhile, the results indicated that the current IVM culture medium should be optimized to compensate for the special need for further development according to this disclosure, as it was a latent strategy to improve the effectiveness of the IVM procedure. Full article

(This article belongs to the Special Issue Molecular Mechanism of Oocyte Maturation)

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6 pages, 788 KiB

Open AccessCommentary

Developing Digital Photomicroscopy

by Kingsley Micklem

Cells 2022, 11(2), 296; https://doi.org/10.3390/cells11020296 - 16 Jan 2022

Viewed by 1649

Abstract

(1) The need for efficient ways of recording and presenting multicolour immunohistochemistry images in a pioneering laboratory developing new techniques motivated a move away from photography to electronic and ultimately digital photomicroscopy. (2) Initially broadcast quality analogue cameras were used in the absence [...] Read more.

(1) The need for efficient ways of recording and presenting multicolour immunohistochemistry images in a pioneering laboratory developing new techniques motivated a move away from photography to electronic and ultimately digital photomicroscopy. (2) Initially broadcast quality analogue cameras were used in the absence of practical digital cameras. This allowed the development of digital image processing, storage and presentation. (3) As early adopters of digital cameras, their advantages and limitations were recognised in implementation. (4) The adoption of immunofluorescence for multiprobe detection prompted further developments, particularly a critical approach to probe colocalization. (5) Subsequently, whole-slide scanning was implemented, greatly enhancing histology for diagnosis, research and teaching. Full article

(This article belongs to the Special Issue Microscope Based Technologies from Clinical Application to Cell Biology: A Themed Issue in Memory of Prof. Kevin C. Gatter and Prof. David Y. Mason)

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16 pages, 5218 KiB

Open AccessArticle

Long-Term High-Fat Diet Consumption Depletes Glial Cells and Tyrosine Hydroxylase–Containing Neurons in the Brain of Middle-Aged Rats

by Mei-Chuan Chou, Hsiang-Chun Lee, Yen-Chin Liu, Patrick Szu-Ying Yen, Ching-Kuan Liu, Chu-Huang Chen, Tzu-Han Hsieh and Shiou-Lan Chen

Cells 2022, 11(2), 295; https://doi.org/10.3390/cells11020295 - 15 Jan 2022

Cited by 7 | Viewed by 3200

Abstract

Epidemiologic studies have indicated that dyslipidemia may facilitate the progression of neuronal degeneration. However, the effects of chronic dyslipidemia on brain function, especially in older individuals, remain unclear. In this study, middle-aged 37-week-old male Wistar-Kyoto rats were fed a normal diet (ND) or [...] Read more.

Epidemiologic studies have indicated that dyslipidemia may facilitate the progression of neuronal degeneration. However, the effects of chronic dyslipidemia on brain function, especially in older individuals, remain unclear. In this study, middle-aged 37-week-old male Wistar-Kyoto rats were fed a normal diet (ND) or a 45% high-fat diet (HFD) for 30 weeks (i.e., until 67 weeks of age). To study the effects of chronic dyslipidemia on the brain, we analyzed spontaneous locomotor activity, cognitive function, and brain tissues in both groups of rats after 30 weeks. Compared with age-matched rats fed a ND, Wistar-Kyoto rats fed a HFD had dyslipidemia and showed decreased movement but normal recognition of a novel object. In our brain analyses, we observed a significant decrease in astrocytes and tyrosine hydroxylase–containing neurons in the substantia nigra and locus coeruleus of rats fed a HFD compared with rats fed a ND. However, hippocampal pyramidal neurons were not affected. Our findings indicate that the long-term consumption of a HFD may cause lipid metabolism overload in the brain and damage to glial cells. The decrease in astrocytes may lead to reduced protection of the brain and affect the survival of tyrosine hydroxylase–containing neurons but not pyramidal neurons of the hippocampus. Full article

