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Cells, Volume 13, Issue 5 (March-1 2024) – 101 articles

Cover Story (view full-size image): Cells (ISSN 2073-4409) is an international, peer-reviewed, open access journal which provides an advanced forum for studies related to cell biology, molecular biology and biophysics. It publishes reviews, research articles, communications and technical notes. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. The Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH) and Society for Regenerative Medicine (Russian Federation) (RPO) are affiliated with Cells, and their members receive discounts on the article processing charges.
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26 pages, 18416 KiB  
Article
High-Resolution Microscopic Characterization of Tunneling Nanotubes in Living U87 MG and LN229 Glioblastoma Cells
by Nicole Matejka, Asieh Amarlou, Jessica Neubauer, Sarah Rudigkeit and Judith Reindl
Cells 2024, 13(5), 464; https://doi.org/10.3390/cells13050464 - 06 Mar 2024
Viewed by 748
Abstract
Tunneling nanotubes (TNTs) are fine, nanometer-sized membrane connections between distant cells that provide an efficient communication tool for cellular organization. TNTs are thought to play a critical role in cellular behavior, particularly in cancer cells. The treatment of aggressive cancers such as glioblastoma [...] Read more.
Tunneling nanotubes (TNTs) are fine, nanometer-sized membrane connections between distant cells that provide an efficient communication tool for cellular organization. TNTs are thought to play a critical role in cellular behavior, particularly in cancer cells. The treatment of aggressive cancers such as glioblastoma remains challenging due to their high potential for developing therapy resistance, high infiltration rates, uncontrolled cell growth, and other aggressive features. A better understanding of the cellular organization via cellular communication through TNTs could help to find new therapeutic approaches. In this study, we investigate the properties of TNTs in two glioblastoma cell lines, U87 MG and LN229, including measurements of their diameter by high-resolution live-cell stimulated emission depletion (STED) microscopy and an analysis of their length, morphology, lifetime, and formation by live-cell confocal microscopy. In addition, we discuss how these fine compounds can ideally be studied microscopically. In particular, we show which membrane-labeling method is suitable for studying TNTs in glioblastoma cells and demonstrate that live-cell studies should be preferred to explore the role of TNTs in cellular behavior. Our observations on TNT formation in glioblastoma cells suggest that TNTs could be involved in cell migration and serve as guidance. Full article
(This article belongs to the Special Issue Recent Advances in Intravital and Live Cell Imaging)
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23 pages, 26412 KiB  
Article
Neutral Sphingomyelinase 2 Inhibition Limits Hepatic Steatosis and Inflammation
by Fatema Al-Rashed, Hossein Arefanian, Ashraf Al Madhoun, Fatemah Bahman, Sardar Sindhu, Halemah AlSaeed, Texy Jacob, Reeby Thomas, Areej Al-Roub, Fawaz Alzaid, MD Zubbair Malik, Rasheeba Nizam, Thangavel Alphonse Thanaraj, Fahd Al-Mulla, Yusuf A. Hannun and Rasheed Ahmad
Cells 2024, 13(5), 463; https://doi.org/10.3390/cells13050463 - 06 Mar 2024
Viewed by 853
Abstract
Non-alcoholic fatty liver disease (NAFLD) is manifested by hepatic steatosis, insulin resistance, hepatocyte death, and systemic inflammation. Obesity induces steatosis and chronic inflammation in the liver. However, the precise mechanism underlying hepatic steatosis in the setting of obesity remains unclear. Here, we report [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is manifested by hepatic steatosis, insulin resistance, hepatocyte death, and systemic inflammation. Obesity induces steatosis and chronic inflammation in the liver. However, the precise mechanism underlying hepatic steatosis in the setting of obesity remains unclear. Here, we report studies that address this question. After 14 weeks on a high-fat diet (HFD) with high sucrose, C57BL/6 mice revealed a phenotype of liver steatosis. Transcriptional profiling analysis of the liver tissues was performed using RNA sequencing (RNA-seq). Our RNA-seq data revealed 692 differentially expressed genes involved in processes of lipid metabolism, oxidative stress, immune responses, and cell proliferation. Notably, the gene encoding neutral sphingomyelinase, SMPD3, was predominantly upregulated in the liver tissues of the mice displaying a phenotype of steatosis. Moreover, nSMase2 activity was elevated in these tissues of the liver. Pharmacological and genetic inhibition of nSMase2 prevented intracellular lipid accumulation and TNFα-induced inflammation in in-vitro HepG2-steatosis cellular model. Furthermore, nSMase2 inhibition ameliorates oxidative damage by rescuing PPARα and preventing cell death associated with high glucose/oleic acid-induced fat accumulation in HepG2 cells. Collectively, our findings highlight the prominent role of nSMase2 in hepatic steatosis, which could serve as a potential therapeutic target for NAFLD and other hepatic steatosis-linked disorders. Full article
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15 pages, 2365 KiB  
Review
Communication between Mast Cells and Group 2 Innate Lymphoid Cells in the Skin
by Yeganeh Mehrani, Solmaz Morovati, Tahmineh Tajik, Soroush Sarmadi, Ali Bitaraf, Zahra Sourani, Mohammad Shahverdi, Helia Javadi, Julia E. Kakish, Byram W. Bridle and Khalil Karimi
Cells 2024, 13(5), 462; https://doi.org/10.3390/cells13050462 - 06 Mar 2024
Viewed by 748
Abstract
The skin is a dynamic organ with a complex immune network critical for maintaining balance and defending against various pathogens. Different types of cells in the skin, such as mast cells (MCs) and group 2 innate lymphoid cells (ILC2s), contribute to immune regulation [...] Read more.
The skin is a dynamic organ with a complex immune network critical for maintaining balance and defending against various pathogens. Different types of cells in the skin, such as mast cells (MCs) and group 2 innate lymphoid cells (ILC2s), contribute to immune regulation and play essential roles in the early immune response to various triggers, including allergens. It is beneficial to dissect cell-to-cell interactions in the skin to elucidate the mechanisms underlying skin immunity. The current manuscript concentrates explicitly on the communication pathways between MCs and ILC2s in the skin, highlighting their ability to regulate immune responses, inflammation, and tissue repair. Furthermore, it discusses how the interactions between MCs and ILC2s play a crucial role in various skin conditions, such as autoimmune diseases, dermatological disorders, and allergic reactions. Understanding the complex interactions between MCs and ILC2s in different skin conditions is crucial to developing targeted treatments for related disorders. The discovery of shared pathways could pave the way for novel therapeutic interventions to restore immunological balance in diseased skin tissues. Full article
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12 pages, 1413 KiB  
Commentary
Overactivation of the Endocannabinoid System in Adolescence Disrupts Adult Adipose Organ Function in Mice
by Kwang-Mook Jung, Lin Lin and Daniele Piomelli
Cells 2024, 13(5), 461; https://doi.org/10.3390/cells13050461 - 06 Mar 2024
Viewed by 644
Abstract
Cannabis use stimulates calorie intake, but epidemiological studies show that people who regularly use it are leaner than those who don’t. Two explanations have been proposed for this paradoxical finding. One posits that Δ9-tetrahydrocannabinol (THC) in cannabis desensitizes adipose CB1 cannabinoid [...] Read more.
