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Editor’s Choice Articles

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

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16 pages, 2836 KiB  
Review
Yeast Chronological Lifespan: Longevity Regulatory Genes and Mechanisms
by Mario G. Mirisola and Valter D. Longo
Cells 2022, 11(10), 1714; https://doi.org/10.3390/cells11101714 - 23 May 2022
Cited by 23 | Viewed by 7401
Abstract
S. cerevisiae plays a pivotal role as a model system in understanding the biochemistry and molecular biology of mammals including humans. A considerable portion of our knowledge on the genes and pathways involved in cellular growth, resistance to toxic agents, and death has [...] Read more.
S. cerevisiae plays a pivotal role as a model system in understanding the biochemistry and molecular biology of mammals including humans. A considerable portion of our knowledge on the genes and pathways involved in cellular growth, resistance to toxic agents, and death has in fact been generated using this model organism. The yeast chronological lifespan (CLS) is a paradigm to study age-dependent damage and longevity. In combination with powerful genetic screening and high throughput technologies, the CLS has allowed the identification of longevity genes and pathways but has also introduced a unicellular “test tube” model system to identify and study macromolecular and cellular damage leading to diseases. In addition, it has played an important role in studying the nutrients and dietary regimens capable of affecting stress resistance and longevity and allowing the characterization of aging regulatory networks. The parallel description of the pro-aging roles of homologs of RAS, S6 kinase, adenylate cyclase, and Tor in yeast and in higher eukaryotes in S. cerevisiae chronological survival studies is valuable to understand human aging and disease. Here we review work on the S. cerevisiae chronological lifespan with a focus on the genes regulating age-dependent macromolecular damage and longevity extension. Full article
(This article belongs to the Special Issue Yeast as a Model in Aging Research)
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9 pages, 795 KiB  
Review
Unveiling the Function of the Mitochondrial Filament-Forming Protein LACTB in Lipid Metabolism and Cancer
by Annunziata Cascone, Maciej Lalowski, Dan Lindholm and Ove Eriksson
Cells 2022, 11(10), 1703; https://doi.org/10.3390/cells11101703 - 20 May 2022
Cited by 8 | Viewed by 3624
Abstract
LACTB is a relatively unknown mitochondrial protein structurally related to the bacterial penicillin-binding and beta-lactamase superfamily of serine proteases. LACTB has recently gained an increased interest due to its potential role in lipid metabolism and tumorigenesis. To date, around ninety studies pertaining to [...] Read more.
LACTB is a relatively unknown mitochondrial protein structurally related to the bacterial penicillin-binding and beta-lactamase superfamily of serine proteases. LACTB has recently gained an increased interest due to its potential role in lipid metabolism and tumorigenesis. To date, around ninety studies pertaining to LACTB have been published, but the exact biochemical and cell biological function of LACTB still remain elusive. In this review, we summarise the current knowledge about LACTB with particular attention to the implications of the recently published study on the cryo-electron microscopy structure of the filamentous form of LACTB. From this and other studies, several specific properties of LACTB emerge, suggesting that the protein has distinct functions in different physiological settings. Resolving these issues by further research may ultimately lead to a unified model of LACTB’s function in cell and organismal physiology. LACTB is the only member of its protein family in higher animals and LACTB may, therefore, be of particular interest for future drug targeting initiatives. Full article
(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Organelle Function)
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29 pages, 1665 KiB  
Review
Pathogenic T-Cell Responses in Immune-Mediated Glomerulonephritis
by Alexandra Linke, Gisa Tiegs and Katrin Neumann
Cells 2022, 11(10), 1625; https://doi.org/10.3390/cells11101625 - 12 May 2022
Cited by 32 | Viewed by 9042
Abstract
Glomerulonephritis (GN) comprises a group of immune-mediated kidney diseases affecting glomeruli and the tubulointerstitium. Glomerular crescent formation is a histopathological characteristic of severe forms of GN, also referred to as crescentic GN (cGN). Based on histological findings, cGN includes anti-neutrophil cytoplasmic antibody (ANCA)-associated [...] Read more.
Glomerulonephritis (GN) comprises a group of immune-mediated kidney diseases affecting glomeruli and the tubulointerstitium. Glomerular crescent formation is a histopathological characteristic of severe forms of GN, also referred to as crescentic GN (cGN). Based on histological findings, cGN includes anti-neutrophil cytoplasmic antibody (ANCA)-associated GN, a severe form of ANCA-associated vasculitis, lupus nephritis associated with systemic lupus erythematosus, Goodpasture’s disease, and IgA nephropathy. The immunopathogenesis of cGN is associated with activation of CD4+ and CD8+ T cells, which particularly accumulate in the periglomerular and tubulointerstitial space but also infiltrate glomeruli. Clinical observations and functional studies in pre-clinical animal models provide evidence for a pathogenic role of Th1 and Th17 cell-mediated immune responses in cGN. Emerging evidence further argues that CD8+ T cells have a role in disease pathology and the mechanisms of activation and function of recently identified tissue-resident CD4+ and CD8+ T cells in cGN are currently under investigation. This review summarizes the mechanisms of pathogenic T-cell responses leading to glomerular damage and renal inflammation in cGN. Advanced knowledge of the underlying immune mechanisms involved with cGN will enable the identification of novel therapeutic targets for the replacement or reduction in standard immunosuppressive therapy or the treatment of refractory disease. Full article
(This article belongs to the Special Issue Immune Mechanisms in Glomerulonephritis)
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20 pages, 1732 KiB  
Review
Evaluation of Proteasome Inhibitors in the Treatment of Idiopathic Pulmonary Fibrosis
by I-Chen Chen, Yi-Ching Liu, Yen-Hsien Wu, Shih-Hsing Lo, Zen-Kong Dai, Jong-Hau Hsu and Yu-Hsin Tseng
Cells 2022, 11(9), 1543; https://doi.org/10.3390/cells11091543 - 4 May 2022
Cited by 9 | Viewed by 4248
Abstract
Idiopathic pulmonary fibrosis (IPF) is the most common form of idiopathic interstitial pneumonia, and it has a worse prognosis than non-small cell lung cancer. The pathomechanism of IPF is not fully understood, but it has been suggested that repeated microinjuries of epithelial cells [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is the most common form of idiopathic interstitial pneumonia, and it has a worse prognosis than non-small cell lung cancer. The pathomechanism of IPF is not fully understood, but it has been suggested that repeated microinjuries of epithelial cells induce a wound healing response, during which fibroblasts differentiate into myofibroblasts. These activated myofibroblasts express α smooth muscle actin and release extracellular matrix to promote matrix deposition and tissue remodeling. Under physiological conditions, the remodeling process stops once wound healing is complete. However, in the lungs of IPF patients, myofibroblasts re-main active and deposit excess extracellular matrix. This leads to the destruction of alveolar tissue, the loss of lung elastic recoil, and a rapid decrease in lung function. Some evidence has indicated that proteasomal inhibition combats fibrosis by inhibiting the expressions of extracellular matrix proteins and metalloproteinases. However, the mechanisms by which proteasome inhibitors may protect against fibrosis are not known. This review summarizes the current research on proteasome inhibitors for pulmonary fibrosis, and provides a reference for whether proteasome inhibitors have the potential to become new drugs for the treatment of pulmonary fibrosis. Full article
(This article belongs to the Special Issue Advances in Cellular and Molecular Mechanisms of Cardiovascular and Pulmonary Diseases)
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14 pages, 2870 KiB  
Article
Focused Ultrasound Treatment of a Spheroid In Vitro Tumour Model
by Lisa Landgraf, Adam Kozlowski, Xinrui Zhang, Marc Fournelle, Franz-Josef Becker, Steffen Tretbar and Andreas Melzer
Cells 2022, 11(9), 1518; https://doi.org/10.3390/cells11091518 - 30 Apr 2022
Cited by 13 | Viewed by 3809
Abstract
Focused ultrasound (FUS) is a non-invasive technique producing a variety of biological effects by either thermal or mechanical mechanisms of ultrasound interaction with the targeted tissue. FUS could bring benefits, e.g., tumour sensitisation, immune stimulation, and targeted drug delivery, but investigation of FUS [...] Read more.
Focused ultrasound (FUS) is a non-invasive technique producing a variety of biological effects by either thermal or mechanical mechanisms of ultrasound interaction with the targeted tissue. FUS could bring benefits, e.g., tumour sensitisation, immune stimulation, and targeted drug delivery, but investigation of FUS effects at the cellular level is still missing. New techniques are commonly tested in vitro on two-dimensional (2D) monolayer cancer cell culture models. The 3D tumour model—spheroid—is mainly utilised to mimic solid tumours from an architectural standpoint. It is a promising method to simulate the characteristics of tumours in vitro and their various responses to therapeutic alternatives. This study aimed to evaluate the effects of FUS on human prostate and glioblastoma cancer tumour spheroids in vitro. The experimental follow-up enclosed the measurements of spheroid integrity and growth kinetics, DNA damage, and cellular metabolic activity by measuring intracellular ATP content in the spheroids. Our results showed that pulsed FUS treatment induced molecular effects in 3D tumour models. With the disruption of the spheroid integrity, we observed an increase in DNA double-strand breaks, leading to damage in the cancer cells depending on the cancer cell type. Full article
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17 pages, 4131 KiB  
Article
Sarco/Endoplasmic Reticulum Ca2+ ATPase 2 Activator Ameliorates Endothelial Dysfunction; Insulin Resistance in Diabetic Mice
by Toyokazu Kimura, Kazuki Kagami, Atsushi Sato, Ayumu Osaki, Kei Ito, Shunpei Horii, Takumi Toya, Nobuyuki Masaki, Risako Yasuda, Yuji Nagatomo and Takeshi Adachi
Cells 2022, 11(9), 1488; https://doi.org/10.3390/cells11091488 - 28 Apr 2022
Cited by 8 | Viewed by 3358
Abstract
Background: Sarco/endoplasmic reticulum Ca2+-ATPase2 (SERCA2) is impaired in various organs in animal models of diabetes. The purpose of this study was to test the effects of an allosteric SERCA2 activator (CDN1163) on glucose intolerance, hepatosteatosis, skeletal muscle function, and endothelial dysfunction [...] Read more.
Background: Sarco/endoplasmic reticulum Ca2+-ATPase2 (SERCA2) is impaired in various organs in animal models of diabetes. The purpose of this study was to test the effects of an allosteric SERCA2 activator (CDN1163) on glucose intolerance, hepatosteatosis, skeletal muscle function, and endothelial dysfunction in diabetic (db/db) mice. Methods: Either CDN1163 or vehicle was injected intraperitoneally into 16-week-old male control and db/db mice for 5 consecutive days. Results: SERCA2 protein expression was decreased in the aorta of db/db mice. In isometric tension measurements of aortic rings from db/db mice treated with CDN1163, acetylcholine (ACh)-induced relaxation was improved. In vivo intraperitoneal administrations of CDN 1163 also increased ACh-induced relaxation. Moreover, CDN1163 significantly decreased blood glucose in db/db mice at 60 and 120 min during a glucose tolerance test; it also decreased serum insulin levels, hepatosteatosis, and oxygen consumption in skeletal muscle during the early period of exercise in db/db mice. Conclusions: CDN1163 directly improved aortic endothelial dysfunction in db/db mice. Moreover, CDN1163 improved hepatosteatosis, skeletal muscle function, and insulin resistance in db/db mice. The activation of SERCA2 might be a strategy for the all the tissue expressed SERCA2a improvement of endothelial dysfunction and the target for the organs related to insulin resistance. Full article
(This article belongs to the Section Cellular Metabolism)
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22 pages, 1552 KiB  
Review
Interaction of Neural Stem Cells (NSCs) and Mesenchymal Stem Cells (MSCs) as a Promising Approach in Brain Study and Nerve Regeneration
by Agnieszka Kaminska, Klaudia Radoszkiewicz, Paulina Rybkowska, Aleksandra Wedzinska and Anna Sarnowska
Cells 2022, 11(9), 1464; https://doi.org/10.3390/cells11091464 - 26 Apr 2022
Cited by 46 | Viewed by 8113
Abstract
Rapid developments in stem cell research in recent years have provided a solid foundation for their use in medicine. Over the last few years, hundreds of clinical trials have been initiated in a wide panel of indications. Disorders and injuries of the nervous [...] Read more.