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15 pages, 1875 KiB

Open AccessArticle

The Longevity-Associated Variant of BPIFB4 Reduces Senescence in Glioma Cells and in Patients’ Lymphocytes Favoring Chemotherapy Efficacy

by Annibale Alessandro Puca, Valentina Lopardo, Francesco Montella, Paola Di Pietro, Daniela Cesselli, Irene Giulia Rolle, Michela Bulfoni, Veronica Di Sarno, Giorgio Iaconetta, Pietro Campiglia, Carmine Vecchione, Antonio Paolo Beltrami and Elena Ciaglia

Cells 2022, 11(2), 294; https://doi.org/10.3390/cells11020294 - 15 Jan 2022

Cited by 7 | Viewed by 3461

Abstract

Glioblastoma (GBM) is the most common primary brain cancer with the median age at diagnosis around 64 years, thus pointing to aging as an important risk factor. Indeed, aging, by increasing the senescence burden, is configured as a negative prognostic factor for GBM [...] Read more.

Glioblastoma (GBM) is the most common primary brain cancer with the median age at diagnosis around 64 years, thus pointing to aging as an important risk factor. Indeed, aging, by increasing the senescence burden, is configured as a negative prognostic factor for GBM stage. Furthermore, several anti-GBM therapies exist, such as temozolomide (TMZ) and etoposide (ETP), that unfortunately trigger senescence and the secretion of proinflammatory senescence-associated secretory phenotype (SASP) factors that are responsible for the improper burst of (i) tumorigenesis, (ii) cancer metastasis, (iii) immunosuppression, and (iv) tissue dysfunction. Thus, adjuvant therapies that limit senescence are urgently needed. The longevity-associated variant (LAV) of the bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4) gene previously demonstrated a modulatory activity in restoring age-related immune dysfunction and in balancing the low-grade inflammatory status of elderly people. Based on the above findings, we tested LAV-BPIFB4 senotherapeutic effects on senescent glioblastoma U87-MG cells and on T cells from GBM patients. We interrogated SA-β-gal and HLA-E senescence markers, SASP factors, and proliferation and apoptosis assays. The results highlighted a LAV-BPIFB4 remodeling of the senescent phenotype of GBM cells, enhancement of their sensitivity to temozolomide and a selective reduction of the T cells’ senescence from GBM patients. Overall, these findings candidate LAV-BPIFB4 as an adjuvant therapy for GBM. Full article

(This article belongs to the Special Issue Molecular-Cellular Basis of Ageing and Cancer)

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18 pages, 3987 KiB

Open AccessArticle

RNA Molecular Signature Profiling in PBMCs of Sporadic ALS Patients: HSP70 Overexpression Is Associated with Nuclear SOD1

by Maria Garofalo, Cecilia Pandini, Matteo Bordoni, Emanuela Jacchetti, Luca Diamanti, Stephana Carelli, Manuela Teresa Raimondi, Daisy Sproviero, Valeria Crippa, Serena Carra, Angelo Poletti, Orietta Pansarasa, Stella Gagliardi and Cristina Cereda

Cells 2022, 11(2), 293; https://doi.org/10.3390/cells11020293 - 15 Jan 2022

Cited by 7 | Viewed by 3351

Abstract

Superoxide dismutase 1 (SOD1) is one of the causative genes associated with amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder. SOD1 aggregation contributes to ALS pathogenesis. A fraction of the protein is localized in the nucleus (nSOD1), where it seems to be involved in [...] Read more.

Superoxide dismutase 1 (SOD1) is one of the causative genes associated with amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder. SOD1 aggregation contributes to ALS pathogenesis. A fraction of the protein is localized in the nucleus (nSOD1), where it seems to be involved in the regulation of genes participating in the oxidative stress response and DNA repair. Peripheral blood mononuclear cells (PBMCs) were collected from sporadic ALS (sALS) patients (n = 18) and healthy controls (n = 12) to perform RNA-sequencing experiments and differential expression analysis. Patients were stratified into groups with “high” and “low” levels of nSOD1. We obtained different gene expression patterns for high- and low-nSOD1 patients. Differentially expressed genes in high nSOD1 form a cluster similar to controls compared to the low-nSOD1 group. The pathways activated in high-nSOD1 patients are related to the upregulation of HSP70 molecular chaperones. We demonstrated that, in this condition, the DNA damage is reduced, even under oxidative stress conditions. Our findings highlight the importance of the nuclear localization of SOD1 as a protective mechanism in sALS patients. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Neurodegenerative Diseases)