Cannabis use stimulates calorie intake, but epidemiological studies show that people who regularly use it are leaner than those who don’t. Two explanations have been proposed for this paradoxical finding. One posits that Δ9-tetrahydrocannabinol (THC) in cannabis desensitizes adipose CB1 cannabinoid receptors, stopping their stimulating effects on lipogenesis and adipogenesis. Another explanation is that THC exposure in adolescence, when habitual cannabis use typically starts, produces lasting changes in the developing adipose organ, which impacts adult systemic energy use. Here, we consider these possibilities in the light of a study which showed that daily THC administration in adolescent mice produces an adult metabolic phenotype characterized by reduced fat mass, partial resistance to obesity and dyslipidemia, and impaired thermogenesis and lipolysis. The phenotype, whose development requires activation of CB1 receptors in differentiated adipocytes, is associated with overexpression of myocyte proteins in the adipose organ with unchanged CB1 expression. We propose that adolescent exposure to THC causes lasting adipocyte dysfunction and the consequent emergence of a metabolic state that only superficially resembles healthy leanness. A corollary of this hypothesis, which should be addressed in future studies, is that CB1 receptors and their endocannabinoid ligands may contribute to the maintenance of adipocyte differentiation during adolescence. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Adipose Organ Remodelling)
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23 pages, 14499 KiB  
Article
Secretome from Magnetically Stimulated Muscle Exhibits Anticancer Potency: Novel Preconditioning Methodology Highlighting HTRA1 Action
by Yee Kit Tai, Jan Nikolas Iversen, Karen Ka Wing Chan, Charlene Hui Hua Fong, Rafhanah Banu Abdul Razar, Sharanya Ramanan, Lye Yee Jasmine Yap, Jocelyn Naixin Yin, Shi Jie Toh, Craig Jun Kit Wong, Pei Fern Angele Koh, Ruby Yun Ju Huang and Alfredo Franco-Obregón
Cells 2024, 13(5), 460; https://doi.org/10.3390/cells13050460 - 05 Mar 2024
Viewed by 3212
Abstract
Briefly (10 min) exposing C2C12 myotubes to low amplitude (1.5 mT) pulsed electromagnetic fields (PEMFs) generated a conditioned media (pCM) that was capable of mitigating breast cancer cell growth, migration, and invasiveness in vitro, whereas the conditioned media harvested from unexposed myotubes, representing [...] Read more.
Briefly (10 min) exposing C2C12 myotubes to low amplitude (1.5 mT) pulsed electromagnetic fields (PEMFs) generated a conditioned media (pCM) that was capable of mitigating breast cancer cell growth, migration, and invasiveness in vitro, whereas the conditioned media harvested from unexposed myotubes, representing constitutively released secretome (cCM), was less effective. Administering pCM to breast cancer microtumors engrafted onto the chorioallantoic membrane of chicken eggs reduced tumor volume and vascularity. Blood serum collected from PEMF-exposed or exercised mice allayed breast cancer cell growth, migration, and invasiveness. A secretome preconditioning methodology is presented that accentuates the graded anticancer potencies of both the cCM and pCM harvested from myotubes, demonstrating an adaptive response to pCM administered during early myogenesis that emulated secretome-based exercise adaptations observed in vivo. HTRA1 was shown to be upregulated in pCM and was demonstrated to be necessary and sufficient for the anticancer potency of the pCM; recombinant HTRA1 added to basal media recapitulated the anticancer effects of pCM and antibody-based absorption of HTRA1 from pCM precluded its anticancer effects. Brief and non-invasive PEMF stimulation may represent a method to commandeer the secretome response of muscle, both in vitro and in vivo, for clinical exploitation in breast and other cancers. Full article
(This article belongs to the Special Issue Advances in Muscle Research in Health and Disease)
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37 pages, 4128 KiB  
Review
Lysosomes in Cancer—At the Crossroad of Good and Evil
by Ida Eriksson and Karin Öllinger
Cells 2024, 13(5), 459; https://doi.org/10.3390/cells13050459 - 05 Mar 2024
Viewed by 906
Abstract
Although it has been known for decades that lysosomes are central for degradation and recycling in the cell, their pivotal role as nutrient sensing signaling hubs has recently become of central interest. Since lysosomes are highly dynamic and in constant change regarding content [...] Read more.
Although it has been known for decades that lysosomes are central for degradation and recycling in the cell, their pivotal role as nutrient sensing signaling hubs has recently become of central interest. Since lysosomes are highly dynamic and in constant change regarding content and intracellular position, fusion/fission events allow communication between organelles in the cell, as well as cell-to-cell communication via exocytosis of lysosomal content and release of extracellular vesicles. Lysosomes also mediate different forms of regulated cell death by permeabilization of the lysosomal membrane and release of their content to the cytosol. In cancer cells, lysosomal biogenesis and autophagy are increased to support the increased metabolism and allow growth even under nutrient- and oxygen-poor conditions. Tumor cells also induce exocytosis of lysosomal content to the extracellular space to promote invasion and metastasis. However, due to the enhanced lysosomal function, cancer cells are often more susceptible to lysosomal membrane permeabilization, providing an alternative strategy to induce cell death. This review summarizes the current knowledge of cancer-associated alterations in lysosomal structure and function and illustrates how lysosomal exocytosis and release of extracellular vesicles affect disease progression. We focus on functional differences depending on lysosomal localization and the regulation of intracellular transport, and lastly provide insight how new therapeutic strategies can exploit the power of the lysosome and improve cancer treatment. Full article
(This article belongs to the Section Cellular Pathology)
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19 pages, 4317 KiB  
Article
Chlorine-Induced Toxicity on Murine Cornea: Exploring the Potential Therapeutic Role of Antioxidants
by Seungwon An, Khandaker Anwar, Mohammadjavad Ashraf, Kyu-Yeon Han and Ali R. Djalilian
Cells 2024, 13(5), 458; https://doi.org/10.3390/cells13050458 - 05 Mar 2024
Viewed by 713
Abstract
Chlorine (Cl2) exposure poses a significant risk to ocular health, with the cornea being particularly susceptible to its corrosive effects. Antioxidants, known for their ability to neutralize reactive oxygen species (ROS) and alleviate oxidative stress, were explored as potential therapeutic agents [...] Read more.
Chlorine (Cl2) exposure poses a significant risk to ocular health, with the cornea being particularly susceptible to its corrosive effects. Antioxidants, known for their ability to neutralize reactive oxygen species (ROS) and alleviate oxidative stress, were explored as potential therapeutic agents to counteract chlorine-induced damage. In vitro experiments using human corneal epithelial cells showed decreased cell viability by chlorine-induced ROS production, which was reversed by antioxidant incubation. The mitochondrial membrane potential decreased due to both low and high doses of Cl2 exposure; however, it was recovered through antioxidants. The wound scratch assay showed that antioxidants mitigated impaired wound healing after Cl2 exposure. In vivo and ex vivo, after Cl2 exposure, increased corneal fluorescein staining indicates damaged corneal epithelial and stromal layers of mice cornea. Likewise, Cl2 exposure in human ex vivo corneas led to corneal injury characterized by epithelial fluorescein staining and epithelial erosion. However, antioxidants protected Cl2-induced damage. These results highlight the effects of Cl2 on corneal cells using in vitro, ex vivo, and in vivo models while also underscoring the potential of antioxidants, such as vitamin A, vitamin C, resveratrol, and melatonin, as protective agents against acute chlorine toxicity-induced corneal injury. Further investigation is needed to confirm the antioxidants’ capacity to alleviate oxidative stress and enhance the corneal healing process. Full article
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26 pages, 1399 KiB  
Review
Emerging Roles and Mechanisms of RNA Modifications in Neurodegenerative Diseases and Glioma
by Ami Kobayashi, Yosuke Kitagawa, Ali Nasser, Hiroaki Wakimoto, Keisuke Yamada and Shota Tanaka
Cells 2024, 13(5), 457; https://doi.org/10.3390/cells13050457 - 05 Mar 2024
Viewed by 901
Abstract
Despite a long history of research, neurodegenerative diseases and malignant brain tumor gliomas are both considered incurable, facing challenges in the development of treatments. Recent evidence suggests that RNA modifications, previously considered as static components of intracellular RNAs, are in fact dynamically regulated [...] Read more.
