Cells

13 pages, 962 KiB

Open AccessArticle

Exosomal MALAT1 from Rapid Electrical Stimulation-Treated Atrial Fibroblasts Enhances Sox-6 Expression by Downregulating miR-499a-5p

by Cheng-Yen Chuang, Bao-Wei Wang, Ying-Ju Yu, Wei-Jen Fang, Chiu-Mei Lin, Kou-Gi Shyu and Su-Kiat Chua

Cells 2024, 13(23), 1942; https://doi.org/10.3390/cells13231942 - 22 Nov 2024

Abstract

Background: Atrial fibrillation (AF) is a common cardiac arrhythmia associated with significant morbidity and mortality. Rapid electrical stimulation (RES) of atrial fibroblasts plays a crucial role in AF pathogenesis, but the underlying molecular mechanisms remain unclear. This study investigates the regulatory axis involving [...] Read more.

Background: Atrial fibrillation (AF) is a common cardiac arrhythmia associated with significant morbidity and mortality. Rapid electrical stimulation (RES) of atrial fibroblasts plays a crucial role in AF pathogenesis, but the underlying molecular mechanisms remain unclear. This study investigates the regulatory axis involving MALAT1, miR-499a-5p, and SOX6 in human cardiac fibroblasts from adult atria (HCF-aa) under RES conditions. Methods: HCF-aa were subjected to RES at 0.5V/cm and 10 Hz. The expression levels of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), miR-499a-5p, and SRY-Box Transcription Factor 6 (SOX6) were measured using qPCR and Western blot analyses. Luciferase reporter assays were performed to confirm target relationships. The effects of MALAT1 siRNA, miR-499a-5p mimics/inhibitors, and SOX6 overexpression on gene expression and apoptosis were assessed. Results: RES increased exosomal MALAT1 expression, peaking at 2 h. MiR-499a-5p levels initially increased, then decreased at 2 h, coinciding with peak MALAT1 expression. SOX6 mRNA and protein levels increased, peaking at 4 and 6 h, respectively. Luciferase assays confirmed MALAT1 and SOX6 as miR-499a-5p targets. MALAT1 knockdown increased miR-499a-5p levels and reduced SOX6 expression. MiR-499a-5p overexpression decreased SOX6 levels and inhibited RES-induced apoptosis. Conclusion: In HCF-aa under RES, increased exosomal MALAT1 expression counteracts miR-499-5p’s suppression of SOX6, suggesting that MALAT1-containing exsosomes derived from HCF-aa may offer a novel cell-free therapeutic approach for AF. Full article

(This article belongs to the Collection Cardiovascular Disease: From Molecular and Cellular Mechanisms to Therapeutic Opportunities)

30 pages, 1068 KiB

Open AccessArticle

Peripheral Blood Leukocyte Subpopulation Changes in Reaction to an Acute Psychosocial Stressor as Compared to an Active Placebo-Stressor in Healthy Young Males: Mediating Effects of Major Stress-Reactive Endocrine Parameters

by Lisa-Marie Walther, Angelina Gideon, Christine Sauter, Marcel Leist and Petra H. Wirtz

Cells 2024, 13(23), 1941; https://doi.org/10.3390/cells13231941 - 22 Nov 2024

Abstract

Psychosocial stress has been proposed to induce a redistribution of immune cells, but a comparison with an active placebo-psychosocial stress control condition is lacking so far. We investigated immune cell redistribution due to psychosocial stress compared to that resulting from an active placebo-psychosocial [...] Read more.