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26 pages, 5040 KiB

Open AccessFeature PaperArticle

Identification of the Cysteine Protease Legumain as a Potential Chronic Hypoxia-Specific Multiple Myeloma Target Gene

by Ada-Sophia Clees, Verena Stolp, Björn Häupl, Dominik C. Fuhrmann, Frank Wempe, Marcel Seibert, Sarah Weber, Antje Banning, Ritva Tikkanen, Richard Williams, Bernhard Brüne, Hubert Serve, Frank Schnütgen, Ivana von Metzler and Nina Kurrle

Cells 2022, 11(2), 292; https://doi.org/10.3390/cells11020292 - 15 Jan 2022

Cited by 4 | Viewed by 3828

Abstract

Multiple myeloma (MM) is the second most common hematologic malignancy, which is characterized by clonal proliferation of neoplastic plasma cells in the bone marrow. This microenvironment is characterized by low oxygen levels (1–6% O₂), known as hypoxia. For MM cells, hypoxia [...] Read more.

Multiple myeloma (MM) is the second most common hematologic malignancy, which is characterized by clonal proliferation of neoplastic plasma cells in the bone marrow. This microenvironment is characterized by low oxygen levels (1–6% O₂), known as hypoxia. For MM cells, hypoxia is a physiologic feature that has been described to promote an aggressive phenotype and to confer drug resistance. However, studies on hypoxia are scarce and show little conformity. Here, we analyzed the mRNA expression of previously determined hypoxia markers to define the temporal adaptation of MM cells to chronic hypoxia. Subsequent analyses of the global proteome in MM cells and the stromal cell line HS-5 revealed hypoxia-dependent regulation of proteins, which directly or indirectly upregulate glycolysis. In addition, chronic hypoxia led to MM-specific regulation of nine distinct proteins. One of these proteins is the cysteine protease legumain (LGMN), the depletion of which led to a significant growth disadvantage of MM cell lines that is enhanced under hypoxia. Thus, herein, we report a methodologic strategy to examine MM cells under physiologic hypoxic conditions in vitro and to decipher and study previously masked hypoxia-specific therapeutic targets such as the cysteine protease LGMN. Full article

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

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20 pages, 4752 KiB

Open AccessArticle

Glucose Regulates m⁶A Methylation of RNA in Pancreatic Islets

by Florine Bornaque, Clément Philippe Delannoy, Emilie Courty, Nabil Rabhi, Charlène Carney, Laure Rolland, Maeva Moreno, Xavier Gromada, Cyril Bourouh, Pauline Petit, Emmanuelle Durand, François Pattou, Julie Kerr-Conte, Philippe Froguel, Amélie Bonnefond, Frédérik Oger and Jean-Sébastien Annicotte

Cells 2022, 11(2), 291; https://doi.org/10.3390/cells11020291 - 15 Jan 2022

Cited by 18 | Viewed by 4147

Abstract

Type 2 diabetes is characterized by chronic hyperglycemia associated with impaired insulin action and secretion. Although the heritability of type 2 diabetes is high, the environment, including blood components, could play a major role in the development of the disease. Amongst environmental effects, [...] Read more.

Type 2 diabetes is characterized by chronic hyperglycemia associated with impaired insulin action and secretion. Although the heritability of type 2 diabetes is high, the environment, including blood components, could play a major role in the development of the disease. Amongst environmental effects, epitranscriptomic modifications have been recently shown to affect gene expression and glucose homeostasis. The epitranscriptome is characterized by reversible chemical changes in RNA, with one of the most prevalent being the m⁶A methylation of RNA. Since pancreatic β cells fine tune glucose levels and play a major role in type 2 diabetes physiopathology, we hypothesized that the environment, through variations in blood glucose or blood free fatty acid concentrations, could induce changes in m⁶A methylation of RNAs in pancreatic β cells. Here we observe a significant decrease in m⁶A methylation upon high glucose concentration, both in mice and human islets, associated with altered expression levels of m⁶A demethylases. In addition, the use of siRNA and/or specific inhibitors against selected m⁶A enzymes demonstrate that these enzymes modulate the expression of genes involved in pancreatic β-cell identity and glucose-stimulated insulin secretion. Our data suggest that environmental variations, such as glucose, control m⁶A methylation in pancreatic β cells, playing a key role in the control of gene expression and pancreatic β-cell functions. Our results highlight novel causes and new mechanisms potentially involved in type 2 diabetes physiopathology and may contribute to a better understanding of the etiology of this disease. Full article