Despite a long history of research, neurodegenerative diseases and malignant brain tumor gliomas are both considered incurable, facing challenges in the development of treatments. Recent evidence suggests that RNA modifications, previously considered as static components of intracellular RNAs, are in fact dynamically regulated across various RNA species in cells and play a critical role in major biological processes in the nervous system. Innovations in next-generation sequencing have enabled the accurate detection of modifications on bases and sugars within various RNA molecules. These RNA modifications influence the stability and transportation of RNA, and crucially affect its translation. This review delves into existing knowledge on RNA modifications to offer a comprehensive inventory of these modifications across different RNA species. The detailed regulatory functions and roles of RNA modifications within the nervous system are discussed with a focus on neurodegenerative diseases and gliomas. This article presents a comprehensive overview of the fundamental mechanisms and emerging roles of RNA modifications in these diseases, which can facilitate the creation of innovative diagnostics and therapeutics for these conditions. Full article
(This article belongs to the Special Issue RNA in Focus)
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15 pages, 4785 KiB  
Article
LncRNA NEAT1/miR-146a-5p Axis Restores Normal Angiogenesis in Diabetic Foot Ulcers by Targeting mafG
by TCA Architha, George Raj Juanitaa, Ramanarayanan Vijayalalitha, Ravichandran Jayasuriya, Gopinathan Athira, Ramachandran Balamurugan, Kumar Ganesan and Kunka Mohanram Ramkumar
Cells 2024, 13(5), 456; https://doi.org/10.3390/cells13050456 - 05 Mar 2024
Viewed by 710
Abstract
Non-healing lesions in diabetic foot ulcers are a significant effect of poor angiogenesis. Epigenetic regulators, mainly lncRNA and miRNA, are recognized for their important roles in disease progression. We deciphered the regulation of lncRNA NEAT1 through the miR-146a-5p/mafG axis in the progression of [...] Read more.
Non-healing lesions in diabetic foot ulcers are a significant effect of poor angiogenesis. Epigenetic regulators, mainly lncRNA and miRNA, are recognized for their important roles in disease progression. We deciphered the regulation of lncRNA NEAT1 through the miR-146a-5p/mafG axis in the progression of DFU. A lowered expression of lncRNA NEAT1 was associated with dysregulated angiogenesis through the reduced expression of mafG, SDF-1α, and VEGF in chronic ulcer subjects compared to acute DFU. This was validated by silencing NEAT1 by SiRNA in the endothelial cells which resulted in the transcriptional repression of target genes. Our in silico analysis identified miR-146a-5p as a potential target of lncRNA NEAT1. Further, silencing NEAT1 led to an increase in the levels of miR-146a-5p in chronic DFU subjects. This research presents the role of the lncRNA NEAT1/miR-146a-5p/mafG axis in enhancing angiogenesis in DFU. Full article
(This article belongs to the Special Issue Advances in the Biogenesis, Biology, and Functions of Noncoding RNAs)
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14 pages, 3276 KiB  
Article
Nicotinamide Riboside Augments Human Macrophage Migration via SIRT3-Mediated Prostaglandin E2 Signaling
by Jing Wu, Maximilian Bley, Russell S. Steans, Allison M. Meadows, Rebecca D. Huffstutler, Rong Tian, Julian L. Griffin and Michael N. Sack
Cells 2024, 13(5), 455; https://doi.org/10.3390/cells13050455 - 05 Mar 2024
Viewed by 1032
Abstract
NAD+ boosting via nicotinamide riboside (NR) confers anti-inflammatory effects. However, its underlying mechanisms and therapeutic potential remain incompletely defined. Here, we showed that NR increased the expression of CC-chemokine receptor 7 (CCR7) in human M1 macrophages by flow cytometric analysis of cell [...] Read more.
NAD+ boosting via nicotinamide riboside (NR) confers anti-inflammatory effects. However, its underlying mechanisms and therapeutic potential remain incompletely defined. Here, we showed that NR increased the expression of CC-chemokine receptor 7 (CCR7) in human M1 macrophages by flow cytometric analysis of cell surface receptors. Consequently, chemokine ligand 19 (CCL19, ligand for CCR7)-induced macrophage migration was enhanced following NR administration. Metabolomics analysis revealed that prostaglandin E2 (PGE2) was increased by NR in human monocytes and in human serum following in vivo NR supplementation. Furthermore, NR-mediated upregulation of macrophage migration through CCL19/CCR7 was dependent on PGE2 synthesis. We also demonstrated that NR upregulated PGE2 synthesis through SIRT3-dependent post-transcriptional regulation of cyclooxygenase 2 (COX-2). The NR/SIRT3/migration axis was further validated using the scratch-test model where NR and SIRT3 promoted more robust migration across a uniformly disrupted macrophage monolayer. Thus, NR-mediated metabolic regulation of macrophage migration and wound healing may have therapeutic potential for the topical management of chronic wound healing. Full article
(This article belongs to the Special Issue Advances in Leukocyte Migration and Location in Health and Disease)
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14 pages, 3195 KiB  
Article
Quantification of Polystyrene Uptake by Different Cell Lines Using Fluorescence Microscopy and Label-Free Visualization of Intracellular Polystyrene Particles by Raman Microspectroscopic Imaging
by Amelie Roth, Astrid Tannert, Nadja Ziller, Simone Eiserloh, Bianca Göhrig, Rustam R. Guliev, María José Gonzalez Vazquez, Max Naumann, Alexander S. Mosig, Sven Stengel, Astrid R. R. Heutelbeck and Ute Neugebauer
Cells 2024, 13(5), 454; https://doi.org/10.3390/cells13050454 - 05 Mar 2024
Viewed by 895
Abstract
Environmental pollution caused by plastic is a present problem. Polystyrene is a widely used packaging material (e.g., Styrofoam) that can be broken down into microplastics through abrasion. Once the plastic is released into the environment, it is dispersed by wind and atmospheric dust. [...] Read more.
Environmental pollution caused by plastic is a present problem. Polystyrene is a widely used packaging material (e.g., Styrofoam) that can be broken down into microplastics through abrasion. Once the plastic is released into the environment, it is dispersed by wind and atmospheric dust. In this study, we investigated the uptake of polystyrene particles into human cells using A549 cells as a model of the alveolar epithelial barrier, CaCo-2 cells as a model of the intestinal epithelial barrier, and THP-1 cells as a model of immune cells to simulate a possible uptake of microplastics by inhalation, oral uptake, and interaction with the cellular immune system, respectively. The uptake of fluorescence-labeled beads by the different cell types was investigated by confocal laser scanning microscopy in a semi-quantitative, concentration-dependent manner. Additionally, we used Raman spectroscopy as a complementary method for label-free qualitative detection and the visualization of polystyrene within cells. The uptake of polystyrene beads by all investigated cell types was detected, while the uptake behavior of professional phagocytes (THP-1) differed from that of adherent epithelial cells. Full article
(This article belongs to the Section Cell Methods)
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17 pages, 1163 KiB  
Review
A Review on the Role and Function of Cinnabarinic Acid, a “Forgotten” Metabolite of the Kynurenine Pathway
by Kinga Gawel
Cells 2024, 13(5), 453; https://doi.org/10.3390/cells13050453 - 05 Mar 2024
Viewed by 898
Abstract
In the human body, the majority of tryptophan is metabolized through the kynurenine pathway. This consists of several metabolites collectively called the kynurenines and includes, among others, kynurenic acid, L-kynurenine, or quinolinic acid. The wealth of metabolites, as well as the associated molecular targets [...] Read more.