Psychosocial stress has been proposed to induce a redistribution of immune cells, but a comparison with an active placebo-psychosocial stress control condition is lacking so far. We investigated immune cell redistribution due to psychosocial stress compared to that resulting from an active placebo-psychosocial stress but otherwise identical control condition. Moreover, we tested for mediating effects of endocrine parameters and blood volume changes. The final study sample comprised 64 healthy young men who underwent either a psychosocial stress condition (Trier Social Stress Test; TSST; n = 38) or an active placebo-psychosocial stress control condition (PlacTSST; n = 26). Immune cell counts and hemoglobin, epinephrine, norepinephrine, ACTH, renin, and aldosterone levels, as well as those of saliva cortisol, were determined before and up to 30 min after the TSST/PlacTSST. The TSST induced greater increases in total leukocyte, monocyte, and lymphocyte levels as compared to the PlacTSST (p’s ≤ 0.001), but in not granulocyte counts. Neutrophil granulocyte counts increased in reaction to both the TSST and PlacTSST (p’s ≤ 0.001), while eosinophil and basophil granulocyte counts did not. The psychosocial stress-induced increases in immune cell counts from baseline to peak (i.e., +1 min after TSST cessation) were independently mediated by parallel increases in epinephrine (ab’s ≤ −0.43; 95% CIs [LLs ≤ −0.66; ULs ≤ −0.09]). Subsequent decreases in immune cell counts from +1 min to +10 min after psychosocial stress cessation were mediated by parallel epinephrine, renin, and blood volume decreases (ab’s ≥ 0.17; 95% CIs [LLs ≥ 0.02; ULs ≥ 0.35]). Our findings indicate that psychosocial stress specifically induces immune cell count increases in most leukocyte subpopulations that are not secondary to the physical or cognitive demands of the stress task. Increases in the number of circulating neutrophil granulocytes, however, are not psychosocial stress-specific and even occur in situations with a low probability of threat or harm. Our findings point to a major role of epinephrine in mediating stress-induced immune cell count increases and of epinephrine, renin, and blood volume changes in mediating subsequent immune cell count decreases from +1 min to +10 min after psychosocial stress cessation. Full article

(This article belongs to the Special Issue Innate Immunity in Health and Disease)

42 pages, 2107 KiB

Open AccessReview

Impact of Physical Activity on Cellular Metabolism Across Both Neurodegenerative and General Neurological Conditions: A Narrative Review

by Vicente Javier Clemente-Suárez, Alejandro Rubio-Zarapuz, Pedro Belinchón-deMiguel, Ana Isabel Beltrán-Velasco, Alexandra Martín-Rodríguez and José Francisco Tornero-Aguilera

Cells 2024, 13(23), 1940; https://doi.org/10.3390/cells13231940 - 22 Nov 2024

Abstract

Background: Regular physical activity plays a crucial role in modulating cellular metabolism and mitigating the progression of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Multiple Sclerosis. Objective: The objective of this review is to evaluate the molecular mechanisms by which exercise influences cellular [...] Read more.

Background: Regular physical activity plays a crucial role in modulating cellular metabolism and mitigating the progression of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Multiple Sclerosis. Objective: The objective of this review is to evaluate the molecular mechanisms by which exercise influences cellular metabolism, with a focus on its potential as a therapeutic intervention for neurological disorders. Methods: A comprehensive literature review was conducted using peer-reviewed scientific articles, with a focus on the period between 2015 and 2024, to analyze the effects of exercise on mitochondrial function, oxidative stress, and metabolic health. Results: The findings indicate that exercise promotes mitochondrial biogenesis, enhances oxidative phosphorylation, and reduces reactive oxygen species, contributing to improved energy production and cellular resilience. These metabolic adaptations are associated with delayed disease progression and reduced symptoms in patients with neurodegenerative conditions. Additionally, integrating exercise with nutritional strategies may further enhance therapeutic outcomes by addressing metabolic disturbances comprehensively. Conclusion: This review concludes that personalized exercise protocols should be developed to optimize metabolic benefits for patients with neurological diseases, while future research should focus on biomarker development for individualized treatment approaches. These findings highlight the importance of non-pharmacological interventions in managing neurodegenerative diseases. Full article

(This article belongs to the Special Issue Cell-to-Cell Crosstalk as a Target of Therapies)

17 pages, 8975 KiB

Open AccessArticle

A Novel Class of FKBP12 Ligands Rescues Premature Aging Phenotypes Associated with Myotonic Dystrophy Type 1

by Mikel García-Puga, Gorka Gerenu, Ariadna Bargiela, Jorge Espinosa-Espinosa, Laura Mosqueira-Martín, Maialen Sagartzazu-Aizpurua, Jesús M. Aizpurua, Ainara Vallejo-Illarramendi, Rubén Artero, Adolfo López de Munain and Ander Matheu

Cells 2024, 13(23), 1939; https://doi.org/10.3390/cells13231939 - 22 Nov 2024

Abstract

Background: Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder clinically characterized by progressive muscular weakness and multisystem degeneration, which correlates with the size of CTG expansion and MBLN decrease. These changes induce a calcium and redox homeostasis imbalance in several models [...] Read more.