(This article belongs to the Special Issue Cellular and Molecular Biology of the Beta Cell)

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16 pages, 1954 KiB

Open AccessArticle

The Electrostatic Basis of Diacylglycerol Pyrophosphate—Protein Interaction

by Zachary Graber, Desmond Owusu Kwarteng, Shannon M. Lange, Yannis Koukounas, Hady Khalifa, Jean W. Mutambuze and Edgar E. Kooijman

Cells 2022, 11(2), 290; https://doi.org/10.3390/cells11020290 - 15 Jan 2022

Cited by 3 | Viewed by 2496

Abstract

Diacylglycerol pyrophosphate (DGPP) is an anionic phospholipid formed in plants, yeast, and parasites under multiple stress stimuli. It is synthesized by the phosphorylation action of phosphatidic acid (PA) kinase on phosphatidic acid, a signaling lipid with multifunctional properties. PA functions in the membrane [...] Read more.

Diacylglycerol pyrophosphate (DGPP) is an anionic phospholipid formed in plants, yeast, and parasites under multiple stress stimuli. It is synthesized by the phosphorylation action of phosphatidic acid (PA) kinase on phosphatidic acid, a signaling lipid with multifunctional properties. PA functions in the membrane through the interaction of its negatively charged phosphomonoester headgroup with positively charged proteins and ions. DGPP, like PA, can interact electrostatically via the electrostatic-hydrogen bond switch mechanism but differs from PA in its overall charge and shape. The formation of DGPP from PA alters the physicochemical properties as well as the structural dynamics of the membrane. This potentially impacts the molecular and ionic binding of cationic proteins and ions with the DGPP enriched membrane. However, the results of these important interactions in the stress response and in DGPP’s overall intracellular function is unknown. Here, using ³¹P MAS NMR, we analyze the effect of the interaction of low DGPP concentrations in model membranes with the peptides KALP23 and WALP23, which are flanked by positively charged Lysine and neutral Tryptophan residues, respectively. Our results show a significant effect of KALP23 on the charge of DGPP as compared to WALP23. There was, however, no significant effect on the charge of the phosphomonoester of DGPP due to the interaction with positively charged lipids, dioleoyl trimethylammonium propane (DOTAP) and dioleoyl ethyl-phosphatidylcholine (EtPC). Divalent calcium and magnesium cations induce deprotonation of the DGPP headgroup but showed no noticeable differences on DGPP’s charge. Our results lead to a novel model for DGPP—protein interaction. Full article

(This article belongs to the Collection Membrane Lipids in the Interaction of Plants with Their Abiotic and Biotic Environment)

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16 pages, 737 KiB

Open AccessReview

Golgi Metal Ion Homeostasis in Human Health and Diseases

by Jie Li and Yanzhuang Wang

Cells 2022, 11(2), 289; https://doi.org/10.3390/cells11020289 - 15 Jan 2022

Cited by 20 | Viewed by 5034

Abstract

The Golgi apparatus is a membrane organelle located in the center of the protein processing and trafficking pathway. It consists of sub-compartments with distinct biochemical compositions and functions. Main functions of the Golgi, including membrane trafficking, protein glycosylation, and sorting, require a well-maintained [...] Read more.