In the human body, the majority of tryptophan is metabolized through the kynurenine pathway. This consists of several metabolites collectively called the kynurenines and includes, among others, kynurenic acid, L-kynurenine, or quinolinic acid. The wealth of metabolites, as well as the associated molecular targets and biological pathways, bring about a situation wherein even a slight imbalance in the kynurenine levels, both in the periphery and central nervous system, have broad consequences regarding general health. Cinnabarinic acid (CA) is the least known trace kynurenine, and its physiological and pathological roles are not widely understood. Some studies, however, indicate that it might be neuroprotective. Information on its hepatoprotective properties have also emerged, although these are pioneering studies and need to be replicated. Therefore, in this review, I aim to present and critically discuss the current knowledge on CA and its role in physiological and pathological settings to guide future studies. Full article
(This article belongs to the Special Issue Kynurenine Pathway in Health and Disease)
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0 pages, 1645 KiB  
Review
Unraveling the Heterogeneity of ALS—A Call to Redefine Patient Stratification for Better Outcomes in Clinical Trials
by Laura Tzeplaeff, Alexandra V. Jürs, Camilla Wohnrade and Antonia F. Demleitner
Cells 2024, 13(5), 452; https://doi.org/10.3390/cells13050452 - 05 Mar 2024
Cited by 1 | Viewed by 1331
Abstract
Despite tremendous efforts in basic research and a growing number of clinical trials aiming to find effective treatments, amyotrophic lateral sclerosis (ALS) remains an incurable disease. One possible reason for the lack of effective causative treatment options is that ALS may not be [...] Read more.
Despite tremendous efforts in basic research and a growing number of clinical trials aiming to find effective treatments, amyotrophic lateral sclerosis (ALS) remains an incurable disease. One possible reason for the lack of effective causative treatment options is that ALS may not be a single disease entity but rather may represent a clinical syndrome, with diverse genetic and molecular causes, histopathological alterations, and subsequent clinical presentations contributing to its complexity and variability among individuals. Defining a way to subcluster ALS patients is becoming a central endeavor in the field. Identifying specific clusters and applying them in clinical trials could enable the development of more effective treatments. This review aims to summarize the available data on heterogeneity in ALS with regard to various aspects, e.g., clinical, genetic, and molecular. Full article
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21 pages, 1846 KiB  
Review
Building a Better Defense: Expanding and Improving Natural Killer Cells for Adoptive Cell Therapy
by Andreia Maia, Mubin Tarannum, Joana R. Lérias, Sara Piccinelli, Luis Miguel Borrego, Markus Maeurer, Rizwan Romee and Mireia Castillo-Martin
Cells 2024, 13(5), 451; https://doi.org/10.3390/cells13050451 - 05 Mar 2024
Viewed by 1943
Abstract
Natural killer (NK) cells have gained attention as a promising adoptive cell therapy platform for their potential to improve cancer treatments. NK cells offer distinct advantages over T-cells, including major histocompatibility complex class I (MHC-I)-independent tumor recognition and low risk of toxicity, even [...] Read more.
Natural killer (NK) cells have gained attention as a promising adoptive cell therapy platform for their potential to improve cancer treatments. NK cells offer distinct advantages over T-cells, including major histocompatibility complex class I (MHC-I)-independent tumor recognition and low risk of toxicity, even in an allogeneic setting. Despite this tremendous potential, challenges persist, such as limited in vivo persistence, reduced tumor infiltration, and low absolute NK cell numbers. This review outlines several strategies aiming to overcome these challenges. The developed strategies include optimizing NK cell expansion methods and improving NK cell antitumor responses by cytokine stimulation and genetic manipulations. Using K562 cells expressing membrane IL-15 or IL-21 with or without additional activating ligands like 4-1BBL allows “massive” NK cell expansion and makes multiple cell dosing and “off-the-shelf” efforts feasible. Further improvements in NK cell function can be reached by inducing memory-like NK cells, developing chimeric antigen receptor (CAR)-NK cells, or isolating NK-cell-based tumor-infiltrating lymphocytes (TILs). Memory-like NK cells demonstrate higher in vivo persistence and cytotoxicity, with early clinical trials demonstrating safety and promising efficacy. Recent trials using CAR-NK cells have also demonstrated a lack of any major toxicity, including cytokine release syndrome, and, yet, promising clinical activity. Recent data support that the presence of TIL-NK cells is associated with improved overall patient survival in different types of solid tumors such as head and neck, colorectal, breast, and gastric carcinomas, among the most significant. In conclusion, this review presents insights into the diverse strategies available for NK cell expansion, including the roles played by various cytokines, feeder cells, and culture material in influencing the activation phenotype, telomere length, and cytotoxic potential of expanded NK cells. Notably, genetically modified K562 cells have demonstrated significant efficacy in promoting NK cell expansion. Furthermore, culturing NK cells with IL-2 and IL-15 has been shown to improve expansion rates, while the presence of IL-12 and IL-21 has been linked to enhanced cytotoxic function. Overall, this review provides an overview of NK cell expansion methodologies, highlighting the current landscape of clinical trials and the key advancements to enhance NK-cell-based adoptive cell therapy. Full article
(This article belongs to the Special Issue Advances in the Study of Natural Killer (NK) Cells)
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24 pages, 1565 KiB  
Review
A Possible Therapeutic Application of the Selective Inhibitor of Urate Transporter 1, Dotinurad, for Metabolic Syndrome, Chronic Kidney Disease, and Cardiovascular Disease
by Hidekatsu Yanai, Hiroki Adachi, Mariko Hakoshima, Sakura Iida and Hisayuki Katsuyama
Cells 2024, 13(5), 450; https://doi.org/10.3390/cells13050450 - 04 Mar 2024
Viewed by 1038
Abstract
The reabsorption of uric acid (UA) is mainly mediated by urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) in the kidneys. Dotinurad inhibits URAT1 but does not inhibit other UA transporters, such as GLUT9, ATP-binding cassette transporter G2 (ABCG2), and organic anion [...] Read more.
The reabsorption of uric acid (UA) is mainly mediated by urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) in the kidneys. Dotinurad inhibits URAT1 but does not inhibit other UA transporters, such as GLUT9, ATP-binding cassette transporter G2 (ABCG2), and organic anion transporter 1/3 (OAT1/3). We found that dotinurad ameliorated the metabolic parameters and renal function in hyperuricemic patients. We consider the significance of the highly selective inhibition of URAT1 by dotinurad for metabolic syndrome, chronic kidney disease (CKD), and cardiovascular disease (CVD). The selective inhibition of URAT1 by dotinurad increases urinary UA in the proximal tubules, and this un-reabsorbed UA may compete with urinary glucose for GLUT9, reducing glucose reabsorption. The inhibition by dotinurad of UA entry via URAT1 into the liver and adipose tissues increased energy expenditure and decreased lipid synthesis and inflammation in rats. Such effects may improve metabolic parameters. CKD patients accumulate uremic toxins, including indoxyl sulfate (IS), in the body. ABCG2 regulates the renal and intestinal excretion of IS, which strongly affects CKD. OAT1/3 inhibitors suppress IS uptake into the kidneys, thereby increasing plasma IS, which produces oxidative stress and induces vascular endothelial dysfunction in CKD patients. The highly selective inhibition of URAT1 by dotinurad may be beneficial for metabolic syndrome, CKD, and CVD. Full article
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16 pages, 792 KiB  
Review
Proximity-Induced Pharmacology for Amyloid-Related Diseases
by Andrea Bertran-Mostazo, Gabrielė Putriūtė, Irene Álvarez-Berbel, Maria Antònia Busquets, Carles Galdeano, Alba Espargaró and Raimon Sabate
Cells 2024, 13(5), 449; https://doi.org/10.3390/cells13050449 - 04 Mar 2024
Viewed by 921
Abstract
Proximity-induced pharmacology (PIP) for amyloid-related diseases is a cutting-edge approach to treating conditions such as Alzheimer’s disease and other forms of dementia. By bringing small molecules close to amyloid-related proteins, these molecules can induce a plethora of effects that can break down pathogenic [...] Read more.