Background: Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder clinically characterized by progressive muscular weakness and multisystem degeneration, which correlates with the size of CTG expansion and MBLN decrease. These changes induce a calcium and redox homeostasis imbalance in several models that recapitulate the features of premature tissue aging. In this study, we characterized the impact of a new family of FKBP12 ligands (generically named MPs or MP compounds) designed to stabilize FKBP12 binding to the ryanodine receptors and normalize calcium dysregulation under oxidative stress. Methods: Human primary fibroblasts from DM1 patients and control donors, treated with MP compounds or not, were used for functional studies of cell viability, proliferation, and metabolism. The gene expression profile in treated cells was determined using RNA sequencing. The impact of MP compounds in vivo was evaluated in a Drosophila model of the disease using locomotor activity and longevity studies. Results: The treatment with different MP compounds reversed oxidative stress and impaired cell viability and proliferation, mitochondrial activity, and metabolic defects in DM1-derived primary fibroblasts. RNA sequencing analysis confirmed the restoration of molecular pathways related to calcium and redox homeostasis and additional pathways, including the cell cycle and metabolism. This analysis also revealed the rescue of alternative splicing events in DM1 fibroblasts treated with MP compounds. Importantly, treatment with MP compounds significantly extended the lifespan and improved the locomotor activity of a Drosophila model of the DM1 disease, and restored molecular defects characteristic of the disease in vivo. Conclusions: Our results revealed that MP compounds rescue multiple premature aging phenotypes described in DM1 models and decipher the benefits of this new family of compounds in the pre-clinical setting of DM1. Full article

(This article belongs to the Collection Collection of Cell Aging—The Road Map of Aging)

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20 pages, 4672 KiB

Open AccessArticle

Investigation of Biological Activity of Fucoidan and Laminarin as Bioactive Polysaccharides from Irish Brown Macroalgae

by Shanmugapriya Karuppusamy, Janith Wanigasekara, Stephen Fitzpatrick, Henry Lyons, James Curtin, Gaurav Rajauria, Brijesh K. Tiwari and Colm O’Donnell

Cells 2024, 13(23), 1938; https://doi.org/10.3390/cells13231938 - 22 Nov 2024

Abstract

This study aimed to investigate the biological activity of crude and purified laminarin and fucoidan samples extracted from Irish brown macroalgae species Laminaria digitata and Fucus vesiculosus. The antioxidant capacity of the samples was evaluated using the 2,2-diphenyl-1-picrylhydrazyl and ferric-reducing antioxidant power [...] Read more.

This study aimed to investigate the biological activity of crude and purified laminarin and fucoidan samples extracted from Irish brown macroalgae species Laminaria digitata and Fucus vesiculosus. The antioxidant capacity of the samples was evaluated using the 2,2-diphenyl-1-picrylhydrazyl and ferric-reducing antioxidant power assays. The anti-inflammatory potential of the samples was analysed using the cyclooxygenases inhibition activity, and the antidiabetic activity was evaluated using a dipeptidyl peptidase-4 inhibitor screening assay. The cytotoxicity of the samples was measured using the Alamar Blue™ assay with different types of cancer cell lines. The crude laminarin and fucoidan samples exhibited higher antioxidant activity (p < 0.05) than the purified samples and commercial standards. Similarly, the crude extracts showed stronger anti-inflammatory and antidiabetic effects compared to the purified samples. Additionally, the crude laminarin and fucoidan samples showed higher cytotoxic activity. Specifically, as confirmed in the flow cytometry analysis, 3D tumour spheres using different cancer cell lines showed significantly higher resistance to bioactive compounds compared to 2D monolayer cells. The laminarin and fucoidan polysaccharide samples investigated are suitable for potential nutraceutical applications based on the biological activity values observed. Future research is necessary to purify the bioactive compounds investigated and improve their selectivity for targeted therapeutic uses in food and biomedical applications. Full article

(This article belongs to the Section Plant, Algae and Fungi Cell Biology)