The Golgi apparatus is a membrane organelle located in the center of the protein processing and trafficking pathway. It consists of sub-compartments with distinct biochemical compositions and functions. Main functions of the Golgi, including membrane trafficking, protein glycosylation, and sorting, require a well-maintained stable microenvironment in the sub-compartments of the Golgi, along with metal ion homeostasis. Metal ions, such as Ca²⁺, Mn²⁺, Zn²⁺, and Cu²⁺, are important cofactors of many Golgi resident glycosylation enzymes. The homeostasis of metal ions in the secretory pathway, which is required for proper function and stress response of the Golgi, is tightly regulated and maintained by transporters. Mutations in the transporters cause human diseases. Here we provide a review specifically focusing on the transporters that maintain Golgi metal ion homeostasis under physiological conditions and their alterations in diseases. Full article

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

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14 pages, 1004 KiB

Open AccessReview

Role of Mitochondrial Cytochrome P450 2E1 in Healthy and Diseased Liver

by Julie Massart, Karima Begriche, Jessica H. Hartman and Bernard Fromenty

Cells 2022, 11(2), 288; https://doi.org/10.3390/cells11020288 - 15 Jan 2022

Cited by 44 | Viewed by 6076

Abstract

Cytochrome P450 2E1 (CYP2E1) is pivotal in hepatotoxicity induced by alcohol abuse and different xenobiotics. In this setting, CYP2E1 generates reactive metabolites inducing oxidative stress, mitochondrial dysfunction and cell death. In addition, this enzyme appears to play a role in the progression of [...] Read more.

Cytochrome P450 2E1 (CYP2E1) is pivotal in hepatotoxicity induced by alcohol abuse and different xenobiotics. In this setting, CYP2E1 generates reactive metabolites inducing oxidative stress, mitochondrial dysfunction and cell death. In addition, this enzyme appears to play a role in the progression of obesity-related fatty liver to nonalcoholic steatohepatitis. Indeed, increased CYP2E1 activity in nonalcoholic fatty liver disease (NAFLD) is deemed to induce reactive oxygen species overproduction, which in turn triggers oxidative stress, necroinflammation and fibrosis. In 1997, Avadhani’s group reported for the first time the presence of CYP2E1 in rat liver mitochondria, and subsequent investigations by other groups confirmed that mitochondrial CYP2E1 (mtCYP2E1) could be found in different experimental models. In this review, we first recall the main features of CYP2E1 including its role in the biotransformation of endogenous and exogenous molecules, the regulation of its expression and activity and its involvement in different liver diseases. Then, we present the current knowledge on the physiological role of mtCYP2E1, its contribution to xenobiotic biotransformation as well as the mechanism and regulation of CYP2E1 targeting to mitochondria. Finally, we discuss experimental investigations suggesting that mtCYP2E1 could have a role in alcohol-associated liver disease, xenobiotic-induced hepatotoxicity and NAFLD. Full article

(This article belongs to the Section Mitochondria)

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13 pages, 3200 KiB

Open AccessArticle

by Khaled Bin Satter, Paul Minh Huy Tran, Lynn Kim Hoang Tran, Zach Ramsey, Katheine Pinkerton, Shan Bai, Natasha M. Savage, Sravan Kavuri, Martha K. Terris, Jin-Xiong She and Sharad Purohit

Cells 2022, 11(2), 287; https://doi.org/10.3390/cells11020287 - 15 Jan 2022

Cited by 6 | Viewed by 2673

Abstract

Publicly available gene expression datasets were analyzed to develop a chromophobe and oncocytoma related gene signature (COGS) to distinguish chRCC from RO. The datasets GSE11151, GSE19982, GSE2109, GSE8271 and GSE11024 were combined into a discovery dataset. The transcriptomic differences were identified with unsupervised [...] Read more.

Publicly available gene expression datasets were analyzed to develop a chromophobe and oncocytoma related gene signature (COGS) to distinguish chRCC from RO. The datasets GSE11151, GSE19982, GSE2109, GSE8271 and GSE11024 were combined into a discovery dataset. The transcriptomic differences were identified with unsupervised learning in the discovery dataset (97.8% accuracy) with density based UMAP (DBU). The top 30 genes were identified by univariate gene expression analysis and ROC analysis, to create a gene signature called COGS. COGS, combined with DBU, was able to differentiate chRCC from RO in the discovery dataset with an accuracy of 97.8%. The classification accuracy of COGS was validated in an independent meta-dataset consisting of TCGA-KICH and GSE12090, where COGS could differentiate chRCC from RO with 100% accuracy. The differentially expressed genes were involved in carbohydrate metabolism, transcriptomic regulation by TP53, beta-catenin-dependent Wnt signaling, and cytokine (IL-4 and IL-13) signaling highly active in cancer cells. Using multiple datasets and machine learning, we constructed and validated COGS as a tool that can differentiate chRCC from RO and complement histology in routine clinical practice to distinguish these two tumors. Full article