Rapid developments in stem cell research in recent years have provided a solid foundation for their use in medicine. Over the last few years, hundreds of clinical trials have been initiated in a wide panel of indications. Disorders and injuries of the nervous system still remain a challenge for the regenerative medicine. Neural stem cells (NSCs) are the optimal cells for the central nervous system restoration as they can differentiate into mature cells and, most importantly, functional neurons and glial cells. However, their application is limited by multiple factors such as difficult access to source material, limited cells number, problematic, long and expensive cultivation in vitro, and ethical considerations. On the other hand, according to the available clinical databases, most of the registered clinical trials involving cell therapies were carried out with the use of mesenchymal stem/stromal/signalling cells (MSCs) obtained from afterbirth or adult human somatic tissues. MSCs are the multipotent cells which can also differentiate into neuron-like and glia-like cells under proper conditions in vitro; however, their main therapeutic effect is more associated with secretory and supportive properties. MSCs, as a natural component of cell niche, affect the environment through immunomodulation as well as through the secretion of the trophic factors. In this review, we discuss various therapeutic strategies and activated mechanisms related to bilateral MSC–NSC interactions, differentiation of MSCs towards the neural cells (subpopulation of crest-derived cells) under the environmental conditions, bioscaffolds, or co-culture with NSCs by recreating the conditions of the neural cell niche. Full article
(This article belongs to the Special Issue Neural Stem Cells: Developmental Mechanisms and Disease Modelling)
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29 pages, 7944 KiB  
Article
Obesity Affects the Proliferative Potential of Equine Endometrial Progenitor Cells and Modulates Their Molecular Phenotype Associated with Mitochondrial Metabolism
by Agnieszka Smieszek, Klaudia Marcinkowska, Ariadna Pielok, Mateusz Sikora, Lukas Valihrach, Elaine Carnevale and Krzysztof Marycz
Cells 2022, 11(9), 1437; https://doi.org/10.3390/cells11091437 - 24 Apr 2022
Cited by 9 | Viewed by 3615
Abstract
The study aimed to investigate the influence of obesity on cellular features of equine endometrial progenitor cells (Eca EPCs), including viability, proliferation capacity, mitochondrial metabolism, and oxidative homeostasis. Eca EPCs derived from non-obese (non-OB) and obese (OB) mares were characterized by cellular phenotype [...] Read more.
The study aimed to investigate the influence of obesity on cellular features of equine endometrial progenitor cells (Eca EPCs), including viability, proliferation capacity, mitochondrial metabolism, and oxidative homeostasis. Eca EPCs derived from non-obese (non-OB) and obese (OB) mares were characterized by cellular phenotype and multipotency. Obesity-induced changes in the activity of Eca EPCs include the decline of their proliferative activity, clonogenic potential, mitochondrial metabolism, and enhanced oxidative stress. Eca EPCs isolated from obese mares were characterized by an increased occurrence of early apoptosis, loss of mitochondrial dynamics, and senescence-associated phenotype. Attenuated metabolism of Eca EPCs OB was related to increased expression of pro-apoptotic markers (CASP9, BAX, P53, P21), enhanced expression of OPN, PI3K, and AKT, simultaneously with decreased signaling stabilizing cellular homeostasis (including mitofusin, SIRT1, FOXP3). Obesity alters functional features and the self-renewal potential of endometrial progenitor cells. The impaired cytophysiology of progenitor cells from obese endometrium predicts lower regenerative capacity if used as autologous transplants. Full article
(This article belongs to the Special Issue Cellular and Clinical Mechanisms of Obesity and Its Complications)
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20 pages, 2737 KiB  
Article
Cannabinoids Alleviate the LPS-Induced Cytokine Storm via Attenuating NLRP3 Inflammasome Signaling and TYK2-Mediated STAT3 Signaling Pathways In Vitro
by Santosh V. Suryavanshi, Mariia Zaiachuk, Nazar Pryimak, Igor Kovalchuk and Olga Kovalchuk
Cells 2022, 11(9), 1391; https://doi.org/10.3390/cells11091391 - 20 Apr 2022
Cited by 47 | Viewed by 6528
Abstract
Cannabinoids, mainly cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), are the most studied group of compounds obtained from Cannabis sativa because of their several pharmaceutical properties. Current evidence suggests a crucial role of cannabinoids as potent anti-inflammatory agents for the treatment of chronic [...] Read more.
Cannabinoids, mainly cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), are the most studied group of compounds obtained from Cannabis sativa because of their several pharmaceutical properties. Current evidence suggests a crucial role of cannabinoids as potent anti-inflammatory agents for the treatment of chronic inflammatory diseases; however, the mechanisms remain largely unclear. Cytokine storm, a dysregulated severe inflammatory response by our immune system, is involved in the pathogenesis of numerous chronic inflammatory disorders, including coronavirus disease 2019 (COVID-19), which results in the accumulation of pro-inflammatory cytokines. Therefore, we hypothesized that CBD and THC reduce the levels of pro-inflammatory cytokines by inhibiting key inflammatory signaling pathways. The nucleotide-binding and oligomerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome signaling has been implicated in a variety of chronic inflammatory diseases, which results in the release of pyroptotic cytokines, interleukin-1β (IL-1β) and IL-18. Likewise, the activation of the signal transducer and activator of transcription-3 (STAT3) causes increased expression of pro-inflammatory cytokines. We studied the effects of CBD and THC on lipopolysaccharide (LPS)-induced inflammatory response in human THP-1 macrophages and primary human bronchial epithelial cells (HBECs). Our results revealed that CBD and, for the first time, THC significantly inhibited NLRP3 inflammasome activation following LPS + ATP stimulation, leading to a reduction in the levels of IL-1β in THP-1 macrophages and HBECs. CBD attenuated the phosphorylation of nuclear factor-κB (NF-κB), and both cannabinoids inhibited the generation of oxidative stress post-LPS. Our multiplex ELISA data revealed that CBD and THC significantly diminished the levels of IL-6, IL-8, and tumor necrosis factor-α (TNF-α) after LPS treatment in THP-1 macrophages and HBECs. In addition, the phosphorylation of STAT3 was significantly downregulated by CBD and THC in THP-1 macrophages and HBECs, which was in turn attributed to the reduced phosphorylation of tyrosine kinase-2 (TYK2) by CBD and THC after LPS stimulation in these cells. Overall, CBD and THC were found to be effective in alleviating the LPS-induced cytokine storm in human macrophages and primary HBECs, at least via modulation of NLRP3 inflammasome and STAT3 signaling pathways. The encouraging results from this study warrant further investigation of these cannabinoids in vivo. Full article
(This article belongs to the Collection Novel Insights into Cannabinoid Receptors, Molecular Targets, and Therapeutic Potentials)
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18 pages, 2166 KiB  
Article
NFAT Factors Are Dispensable for the Development but Are Critical for the Maintenance of Foxp3+ Regulatory T Cells
by Carlotta Barahona de Brito and Amiya Kumar Patra
Cells 2022, 11(9), 1397; https://doi.org/10.3390/cells11091397 - 20 Apr 2022
Cited by 1 | Viewed by 2651
Abstract
The transcription factors of the nuclear factor of activated T cell (NFAT) family play a crucial role in multiple aspects of T cell function. It has recently been reported that NFATs play an important role in the suppressive function of CD4+CD25 [...] Read more.
The transcription factors of the nuclear factor of activated T cell (NFAT) family play a crucial role in multiple aspects of T cell function. It has recently been reported that NFATs play an important role in the suppressive function of CD4+CD25+Foxp3+ regulatory T (Treg) cells. In this study, we have investigated the role of NFATs in the thymic development of Treg cells in mice. We show that NFAT factors are dispensable for the development of Foxp3+ Treg cells in the thymus but are critical for the maintenance of both the phenotype and survival of Treg cells in the thymus as well as in peripheral lymphoid organs. Specifically, the homeostasis of CD4+CD25+Foxp3+ but not the CD4+CD25−Foxp3+ fraction is severely perturbed when NFAT signaling is blocked, leading to a strongly reduced Treg population. We underscored this intriguing effect of NFAT on CD4+CD25+Foxp3+ Treg cells to the disruption of survival signals provided by interleukin 2 (IL-2). Accordingly, blocking Treg cell death by abolishing the activity of pro-apoptotic Bcl-2 family member Bim, compensated for the survival defects induced due to a lack of NFAT-IL-2-IL-2R signaling. Inhibition of NFAT activity led to a strong reduction in the number of Foxp3+ Treg cells; however, it did not influence the level of Foxp3 expression on an individual cell basis. In addition, we show a differential effect of IL-2 and IL-7 signaling on Foxp3+ Treg versus CD4+CD25− T cell development, again underlining the dispensability of NFAT signaling in the development, but not in the maintenance of Foxp3+ Treg cells. Full article
(This article belongs to the Section Cellular Immunology)
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18 pages, 1180 KiB  
Review
Key Signaling in Alcohol-Associated Liver Disease: The Role of Bile Acids
by Grayson W. Way, Kaitlyn G. Jackson, Shreya R. Muscu and Huiping Zhou
Cells 2022, 11(8), 1374; https://doi.org/10.3390/cells11081374 - 18 Apr 2022
Cited by 22 | Viewed by 43288
Abstract
Alcohol-associated liver disease (ALD) is a spectrum of diseases, the onset and progression of which are due to chronic alcohol use. ALD ranges, by increasing severity, from hepatic steatosis to alcoholic hepatitis (AH) and alcohol-associated cirrhosis (AC), and in some cases, can lead [...] Read more.
Alcohol-associated liver disease (ALD) is a spectrum of diseases, the onset and progression of which are due to chronic alcohol use. ALD ranges, by increasing severity, from hepatic steatosis to alcoholic hepatitis (AH) and alcohol-associated cirrhosis (AC), and in some cases, can lead to the development of hepatocellular carcinoma (HCC). ALD continues to be a significant health burden and is now the main cause of liver transplantations in the United States. ALD leads to biological, microbial, physical, metabolic, and inflammatory changes in patients that vary depending on disease severity. ALD deaths have been increasing in recent years and are projected to continue to increase. Current treatment centers focus on abstinence and symptom management, with little in the way of resolving disease progression. Due to the metabolic disruption and gut dysbiosis in ALD, bile acid (BA) signaling and metabolism are also notably affected and play a prominent role in disease progression in ALD, as well as other liver disease states, such as non-alcoholic fatty liver disease (NAFLD). In this review, we summarize the recent advances in the understanding of the mechanisms by which alcohol consumption induces hepatic injury and the role of BA-mediated signaling in the pathogenesis of ALD. Full article
(This article belongs to the Special Issue New Aspects and Mechanisms in Liver Diseases)
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42 pages, 1307 KiB  
Review
Blood-Based Biomarkers for Alzheimer’s Disease Diagnosis and Progression: An Overview
by Angelica Varesi, Adelaide Carrara, Vitor Gomes Pires, Valentina Floris, Elisa Pierella, Gabriele Savioli, Sakshi Prasad, Ciro Esposito, Giovanni Ricevuti, Salvatore Chirumbolo and Alessia Pascale
Cells 2022, 11(8), 1367; https://doi.org/10.3390/cells11081367 - 17 Apr 2022
Cited by 75 | Viewed by 14633
Abstract
Alzheimer’s Disease (AD) is a progressive neurodegenerative disease characterized by amyloid-β (Aβ) plaque deposition and neurofibrillary tangle accumulation in the brain. Although several studies have been conducted to unravel the complex and interconnected pathophysiology of AD, clinical trial failure rates have been high, [...] Read more.
Alzheimer’s Disease (AD) is a progressive neurodegenerative disease characterized by amyloid-β (Aβ) plaque deposition and neurofibrillary tangle accumulation in the brain. Although several studies have been conducted to unravel the complex and interconnected pathophysiology of AD, clinical trial failure rates have been high, and no disease-modifying therapies are presently available. Fluid biomarker discovery for AD is a rapidly expanding field of research aimed at anticipating disease diagnosis and following disease progression over time. Currently, Aβ1–42, phosphorylated tau, and total tau levels in the cerebrospinal fluid are the best-studied fluid biomarkers for AD, but the need for novel, cheap, less-invasive, easily detectable, and more-accessible markers has recently led to the search for new blood-based molecules. However, despite considerable research activity, a comprehensive and up-to-date overview of the main blood-based biomarker candidates is still lacking. In this narrative review, we discuss the role of proteins, lipids, metabolites, oxidative-stress-related molecules, and cytokines as possible disease biomarkers. Furthermore, we highlight the potential of the emerging miRNAs and long non-coding RNAs (lncRNAs) as diagnostic tools, and we briefly present the role of vitamins and gut-microbiome-related molecules as novel candidates for AD detection and monitoring, thus offering new insights into the diagnosis and progression of this devastating disease. Full article
(This article belongs to the Special Issue Biomarkers of Alzheimer’s Disease: New Insights)
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21 pages, 4959 KiB  
Article
Human iPSC-Derived Renal Cells Change Their Immunogenic Properties during Maturation: Implications for Regenerative Therapies
by Bella Rossbach, Krithika Hariharan, Nancy Mah, Su-Jun Oh, Hans-Dieter Volk, Petra Reinke and Andreas Kurtz
Cells 2022, 11(8), 1328; https://doi.org/10.3390/cells11081328 - 13 Apr 2022
Cited by 5 | Viewed by 3242
Abstract
The success of human induced pluripotent stem cell (hiPSC)-based therapy critically depends on understanding and controlling the immunological effects of the hiPSC-derived transplant. While hiPSC-derived cells used for cell therapy are often immature with post-grafting maturation, immunological properties may change, with adverse effects [...] Read more.