Proximity-induced pharmacology (PIP) for amyloid-related diseases is a cutting-edge approach to treating conditions such as Alzheimer’s disease and other forms of dementia. By bringing small molecules close to amyloid-related proteins, these molecules can induce a plethora of effects that can break down pathogenic proteins and reduce the buildup of plaques. One of the most promising aspects of this drug discovery modality is that it can be used to target specific types of amyloid proteins, such as the beta-amyloid protein that is commonly associated with Alzheimer’s disease. This level of specificity could allow for more targeted and effective treatments. With ongoing research and development, it is hoped that these treatments can be refined and optimized to provide even greater benefits to patients. As our understanding of the underlying mechanisms of these diseases continues to grow, proximity-induced pharmacology treatments may become an increasingly important tool in the fight against dementia and other related conditions. Full article
(This article belongs to the Special Issue Molecular Insights into Neurodegenerative Diseases)
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20 pages, 12815 KiB  
Article
GRAF1 Acts as a Downstream Mediator of Parkin to Regulate Mitophagy in Cardiomyocytes
by Qiang Zhu, Matthew E. Combs, Dawn E. Bowles, Ryan T. Gross, Michelle Mendiola Pla, Christopher P. Mack and Joan M. Taylor
Cells 2024, 13(5), 448; https://doi.org/10.3390/cells13050448 - 04 Mar 2024
Viewed by 1238
Abstract
Cardiomyocytes rely on proper mitochondrial homeostasis to maintain contractility and achieve optimal cardiac performance. Mitochondrial homeostasis is controlled by mitochondrial fission, fusion, and mitochondrial autophagy (mitophagy). Mitophagy plays a particularly important role in promoting the degradation of dysfunctional mitochondria in terminally differentiated cells. [...] Read more.
Cardiomyocytes rely on proper mitochondrial homeostasis to maintain contractility and achieve optimal cardiac performance. Mitochondrial homeostasis is controlled by mitochondrial fission, fusion, and mitochondrial autophagy (mitophagy). Mitophagy plays a particularly important role in promoting the degradation of dysfunctional mitochondria in terminally differentiated cells. However, the precise mechanisms by which this is achieved in cardiomyocytes remain opaque. Our study identifies GRAF1 as an important mediator in PINK1-Parkin pathway-dependent mitophagy. Depletion of GRAF1 (Arhgap26) in cardiomyocytes results in actin remodeling defects, suboptimal mitochondria clustering, and clearance. Mechanistically, GRAF1 promotes Parkin-LC3 complex formation and directs autophagosomes to damaged mitochondria. Herein, we found that these functions are regulated, at least in part, by the direct binding of GRAF1 to phosphoinositides (PI(3)P, PI(4)P, and PI(5)P) on autophagosomes. In addition, PINK1-dependent phosphorylation of Parkin promotes Parkin-GRAF1-LC3 complex formation, and PINK1-dependent phosphorylation of GRAF1 (on S668 and S671) facilitates the clustering and clearance of mitochondria. Herein, we developed new phosphor-specific antibodies to these sites and showed that these post-translational modifications are differentially modified in human hypertrophic cardiomyopathy and dilated cardiomyopathy. Furthermore, our metabolic studies using serum collected from isoproterenol-treated WT and GRAF1CKO mice revealed defects in mitophagy-dependent cardiomyocyte fuel flexibility that have widespread impacts on systemic metabolism. In summary, our study reveals that GRAF1 co-regulates actin and membrane dynamics to promote cardiomyocyte mitophagy and that dysregulation of GRAF1 post-translational modifications may underlie cardiac disease pathogenesis. Full article
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32 pages, 3539 KiB  
Review
Emerging Role of Autophagy in Governing Cellular Dormancy, Metabolic Functions, and Therapeutic Responses of Cancer Stem Cells
by Meenakshi Tiwari, Pransu Srivastava, Sabiya Abbas, Janani Jegatheesan, Ashish Ranjan, Sadhana Sharma, Ved Prakash Maurya, Ajit Kumar Saxena and Lokendra Kumar Sharma
Cells 2024, 13(5), 447; https://doi.org/10.3390/cells13050447 - 04 Mar 2024
Viewed by 1085
Abstract
Tumors are composed of heterogeneous populations of dysregulated cells that grow in specialized niches that support their growth and maintain their properties. Tumor heterogeneity and metastasis are among the major hindrances that exist while treating cancer patients, leading to poor clinical outcomes. Although [...] Read more.
Tumors are composed of heterogeneous populations of dysregulated cells that grow in specialized niches that support their growth and maintain their properties. Tumor heterogeneity and metastasis are among the major hindrances that exist while treating cancer patients, leading to poor clinical outcomes. Although the factors that determine tumor complexity remain largely unknown, several genotypic and phenotypic changes, including DNA mutations and metabolic reprograming provide cancer cells with a survival advantage over host cells and resistance to therapeutics. Furthermore, the presence of a specific population of cells within the tumor mass, commonly known as cancer stem cells (CSCs), is thought to initiate tumor formation, maintenance, resistance, and recurrence. Therefore, these CSCs have been investigated in detail recently as potential targets to treat cancer and prevent recurrence. Understanding the molecular mechanisms involved in CSC proliferation, self-renewal, and dormancy may provide important clues for developing effective therapeutic strategies. Autophagy, a catabolic process, has long been recognized to regulate various physiological and pathological processes. In addition to regulating cancer cells, recent studies have identified a critical role for autophagy in regulating CSC functions. Autophagy is activated under various adverse conditions and promotes cellular maintenance, survival, and even cell death. Thus, it is intriguing to address whether autophagy promotes or inhibits CSC functions and whether autophagy modulation can be used to regulate CSC functions, either alone or in combination. This review describes the roles of autophagy in the regulation of metabolic functions, proliferation and quiescence of CSCs, and its role during therapeutic stress. The review further highlights the autophagy-associated pathways that could be used to regulate CSCs. Overall, the present review will help to rationalize various translational approaches that involve autophagy-mediated modulation of CSCs in controlling cancer progression, metastasis, and recurrence. Full article
(This article belongs to the Special Issue Metabolic Regulation of Stem Cell Behavior, Function and Aging)
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17 pages, 4069 KiB  
Article
Coupling of a Major Allergen to the Surface of Immune Cells for Use in Prophylactic Cell Therapy for the Prevention of IgE-Mediated Allergy
by Konstantinos Mengrelis, Gerhard Niederacher, Lisa Prickler, Verena Kainz, Anna Marianne Weijler, Elisa Rudolph, Victoria Stanek, Julia Eckl-Dorna, Ulrike Baranyi, Andreas Spittler, Margarete Focke-Tejkl, Barbara Bohle, Rudolf Valenta, Christian Friedrich Wilhelm Becker, Thomas Wekerle and Birgit Linhart
Cells 2024, 13(5), 446; https://doi.org/10.3390/cells13050446 - 03 Mar 2024
Viewed by 795
Abstract
Up to a third of the world’s population suffers from allergies, yet the effectiveness of available preventative measures remains, at large, poor. Consequently, the development of successful prophylactic strategies for the induction of tolerance against allergens is crucial. In proof-of-concept studies, our laboratory [...] Read more.