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24 pages, 1241 KiB

Open AccessReview

Exploring the Immunoresponse in Bladder Cancer Immunotherapy

by Inmaculada Ruiz-Lorente, Lourdes Gimeno, Alicia López-Abad, Pedro López Cubillana, Tomás Fernández Aparicio, Lucas Jesús Asensio Egea, Juan Moreno Avilés, Gloria Doñate Iñiguez, Pablo Luis Guzmán Martínez-Valls, Gerardo Server, José Félix Escudero-Bregante, Belén Ferri, José Antonio Campillo, Eduardo Pons-Fuster, María Dolores Martínez Hernández, María Victoria Martínez-Sánchez, Diana Ceballos and Alfredo Minguela

Cells 2024, 13(23), 1937; https://doi.org/10.3390/cells13231937 - 22 Nov 2024

Abstract

Bladder cancer (BC) represents a wide spectrum of diseases, ranging from recurrent non-invasive tumors to advanced stages that require intensive treatments. BC accounts for an estimated 500,000 new cases and 200,000 deaths worldwide every year. Understanding the biology of BC has changed how [...] Read more.

Bladder cancer (BC) represents a wide spectrum of diseases, ranging from recurrent non-invasive tumors to advanced stages that require intensive treatments. BC accounts for an estimated 500,000 new cases and 200,000 deaths worldwide every year. Understanding the biology of BC has changed how this disease is diagnosed and treated. Bladder cancer is highly immunogenic, involving innate and adaptive components of the immune system. Although little is still known of how immune cells respond to BC, immunotherapy with bacillus Calmette–Guérin (BCG) remains the gold standard in high-risk non-muscle invasive BC. For muscle-invasive BC and metastatic stages, immune checkpoint inhibitors targeting CTLA-4, PD-1, and PD-L1 have emerged as potent therapies, enhancing immune surveillance and tumor cell elimination. This review aims to unravel the immune responses involving innate and adaptive immune cells in BC that will contribute to establishing new and promising therapeutic options, while reviewing the immunotherapies currently in use in bladder cancer. Full article

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Graphical abstract

23 pages, 3349 KiB

Open AccessArticle

Evidence for a Role of the Long Non-Coding RNA ITGB2-AS1 in Eosinophil Differentiation and Functions

by Timothée Fettrelet, Aref Hosseini, Jacqueline Wyss, Joanna Boros-Majewska, Darko Stojkov, Shida Yousefi and Hans-Uwe Simon

Cells 2024, 13(23), 1936; https://doi.org/10.3390/cells13231936 - 22 Nov 2024

Abstract

Eosinophils, a type of granulocyte derived from myeloid precursors in the bone marrow, are distinguished by their cytoplasmic granules. They play crucial roles in immunoregulation, tissue homeostasis, and host defense, while also contributing to the pathogenesis of various inflammatory diseases. Although long non-coding [...] Read more.

Eosinophils, a type of granulocyte derived from myeloid precursors in the bone marrow, are distinguished by their cytoplasmic granules. They play crucial roles in immunoregulation, tissue homeostasis, and host defense, while also contributing to the pathogenesis of various inflammatory diseases. Although long non-coding RNAs (lncRNAs) are known to be involved in eosinophilic conditions, their specific expression and functions within eosinophils have not been thoroughly investigated, largely due to the reliance on tissue homogenates. In an effort to address this gap, we analyzed publicly available high-throughput RNA sequencing data to identify lncRNAs associated with eosinophilic conditions. Among the identified lncRNAs, ITGB2 antisense RNA 1 (ITGB2-AS1) was significantly downregulated in blood eosinophils from patients with hypereosinophilia. To further explore its role in eosinophil biology, we generated a stable ITGB2-AS1 knockdown in the HL-60 cell line. Interestingly, ITGB2-AS1 deficiency led to impaired eosinophil differentiation, as evidenced by a reduction in cytoplasmic granules and decreased expression of key eosinophil granule proteins, including eosinophil peroxidase (EPX) and major basic protein-1 (MBP-1). Additionally, ITGB2-AS1-deficient cells exhibited compromised eosinophil effector functions, with reduced degranulation and impaired production of reactive oxygen species (ROS). These findings suggest that ITGB2-AS1 plays a pivotal role in eosinophil differentiation and function, positioning it as a novel regulator in eosinophil biology. Full article