The success of human induced pluripotent stem cell (hiPSC)-based therapy critically depends on understanding and controlling the immunological effects of the hiPSC-derived transplant. While hiPSC-derived cells used for cell therapy are often immature with post-grafting maturation, immunological properties may change, with adverse effects on graft tolerance and control. In the present study, the allogeneic and autologous cellular immunity of hiPSC-derived progenitor and terminally differentiated cells were investigated in vitro. In contrast to allogeneic primary cells, hiPSC-derived early renal progenitors and mature renal epithelial cells are both tolerated not only by autologous but also by allogeneic T cells. These immune-privileged properties result from active immunomodulation and low immune visibility, which decrease during the process of cell maturation. However, autologous and allogeneic natural killer (NK) cell responses are not suppressed by hiPSC-derived renal cells and effectively change NK cell activation status. These findings clearly show a dynamic stage-specific dependency of autologous and allogeneic T and NK cell responses, with consequences for effective cell therapies. The study suggests that hiPSC-derived early progenitors may provide advantageous immune-suppressive properties when applied in cell therapy. The data furthermore indicate a need to suppress NK cell activation in allogeneic as well as autologous settings. Full article
(This article belongs to the Special Issue Stem Cells in Personalized Medicine 2021)
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23 pages, 1791 KiB  
Review
GBA Variants and Parkinson Disease: Mechanisms and Treatments
by Laura Smith and Anthony H. V. Schapira
Cells 2022, 11(8), 1261; https://doi.org/10.3390/cells11081261 - 8 Apr 2022
Cited by 121 | Viewed by 16095
Abstract
The GBA gene encodes for the lysosomal enzyme glucocerebrosidase (GCase), which maintains glycosphingolipid homeostasis. Approximately 5–15% of PD patients have mutations in the GBA gene, making it numerically the most important genetic risk factor for Parkinson disease (PD). Clinically, GBA-associated PD is [...] Read more.
The GBA gene encodes for the lysosomal enzyme glucocerebrosidase (GCase), which maintains glycosphingolipid homeostasis. Approximately 5–15% of PD patients have mutations in the GBA gene, making it numerically the most important genetic risk factor for Parkinson disease (PD). Clinically, GBA-associated PD is identical to sporadic PD, aside from the earlier age at onset (AAO), more frequent cognitive impairment and more rapid progression. Mutations in GBA can be associated with loss- and gain-of-function mechanisms. A key hallmark of PD is the presence of intraneuronal proteinaceous inclusions named Lewy bodies, which are made up primarily of alpha-synuclein. Mutations in the GBA gene may lead to loss of GCase activity and lysosomal dysfunction, which may impair alpha-synuclein metabolism. Models of GCase deficiency demonstrate dysfunction of the autophagic-lysosomal pathway and subsequent accumulation of alpha-synuclein. This dysfunction can also lead to aberrant lipid metabolism, including the accumulation of glycosphingolipids, glucosylceramide and glucosylsphingosine. Certain mutations cause GCase to be misfolded and retained in the endoplasmic reticulum (ER), activating stress responses including the unfolded protein response (UPR), which may contribute to neurodegeneration. In addition to these mechanisms, a GCase deficiency has also been associated with mitochondrial dysfunction and neuroinflammation, which have been implicated in the pathogenesis of PD. This review discusses the pathways associated with GBA-PD and highlights potential treatments which may act to target GCase and prevent neurodegeneration. Full article
(This article belongs to the Special Issue Parkinson’s Disease (PD): Molecular Mechanisms and Novel Treatment Strategies)
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23 pages, 3565 KiB  
Review
Brain Microvascular Pericytes—More than Bystanders in Breast Cancer Brain Metastasis
by Danyyl Ippolitov, Leanne Arreza, Maliha Nuzhat Munir and Sabine Hombach-Klonisch
Cells 2022, 11(8), 1263; https://doi.org/10.3390/cells11081263 - 8 Apr 2022
Cited by 7 | Viewed by 4714
Abstract
Brain tissue contains the highest number of perivascular pericytes compared to other organs. Pericytes are known to regulate brain perfusion and to play an important role within the neurovascular unit (NVU). The high phenotypic and functional plasticity of pericytes make this cell type [...] Read more.
Brain tissue contains the highest number of perivascular pericytes compared to other organs. Pericytes are known to regulate brain perfusion and to play an important role within the neurovascular unit (NVU). The high phenotypic and functional plasticity of pericytes make this cell type a prime candidate to aid physiological adaptations but also propose pericytes as important modulators in diverse pathologies in the brain. This review highlights known phenotypes of pericytes in the brain, discusses the diverse markers for brain pericytes, and reviews current in vitro and in vivo experimental models to study pericyte function. Our current knowledge of pericyte phenotypes as it relates to metastatic growth patterns in breast cancer brain metastasis is presented as an example for the crosstalk between pericytes, endothelial cells, and metastatic cells. Future challenges lie in establishing methods for real-time monitoring of pericyte crosstalk to understand causal events in the brain metastatic process. Full article
(This article belongs to the Section Cell Microenvironment)
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18 pages, 3211 KiB  
Article
Decellularized Organ-Derived Scaffold Is a Promising Carrier for Human Induced Pluripotent Stem Cells-Derived Hepatocytes
by Hideaki Kojima, Hiroshi Yagi, Hiroko Kushige, Yukiko Toda, Kazuo Takayama, Shinako Masuda, Toshinori Morisaku, Tomonori Tsuchida, Kohei Kuroda, Kazuya Hirukawa, Jumpei Inui, Kotaro Nishi, Yutaka Nakano, Masayuki Tanaka, Shutaro Hori, Yasushi Hasegawa, Yuta Abe, Minoru Kitago, Shungo Adachi, Masatoshi Tomi, Katsuhisa Matsuura, Hiroyuki Mizuguchi and Yuko Kitagawaadd Show full author list remove Hide full author list
Cells 2022, 11(8), 1258; https://doi.org/10.3390/cells11081258 - 7 Apr 2022
Cited by 9 | Viewed by 3688
Abstract
Human induced pluripotent stem cells (hiPSCs) are a promising cell source for elucidating disease pathology and therapy. The mass supply of hiPSC-derived cells is technically feasible. Carriers that can contain a large number of hiPSC-derived cells and evaluate their functions in vivo-like environments [...] Read more.
Human induced pluripotent stem cells (hiPSCs) are a promising cell source for elucidating disease pathology and therapy. The mass supply of hiPSC-derived cells is technically feasible. Carriers that can contain a large number of hiPSC-derived cells and evaluate their functions in vivo-like environments will become increasingly important for understanding disease pathogenesis or treating end-stage organ failure. hiPSC-derived hepatocyte-like cells (hiPSC-HLCs; 5 × 108) were seeded into decellularized organ-derived scaffolds under circumfusion culture. The scaffolds were implanted into immunodeficient microminiature pigs to examine their applicability in vivo. The seeded hiPSC-HLCs demonstrated increased albumin secretion and up-regulated cytochrome P450 activities compared with those in standard two-dimensional culture conditions. Moreover, they showed long-term survival accompanied by neovascularization in vivo. The decellularized organ-derived scaffold is a promising carrier for hiPSC-derived cells for ex vivo and in vivo use and is an essential platform for regenerative medicine and research. Full article
(This article belongs to the Special Issue Current Progress in Organ Regeneration: Cells, Organoids and Organs)
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24 pages, 5474 KiB  
Article
Proteomics and Metabolomics Profiling of Platelets and Plasma Mediators of Thrombo-Inflammation in Gestational Hypertension and Preeclampsia
by Luiz Gustavo N. de Almeida, Daniel Young, Lorraine Chow, Joshua Nicholas, Adrienne Lee, Man-Chiu Poon, Antoine Dufour and Ejaife O. Agbani
Cells 2022, 11(8), 1256; https://doi.org/10.3390/cells11081256 - 7 Apr 2022
Cited by 26 | Viewed by 6679
Abstract
Platelets may be pivotal mediators of the thrombotic and coagulopathic complications of preeclampsia (PE), linking inflammation and thrombosis with endothelial and vascular dysfunction. Both PE and gestational hypertension (GH) fall within the spectrum of hypertensive complications of pregnancy, with GH being a risk [...] Read more.
Platelets may be pivotal mediators of the thrombotic and coagulopathic complications of preeclampsia (PE), linking inflammation and thrombosis with endothelial and vascular dysfunction. Both PE and gestational hypertension (GH) fall within the spectrum of hypertensive complications of pregnancy, with GH being a risk factor for preeclampsia. However, it is unclear what biomarkers distinguish PE from GH. Using a discovery size cohort, we aimed to characterize specific plasma and platelet thrombo-inflammatory drivers indicative of PE and differentiate PE from GH. We performed multiplex immunoassays, platelet and plasma quantitative proteomics and metabolomics of PE patients, comparing with non-pregnant (NP), healthy pregnant controls (PC) and GH participants. The expression pattern of plasma proteins and metabolites in PE/GH platelets was distinct from that of NP and PC. Whilst procoagulation in PC may be fibrinogen driven, inter-alpha-trypsin inhibitors ITIH2 and ITIH3 are likely mediators of thrombo-inflammation in GH and PE, and fibronectin and S100A8/9 may be major procoagulant agonists in PE only. Also enriched in PE were CCL1 and CCL27 plasma cytokines, and the platelet leucine-rich repeat-containing protein 27 and 42 (LRRC27/42), whose effects on platelets were explored using STRING analysis. Through protein-protein interactions analysis, we generated a new hypothesis for platelets’ contribution to the thrombo-inflammatory states of preeclampsia. Full article
(This article belongs to the Special Issue Platelets as Pathophysiological Drivers of Thrombo-Inflammation and Immune Response)
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19 pages, 29063 KiB  
Article
CARD19 Interacts with Mitochondrial Contact Site and Cristae Organizing System Constituent Proteins and Regulates Cristae Morphology
by Kariana E. Rios, Ming Zhou, Nathaniel M. Lott, Chelsi R. Beauregard, Dennis P. McDaniel, Thomas P. Conrads and Brian C. Schaefer
Cells 2022, 11(7), 1175; https://doi.org/10.3390/cells11071175 - 31 Mar 2022
Cited by 3 | Viewed by 4511
Abstract
CARD19 is a mitochondrial protein of unknown function. While CARD19 was originally reported to regulate TCR-dependent NF-κB activation via interaction with BCL10, this function is not recapitulated ex vivo in primary murine CD8+ T cells. Here, we employ a combination of SIM, [...] Read more.
CARD19 is a mitochondrial protein of unknown function. While CARD19 was originally reported to regulate TCR-dependent NF-κB activation via interaction with BCL10, this function is not recapitulated ex vivo in primary murine CD8+ T cells. Here, we employ a combination of SIM, TEM, and confocal microscopy, along with proteinase K protection assays and proteomics approaches, to identify interacting partners of CARD19 in macrophages. Our data show that CARD19 is specifically localized to the outer mitochondrial membrane. Through deletion of functional domains, we demonstrate that both the distal C-terminus and transmembrane domain are required for mitochondrial targeting, whereas the CARD is not. Importantly, mass spectrometry analysis of 3×Myc-CARD19 immunoprecipitates reveals that CARD19 interacts with the components of the mitochondrial intermembrane bridge (MIB), consisting of mitochondrial contact site and cristae organizing system (MICOS) components MIC19, MIC25, and MIC60, and MICOS-interacting proteins SAMM50 and MTX2. These CARD19 interactions are in part dependent on a properly folded CARD. Consistent with previously reported phenotypes upon siRNA silencing of MICOS subunits, absence of CARD19 correlates with irregular cristae morphology. Based on these data, we propose that CARD19 is a previously unknown interacting partner of the MIB and the MIC19–MIC25–MIC60 MICOS subcomplex that regulates cristae morphology. Full article
(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Organelle Function)
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16 pages, 2490 KiB  
Article
Alterations in Protein Translation and Carboxylic Acid Catabolic Processes in Diabetic Kidney Disease
by Kimberly S. Collins, Michael T. Eadon, Ying-Hua Cheng, Daria Barwinska, Ricardo Melo Ferreira, Thomas W. McCarthy, Danielle Janosevic, Farooq Syed, Bernhard Maier, Tarek M. El-Achkar, Katherine J. Kelly, Carrie L. Phillips, Takashi Hato, Timothy A. Sutton and Pierre C. Dagher
Cells 2022, 11(7), 1166; https://doi.org/10.3390/cells11071166 - 30 Mar 2022
Cited by 7 | Viewed by 3168
Abstract
Diabetic kidney disease (DKD) remains the leading cause of end-stage kidney disease despite decades of study. Alterations in the glomerulus and kidney tubules both contribute to the pathogenesis of DKD although the majority of investigative efforts have focused on the glomerulus. We sought [...] Read more.