(This article belongs to the Special Issue New Insights into Kidney Cancer)

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17 pages, 1620 KiB

Open AccessReview

Implication of Adult Hippocampal Neurogenesis in Alzheimer’s Disease and Potential Therapeutic Approaches

by Hesham Essa, Lee Peyton, Whidul Hasan, Brandon Emanuel León and Doo-Sup Choi

Cells 2022, 11(2), 286; https://doi.org/10.3390/cells11020286 - 15 Jan 2022

Cited by 13 | Viewed by 4751

Abstract

Alzheimer’s disease is the most common neurodegenerative disease, affecting more than 6 million US citizens and representing the most prevalent cause for dementia. Neurogenesis has been repeatedly reported to be impaired in AD mouse models, but the reason for this impairment remains unclear. [...] Read more.

Alzheimer’s disease is the most common neurodegenerative disease, affecting more than 6 million US citizens and representing the most prevalent cause for dementia. Neurogenesis has been repeatedly reported to be impaired in AD mouse models, but the reason for this impairment remains unclear. Several key factors play a crucial role in AD including Aβ accumulation, intracellular neurofibrillary tangles accumulation, and neuronal loss (specifically in the dentate gyrus of the hippocampus). Neurofibrillary tangles have been long associated with the neuronal loss in the dentate gyrus. Of note, Aβ accumulation plays an important role in the impairment of neurogenesis, but recent studies started to shed a light on the role of APP gene expression on the neurogenesis process. In this review, we will discuss the recent approaches to neurogenesis in Alzheimer disease and update the development of therapeutic methods. Full article

(This article belongs to the Special Issue Frontiers in Neurogenesis)

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14 pages, 2836 KiB

Open AccessArticle

Microfluidic Platforms Designed for Morphological and Photosynthetic Investigations of Chlamydomonas reinhardtii on a Single-Cell Level

by Eszter Széles, Krisztina Nagy, Ágnes Ábrahám, Sándor Kovács, Anna Podmaniczki, Valéria Nagy, László Kovács, Péter Galajda and Szilvia Z. Tóth

Cells 2022, 11(2), 285; https://doi.org/10.3390/cells11020285 - 14 Jan 2022

Cited by 9 | Viewed by 3504

Abstract

Chlamydomonas reinhardtii is a model organism of increasing biotechnological importance, yet, the evaluation of its life cycle processes and photosynthesis on a single-cell level is largely unresolved. To facilitate the study of the relationship between morphology and photochemistry, we established microfluidics in combination [...] Read more.

Chlamydomonas reinhardtii is a model organism of increasing biotechnological importance, yet, the evaluation of its life cycle processes and photosynthesis on a single-cell level is largely unresolved. To facilitate the study of the relationship between morphology and photochemistry, we established microfluidics in combination with chlorophyll a fluorescence induction measurements. We developed two types of microfluidic platforms for single-cell investigations: (i) The traps of the “Tulip” device are suitable for capturing and immobilizing single cells, enabling the assessment of their photosynthesis for several hours without binding to a solid support surface. Using this “Tulip” platform, we performed high-quality non-photochemical quenching measurements and confirmed our earlier results on bulk cultures that non-photochemical quenching is higher in ascorbate-deficient mutants (Crvtc2-1) than in the wild-type. (ii) The traps of the “Pot” device were designed for capturing single cells and allowing the growth of the daughter cells within the traps. Using our most performant “Pot” device, we could demonstrate that the F_V/F_M parameter, an indicator of photosynthetic efficiency, varies considerably during the cell cycle. Our microfluidic devices, therefore, represent versatile platforms for the simultaneous morphological and photosynthetic investigations of C. reinhardtii on a single-cell level. Full article