(This article belongs to the Special Issue Eosinophils and Their Role in Allergy and Related Diseases)

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26 pages, 752 KiB

Open AccessReview

MicroRNAs and RNA-Binding Protein-Based Regulation of Bone Metastasis from Hepatobiliary Cancers and Potential Therapeutic Strategies

by Sharmila Fagoonee and Ralf Weiskirchen

Cells 2024, 13(23), 1935; https://doi.org/10.3390/cells13231935 - 21 Nov 2024

Abstract

Hepatobiliary cancers, such as hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are among the deadliest malignancies worldwide, leading to a significant number of cancer-related deaths. While bone metastases from these cancers are rare, they are highly aggressive and linked to poor prognosis. This review [...] Read more.

Hepatobiliary cancers, such as hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are among the deadliest malignancies worldwide, leading to a significant number of cancer-related deaths. While bone metastases from these cancers are rare, they are highly aggressive and linked to poor prognosis. This review focuses on RNA-based molecular mechanisms that contribute to bone metastasis from hepatobiliary cancers. Specifically, the role of two key factors, microRNAs (miRNAs) and RNA-binding proteins (RBPs), which have not been extensively studied in the context of HCC and CCA, is discussed. These molecules often exhibit abnormal expression in hepatobiliary tumors, influencing cancer cell spread and metastasis by disrupting bone homeostasis, thereby aiding tumor cell migration and survival in the bone microenvironment. This review also discusses potential therapeutic strategies targeting these RNA-based pathways to reduce bone metastasis and improve patient outcomes. Further research is crucial for developing effective miRNA- and RBP-based diagnostic and prognostic biomarkers and treatments to prevent bone metastases in hepatobiliary cancers. Full article

(This article belongs to the Special Issue Molecular Mechanism of Bone Disease)

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17 pages, 3224 KiB

Open AccessArticle

Impact of Nannochloropsis oceanica and Chlorococcum amblystomatis Extracts on UVA-Irradiated on 3D Cultured Melanoma Cells: A Proteomic Insight

by Agnieszka Gęgotek, Tiago Conde, Maria Rosário Domingues, Pedro Domingues and Elżbieta Skrzydlewska

Cells 2024, 13(23), 1934; https://doi.org/10.3390/cells13231934 - 21 Nov 2024

Abstract

Melanoma is one of the most malignant forms of skin cancer, characterised by the highest mortality rate among affected patients. This study aims to analyse and compare the effects of lipid extracts from the microalgae Nannochloropsis oceanica (N.o.) and Chlorococcum amblystomatis [...] Read more.

Melanoma is one of the most malignant forms of skin cancer, characterised by the highest mortality rate among affected patients. This study aims to analyse and compare the effects of lipid extracts from the microalgae Nannochloropsis oceanica (N.o.) and Chlorococcum amblystomatis (C.a.) on the intra and extracellular proteome of UVA-irradiated melanoma cells using a three-dimensional model. Proteomic analysis revealed that UVA radiation significantly increases the levels of pro-inflammatory proteins in melanoma cells. Treatment with algae extracts reduced these protein levels in both non-irradiated and irradiated cells. Furthermore, untreated cells released proteins responsible for cell growth and proliferation into the medium, a process hindered by UVA radiation through the promotion of pro-inflammatory molecules secretion. The treatment with algae extracts effectively mitigated UVA-induced alterations. Notably, UVA radiation significantly induced the formation of 4-HNE and 15-PGJ2 protein adducts in both cells and the medium, while treatment with algae extracts stimulated the formation of 4-HNE-protein adducts and reduced the level of 15-PGJ2-protein adducts. However, both algae extracts successfully prevented these UVA-induced modifications. In conclusion, lipid extracts from N.o. and C.a. appear to be promising agents in supporting anti-melanoma therapy. However, their potent protective capacity may limit their applicability, particularly following cells exposure to UVA. Full article

(This article belongs to the Special Issue Melanoma: From Molecular Mechanisms to Therapeutic Opportunities—Series 2)

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20 pages, 10684 KiB

Open AccessFeature PaperArticle

Environmental Enrichment Attenuates Repetitive Behavior and Alters the Functional Connectivity of Pain and Sensory Pathways in C58 Mice

by Anna L. Farmer, Marcelo Febo, Bradley J. Wilkes and Mark H. Lewis

Cells 2024, 13(23), 1933; https://doi.org/10.3390/cells13231933 - 21 Nov 2024

Abstract

Restricted repetitive behaviors (RRB) encompass a variety of inflexible behaviors, which are diagnostic for autism spectrum disorder (ASD). Despite being requisite diagnostic criteria, the neurocircuitry of these behaviors remains poorly understood, limiting treatment development. Studies in translational animal models show environmental enrichment (EE) [...] Read more.