Diabetic kidney disease (DKD) remains the leading cause of end-stage kidney disease despite decades of study. Alterations in the glomerulus and kidney tubules both contribute to the pathogenesis of DKD although the majority of investigative efforts have focused on the glomerulus. We sought to examine the differential expression signature of human DKD in the glomerulus and proximal tubule and corroborate our findings in the db/db mouse model of diabetes. A transcriptogram network analysis of RNAseq data from laser microdissected (LMD) human glomerulus and proximal tubule of DKD and reference nephrectomy samples revealed enriched pathways including rhodopsin-like receptors, olfactory signaling, and ribosome (protein translation) in the proximal tubule of human DKD biopsy samples. The translation pathway was also enriched in the glomerulus. Increased translation in diabetic kidneys was validated using polyribosomal profiling in the db/db mouse model of diabetes. Using single nuclear RNA sequencing (snRNAseq) of kidneys from db/db mice, we prioritized additional pathways identified in human DKD. The top overlapping pathway identified in the murine snRNAseq proximal tubule clusters and the human LMD proximal tubule compartment was carboxylic acid catabolism. Using ultra-performance liquid chromatography–mass spectrometry, the fatty acid catabolism pathway was also found to be dysregulated in the db/db mouse model. The Acetyl-CoA metabolite was down-regulated in db/db mice, aligning with the human differential expression of the genes ACOX1 and ACACB. In summary, our findings demonstrate that proximal tubular alterations in protein translation and carboxylic acid catabolism are key features in both human and murine DKD. Full article
(This article belongs to the Special Issue Metabolomics as a Tool for Functional Genomics)
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23 pages, 2557 KiB  
Review
Vitamin D Receptor Influences Intestinal Barriers in Health and Disease
by Jun Sun and Yong-Guo Zhang
Cells 2022, 11(7), 1129; https://doi.org/10.3390/cells11071129 - 27 Mar 2022
Cited by 46 | Viewed by 8108
Abstract
Vitamin D receptor (VDR) executes most of the biological functions of vitamin D. Beyond this, VDR is a transcriptional factor regulating the expression levels of many target genes, such as genes for tight junction proteins claudin-2, -5, -12, and -15. In this review, [...] Read more.
Vitamin D receptor (VDR) executes most of the biological functions of vitamin D. Beyond this, VDR is a transcriptional factor regulating the expression levels of many target genes, such as genes for tight junction proteins claudin-2, -5, -12, and -15. In this review, we discuss the progress of research on VDR that influences intestinal barriers in health and disease. We searched PubMed and Google Scholar using key words vitamin D, VDR, tight junctions, cancer, inflammation, and infection. We summarize the literature and progress reports on VDR regulation of tight junction distribution, cellular functions, and mechanisms (directly or indirectly). We review the impacts of VDR on barriers in various diseases, e.g., colon cancer, infection, inflammatory bowel disease, and chronic inflammatory lung diseases. We also discuss the limits of current studies and future directions. Deeper understanding of the mechanisms by which the VDR signaling regulates intestinal barrier functions allow us to develop efficient and effective therapeutic strategies based on levels of tight junction proteins and vitamin D/VDR statuses for human diseases. Full article
(This article belongs to the Special Issue Cell-Cell Interactions and Cell Adhesion Signaling in Disease States)
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18 pages, 2050 KiB  
Article
Activin A Causes Muscle Atrophy through MEF2C-Dependent Impaired Myogenesis
by Audrey Loumaye, Pascale Lause, Xiaoling Zhong, Teresa A. Zimmers, Laure B. Bindels and Jean-Paul Thissen
Cells 2022, 11(7), 1119; https://doi.org/10.3390/cells11071119 - 25 Mar 2022
Cited by 16 | Viewed by 3930
Abstract
Activin A (ActA) is considered to play a major role in cancer-induced cachexia (CC). Indeed, circulating ActA levels are elevated and predict survival in patients with CC. However, the mechanisms by which ActA mediates CC development and in particular skeletal muscle (SM) atrophy [...] Read more.
Activin A (ActA) is considered to play a major role in cancer-induced cachexia (CC). Indeed, circulating ActA levels are elevated and predict survival in patients with CC. However, the mechanisms by which ActA mediates CC development and in particular skeletal muscle (SM) atrophy in humans are not yet fully understood. In this work, we aimed to investigate the effects of ActA on human SM and in mouse models of CC. We used a model of human muscle cells in culture to explore how ActA acts towards human SM. In this model, recombinant ActA induced myotube atrophy associated with the decline of MyHC-β/slow, the main myosin isoform in human muscle cells studied. Moreover, ActA inhibited the expression and activity of MEF2C, the transcription factor regulating MYH7, the gene which codes for MyHC-β/slow. This decrease in MEF2C was involved in the decline of MyHC-β/slow expression, since inhibition of MEF2C by a siRNA leads to the decrease in MyHC-β/slow expression. The relevance of this ActA/MEF2C pathway in vivo was supported by the parallel decline of MEF2C expression and SM mass, which are both blunted by ActA inhibition, in animal models of CC. In this work, we showed that ActA is a potent negative regulator of SM mass by inhibiting MyHC-β/slow synthesis through downregulation of MEF2C. This observation highlights a novel interaction between ActA signaling and MEF2C transcriptional activity which contributes to SM atrophy in CC models. Full article
(This article belongs to the Special Issue Cancer-Induced Cachexia)
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15 pages, 2048 KiB  
Review
Metabotropic Glutamate Receptors at Ribbon Synapses in the Retina and Cochlea
by Lisa Klotz-Weigand and Ralf Enz
Cells 2022, 11(7), 1097; https://doi.org/10.3390/cells11071097 - 24 Mar 2022
Cited by 4 | Viewed by 4368
Abstract
Our senses define our view of the world. They allow us to adapt to environmental stimuli and are essential for communication and social behaviour. For most humans, seeing and hearing are central senses for their daily life. Our eyes and ears respond to [...] Read more.
Our senses define our view of the world. They allow us to adapt to environmental stimuli and are essential for communication and social behaviour. For most humans, seeing and hearing are central senses for their daily life. Our eyes and ears respond to an extraordinary broad range of stimuli covering about 12 log units of light intensity or acoustic power, respectively. The cellular basis is represented by sensory cells (photoreceptors in the retina and inner hair cells in the cochlea) that convert sensory inputs into electrical signals. Photoreceptors and inner hair cells have developed a specific pre-synaptic structure, termed synaptic ribbon, that is decorated with numerous vesicles filled with the excitatory neurotransmitter glutamate. At these ribbon synapses, glutamatergic signal transduction is guided by distinct sets of metabotropic glutamate receptors (mGluRs). MGluRs belong to group II and III of the receptor classification can inhibit neuronal activity, thus protecting neurons from overstimulation and subsequent degeneration. Consequently, dysfunction of mGluRs is associated with vision and hearing disorders. In this review, we introduce the principle characteristics of ribbon synapses and describe group II and III mGluRs in these fascinating structures in the retina and cochlea. Full article
(This article belongs to the Special Issue The Role of Metabotropic Glutamate Receptors in Health and Disease)
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21 pages, 7496 KiB  
Article
Protective Effect of Human-Neural-Crest-Derived Nasal Turbinate Stem Cells against Amyloid-β Neurotoxicity through Inhibition of Osteopontin in a Human Cerebral Organoid Model of Alzheimer’s Disease
by Jung Yeon Lim, Jung Eun Lee, Soon A Park, Sang In Park, Jung-Min Yon, Jeong-Ah Park, Sin-Soo Jeun, Seung Joon Kim, Hong Jun Lee, Sung Won Kim and Seung Ho Yang
Cells 2022, 11(6), 1029; https://doi.org/10.3390/cells11061029 - 18 Mar 2022
Cited by 10 | Viewed by 3654
Abstract
The aim of this study was to validate the use of human brain organoids (hBOs) to investigate the therapeutic potential and mechanism of human-neural-crest-derived nasal turbinate stem cells (hNTSCs) in models of Alzheimer’s disease (AD). We generated hBOs from human induced pluripotent stem [...] Read more.
The aim of this study was to validate the use of human brain organoids (hBOs) to investigate the therapeutic potential and mechanism of human-neural-crest-derived nasal turbinate stem cells (hNTSCs) in models of Alzheimer’s disease (AD). We generated hBOs from human induced pluripotent stem cells, investigated their characteristics according to neuronal markers and electrophysiological features, and then evaluated the protective effect of hNTSCs against amyloid-β peptide (Aβ1–42) neurotoxic activity in vitro in hBOs and in vivo in a mouse model of AD. Treatment of hBOs with Aβ1–42 induced neuronal cell death concomitant with decreased expression of neuronal markers, which was suppressed by hNTSCs cocultured under Aβ1–42 exposure. Cytokine array showed a significantly decreased level of osteopontin (OPN) in hBOs with hNTSC coculture compared with hBOs only in the presence of Aβ1–42. Silencing OPN via siRNA suppressed Aβ-induced neuronal cell death in cell culture. Notably, compared with PBS, hNTSC transplantation significantly enhanced performance on the Morris water maze, with reduced levels of OPN after transplantation in a mouse model of AD. These findings reveal that hBO models are useful to evaluate the therapeutic effect and mechanism of stem cells for application in treating AD. Full article
(This article belongs to the Section Stem Cells)
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14 pages, 989 KiB  
Article
Cerebrospinal Fluid Proteome Alterations Associated with Neuropsychiatric Symptoms in Cognitive Decline and Alzheimer’s Disease
by Magdalena Mroczek, Christopher Clark, Loïc Dayon, Gene L. Bowman and Julius Popp
Cells 2022, 11(6), 1030; https://doi.org/10.3390/cells11061030 - 18 Mar 2022
Cited by 11 | Viewed by 3277
Abstract
Although neuropsychiatric symptoms (NPS) are common and severely affect older people with cognitive decline, little is known about their underlying molecular mechanisms and relationships with Alzheimer’s disease (AD). The aim of this study was to identify and characterize cerebrospinal fluid (CSF) proteome alterations [...] Read more.
Although neuropsychiatric symptoms (NPS) are common and severely affect older people with cognitive decline, little is known about their underlying molecular mechanisms and relationships with Alzheimer’s disease (AD). The aim of this study was to identify and characterize cerebrospinal fluid (CSF) proteome alterations related to NPS. In a longitudinally followed-up cohort of subjects with normal cognition and patients with cognitive impairment (MCI and mild dementia) from a memory clinic setting, we quantified a panel of 790 proteins in CSF using an untargeted shotgun proteomic workflow. Regression models and pathway enrichment analysis were used to investigate protein alterations related to NPS, and to explore relationships with AD pathology and cognitive decline at follow-up visits. Regression analysis selected 27 CSF proteins associated with NPS. These associations were independent of the presence of cerebral AD pathology (defined as CSF p-tau181/Aβ1–42 > 0.0779, center cutoff). Gene ontology enrichment showed abundance alterations of proteins related to cell adhesion, immune response, and lipid metabolism, among others, in relation to NPS. Out of the selected proteins, three were associated with accelerated cognitive decline at follow-up visits after controlling for possible confounders. Specific CSF proteome alterations underlying NPS may both represent pathophysiological processes independent from AD and accelerate clinical disease progression. Full article
(This article belongs to the Special Issue Alzheimer's Disease: Molecular Mechanisms and Novel Treatment Strategies)
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12 pages, 876 KiB  
Review
Hydrogen Sulfide Produced by Gut Bacteria May Induce Parkinson’s Disease
by Kari Erik Murros
Cells 2022, 11(6), 978; https://doi.org/10.3390/cells11060978 - 12 Mar 2022
Cited by 57 | Viewed by 10934
Abstract
Several bacterial species can generate hydrogen sulfide (H2S). Study evidence favors the view that the microbiome of the colon harbors increased amounts of H2S producing bacteria in Parkinson’s disease. Additionally, H2S can easily penetrate cell membranes and [...] Read more.
Several bacterial species can generate hydrogen sulfide (H2S). Study evidence favors the view that the microbiome of the colon harbors increased amounts of H2S producing bacteria in Parkinson’s disease. Additionally, H2S can easily penetrate cell membranes and enter the cell interior. In the cells, excessive amounts of H2S can potentially release cytochrome c protein from the mitochondria, increase the iron content of the cytosolic iron pool, and increase the amount of reactive oxygen species. These events can lead to the formation of alpha-synuclein oligomers and fibrils in cells containing the alpha-synuclein protein. In addition, bacterially produced H2S can interfere with the body urate metabolism and affect the blood erythrocytes and lymphocytes. Gut bacteria responsible for increased H2S production, especially the mucus-associated species of the bacterial genera belonging to the Desulfovibrionaceae and Enterobacteriaceae families, are likely play a role in the pathogenesis of Parkinson’s disease. Special attention should be devoted to changes not only in the colonic but also in the duodenal microbiome composition with regard to the pathogenesis of Parkinson’s disease. Influenza infections may increase the risk of Parkinson’s disease by causing the overgrowth of H2S-producing bacteria both in the colon and duodenum. Full article
(This article belongs to the Special Issue Focus on Cellular Parkinson’s Disease—from Gut to Brain)
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29 pages, 1908 KiB  
Review
Novel Insights into the Therapeutic Potential of Lung-Targeted Gene Transfer in the Most Common Respiratory Diseases
by Malik Bisserier, Xiao-Qing Sun, Shahood Fazal, Irene C. Turnbull, Sébastien Bonnet and Lahouaria Hadri
Cells 2022, 11(6), 984; https://doi.org/10.3390/cells11060984 - 12 Mar 2022
Cited by 19 | Viewed by 11528
Abstract
Over the past decades, a better understanding of the genetic and molecular alterations underlying several respiratory diseases has encouraged the development of new therapeutic strategies. Gene therapy offers new therapeutic alternatives for inherited and acquired diseases by delivering exogenous genetic materials into cells [...] Read more.