Up to a third of the world’s population suffers from allergies, yet the effectiveness of available preventative measures remains, at large, poor. Consequently, the development of successful prophylactic strategies for the induction of tolerance against allergens is crucial. In proof-of-concept studies, our laboratory has previously shown that the transfer of autologous hematopoietic stem cells (HSC) or autologous B cells expressing a major grass pollen allergen, Phl p 5, induces robust tolerance in mice. However, eventual clinical translation would require safe allergen expression without the need for retroviral transduction. Therefore, we aimed to chemically couple Phl p 5 to the surface of leukocytes and tested their ability to induce tolerance. Phl p 5 was coupled by two separate techniques, either by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) or by linkage via a lipophilic anchor, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol)-maleimide (DSPE-PEG-Mal). The effectiveness was assessed in fresh and cultured Phl p 5-coupled cells by flow cytometry, image cytometry, and immunofluorescence microscopy. Chemical coupling of Phl p 5 using EDC was robust but was followed by rapid apoptosis. DSPE-PEG-Mal-mediated linkage was also strong, but antigen levels declined due to antigen internalization. Cells coupled with Phl p 5 by either method were transferred into autologous mice. While administration of EDC-coupled splenocytes together with short course immunosuppression initially reduced Phl p 5-specific antibody levels to a moderate degree, both methods did not induce sustained tolerance towards Phl p 5 upon several subcutaneous immunizations with the allergen. Overall, our results demonstrate the successful chemical linkage of an allergen to leukocytes using two separate techniques, eliminating the risks of genetic modifications. More durable surface expression still needs to be achieved for use in prophylactic cell therapy protocols. Full article
(This article belongs to the Section Cellular Immunology)
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24 pages, 5762 KiB  
Article
Exploiting Leishmania—Primed Dendritic Cells as Potential Immunomodulators of Canine Immune Response
by Ana Valério-Bolas, Mafalda Meunier, Joana Palma-Marques, Armanda Rodrigues, Ana Margarida Santos, Telmo Nunes, Rui Ferreira, Ana Armada, João Carlos Alves, Wilson Antunes, Inês Cardoso, Sofia Mesquita-Gabriel, Lis Lobo, Graça Alexandre-Pires, Luís Marques, Isabel Pereira da Fonseca and Gabriela Santos-Gomes
Cells 2024, 13(5), 445; https://doi.org/10.3390/cells13050445 - 03 Mar 2024
Viewed by 922
Abstract
Dendritic cells (DCs) capture pathogens and process antigens, playing a crucial role in activating naïve T cells, bridging the gap between innate and acquired immunity. However, little is known about DC activation when facing Leishmania parasites. Thus, this study investigates in vitro activity [...] Read more.
Dendritic cells (DCs) capture pathogens and process antigens, playing a crucial role in activating naïve T cells, bridging the gap between innate and acquired immunity. However, little is known about DC activation when facing Leishmania parasites. Thus, this study investigates in vitro activity of canine peripheral blood-derived DCs (moDCs) exposed to L. infantum and L. amazonensis parasites and their extracellular vesicles (EVs). L. infantum increased toll-like receptor 4 gene expression in synergy with nuclear factor κB activation and the generation of pro-inflammatory cytokines. This parasite also induced the expression of class II molecules of major histocompatibility complex (MHC) and upregulated co-stimulatory molecule CD86, which, together with the release of chemokine CXCL16, can attract and help in T lymphocyte activation. In contrast, L. amazonensis induced moDCs to generate a mix of pro- and anti-inflammatory cytokines, indicating that this parasite can establish a different immune relationship with DCs. EVs promoted moDCs to express class I MHC associated with the upregulation of co-stimulatory molecules and the release of CXCL16, suggesting that EVs can modulate moDCs to attract cytotoxic CD8+ T cells. Thus, these parasites and their EVs can shape DC activation. A detailed understanding of DC activation may open new avenues for the development of advanced leishmaniasis control strategies. Full article
(This article belongs to the Special Issue Dendritic Cells in Health and Disease)
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20 pages, 19309 KiB  
Article
Amygdalin Alleviates DSS-Induced Colitis by Restricting Cell Death and Inflammatory Response, Maintaining the Intestinal Barrier, and Modulating Intestinal Flora
by Dianwen Xu, Yachun Xie, Ji Cheng, Dewei He, Juxiong Liu, Shoupeng Fu and Guiqiu Hu
Cells 2024, 13(5), 444; https://doi.org/10.3390/cells13050444 - 03 Mar 2024
Viewed by 975
Abstract
Inflammatory bowel disease (IBD) refers to a cluster of intractable gastrointestinal disorders with an undetermined etiology and a lack of effective therapeutic agents. Amygdalin (Amy) is a glycoside extracted from the seeds of apricot and other Rosaceae plants and it exhibits a wide [...] Read more.
Inflammatory bowel disease (IBD) refers to a cluster of intractable gastrointestinal disorders with an undetermined etiology and a lack of effective therapeutic agents. Amygdalin (Amy) is a glycoside extracted from the seeds of apricot and other Rosaceae plants and it exhibits a wide range of pharmacological properties. Here, the effects and mechanisms of Amy on colitis were examined via 16S rRNA sequencing, ELISA, transmission electron microscopy, Western blot, and immunofluorescence. The results showed that Amy administration remarkably attenuated the signs of colitis (reduced body weight, increased disease activity index, and shortened colon length) and histopathological damage in dextran sodium sulfate (DSS)-challenged mice. Further studies revealed that Amy administration significantly diminished DSS-triggered gut barrier dysfunction by lowering pro-inflammatory mediator levels, inhibiting oxidative stress, and reducing intestinal epithelial apoptosis and ferroptosis. Notably, Amy administration remarkably lowered DSS-triggered TLR4 expression and the phosphorylation of proteins related to the NF-κB and MAPK pathways. Furthermore, Amy administration modulated the balance of intestinal flora, including a selective rise in the abundance of S24-7 and a decline in the abundance of Allobaculum, Oscillospira, Bacteroides, Sutterella, and Shigella. In conclusion, Amy can alleviate colitis, which provides data to support the utility of Amy in combating IBD. Full article
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20 pages, 3888 KiB  
Review
Scarring and Skin Fibrosis Reversal with Regenerative Surgery and Stem Cell Therapy
by Aurora Almadori and Peter EM Butler
Cells 2024, 13(5), 443; https://doi.org/10.3390/cells13050443 - 03 Mar 2024
Viewed by 1306
Abstract
Skin scarring and fibrosis affect millions of people worldwide, representing a serious clinical problem causing physical and psychological challenges for patients. Stem cell therapy and regenerative surgery represent a new area of treatment focused on promoting the body’s natural ability to repair damaged [...] Read more.
Skin scarring and fibrosis affect millions of people worldwide, representing a serious clinical problem causing physical and psychological challenges for patients. Stem cell therapy and regenerative surgery represent a new area of treatment focused on promoting the body’s natural ability to repair damaged tissue. Adipose-derived stem cells (ASCs) represent an optimal choice for practical regenerative medicine due to their abundance, autologous tissue origin, non-immunogenicity, and ease of access with minimal morbidity for patients. This review of the literature explores the current body of evidence around the use of ASCs-based regenerative strategies for the treatment of scarring and skin fibrosis, exploring the different surgical approaches and their application in multiple fibrotic skin conditions. Human, animal, and in vitro studies demonstrate that ASCs present potentialities in modifying scar tissue and fibrosis by suppressing extracellular matrix (ECM) synthesis and promoting the degradation of their constituents. Through softening skin fibrosis, function and overall quality of life may be considerably enhanced in different patient cohorts presenting with scar-related symptoms. The use of stem cell therapies for skin scar repair and regeneration represents a paradigm shift, offering potential alternative therapeutic avenues for fibrosis, a condition that currently lacks a cure. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Organ Fibrosis)
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13 pages, 1399 KiB  
Article
Examining the Relationship between Systemic Immune–Inflammation Index and Disease Severity in Juvenile Idiopathic Arthritis
by Delia-Maria Nicoară, Andrei-Ioan Munteanu, Alexandra-Cristina Scutca, Giorgiana-Flavia Brad, Iulius Jugănaru, Meda-Ada Bugi, Raluca Asproniu and Otilia Mărginean
Cells 2024, 13(5), 442; https://doi.org/10.3390/cells13050442 - 03 Mar 2024
Viewed by 893
Abstract
Juvenile Idiopathic Arthritis (JIA), the leading childhood rheumatic condition, has a chronic course in which persistent disease activity leads to long-term consequences. In the era of biologic therapy and tailored treatment, precise disease activity assessment and aggressive intervention for high disease activity are [...] Read more.