Restricted repetitive behaviors (RRB) encompass a variety of inflexible behaviors, which are diagnostic for autism spectrum disorder (ASD). Despite being requisite diagnostic criteria, the neurocircuitry of these behaviors remains poorly understood, limiting treatment development. Studies in translational animal models show environmental enrichment (EE) reduces the expression of RRB, although the underlying mechanisms are largely unknown. This study used functional magnetic resonance imaging to identify functional connectivity alterations associated with RRB and its attenuation by EE in C58 mice, an animal model of RRB. Extensive differences were observed between C58 mice and C57BL/6 control mice. Higher RRB was associated with altered connectivity between the somatosensory network and reticular thalamic nucleus and between striatal and sensory processing regions. Animals housed in EE displayed increased connectivity between the somatosensory network and the anterior pretectal nucleus and hippocampus, as well as reduced connectivity between the visual network and area prostriata. These results suggest aberrant sensory perception is associated with RRB in C58 mice. EE may reduce RRB by altering functional connectivity in pain and visual networks. This study raises questions about the role of sensory processing and pain in RRB development and identifies new potential intervention targets. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Autism Spectrum Disorder)

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15 pages, 2925 KiB

Open AccessArticle

Influence of Soft and Stiff Matrices on Cytotoxicity in Gingival Fibroblasts: Implications for Soft Tissue Biocompatibility

by Ye-Jin Yang, Dong-Hyeon Yeo, Seong-Jin Shin, Jun-Hee Lee and Jung-Hwan Lee

Cells 2024, 13(23), 1932; https://doi.org/10.3390/cells13231932 - 21 Nov 2024

Abstract

The biocompatibility of dental materials is critical for ensuring safety in clinical applications. However, standard in vitro cytotoxicity assays often rely on stiff tissue culture plastic (TCP), which does not accurately replicate the biomechanical properties of soft oral tissues. In this study, we [...] Read more.

The biocompatibility of dental materials is critical for ensuring safety in clinical applications. However, standard in vitro cytotoxicity assays often rely on stiff tissue culture plastic (TCP), which does not accurately replicate the biomechanical properties of soft oral tissues. In this study, we compared human gingival fibroblasts (HGFs) cultured on soft, gel-based substrates mimicking gingival tissue stiffness (0.2 kPa) with those cultured on conventional TCP (3 GPa) to assess the influence of substrate stiffness on the cytotoxicity of methyl methacrylate (MMA), as well as other cytotoxic agents, including DMSO and H₂O₂. The results demonstrated that cells cultured on softer substrates exhibited enhanced resistance to cytotoxic stress, with increased viability and decreased apoptosis and DNA damage following exposure to MMA, DMSO, and H₂O₂. Notably, HGFs on soft substrates showed significantly greater resilience to MMA-induced cytotoxicity compared to those cultured on TCP. These findings emphasize the critical role of substrate stiffness in modulating cellular responses to toxic agents and highlight the necessity of using physiologically relevant models for cytotoxicity testing of dental materials. This study provides valuable insights for improving biocompatibility assessment protocols in clinical settings. Full article

(This article belongs to the Special Issue Recent Advances in Regenerative Dentistry—Second Edition)

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31 pages, 12498 KiB

Open AccessReview

Using Small Molecules to Reprogram RPE Cells in Regenerative Medicine for Degenerative Eye Disease

by Lyubov A. Rzhanova, Elena V. Alpeeva and Maria A. Aleksandrova

Cells 2024, 13(23), 1931; https://doi.org/10.3390/cells13231931 - 21 Nov 2024

Abstract

The main purpose of regenerative medicine for degenerative eye diseases is to create cells to replace lost or damaged ones. Due to their anatomical, genetic, and epigenetic features, characteristics of origin, evolutionary inheritance, capacity for dedifferentiation, proliferation, and plasticity, mammalian and human RPE [...] Read more.