Over the past decades, a better understanding of the genetic and molecular alterations underlying several respiratory diseases has encouraged the development of new therapeutic strategies. Gene therapy offers new therapeutic alternatives for inherited and acquired diseases by delivering exogenous genetic materials into cells or tissues to restore physiological protein expression and/or activity. In this review, we review (1) different types of viral and non-viral vectors as well as gene-editing techniques; and (2) the application of gene therapy for the treatment of respiratory diseases and disorders, including pulmonary arterial hypertension, idiopathic pulmonary fibrosis, cystic fibrosis, asthma, alpha-1 antitrypsin deficiency, chronic obstructive pulmonary disease, non-small-cell lung cancer, and COVID-19. Further, we also provide specific examples of lung-targeted therapies and discuss the major limitations of gene therapy. Full article
(This article belongs to the Collection Cellular and Molecular Pathophysiology of Vascular Proliferative Diseases)
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14 pages, 654 KiB  
Review
MicroRNA Roles in Cell Reprogramming Mechanisms
by Emilia Pascale, Carmen Caiazza, Martina Paladino, Silvia Parisi, Fabiana Passaro and Massimiliano Caiazzo
Cells 2022, 11(6), 940; https://doi.org/10.3390/cells11060940 - 10 Mar 2022
Cited by 19 | Viewed by 6848
Abstract
Cell reprogramming is a groundbreaking technology that, in few decades, generated a new paradigm in biomedical science. To date we can use cell reprogramming to potentially generate every cell type by converting somatic cells and suitably modulating the expression of key transcription factors. [...] Read more.
Cell reprogramming is a groundbreaking technology that, in few decades, generated a new paradigm in biomedical science. To date we can use cell reprogramming to potentially generate every cell type by converting somatic cells and suitably modulating the expression of key transcription factors. This approach can be used to convert skin fibroblasts into pluripotent stem cells as well as into a variety of differentiated and medically relevant cell types, including cardiomyocytes and neural cells. The molecular mechanisms underlying such striking cell phenotypes are still largely unknown, but in the last decade it has been proven that cell reprogramming approaches are significantly influenced by non-coding RNAs. Specifically, this review will focus on the role of microRNAs in the reprogramming processes that lead to the generation of pluripotent stem cells, neurons, and cardiomyocytes. As highlighted here, non-coding RNA-forced expression can be sufficient to support some cell reprogramming processes, and, therefore, we will also discuss how these molecular determinants could be used in the future for biomedical purposes. Full article
(This article belongs to the Special Issue Role of Non-coding RNA in Health and Disease)
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11 pages, 1007 KiB  
Review
Calcium Channels in the Heart: Disease States and Drugs
by Kajol Shah, Sarah Seeley, Castin Schulz, Jacqueline Fisher and Shubha Gururaja Rao
Cells 2022, 11(6), 943; https://doi.org/10.3390/cells11060943 - 10 Mar 2022
Cited by 54 | Viewed by 15526
Abstract
Calcium ions are the major signaling ions in the cells. They regulate muscle contraction, neurotransmitter secretion, cell growth and migration, and the activity of several proteins including enzymes and ion channels and transporters. They participate in various signal transduction pathways, thereby regulating major [...] Read more.
Calcium ions are the major signaling ions in the cells. They regulate muscle contraction, neurotransmitter secretion, cell growth and migration, and the activity of several proteins including enzymes and ion channels and transporters. They participate in various signal transduction pathways, thereby regulating major physiological functions. Calcium ion entry into the cells is regulated by specific calcium channels and transporters. There are mainly six types of calcium channels, of which only two are prominent in the heart. In cardiac tissues, the two types of calcium channels are the L type and the T type. L-type channels are found in all cardiac cells and T-type are expressed in Purkinje cells, pacemaker and atrial cells. Both these types of channels contribute to atrioventricular conduction as well as pacemaker activity. Given the crucial role of calcium channels in the cardiac conduction system, mutations and dysfunctions of these channels are known to cause several diseases and disorders. Drugs targeting calcium channels hence are used in a wide variety of cardiac disorders including but not limited to hypertension, angina, and arrhythmias. This review summarizes the type of cardiac calcium channels, their function, and disorders caused by their mutations and dysfunctions. Finally, this review also focuses on the types of calcium channel blockers and their use in a variety of cardiac disorders. Full article
(This article belongs to the Special Issue Calcium Signaling in Health and Diseases)
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18 pages, 2825 KiB  
Article
Viral Interference of Hepatitis C and E Virus Replication in Novel Experimental Co-Infection Systems
by Thomas Burkard, Nora Proske, Kathrin Resner, Laura Collignon, Leonard Knegendorf, Martina Friesland, Lieven Verhoye, Ibrahim M. Sayed, Yannick Brüggemann, Maximilian K. Nocke, Patrick Behrendt, Heiner Wedemeyer, Philip Meuleman, Daniel Todt and Eike Steinmann
Cells 2022, 11(6), 927; https://doi.org/10.3390/cells11060927 - 8 Mar 2022
Cited by 7 | Viewed by 4772
Abstract
Background: Hepatitis C virus (HCV) constitutes a global health problem, while hepatitis E virus (HEV) is the major cause of acute viral hepatitis globally. HCV/HEV co-infections have been poorly characterized, as they are hampered by the lack of robust HEV cell culture systems. [...] Read more.
Background: Hepatitis C virus (HCV) constitutes a global health problem, while hepatitis E virus (HEV) is the major cause of acute viral hepatitis globally. HCV/HEV co-infections have been poorly characterized, as they are hampered by the lack of robust HEV cell culture systems. This study developed experimental models to study HCV/HEV co-infections and investigate viral interference in cells and humanized mice. Methods: We used state-of-the art human hepatocytes tissue culture models to assess HEV and HCV replication in co- or super-transfection settings. Findings were confirmed by co- and super-infection experiments in human hepatocytes and in vivo in human liver chimeric mice. Results: HEV was inhibited by concurrent HCV replication in human hepatocytes. This exclusion phenotype was linked to the protease activity of HCV. These findings were corroborated by the fact that in HEV on HCV super-infected mice, HEV viral loads were reduced in individual mice. Similarly, HCV on HEV super-infected mice showed reduced HCV viral loads. Conclusion: Direct interference of both viruses with HCV NS3/4A as the determinant was observed. In vivo, we detected reduced replication of both viruses after super-infection in individual mice. These findings provide new insights into the pathogenesis of HCV-HEV co-infections and should contribute to its clinical management in the future. Full article
(This article belongs to the Special Issue Cells as Viral Hosts)
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19 pages, 1027 KiB  
Review
Biomarkers Associated with Cardiovascular Disease in COVID-19
by Christoph C. Kaufmann, Amro Ahmed, Achim Leo Burger, Marie Muthspiel, Bernhard Jäger, Johann Wojta and Kurt Huber
Cells 2022, 11(6), 922; https://doi.org/10.3390/cells11060922 - 8 Mar 2022
Cited by 18 | Viewed by 5676
Abstract
Coronavirus disease-19 (COVID-19) emerged late December 2019 in the city of Wuhan, China and has since spread rapidly all over the world causing a global pandemic. While the respiratory system is the primary target of disease manifestation, COVID-19 has been shown to also [...] Read more.
Coronavirus disease-19 (COVID-19) emerged late December 2019 in the city of Wuhan, China and has since spread rapidly all over the world causing a global pandemic. While the respiratory system is the primary target of disease manifestation, COVID-19 has been shown to also affect several other organs, making it a rather complex, multi-system disease. As such, cardiovascular involvement has been a topic of discussion since the beginning of the COVID-19 pandemic, primarily due to early reports of excessive myocardial injury in these patients. Treating physicians are faced with multiple challenges in the management and early triage of patients with COVID-19, as disease severity is highly variable ranging from an asymptomatic infection to critical cases rapidly deteriorating to intensive care treatment or even fatality. Laboratory biomarkers provide important prognostic information which can guide decision making in the emergency department, especially in patients with atypical presentations. Several cardiac biomarkers, most notably high-sensitive cardiac troponin (hs-cTn) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), have emerged as valuable predictors of prognosis in patients with COVID-19. The purpose of this review was to offer a concise summary on prognostic cardiac biomarkers in COVID-19 and discuss whether routine measurements of these biomarkers are warranted upon hospital admission. Full article
(This article belongs to the Special Issue Understanding Biomarkers in Cardiology)
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15 pages, 3037 KiB  
Article
Pathological Relevance of Post-Translationally Modified Alpha-Synuclein (pSer87, pSer129, nTyr39) in Idiopathic Parkinson’s Disease and Multiple System Atrophy
by Berkiye Sonustun, Melek Firat Altay, Catherine Strand, Kirsten Ebanks, Geshanthi Hondhamuni, Thomas T. Warner, Hilal A. Lashuel and Rina Bandopadhyay
Cells 2022, 11(5), 906; https://doi.org/10.3390/cells11050906 - 6 Mar 2022
Cited by 27 | Viewed by 4929
Abstract
Aggregated alpha-synuclein (α-synuclein) is the main component of Lewy bodies (LBs), Lewy neurites (LNs), and glial cytoplasmic inclusions (GCIs), which are pathological hallmarks of idiopathic Parkinson’s disease (IPD) and multiple system atrophy (MSA). Initiating factors that culminate in forming LBs/LNs/GCIs remain elusive. Several [...] Read more.
Aggregated alpha-synuclein (α-synuclein) is the main component of Lewy bodies (LBs), Lewy neurites (LNs), and glial cytoplasmic inclusions (GCIs), which are pathological hallmarks of idiopathic Parkinson’s disease (IPD) and multiple system atrophy (MSA). Initiating factors that culminate in forming LBs/LNs/GCIs remain elusive. Several species of α-synuclein exist, including phosphorylated and nitrated forms. It is unclear which α-synuclein post-translational modifications (PTMs) appear within aggregates throughout disease pathology. Herein we aimed to establish the predominant α-synuclein PTMs in postmortem IPD and MSA pathology using immunohistochemistry. We examined the patterns of three α-synuclein PTMs (pS87, pS129, nY39) simultaneously in pathology-affected regions of 15 IPD cases, 5 MSA cases, and 6 neurologically normal controls. All antibodies recognized LBs, LNs, and GCIs, albeit to a variable extent. pS129 α-synuclein antibody was particularly immunopositive for LNs and synaptic dot-like structures, followed by nY39 α-synuclein antibody. GCIs, neuronal inclusions, and small threads were positive for nY39 α-synuclein in MSA. Quantification of the LB scores revealed that pS129 α-synuclein was the dominant and earliest α-synuclein PTM, followed by nY39 α-synuclein, while lower amounts of pSer87 α-synuclein appeared later in disease progression in PD. These results may have implications for novel biomarker and therapeutic developments. Full article
(This article belongs to the Special Issue Parkinson’s Disease (PD): Molecular Mechanisms and Novel Treatment Strategies)
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14 pages, 2119 KiB  
Article
PTH-Induced Bone Regeneration and Vascular Modulation Are Both Dependent on Endothelial Signaling
by Doron Cohn-Schwartz, Yeshai Schary, Eran Yalon, Zoe Krut, Xiaoyu Da, Edward M. Schwarz, Dan Gazit, Gadi Pelled and Zulma Gazit
Cells 2022, 11(5), 897; https://doi.org/10.3390/cells11050897 - 5 Mar 2022
Cited by 9 | Viewed by 2780
Abstract
The use of a bone allograft presents a promising approach for healing nonunion fractures. We have previously reported that parathyroid hormone (PTH) therapy induced allograft integration while modulating angiogenesis at the allograft proximity. Here, we hypothesize that PTH-induced vascular modulation and the osteogenic [...] Read more.