(This article belongs to the Special Issue Research on Chlamydomonas Cell Biology)

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28 pages, 1706 KiB

Open AccessReview

Probiotics in the Prevention of the Calcium Oxalate Urolithiasis

by Paulina Wigner, Michał Bijak and Joanna Saluk-Bijak

Cells 2022, 11(2), 284; https://doi.org/10.3390/cells11020284 - 14 Jan 2022

Cited by 38 | Viewed by 8558

Abstract

Nephrolithiasis ranks third among urological diseases in terms of prevalence, making up about 15% of cases. The continued increase in the incidence of nephrolithiasis is most probably due to changes in eating habits (high protein, sodium, and sugar diets) and lifestyle (reduced physical [...] Read more.

Nephrolithiasis ranks third among urological diseases in terms of prevalence, making up about 15% of cases. The continued increase in the incidence of nephrolithiasis is most probably due to changes in eating habits (high protein, sodium, and sugar diets) and lifestyle (reduced physical activity) in all developed countries. Some 80% of all kidney stones cases are oxalate urolithiasis, which is also characterized by the highest risk of recurrence. Frequent relapses of nephrolithiasis contribute to severe complications and high treatment costs. Unfortunately, there is no known effective way to prevent urolithiasis at present. In cases of diet-related urolithiasis, dietary changes may prevent recurrence. However, in some patients, the condition is unrelated to diet; in such cases, there is evidence to support the use of stone-related medications. Interestingly, a growing body of evidence indicates the potential of the microbiome to reduce the risk of developing renal colic. Previous studies have primarily focused on the use of Oxalobacterformigenes in patients with urolithiasis. Unfortunately, this bacterium is not an ideal probiotic due to its antibiotic sensitivity and low pH. Therefore, subsequent studies sought to find bacteria which are capable of oxalate degradation, focusing on well-known probiotics including Lactobacillus and Bifidobacterium strains, Eubacterium lentum, Enterococcus faecalis, and Escherichia coli. Full article

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13 pages, 2587 KiB

Open AccessArticle

Structure and Function of the ABCD1 Variant Database: 20 Years, 940 Pathogenic Variants, and 3400 Cases of Adrenoleukodystrophy

by Eric J. Mallack, Kerry Gao, Marc Engelen and Stephan Kemp

Cells 2022, 11(2), 283; https://doi.org/10.3390/cells11020283 - 14 Jan 2022

Cited by 27 | Viewed by 4985

Abstract

The progressive neurometabolic disorder X-linked adrenoleukodystrophy (ALD) is caused by pathogenic variants in the ABCD1 gene, which encodes the peroxisomal ATP-binding transporter for very-long-chain fatty acids. The clinical spectrum of ALD includes adrenal insufficiency, myelopathy, and/or leukodystrophy. A complicating factor in disease management [...] Read more.

The progressive neurometabolic disorder X-linked adrenoleukodystrophy (ALD) is caused by pathogenic variants in the ABCD1 gene, which encodes the peroxisomal ATP-binding transporter for very-long-chain fatty acids. The clinical spectrum of ALD includes adrenal insufficiency, myelopathy, and/or leukodystrophy. A complicating factor in disease management is the absence of a genotype–phenotype correlation in ALD. Since 1999, most ABCD1 (likely) pathogenic and benign variants have been reported in the ABCD1 Variant Database. In 2017, following the expansion of ALD newborn screening, the database was rebuilt. To add an additional level of confidence with respect to pathogenicity, for each variant, it now also reports the number of cases identified and, where available, experimental data supporting the pathogenicity of the variant. The website also provides information on a number of ALD-related topics in several languages. Here, we provide an updated analysis of the known variants in ABCD1. The order of pathogenic variant frequency, overall clustering of disease-causing variants in exons 1–2 (transmembrane domain spanning region) and 6–9 (ATP-binding domain), and the most commonly reported pathogenic variant p.Gln472Argfs*83 in exon 5 are consistent with the initial reports of the mutation database. Novel insights include nonrandom clustering of high-density missense variant hotspots within exons 1, 2, 6, 8, and 9. Perhaps more importantly, we illustrate the importance of collaboration and utility of the database as a scientific, clinical, and ALD-community-wide resource. Full article