The main purpose of regenerative medicine for degenerative eye diseases is to create cells to replace lost or damaged ones. Due to their anatomical, genetic, and epigenetic features, characteristics of origin, evolutionary inheritance, capacity for dedifferentiation, proliferation, and plasticity, mammalian and human RPE cells are of great interest as endogenous sources of new photoreceptors and other neurons for the degrading retina. Promising methods for the reprogramming of RPE cells into retinal cells include genetic methods and chemical methods under the influence of certain low-molecular-weight compounds, so-called small molecules. Depending on the goal, which can be the preservation or the replacement of lost RPE cells and cellular structures, various small molecules are used to influence certain biological processes at different levels of cellular regulation. This review discusses the potential of the chemical reprogramming of RPE cells in comparison with other somatic cells and induced pluripotent stem cells (iPSCs) into neural cells of the brain and retina. Possible mechanisms of the chemically induced reprogramming of somatic cells under the influence of small molecules are explored and compared. This review also considers other possibilities in using them in the treatment of retinal degenerative diseases based on the protection, preservation, and support of survived RPE and retinal cells. Full article

(This article belongs to the Special Issue Mechanism of Cell Signaling during Eye Development and Diseases)

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17 pages, 6700 KiB

Open AccessArticle

The Role of Plzf in Spermatogonial Stem Cell Maintenance and Differentiation: Mapping the Transcriptional Dynamics and Key Interactions

by Nima Ghasemi, Hossein Azizi, Seyedeh-Kiana Razavi-Amoli and Thomas Skutella

Cells 2024, 13(23), 1930; https://doi.org/10.3390/cells13231930 - 21 Nov 2024

Abstract

Spermatogonial stem cells (SSCs) sustain and modulate spermatogenesis through intricate signaling pathways and transcription factors. Promyelocytic leukemia zinc-finger (Plzf, also known as Zbtb16) has been identified as a critical transcription factor influencing various signaling and differentiation pathways. Plzf plays a [...] Read more.

Spermatogonial stem cells (SSCs) sustain and modulate spermatogenesis through intricate signaling pathways and transcription factors. Promyelocytic leukemia zinc-finger (Plzf, also known as Zbtb16) has been identified as a critical transcription factor influencing various signaling and differentiation pathways. Plzf plays a pivotal role in regulating the differentiation properties of SSCs and is essential for the proper maintenance of spermatogenesis. However, the transcription patterns of Plzf along the seminiferous tubules and its interaction network with adjacent partners still need to be fully elucidated. This study employed immunostaining techniques coupled with Fluidigm quantitative real-time polymerase chain reaction (Fluidigm qPCR) to quantify Plzf expression in undifferentiated and differentiated spermatogonia. Furthermore, we utilized bioinformatics analyses to identify Plzf partners and their associations with other regulatory factors. Immunohistostaining (IMH) revealed a high expression of Plzf in cells near the basal membrane of seminiferous tubules and a lower expression in the middle regions in vivo. Immunocytochemistry (ICC) demonstrated that undifferentiated spermatogonia exhibited significant Plzf positivity, whereas differentiated spermatogonia showed reduced Plzf expression in vitro. Fluidigm qPCR confirmed a significant differential expression of Plzf between undifferentiated and differentiated spermatogonia. In silico differential expression analysis between undifferentiated spermatogonia and spermatids indicated that Plzf is closely associated with Mycn, Lin28a, Kras, Ccnd1, and Jak1, highlighting the importance of these partnerships during spermatogenesis. Our findings suggest that the network of Plzf-related partners and their associated proteins involves differentiation, localization, apoptosis, and signal transduction. This comprehensive approach advances our understanding of Plzf transcription patterns and sheds light on its interactions with other cellular factors, revealing previously obscure pathways and interactions. These insights could lead to more effective diagnostic strategies for reproductive system-related diseases and inform the development of improved therapeutic and clinical applications. Full article

(This article belongs to the Special Issue Advance in Spermatogenesis)

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24 pages, 13352 KiB

Open AccessArticle

A Dual Role of the Senescence Marker P16Ink4a in Liver Endothelial Cell Function

by Kay-Dietrich Wagner, Hasan Safwan-Zaiter and Nicole Wagner

Cells 2024, 13(23), 1929; https://doi.org/10.3390/cells13231929 - 21 Nov 2024

Abstract

P16Ink4a is a well-established marker of senescence. Although P16Ink4a is expressed in endothelial cells, little is known about its function in these cells. Using isolated liver endothelial cells with silencing or overexpression of P16Ink4a, we show here that dependent on P16Ink4a levels, different [...] Read more.