The use of a bone allograft presents a promising approach for healing nonunion fractures. We have previously reported that parathyroid hormone (PTH) therapy induced allograft integration while modulating angiogenesis at the allograft proximity. Here, we hypothesize that PTH-induced vascular modulation and the osteogenic effect of PTH are both dependent on endothelial PTH receptor-1 (PTHR1) signaling. To evaluate our hypothesis, we used multiple transgenic mouse lines, and their wild-type counterparts as a control. In addition to endothelial-specific PTHR1 knock-out mice, we used mice in which PTHR1 was engineered to be constitutively active in collagen-1α+ osteoblasts, to assess the effect of PTH signaling activation exclusively in osteoprogenitors. To characterize resident cell recruitment and osteogenic activity, mice in which the Luciferase reporter gene is expressed under the Osteocalcin promoter (Oc-Luc) were used. Mice were implanted with calvarial allografts and treated with either PTH or PBS. A micro-computed tomography-based structural analysis indicated that the induction of bone formation by PTH, as observed in wild-type animals, was not maintained when PTHR1 was removed from endothelial cells. Furthermore, the induction of PTH signaling exclusively in osteoblasts resulted in significantly less bone formation compared to systemic PTH treatment, and significantly less osteogenic activity was measured by bioluminescence imaging of the Oc-Luc mice. Deletion of the endothelial PTHR1 significantly decreased the PTH-induced formation of narrow blood vessels, formerly demonstrated in wild-type mice. However, the exclusive activation of PTH signaling in osteoblasts was sufficient to re-establish the observed PTH effect. Collectively, our results show that endothelial PTHR1 signaling plays a key role in PTH-induced osteogenesis and has implications in angiogenesis. Full article
(This article belongs to the Special Issue Advances in Bone Metabolism)
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16 pages, 4607 KiB  
Article
Transcriptomics Reveals Discordant Lipid Metabolism Effects between In Vitro Models Exposed to Elafibranor and Liver Samples of NAFLD Patients after Bariatric Surgery
by Joost Boeckmans, Alexandra Gatzios, Anja Heymans, Matthias Rombaut, Vera Rogiers, Joery De Kock, Tamara Vanhaecke and Robim M. Rodrigues
Cells 2022, 11(5), 893; https://doi.org/10.3390/cells11050893 - 4 Mar 2022
Cited by 10 | Viewed by 4654
Abstract
Background and aims: Non-alcoholic steatohepatitis (NASH) is a life-threatening stage of non-alcoholic fatty liver disease (NAFLD) for which no drugs have been approved. We have previously shown that human-derived hepatic in vitro models can be used to mimic key cellular mechanisms involved in [...] Read more.
Background and aims: Non-alcoholic steatohepatitis (NASH) is a life-threatening stage of non-alcoholic fatty liver disease (NAFLD) for which no drugs have been approved. We have previously shown that human-derived hepatic in vitro models can be used to mimic key cellular mechanisms involved in the progression of NASH. In the present study, we first characterize the transcriptome of multiple in vitro NASH models. Subsequently, we investigate how elafibranor, which is a peroxisome proliferator-activated receptor (PPAR)-α/δ agonist that has recently failed a phase 3 clinical trial as a potential anti-NASH compound, modulates the transcriptome of these models. Finally, we compare the elafibranor-induced gene expression modulation to transcriptome data of patients with improved/resolved NAFLD/NASH upon bariatric surgery, which is the only proven clinical NASH therapy. Methods: Human whole genome microarrays were used for the transcriptomics evaluation of hepatic in vitro models. Comparison to publicly available clinical datasets was conducted using multiple bioinformatic application tools. Results: Primary human hepatocytes (PHH), HepaRG, and human skin stem cell-derived hepatic progenitors (hSKP-HPC) exposed to NASH-inducing triggers exhibit up to 35% overlap with datasets of liver samples from NASH patients. Exposure of the in vitro NASH models to elafibranor partially reversed the transcriptional modulations, predicting an inhibition of toll-like receptor (TLR)-2/4/9-mediated inflammatory responses, NFκB-signaling, hepatic fibrosis, and leukocyte migration. These transcriptomic changes were also observed in the datasets of liver samples of patients with resolved NASH. Peroxisome Proliferator Activated Receptor Alpha (PPARA), PPARG Coactivator 1 Alpha (PPARGC1A), and Sirtuin 1 (SIRT1) were identified as the major common upstream regulators upon exposure to elafibranor. Analysis of the downstream mechanistic networks further revealed that angiopoietin Like 4 (ANGPTL4), pyruvate dehydrogenase kinase 4 (PDK4), and perilipin 2 (PLIN2), which are involved in the promotion of hepatic lipid accumulation, were also commonly upregulated by elafibranor in all in vitro NASH models. Contrarily, these genes were not upregulated in liver samples of patients with resolved NASH. Conclusion: Transcriptomics comparison between in vitro NASH models exposed to elafibranor and clinical datasets of NAFLD patients after bariatric surgery reveals commonly modulated anti-inflammatory responses, but discordant modulations of key factors in lipid metabolism. This discordant adverse effect of elafibranor deserves further investigation when assessing PPAR-α/δ agonism as a potential anti-NASH therapy. Full article
(This article belongs to the Special Issue The Role of PPARs in Disease II)
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16 pages, 1417 KiB  
Review
Metabolic Contribution and Cerebral Blood Flow Regulation by Astrocytes in the Neurovascular Unit
by Shinichi Takahashi
Cells 2022, 11(5), 813; https://doi.org/10.3390/cells11050813 - 25 Feb 2022
Cited by 49 | Viewed by 11462
Abstract
The neurovascular unit (NVU) is a conceptual framework that has been proposed to better explain the relationships between the neural cells and blood vessels in the human brain, focused mainly on the brain gray matter. The major components of the NVU are the [...] Read more.
The neurovascular unit (NVU) is a conceptual framework that has been proposed to better explain the relationships between the neural cells and blood vessels in the human brain, focused mainly on the brain gray matter. The major components of the NVU are the neurons, astrocytes (astroglia), microvessels, pericytes, and microglia. In addition, we believe that oligodendrocytes should also be included as an indispensable component of the NVU in the white matter. Of all these components, astrocytes in particular have attracted the interest of researchers because of their unique anatomical location; these cells are interposed between the neurons and the microvessels of the brain. Their location suggests that astrocytes might regulate the cerebral blood flow (CBF) in response to neuronal activity, so as to ensure an adequate supply of glucose and oxygen to meet the metabolic demands of the neurons. In fact, the adult human brain, which accounts for only 2% of the entire body weight, consumes approximately 20–25% of the total amount of glucose and oxygen consumed by the whole body. The brain needs a continuous supply of these essential energy sources through the CBF, because there are practically no stores of glucose or oxygen in the brain; both acute and chronic cessation of CBF can adversely affect brain functions. In addition, another important putative function of the NVU is the elimination of heat and waste materials produced by neuronal activity. Recent evidence suggests that astrocytes play pivotal roles not only in supplying glucose, but also fatty acids and amino acids to neurons. Loss of astrocytic support can be expected to lead to malfunction of the NVU as a whole, which underlies numerous neurological disorders. In this review, we shall focus on historical and recent findings with regard to the metabolic contributions of astrocytes in the NVU. Full article
(This article belongs to the Special Issue Remodeling and Recovery in the Neurovascular Unit)
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18 pages, 2045 KiB  
Review
The Role of Mitochondria in Human Fertility and Early Embryo Development: What Can We Learn for Clinical Application of Assessing and Improving Mitochondrial DNA?
by Amira Podolak, Izabela Woclawek-Potocka and Krzysztof Lukaszuk
Cells 2022, 11(5), 797; https://doi.org/10.3390/cells11050797 - 24 Feb 2022
Cited by 37 | Viewed by 9085
Abstract
Mitochondria are well known as ‘the powerhouses of the cell’. Indeed, their major role is cellular energy production driven by both mitochondrial and nuclear DNA. Such a feature makes these organelles essential for successful fertilisation and proper embryo implantation and development. Generally, mitochondrial [...] Read more.
Mitochondria are well known as ‘the powerhouses of the cell’. Indeed, their major role is cellular energy production driven by both mitochondrial and nuclear DNA. Such a feature makes these organelles essential for successful fertilisation and proper embryo implantation and development. Generally, mitochondrial DNA is exclusively maternally inherited; oocyte’s mitochondrial DNA level is crucial to provide sufficient ATP content for the developing embryo until the blastocyst stage of development. Additionally, human fertility and early embryogenesis may be affected by either point mutations or deletions in mitochondrial DNA. It was suggested that their accumulation may be associated with ovarian ageing. If so, is mitochondrial dysfunction the cause or consequence of ovarian ageing? Moreover, such an obvious relationship of mitochondria and mitochondrial genome with human fertility and early embryo development gives the field of mitochondrial research a great potential to be of use in clinical application. However, even now, the area of assessing and improving DNA quantity and function in reproductive medicine drives many questions and uncertainties. This review summarises the role of mitochondria and mitochondrial DNA in human reproduction and gives an insight into the utility of their clinical use. Full article
(This article belongs to the Special Issue Molecular and Clinical Advances in Understanding Early Embryo Development)
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17 pages, 5498 KiB  
Article
Response of Astrocyte Subpopulations Following Spinal Cord Injury
by R. Vivian Allahyari, Nicolette M. Heinsinger, Daniel Hwang, David A. Jaffe, Javad Rasouli, Stephanie Shiers, Samantha J. Thomas, Theodore J. Price, Abdolmohamad Rostami and Angelo C. Lepore
Cells 2022, 11(4), 721; https://doi.org/10.3390/cells11040721 - 18 Feb 2022
Cited by 13 | Viewed by 4591
Abstract
There is growing appreciation for astrocyte heterogeneity both across and within central nervous system (CNS) regions, as well as between intact and diseased states. Recent work identified multiple astrocyte subpopulations in mature brain. Interestingly, one subpopulation (Population C) was shown to possess significantly [...] Read more.
There is growing appreciation for astrocyte heterogeneity both across and within central nervous system (CNS) regions, as well as between intact and diseased states. Recent work identified multiple astrocyte subpopulations in mature brain. Interestingly, one subpopulation (Population C) was shown to possess significantly enhanced synaptogenic properties in vitro, as compared with other astrocyte subpopulations of adult cortex and spinal cord. Following spinal cord injury (SCI), damaged neurons lose synaptic connections with neuronal partners, resulting in persistent functional loss. We determined whether SCI induces an enhanced synaptomodulatory astrocyte phenotype by shifting toward a greater proportion of Population C cells and/or increasing expression of relevant synapse formation-associated genes within one or more astrocyte subpopulations. Using flow cytometry and RNAscope in situ hybridization, we found that astrocyte subpopulation distribution in the spinal cord did not change to a selectively synaptogenic phenotype following mouse cervical hemisection-type SCI. We also found that spinal cord astrocytes expressed synapse formation-associated genes to a similar degree across subpopulations, as well as in an unchanged manner between uninjured and SCI conditions. Finally, we confirmed these astrocyte subpopulations are also present in the human spinal cord in a similar distribution as mouse, suggesting possible conservation of spinal cord astrocyte heterogeneity across species. Full article
(This article belongs to the Collection Cell Biology of Spinal Cord Injury and Repair)
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Graphical abstract

16 pages, 1563 KiB  
Article
Epigenetic Dysregulation of the Homeobox A5 (HOXA5) Gene Associates with Subcutaneous Adipocyte Hypertrophy in Human Obesity
by Luca Parrillo, Rosa Spinelli, Mattia Costanzo, Pasqualina Florese, Serena Cabaro, Antonella Desiderio, Immacolata Prevenzano, Gregory Alexander Raciti, Ulf Smith, Claudia Miele, Pietro Formisano, Raffaele Napoli and Francesco Beguinot
Cells 2022, 11(4), 728; https://doi.org/10.3390/cells11040728 - 18 Feb 2022
Cited by 12 | Viewed by 3077
Abstract
Along with insulin resistance and increased risk of type 2 diabetes (T2D), lean first-degree relatives of T2D subjects (FDR) feature impaired adipogenesis in subcutaneous adipose tissue (SAT) and subcutaneous adipocyte hypertrophy well before diabetes onset. The molecular mechanisms linking these events have only [...] Read more.