Juvenile Idiopathic Arthritis (JIA), the leading childhood rheumatic condition, has a chronic course in which persistent disease activity leads to long-term consequences. In the era of biologic therapy and tailored treatment, precise disease activity assessment and aggressive intervention for high disease activity are crucial for improved outcomes. As inflammation is a fundamental aspect of JIA, evaluating it reflects disease severity. Recently, there has been growing interest in investigating cellular immune inflammation indices such as the neutrophil-to-lymphocyte ratio (NLR) and systemic immune inflammation index (SII) as measures of disease severity. The aim of this retrospective study was to explore the potential of the SII in reflecting both inflammation and disease severity in children with JIA. The study comprised 74 JIA patients and 50 healthy controls. The results reveal a notable increase in median SII values corresponding to disease severity, exhibiting strong correlations with traditional inflammatory markers, including CRP and ESR (ρ = 0.714, ρ = 0.661), as well as the JADAS10 score (ρ = 0.690). Multiple regression analysis revealed the SII to be independently associated with JADAS10. Furthermore, the SII accurately distinguished patients with high disease activity from other severity groups (AUC = 0.827, sensitivity 81.5%, specificity 66%). These findings suggest that integrating the SII as an additional measure holds potential for assessing disease activity in JIA. Full article
(This article belongs to the Special Issue Advances in Arthritis: Focusing on Immune Cells and Targeted Therapy)
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24 pages, 3344 KiB  
Review
The Role of Oxidative Stress in Tumorigenesis and Progression
by Kexin Li, Zhangyuzi Deng, Chunran Lei, Xiaoqing Ding, Jing Li and Changshan Wang
Cells 2024, 13(5), 441; https://doi.org/10.3390/cells13050441 - 02 Mar 2024
Viewed by 1160
Abstract
Oxidative stress refers to the imbalance between the production of reactive oxygen species (ROS) and the endogenous antioxidant defense system. Its involvement in cell senescence, apoptosis, and series diseases has been demonstrated. Advances in carcinogenic research have revealed oxidative stress as a pivotal [...] Read more.
Oxidative stress refers to the imbalance between the production of reactive oxygen species (ROS) and the endogenous antioxidant defense system. Its involvement in cell senescence, apoptosis, and series diseases has been demonstrated. Advances in carcinogenic research have revealed oxidative stress as a pivotal pathophysiological pathway in tumorigenesis and to be involved in lung cancer, glioma, hepatocellular carcinoma, leukemia, and so on. This review combs the effects of oxidative stress on tumorigenesis on each phase and cell fate determination, and three features are discussed. Oxidative stress takes part in the processes ranging from tumorigenesis to tumor death via series pathways and processes like mitochondrial stress, endoplasmic reticulum stress, and ferroptosis. It can affect cell fate by engaging in the complex relationships between senescence, death, and cancer. The influence of oxidative stress on tumorigenesis and progression is a multi-stage interlaced process that includes two aspects of promotion and inhibition, with mitochondria as the core of regulation. A deeper and more comprehensive understanding of the effects of oxidative stress on tumorigenesis is conducive to exploring more tumor therapies. Full article
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21 pages, 2700 KiB  
Article
Alcohol Exposure Induces Nucleolar Stress and Apoptosis in Mouse Neural Stem Cells and Late-Term Fetal Brain
by Yanping Huang, George R. Flentke, Olivia C. Rivera, Nipun Saini, Sandra M. Mooney and Susan M. Smith
Cells 2024, 13(5), 440; https://doi.org/10.3390/cells13050440 - 02 Mar 2024
Viewed by 879
Abstract
Prenatal alcohol exposure (PAE) is a leading cause of neurodevelopmental disability through its induction of neuronal growth dysfunction through incompletely understood mechanisms. Ribosome biogenesis regulates cell cycle progression through p53 and the nucleolar cell stress response. Whether those processes are targeted by alcohol [...] Read more.
Prenatal alcohol exposure (PAE) is a leading cause of neurodevelopmental disability through its induction of neuronal growth dysfunction through incompletely understood mechanisms. Ribosome biogenesis regulates cell cycle progression through p53 and the nucleolar cell stress response. Whether those processes are targeted by alcohol is unknown. Pregnant C57BL/6J mice received 3 g alcohol/kg daily at E8.5–E17.5. Transcriptome sequencing was performed on the E17.5 fetal cortex. Additionally, primary neural stem cells (NSCs) were isolated from the E14.5 cerebral cortex and exposed to alcohol to evaluate nucleolar stress and p53/MDM2 signaling. Alcohol suppressed KEGG pathways involving ribosome biogenesis (rRNA synthesis/processing and ribosomal proteins) and genes that are mechanistic in ribosomopathies (Polr1d, Rpl11; Rpl35; Nhp2); this was accompanied by nucleolar dissolution and p53 stabilization. In primary NSCs, alcohol reduced rRNA synthesis, caused nucleolar loss, suppressed proliferation, stabilized nuclear p53, and caused apoptosis that was prevented by dominant-negative p53 and MDM2 overexpression. Alcohol’s actions were dose-dependent and rapid, and rRNA synthesis was suppressed between 30 and 60 min following alcohol exposure. The alcohol-mediated deficits in ribosomal protein expression were correlated with fetal brain weight reductions. This is the first report describing that pharmacologically relevant alcohol levels suppress ribosome biogenesis, induce nucleolar stress in neuronal populations, and involve the ribosomal/MDM2/p53 pathway to cause growth arrest and apoptosis. This represents a novel mechanism of alcohol-mediated neuronal damage. Full article
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34 pages, 2584 KiB  
Review
Advances and Challenges in Sepsis Management: Modern Tools and Future Directions
by Elena Santacroce, Miriam D’Angerio, Alin Liviu Ciobanu, Linda Masini, Domenico Lo Tartaro, Irene Coloretti, Stefano Busani, Ignacio Rubio, Marianna Meschiari, Erica Franceschini, Cristina Mussini, Massimo Girardis, Lara Gibellini, Andrea Cossarizza and Sara De Biasi
Cells 2024, 13(5), 439; https://doi.org/10.3390/cells13050439 - 02 Mar 2024
Cited by 1 | Viewed by 3108
Abstract
Sepsis, a critical condition marked by systemic inflammation, profoundly impacts both innate and adaptive immunity, often resulting in lymphopenia. This immune alteration can spare regulatory T cells (Tregs) but significantly affects other lymphocyte subsets, leading to diminished effector functions, altered cytokine profiles, and [...] Read more.