(This article belongs to the Special Issue Peroxisomal Disorders: Development of Targeted Therapies)

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16 pages, 4719 KiB

Open AccessArticle

Freeze-Dried Curdlan/Whey Protein Isolate-Based Biomaterial as Promising Scaffold for Matrix-Associated Autologous Chondrocyte Transplantation—A Pilot In-Vitro Study

by Katarzyna Klimek, Marta Tarczynska, Wieslaw Truszkiewicz, Krzysztof Gaweda, Timothy E. L. Douglas and Grazyna Ginalska

Cells 2022, 11(2), 282; https://doi.org/10.3390/cells11020282 - 14 Jan 2022

Cited by 11 | Viewed by 2882

Abstract

The purpose of this pilot study was to establish whether a novel freeze-dried curdlan/whey protein isolate-based biomaterial may be taken into consideration as a potential scaffold for matrix-associated autologous chondrocyte transplantation. For this reason, this biomaterial was initially characterized by the visualization of [...] Read more.

The purpose of this pilot study was to establish whether a novel freeze-dried curdlan/whey protein isolate-based biomaterial may be taken into consideration as a potential scaffold for matrix-associated autologous chondrocyte transplantation. For this reason, this biomaterial was initially characterized by the visualization of its micro- and macrostructures as well as evaluation of its mechanical stability, and its ability to undergo enzymatic degradation in vitro. Subsequently, the cytocompatibility of the biomaterial towards human chondrocytes (isolated from an orthopaedic patient) was assessed. It was demonstrated that the novel freeze-dried curdlan/whey protein isolate-based biomaterial possessed a porous structure and a Young’s modulus close to those of the superficial and middle zones of cartilage. It also exhibited controllable degradability in collagenase II solution over nine weeks. Most importantly, this biomaterial supported the viability and proliferation of human chondrocytes, which maintained their characteristic phenotype. Moreover, quantitative reverse transcription PCR analysis and confocal microscope observations revealed that the biomaterial may protect chondrocytes from dedifferentiation towards fibroblast-like cells during 12-day culture. Thus, in conclusion, this pilot study demonstrated that novel freeze-dried curdlan/whey protein isolate-based biomaterial may be considered as a potential scaffold for matrix-associated autologous chondrocyte transplantation. Full article

(This article belongs to the Collection Advances in Cell Culture and Tissue Engineering)

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15 pages, 36250 KiB

Open AccessArticle

Wnt Signaling Rescues Amyloid Beta-Induced Gut Stem Cell Loss

by Prameet Kaur, Ellora Hui Zhen Chua, Wen Kin Lim, Jiarui Liu, Nathan Harmston and Nicholas S. Tolwinski

Cells 2022, 11(2), 281; https://doi.org/10.3390/cells11020281 - 14 Jan 2022

Cited by 5 | Viewed by 3385

Abstract

Patients with Alzheimer’s disease suffer from a decrease in brain mass and a prevalence of amyloid-β plaques. These plaques are thought to play a role in disease progression, but their exact role is not entirely established. We developed an optogenetic model to induce [...] Read more.

Patients with Alzheimer’s disease suffer from a decrease in brain mass and a prevalence of amyloid-β plaques. These plaques are thought to play a role in disease progression, but their exact role is not entirely established. We developed an optogenetic model to induce amyloid-β intracellular oligomerization to model distinct disease etiologies. Here, we examine the effect of Wnt signaling on amyloid in an optogenetic, Drosophila gut stem cell model. We observe that Wnt activation rescues the detrimental effects of amyloid expression and oligomerization. We analyze the gene expression changes downstream of Wnt that contribute to this rescue and find changes in aging related genes, protein misfolding, metabolism, and inflammation. We propose that Wnt expression reduces inflammation through repression of Toll activating factors. We confirm that chronic Toll activation reduces lifespan, but a decrease in the upstream activator Persephone extends it. We propose that the protective effect observed for lithium treatment functions, at least in part, through Wnt activation and the inhibition of inflammation. Full article

(This article belongs to the Section Cell Signaling)

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