Along with insulin resistance and increased risk of type 2 diabetes (T2D), lean first-degree relatives of T2D subjects (FDR) feature impaired adipogenesis in subcutaneous adipose tissue (SAT) and subcutaneous adipocyte hypertrophy well before diabetes onset. The molecular mechanisms linking these events have only partially been clarified. In the present report, we show that silencing of the transcription factor Homeobox A5 (HOXA5) in human preadipocytes impaired differentiation in mature adipose cells in vitro. The reduced adipogenesis was accompanied by inappropriate WNT-signaling activation. Importantly, in preadipocytes from FDR individuals, HOXA5 expression was attenuated, with hypermethylation of the HOXA5 promoter region found responsible for its downregulation, as revealed by luciferase assay. Both HOXA5 gene expression and DNA methylation were significantly correlated with SAT adipose cell hypertrophy in FDR, whose increased adipocyte size marks impaired adipogenesis. In preadipocytes from FDR, the low HOXA5 expression negatively correlated with enhanced transcription of the WNT signaling downstream genes NFATC1 and WNT2B. In silico evidence indicated that NFATC1 and WNT2B were directly controlled by HOXA5. The HOXA5 promoter region also was hypermethylated in peripheral blood leukocytes from these same FDR individuals, which was further revealed in peripheral blood leukocytes from an independent group of obese subjects. Thus, HOXA5 controlled adipogenesis in humans by suppressing WNT signaling. Altered DNA methylation of the HOXA5 promoter contributed to restricted adipogenesis in the SAT of lean subjects who were FDR of type 2 diabetics and in obese individuals. Full article
(This article belongs to the Special Issue Transcriptional Factors and Epigenetic Mechanisms in Obesity and Related Metabolic Comorbidities)
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19 pages, 2862 KiB  
Article
Aryl Hydrocarbon Receptor (AhR) Limits the Inflammatory Responses in Human Lung Adenocarcinoma A549 Cells via Interference with NF-κB Signaling
by Gerardo Vázquez-Gómez, Martina Karasová, Zuzana Tylichová, Markéta Kabátková, Aleš Hampl, Jason Matthews, Jiří Neča, Miroslav Ciganek, Miroslav Machala and Jan Vondráček
Cells 2022, 11(4), 707; https://doi.org/10.3390/cells11040707 - 17 Feb 2022
Cited by 12 | Viewed by 3401
Abstract
Apart from its role in the metabolism of carcinogens, the aryl hydrocarbon receptor (AhR) has been suggested to be involved in the control of inflammatory responses within the respiratory tract. However, the mechanisms responsible for this are only partially known. In this study, [...] Read more.
Apart from its role in the metabolism of carcinogens, the aryl hydrocarbon receptor (AhR) has been suggested to be involved in the control of inflammatory responses within the respiratory tract. However, the mechanisms responsible for this are only partially known. In this study, we used A549 cell line, as a human model of lung alveolar type II (ATII)-like cells, to study the functional role of the AhR in control of inflammatory responses. Using IL-1β as an inflammation inducer, we found that the induction of cyclooxygenase-2 and secretion of prostaglandins, as well as expression and release of pro-inflammatory cytokines, were significantly higher in the AhR-deficient A549 cells. This was linked with an increased nuclear factor-κB (NF-κB) activity, and significantly enhanced phosphorylation of its regulators, IKKα/β, and their target IκBα, in the AhR-deficient A549 cells. In line with this, when we mimicked the exposure to a complex mixture of airborne pollutants, using an organic extract of reference diesel exhaust particle mixture, an exacerbated inflammatory response was observed in the AhR-deficient cells, as compared with wild-type A549 cells. Together, the present results indicate that the AhR may act as a negative regulator of the inflammatory response in the A549 model, via a direct modulation of NF-κB signaling. Its role(s) in the control of inflammation within the lung alveoli exposed to airborne pollutants, especially those which simultaneously activate the AhR, thus deserve further attention. Full article
(This article belongs to the Special Issue Relationship between Inflammation and Aryl Hydrocarbon Receptor Pathway)
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25 pages, 1312 KiB  
Review
Maintenance of NAD+ Homeostasis in Skeletal Muscle during Aging and Exercise
by Li Li Ji and Dongwook Yeo
Cells 2022, 11(4), 710; https://doi.org/10.3390/cells11040710 - 17 Feb 2022
Cited by 26 | Viewed by 11061
Abstract
Nicotinamide adenine dinucleotide (NAD) is a versatile chemical compound serving as a coenzyme in metabolic pathways and as a substrate to support the enzymatic functions of sirtuins (SIRTs), poly (ADP-ribose) polymerase-1 (PARP-1), and cyclic ADP ribose hydrolase (CD38). Under normal physiological conditions, NAD+ [...] Read more.
Nicotinamide adenine dinucleotide (NAD) is a versatile chemical compound serving as a coenzyme in metabolic pathways and as a substrate to support the enzymatic functions of sirtuins (SIRTs), poly (ADP-ribose) polymerase-1 (PARP-1), and cyclic ADP ribose hydrolase (CD38). Under normal physiological conditions, NAD+ consumption is matched by its synthesis primarily via the salvage pathway catalyzed by nicotinamide phosphoribosyltransferase (NAMPT). However, aging and muscular contraction enhance NAD+ utilization, whereas NAD+ replenishment is limited by cellular sources of NAD+ precursors and/or enzyme expression. This paper will briefly review NAD+ metabolic functions, its roles in regulating cell signaling, mechanisms of its degradation and biosynthesis, and major challenges to maintaining its cellular level in skeletal muscle. The effects of aging, physical exercise, and dietary supplementation on NAD+ homeostasis will be highlighted based on recent literature. Full article
(This article belongs to the Special Issue Redox Control of Cell Signaling in Cardiac and Skeletal Muscle)
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22 pages, 1085 KiB  
Review
Detection of Hypoxia in Cancer Models: Significance, Challenges, and Advances
by Inês Godet, Steven Doctorman, Fan Wu and Daniele M. Gilkes
Cells 2022, 11(4), 686; https://doi.org/10.3390/cells11040686 - 16 Feb 2022
Cited by 72 | Viewed by 11706
Abstract
The rapid proliferation of cancer cells combined with deficient vessels cause regions of nutrient and O2 deprivation in solid tumors. Some cancer cells can adapt to these extreme hypoxic conditions and persist to promote cancer progression. Intratumoral hypoxia has been consistently associated [...] Read more.
The rapid proliferation of cancer cells combined with deficient vessels cause regions of nutrient and O2 deprivation in solid tumors. Some cancer cells can adapt to these extreme hypoxic conditions and persist to promote cancer progression. Intratumoral hypoxia has been consistently associated with a worse patient prognosis. In vitro, 3D models of spheroids or organoids can recapitulate spontaneous O2 gradients in solid tumors. Likewise, in vivo murine models of cancer reproduce the physiological levels of hypoxia that have been measured in human tumors. Given the potential clinical importance of hypoxia in cancer progression, there is an increasing need to design methods to measure O2 concentrations. O2 levels can be directly measured with needle-type probes, both optical and electrochemical. Alternatively, indirect, noninvasive approaches have been optimized, and include immunolabeling endogenous or exogenous markers. Fluorescent, phosphorescent, and luminescent reporters have also been employed experimentally to provide dynamic measurements of O2 in live cells or tumors. In medical imaging, modalities such as MRI and PET are often the method of choice. This review provides a comparative overview of the main methods utilized to detect hypoxia in cell culture and preclinical models of cancer. Full article
(This article belongs to the Special Issue Hypoxia and Cancer: Mechanisms of Resistance and Metastasis)
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20 pages, 1260 KiB  
Review
Implications of Poly(A) Tail Processing in Repeat Expansion Diseases
by Paweł Joachimiak, Adam Ciesiołka, Grzegorz Figura and Agnieszka Fiszer
Cells 2022, 11(4), 677; https://doi.org/10.3390/cells11040677 - 15 Feb 2022
Cited by 5 | Viewed by 4408
Abstract
Repeat expansion diseases are a group of more than 40 disorders that affect mainly the nervous and/or muscular system and include myotonic dystrophies, Huntington’s disease, and fragile X syndrome. The mutation-driven expanded repeat tract occurs in specific genes and is composed of tri- [...] Read more.
Repeat expansion diseases are a group of more than 40 disorders that affect mainly the nervous and/or muscular system and include myotonic dystrophies, Huntington’s disease, and fragile X syndrome. The mutation-driven expanded repeat tract occurs in specific genes and is composed of tri- to dodeca-nucleotide-long units. Mutant mRNA is a pathogenic factor or important contributor to the disease and has great potential as a therapeutic target. Although repeat expansion diseases are quite well known, there are limited studies concerning polyadenylation events for implicated transcripts that could have profound effects on transcript stability, localization, and translation efficiency. In this review, we briefly present polyadenylation and alternative polyadenylation (APA) mechanisms and discuss their role in the pathogenesis of selected diseases. We also discuss several methods for poly(A) tail measurement (both transcript-specific and transcriptome-wide analyses) and APA site identification—the further development and use of which may contribute to a better understanding of the correlation between APA events and repeat expansion diseases. Finally, we point out some future perspectives on the research into repeat expansion diseases, as well as APA studies. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Neurodegenerative Diseases)
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18 pages, 590 KiB  
Systematic Review
Ketamine and Lamotrigine Combination in Psychopharmacology: Systematic Review
by Alina Wilkowska, Mariusz S. Wiglusz, Katarzyna Jakuszkowiak-Wojten and Wiesław J. Cubała
Cells 2022, 11(4), 645; https://doi.org/10.3390/cells11040645 - 12 Feb 2022
Cited by 14 | Viewed by 11493
Abstract
Background and Objectives: Ketamine is a rapid-acting antidepressant with proven efficacy as an add-on agent in unipolar and bipolar treatment-resistant depression. Although many studies have been published, there is still not enough data on the effect of ketamine in combination with other medications. [...] Read more.
Background and Objectives: Ketamine is a rapid-acting antidepressant with proven efficacy as an add-on agent in unipolar and bipolar treatment-resistant depression. Although many studies have been published, there is still not enough data on the effect of ketamine in combination with other medications. Particularly interesting is the combination of ketamine and lamotrigine, and its potential role in bipolar depression. The aim of this review was to identify animal and human studies in which ketamine and lamotrigine were used together in order to find out if there is scientific ground for combining ketamine and lamotrigine in the treatment of mood disorders. Directions for future studies are presented. Materials and Methods: PubMed and Web of Science were searched. Preferred Reporting Items for Systematic Reviews and Meta-Analyses PRISMA 2020 methodology was applied. Results: Seventeen studies were included for review. Animal studies using models of depression suggested a synergistic effect of ketamine and lamotrigine in combination. Studies on healthy humans showed a reduction in ketamine-induced dissociative symptoms with lamotrigine pretreatment. In a study on patients with depression, ketamine and lamotrigine did not have a stronger antidepressant effect than ketamine alone, but in this study only one ketamine infusion was administered. One case series described the antidepressant and anti-suicidal effect of the combination in two bipolar patients. Available clinical studies on patients with mood disorders did not support the hypothesis that lamotrigine reduces ketamine-induced dissociative symptoms. Conclusions: The results of the analyzed studies were not sufficient to answer any of the stated questions; however, they allowed us to delineate future research directions. The identified animal studies suggested a possible synergistic antidepressant effect of ketamine and lamotrigine. The available clinical studies were not conclusive. No controlled studies on large groups of bipolar patients with multiple ketamine infusions combined with lamotrigine treatment have been published so far. There is some evidence for the reduction of ketamine’s side effects by lamotrigine, and there are reports suggesting that lamotrigine can reduce ketamine craving. More studies with follow-up are needed in order to investigate the ketamine–lamotrigine combination in bipolar patients. Full article
(This article belongs to the Special Issue New Molecular Targets for Antipsychotic and Antidepressant Pharmacotherapies)
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19 pages, 2266 KiB  
Review
Drug Resistance and Endoplasmic Reticulum Stress in Hepatocellular Carcinoma
by Jaafar Khaled, Maria Kopsida, Hans Lennernäs and Femke Heindryckx
Cells 2022, 11(4), 632; https://doi.org/10.3390/cells11040632 - 11 Feb 2022
Cited by 57 | Viewed by 6993
Abstract
Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide. It is usually diagnosed in an advanced stage and is characterized by a high intrinsic drug resistance, leading to limited chemotherapeutic efficacy and relapse after treatment. There is therefore a [...] Read more.
Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide. It is usually diagnosed in an advanced stage and is characterized by a high intrinsic drug resistance, leading to limited chemotherapeutic efficacy and relapse after treatment. There is therefore a vast need for understanding underlying mechanisms that contribute to drug resistance and for developing therapeutic strategies that would overcome this. The rapid proliferation of tumor cells, in combination with a highly inflammatory microenvironment, causes a chronic increase of protein synthesis in different hepatic cell populations. This leads to an intensified demand of protein folding, which inevitably causes an accumulation of misfolded or unfolded proteins in the lumen of the endoplasmic reticulum (ER). This process is called ER stress and triggers the unfolded protein response (UPR) in order to restore protein synthesis or—in the case of severe or prolonged ER stress—to induce cell death. Interestingly, the three different arms of the ER stress signaling pathways have been shown to drive chemoresistance in several tumors and could therefore form a promising therapeutic target. This review provides an overview of how ER stress and activation of the UPR contributes to drug resistance in HCC. Full article
(This article belongs to the Special Issue Unfolded Protein Response in Inflammation and Cancer)
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16 pages, 4470 KiB  
Article
Discordant Genome Assemblies Drastically Alter the Interpretation of Single-Cell RNA Sequencing Data Which Can Be Mitigated by a Novel Integration Method
by Helen G. Potts, Madeleine E. Lemieux, Edward S. Rice, Wesley Warren, Robin P. Choudhury and Mathilda T. M. Mommersteeg
Cells 2022, 11(4), 608; https://doi.org/10.3390/cells11040608 - 10 Feb 2022
Cited by 4 | Viewed by 3330
Abstract
Advances in sequencing and assembly technology have led to the creation of genome assemblies for a wide variety of non-model organisms. The rapid production and proliferation of updated, novel assembly versions can create vexing problems for researchers when multiple-genome assembly versions are available [...] Read more.