Sepsis, a critical condition marked by systemic inflammation, profoundly impacts both innate and adaptive immunity, often resulting in lymphopenia. This immune alteration can spare regulatory T cells (Tregs) but significantly affects other lymphocyte subsets, leading to diminished effector functions, altered cytokine profiles, and metabolic changes. The complexity of sepsis stems not only from its pathophysiology but also from the heterogeneity of patient responses, posing significant challenges in developing universally effective therapies. This review emphasizes the importance of phenotyping in sepsis to enhance patient-specific diagnostic and therapeutic strategies. Phenotyping immune cells, which categorizes patients based on clinical and immunological characteristics, is pivotal for tailoring treatment approaches. Flow cytometry emerges as a crucial tool in this endeavor, offering rapid, low cost and detailed analysis of immune cell populations and their functional states. Indeed, this technology facilitates the understanding of immune dysfunctions in sepsis and contributes to the identification of novel biomarkers. Our review underscores the potential of integrating flow cytometry with omics data, machine learning and clinical observations to refine sepsis management, highlighting the shift towards personalized medicine in critical care. This approach could lead to more precise interventions, improving outcomes in this heterogeneously affected patient population. Full article
(This article belongs to the Special Issue The Applications of Flow Cytometry: Advances, Challenges, and Trends)
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17 pages, 2487 KiB  
Review
Exploring Extracellular Matrix Crosslinking as a Therapeutic Approach to Fibrosis
by Sarah M. Lloyd and Yupeng He
Cells 2024, 13(5), 438; https://doi.org/10.3390/cells13050438 - 02 Mar 2024
Viewed by 917
Abstract
The extracellular matrix (ECM) provides structural support for tissues and regulatory signals for resident cells. ECM requires a careful balance between protein accumulation and degradation for homeostasis. Disruption of this balance can lead to pathological processes such as fibrosis in organs across the [...] Read more.
The extracellular matrix (ECM) provides structural support for tissues and regulatory signals for resident cells. ECM requires a careful balance between protein accumulation and degradation for homeostasis. Disruption of this balance can lead to pathological processes such as fibrosis in organs across the body. Post-translational crosslinking modifications to ECM proteins such as collagens alter ECM structure and function. Dysregulation of crosslinking enzymes as well as changes in crosslinking composition are prevalent in fibrosis. Because of the crucial roles these ECM crosslinking pathways play in disease, the enzymes that govern crosslinking events are being explored as therapeutic targets for fibrosis. Here, we review in depth the molecular mechanisms underlying ECM crosslinking, how ECM crosslinking contributes to fibrosis, and the therapeutic strategies being explored to target ECM crosslinking in fibrosis to restore normal tissue structure and function. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Organ Fibrosis)
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18 pages, 8893 KiB  
Article
GLA Mutations Suppress Autophagy and Stimulate Lysosome Generation in Fabry Disease
by Ping Li, Yuqian Xi, Yanping Zhang, Abdus Samad, Wenli Lan, Ya Wu, Jiayu Zhao, Guangxin Chen, Changxin Wu and Qiuhong Xiong
Cells 2024, 13(5), 437; https://doi.org/10.3390/cells13050437 - 01 Mar 2024
Viewed by 817
Abstract
Fabry disease (FD) is an X-linked recessive inheritance lysosomal storage disorder caused by pathogenic mutations in the GLA gene leading to a deficiency of the enzyme alpha-galactosidase A (α-Gal A). Multiple organ systems are implicated in FD, most notably the kidney, heart, and [...] Read more.
Fabry disease (FD) is an X-linked recessive inheritance lysosomal storage disorder caused by pathogenic mutations in the GLA gene leading to a deficiency of the enzyme alpha-galactosidase A (α-Gal A). Multiple organ systems are implicated in FD, most notably the kidney, heart, and central nervous system. In our previous study, we identified four GLA mutations from four independent Fabry disease families with kidney disease or neuropathic pain: c.119C>A (p.P40H), c.280T>C (C94R), c.680G>C (p.R227P) and c.801+1G>A (p.L268fsX3). To reveal the molecular mechanism underlying the predisposition to Fabry disease caused by GLA mutations, we analyzed the effects of these four GLA mutations on the protein structure of α-galactosidase A using bioinformatics methods. The results showed that these mutations have a significant impact on the internal dynamics and structures of GLA, and all these altered amino acids are close to the enzyme activity center and lead to significantly reduced enzyme activity. Furthermore, these mutations led to the accumulation of autophagosomes and impairment of autophagy in the cells, which may in turn negatively regulate autophagy by slightly increasing the phosphorylation of mTOR. Moreover, the overexpression of these GLA mutants promoted the expression of lysosome-associated membrane protein 2 (LAMP2), resulting in an increased number of lysosomes. Our study reveals the pathogenesis of these four GLA mutations in FD and provides a scientific foundation for accurate diagnosis and precise medical intervention for FD. Full article
(This article belongs to the Special Issue Autophagy in Kidney Homeostasis and Disease)
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22 pages, 1765 KiB  
Review
Cutting-Edge Therapies for Lung Cancer
by Anita Silas La’ah and Shih-Hwa Chiou
Cells 2024, 13(5), 436; https://doi.org/10.3390/cells13050436 - 01 Mar 2024
Viewed by 1162
Abstract
Lung cancer remains a formidable global health challenge that necessitates inventive strategies to improve its therapeutic outcomes. The conventional treatments, including surgery, chemotherapy, and radiation, have demonstrated limitations in achieving sustained responses. Therefore, exploring novel approaches encompasses a range of interventions that show [...] Read more.
Lung cancer remains a formidable global health challenge that necessitates inventive strategies to improve its therapeutic outcomes. The conventional treatments, including surgery, chemotherapy, and radiation, have demonstrated limitations in achieving sustained responses. Therefore, exploring novel approaches encompasses a range of interventions that show promise in enhancing the outcomes for patients with advanced or refractory cases of lung cancer. These groundbreaking interventions can potentially overcome cancer resistance and offer personalized solutions. Despite the rapid evolution of emerging lung cancer therapies, persistent challenges such as resistance, toxicity, and patient selection underscore the need for continued development. Consequently, the landscape of lung cancer therapy is transforming with the introduction of precision medicine, immunotherapy, and innovative therapeutic modalities. Additionally, a multifaceted approach involving combination therapies integrating targeted agents, immunotherapies, or traditional cytotoxic treatments addresses the heterogeneity of lung cancer while minimizing its adverse effects. This review provides a brief overview of the latest emerging therapies that are reshaping the landscape of lung cancer treatment. As these novel treatments progress through clinical trials are integrated into standard care, the potential for more effective, targeted, and personalized lung cancer therapies comes into focus, instilling renewed hope for patients facing challenging diagnoses. Full article
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16 pages, 860 KiB  
Review
Cellular and Noncellular Approaches for Repairing the Damaged Blood–CNS–Barrier in Amyotrophic Lateral Sclerosis
by Larai Manora, Cesario V. Borlongan and Svitlana Garbuzova-Davis
Cells 2024, 13(5), 435; https://doi.org/10.3390/cells13050435 - 29 Feb 2024
Viewed by 943
Abstract
Numerous reports have demonstrated the breakdown of the blood–CNS barrier (B-CNS-B) in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease. Re-establishing barrier integrity in the CNS is critical to prevent further motor neuron degeneration from harmful components in systemic circulation. Potential therapeutic strategies [...] Read more.
Numerous reports have demonstrated the breakdown of the blood–CNS barrier (B-CNS-B) in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease. Re-establishing barrier integrity in the CNS is critical to prevent further motor neuron degeneration from harmful components in systemic circulation. Potential therapeutic strategies for repairing the B-CNS-B may be achieved by the replacement of damaged endothelial cells (ECs) via stem cell administration or enhancement of endogenous EC survival through the delivery of bioactive particles secreted by stem cells. These cellular and noncellular approaches are thoroughly discussed in the present review. Specific attention is given to certain stem cell types for EC replacement. Also, various nanoparticles secreted by stem cells as well as other biomolecules are elucidated as promising agents for endogenous EC repair. Although the noted in vitro and in vivo studies show the feasibility of the proposed therapeutic approaches to the repair of the B-CNS-B in ALS, further investigation is needed prior to clinical transition. Full article
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