Advances in sequencing and assembly technology have led to the creation of genome assemblies for a wide variety of non-model organisms. The rapid production and proliferation of updated, novel assembly versions can create vexing problems for researchers when multiple-genome assembly versions are available at once, requiring researchers to work with more than one reference genome. Multiple-genome assemblies are especially problematic for researchers studying the genetic makeup of individual cells, as single-cell RNA sequencing (scRNAseq) requires sequenced reads to be mapped and aligned to a single reference genome. Using the Astyanax mexicanus, this study highlights how the interpretation of a single-cell dataset from the same sample changes when aligned to its two different available genome assemblies. We found that the number of cells and expressed genes detected were drastically different when aligning to the different assemblies. When the genome assemblies were used in isolation with their respective annotations, cell-type identification was confounded, as some classic cell-type markers were assembly-specific, whilst other genes showed differential patterns of expression between the two assemblies. To overcome the problems posed by multiple-genome assemblies, we propose that researchers align to each available assembly and then integrate the resultant datasets to produce a final dataset in which all genome alignments can be used simultaneously. We found that this approach increased the accuracy of cell-type identification and maximised the amount of data that could be extracted from our single-cell sample by capturing all possible cells and transcripts. As scRNAseq becomes more widely available, it is imperative that the single-cell community is aware of how genome assembly alignment can alter single-cell data and their interpretation, especially when reviewing studies on non-model organisms. Full article
(This article belongs to the Special Issue Single Cell Analysis 2.0)
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27 pages, 2888 KiB  
Article
MSK-Mediated Phosphorylation of Histone H3 Ser28 Couples MAPK Signalling with Early Gene Induction and Cardiac Hypertrophy
by Emma L. Robinson, Faye M. Drawnel, Saher Mehdi, Caroline R. Archer, Wei Liu, Hanneke Okkenhaug, Kanar Alkass, Jan Magnus Aronsen, Chandan K. Nagaraju, Ivar Sjaastad, Karin R. Sipido, Olaf Bergmann, J. Simon C. Arthur, Xin Wang and H. Llewelyn Roderick
Cells 2022, 11(4), 604; https://doi.org/10.3390/cells11040604 - 9 Feb 2022
Cited by 15 | Viewed by 4226
Abstract
Heart failure is a leading cause of death that develops subsequent to deleterious hypertrophic cardiac remodelling. MAPK pathways play a key role in coordinating the induction of gene expression during hypertrophy. Induction of the immediate early gene (IEG) response including activator protein 1 [...] Read more.
Heart failure is a leading cause of death that develops subsequent to deleterious hypertrophic cardiac remodelling. MAPK pathways play a key role in coordinating the induction of gene expression during hypertrophy. Induction of the immediate early gene (IEG) response including activator protein 1 (AP-1) complex factors is a necessary and early event in this process. How MAPK and IEG expression are coupled during cardiac hypertrophy is not resolved. Here, in vitro, in rodent models and in human samples, we demonstrate that MAPK-stimulated IEG induction depends on the mitogen and stress-activated protein kinase (MSK) and its phosphorylation of histone H3 at serine 28 (pH3S28). pH3S28 in IEG promoters in turn recruits Brg1, a BAF60 ATP-dependent chromatin remodelling complex component, initiating gene expression. Without MSK activity and IEG induction, the hypertrophic response is suppressed. These studies provide new mechanistic insights into the role of MAPK pathways in signalling to the epigenome and regulation of gene expression during cardiac hypertrophy. Full article
(This article belongs to the Special Issue Cellular Signaling Leading to Heart Failure)
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27 pages, 1228 KiB  
Review
Biomarker Development in Cardiology: Reviewing the Past to Inform the Future
by Katharine A. Kott, Michael Bishop, Christina H. J. Yang, Toby M. Plasto, Daniel C. Cheng, Adam I. Kaplan, Louise Cullen, David S. Celermajer, Peter J. Meikle, Stephen T. Vernon and Gemma A. Figtree
Cells 2022, 11(3), 588; https://doi.org/10.3390/cells11030588 - 8 Feb 2022
Cited by 8 | Viewed by 5588
Abstract
Cardiac biomarkers have become pivotal to the clinical practice of cardiology, but there remains much to discover that could benefit cardiology patients. We review the discovery of key protein biomarkers in the fields of acute coronary syndrome, heart failure, and atherosclerosis, giving an [...] Read more.
Cardiac biomarkers have become pivotal to the clinical practice of cardiology, but there remains much to discover that could benefit cardiology patients. We review the discovery of key protein biomarkers in the fields of acute coronary syndrome, heart failure, and atherosclerosis, giving an overview of the populations they were studied in and the statistics that were used to validate them. We review statistical approaches that are currently in use to assess new biomarkers and overview a framework for biomarker discovery and evaluation that could be incorporated into clinical trials to evaluate cardiovascular outcomes in the future. Full article
(This article belongs to the Special Issue Understanding Biomarkers in Cardiology)
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15 pages, 2208 KiB  
Review
Regulation of Nucleolar Activity by MYC
by Isabella N. Brown, M. Carmen Lafita-Navarro and Maralice Conacci-Sorrell
Cells 2022, 11(3), 574; https://doi.org/10.3390/cells11030574 - 7 Feb 2022
Cited by 11 | Viewed by 4168
Abstract
The nucleolus harbors the machinery necessary to produce new ribosomes which are critical for protein synthesis. Nucleolar size, shape, and density are highly dynamic and can be adjusted to accommodate ribosome biogenesis according to the needs for protein synthesis. In cancer, cells undergo [...] Read more.
The nucleolus harbors the machinery necessary to produce new ribosomes which are critical for protein synthesis. Nucleolar size, shape, and density are highly dynamic and can be adjusted to accommodate ribosome biogenesis according to the needs for protein synthesis. In cancer, cells undergo continuous proliferation; therefore, nucleolar activity is elevated due to their high demand for protein synthesis. The transcription factor and universal oncogene MYC promotes nucleolar activity by enhancing the transcription of ribosomal DNA (rDNA) and ribosomal proteins. This review summarizes the importance of nucleolar activity in mammalian cells, MYC’s role in nucleolar regulation in cancer, and discusses how a better understanding (and the potential inhibition) of aberrant nucleolar activity in cancer cells could lead to novel therapeutics. Full article
(This article belongs to the Special Issue Nucleolar Organization and Functions in Health and Disease II)
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19 pages, 11682 KiB  
Article
Brite Adipocyte FGF21 Attenuates Cardiac Ischemia/Reperfusion Injury in Rat Hearts by Modulating NRF2
by Hanbyeol Moon, Jung-Won Choi, Byeong-Wook Song, Il-Kwon Kim, Soyeon Lim, Seahyoung Lee, Gyoonhee Han, Ki-Chul Hwang and Sang Woo Kim
Cells 2022, 11(3), 567; https://doi.org/10.3390/cells11030567 - 6 Feb 2022
Cited by 12 | Viewed by 3750
Abstract
Although the optimal therapy for myocardial infarction includes reperfusion to restore blood flow to the ischemic area, myocardial injury after ischemia/reperfusion usually leads to an inflammatory response, oxidative stress, and cardiomyocyte apoptosis. In this study, rat adipose-derived stem cells were differentiated into low-thermogenic [...] Read more.
Although the optimal therapy for myocardial infarction includes reperfusion to restore blood flow to the ischemic area, myocardial injury after ischemia/reperfusion usually leads to an inflammatory response, oxidative stress, and cardiomyocyte apoptosis. In this study, rat adipose-derived stem cells were differentiated into low-thermogenic beige adipocytes (LBACs) and high-thermogenic beige adipocytes (HBACs) to study the different cardioprotective effects of heterogeneous expression of brown adipocytes. We found that antioxidant and antiapoptotic factors in H9c2 cardiomyocytes were upregulated by high levels of secreted FGF21 in HBAC conditioned medium (HBAC-CM), whereas FGF21 in HBAC-CM did not affect antioxidative or antiapoptotic cell death in H9c2 cardiomyocytes with Nrf2 knockdown. These results show that NRF2 mediates antioxidative and antiapoptotic effects through the HBAC-secreted factor FGF21. Consistent with this finding, the expression of antioxidant and antiapoptotic genes was upregulated by highly secreted FGF21 after HBAC-CM treatment compared to LBAC-CM treatment in H9c2 cardiomyocytes via NRF2 activation. Furthermore, HBAC-CM significantly attenuated ischemic rat heart tissue injury via NRF2 activation. Based on these findings, we propose that HBAC-CM exerts beneficial effects in rat cardiac ischemia/reperfusion injury by modulating NRF2 and has potential as a promising therapeutic agent for myocardial infarction. Full article
(This article belongs to the Special Issue Fat Is a Matter? The Implication of Adipose Tissue in Cardiovascular Health and Disease)
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26 pages, 1216 KiB  
Review
ISG15 and ISGylation in Human Diseases
by Oygul Mirzalieva, Meredith Juncker, Joshua Schwartzenburg and Shyamal Desai
Cells 2022, 11(3), 538; https://doi.org/10.3390/cells11030538 - 4 Feb 2022
Cited by 58 | Viewed by 13489
Abstract
Type I Interferons (IFNs) induce the expression of >500 genes, which are collectively called ISGs (IFN-stimulated genes). One of the earliest ISGs induced by IFNs is ISG15 (Interferon-Stimulated Gene 15). Free ISG15 protein synthesized from the ISG15 gene is post-translationally conjugated to cellular [...] Read more.
Type I Interferons (IFNs) induce the expression of >500 genes, which are collectively called ISGs (IFN-stimulated genes). One of the earliest ISGs induced by IFNs is ISG15 (Interferon-Stimulated Gene 15). Free ISG15 protein synthesized from the ISG15 gene is post-translationally conjugated to cellular proteins and is also secreted by cells into the extracellular milieu. ISG15 comprises two ubiquitin-like domains (UBL1 and UBL2), each of which bears a striking similarity to ubiquitin, accounting for its earlier name ubiquitin cross-reactive protein (UCRP). Like ubiquitin, ISG15 harbors a characteristic β-grasp fold in both UBL domains. UBL2 domain has a conserved C-terminal Gly-Gly motif through which cellular proteins are appended via an enzymatic cascade similar to ubiquitylation called ISGylation. ISG15 protein is minimally expressed under physiological conditions. However, its IFN-dependent expression is aberrantly elevated or compromised in various human diseases, including multiple types of cancer, neurodegenerative disorders (Ataxia Telangiectasia and Amyotrophic Lateral Sclerosis), inflammatory diseases (Mendelian Susceptibility to Mycobacterial Disease (MSMD), bacteriopathy and viropathy), and in the lumbar spinal cords of veterans exposed to Traumatic Brain Injury (TBI). ISG15 and ISGylation have both inhibitory and/or stimulatory roles in the etiology and pathogenesis of human diseases. Thus, ISG15 is considered a “double-edged sword” for human diseases in which its expression is elevated. Because of the roles of ISG15 and ISGylation in cancer cell proliferation, migration, and metastasis, conferring anti-cancer drug sensitivity to tumor cells, and its elevated expression in cancer, neurodegenerative disorders, and veterans exposed to TBI, both ISG15 and ISGylation are now considered diagnostic/prognostic biomarkers and therapeutic targets for these ailments. In the current review, we shall cover the exciting journey of ISG15, spanning three decades from the bench to the bedside. Full article
(This article belongs to the Special Issue Ubiquitin and Ubiquitin-Like Pathways in Development and Disease)
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20 pages, 2131 KiB  
Review
Endomembrane-Based Signaling by GPCRs and G-Proteins
by Federica Liccardo, Alberto Luini and Rosaria Di Martino
Cells 2022, 11(3), 528; https://doi.org/10.3390/cells11030528 - 3 Feb 2022
Cited by 24 | Viewed by 9898
Abstract
G-protein-coupled receptors (GPCRs) and G-proteins have a range of roles in many physiological and pathological processes and are among the most studied signaling proteins. A plethora of extracellular stimuli can activate the GPCR and can elicit distinct intracellular responses through the activation of [...] Read more.
G-protein-coupled receptors (GPCRs) and G-proteins have a range of roles in many physiological and pathological processes and are among the most studied signaling proteins. A plethora of extracellular stimuli can activate the GPCR and can elicit distinct intracellular responses through the activation of specific transduction pathways. For many years, biologists thought that GPCR signaling occurred entirely on the plasma membrane. However, in recent decades, many lines of evidence have proved that the GPCRs and G-proteins may reside on endomembranes and can start or propagate signaling pathways through the organelles that form the secretory route. How these alternative intracellular signaling pathways of the GPCR and G-proteins influence the physiological and pathological function of the endomembranes is still under investigation. Here, we review the general role and classification of GPCRs and G-proteins with a focus on their signaling pathways in the membrane transport apparatus. Full article
(This article belongs to the Section Intracellular and Plasma Membranes)
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