P16Ink4a is a well-established marker of senescence. Although P16Ink4a is expressed in endothelial cells, little is known about its function in these cells. Using isolated liver endothelial cells with silencing or overexpression of P16Ink4a, we show here that dependent on P16Ink4a levels, different pathways and functions are affected. High levels of P16Ink4a reduce proliferation and induce senescence, while low levels have the opposite effects. Only high P16Ink4a expression reduces in vitro angiogenesis. Expression profiling reveals an inflammatory phenotype upon silencing of P16Ink4a, while P16Ink4a overexpression is associated with a profile associated with DNA damage, repair and senescence. Low levels of P16Ink4a induce reactive oxygen species (ROS) generation and increase endothelial cell leakage. Collectively, P16Ink4a represents an “antagonistic pleiotropy” gene, which is, on the one hand, required to prevent ROS generation and endothelial damage and, on the other hand, inhibits angiogenesis through induction of senescence at high levels. Full article

(This article belongs to the Section Cells of the Cardiovascular System)

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15 pages, 1123 KiB

Open AccessArticle

Activation of BDNF–TrkB Signaling in Specific Structures of the Sheep Brain by Kynurenic Acid

by Katarzyna Roszkowicz-Ostrowska, Patrycja Młotkowska, Elżbieta Marciniak, Michał Szlis, Marcin Barszcz and Tomasz Misztal

Cells 2024, 13(23), 1928; https://doi.org/10.3390/cells13231928 - 21 Nov 2024

Abstract

Fluctuations in kynurenic acid (KYNA) and brain-derived neurotrophic factor (BDNF) levels in the brain reflect its neurological status. The aim of the study was to investigate the effect of transiently elevated KYNA concentrations in the cerebroventricular circulation on the expression of BDNF and [...] Read more.

Fluctuations in kynurenic acid (KYNA) and brain-derived neurotrophic factor (BDNF) levels in the brain reflect its neurological status. The aim of the study was to investigate the effect of transiently elevated KYNA concentrations in the cerebroventricular circulation on the expression of BDNF and its high-affinity tropomyosin-related kinase receptor B (TrkB) in specific structures of the sheep brain. Intracerebroventricularly cannulated anestrous sheep were subjected to a series of four 30 min infusions of KYNA: 4 × 5 μg/60 μL/30 min (KYNA20, n = 6) and 4 × 25 μg/60 μL/30 min (KYNA100, n = 6) or a control infusion (n = 6), at 30 min intervals. Sections of the hippocampal CA3 field, amygdala (AMG), prefrontal cortex (PCx), and the hypothalamic medial-basal (MBH) and preoptic (POA) areas were dissected from the brain immediately after the experiment. The highest concentration of BDNF protein was found in the CA3 field (p < 0.001), which was 8-fold higher than in the AMG and 12-fold higher than that in the PCx (MBH and POA were not analyzed). The most pronounced BDNF mRNA expression was observed in the MBH, followed by the PCx, POA, AMG and CA3, while the highest abundance of TrkB mRNA was recorded in the AMG, followed by the MBH, PCx, CA3, and POA. KYNA increased (p < 0.05–p < 0.01) BDNF protein levels and the expression of its gene in the brain structures were examined, with the effect varying by dose and brain region. KYNA, particularly at the KYNA100 dose, also increased (p < 0.01) TrkB gene expression, except for the AMG, where the lower KYNA20 dose was more effective (p < 0.01). These findings suggest a positive relationship between KYNA levels in the cerebroventricular circulation and BDNF–TrkB expression in specific brain regions in a sheep model. This indicates that a transient increase in the CSF KYNA concentration can potentially restore BDNF production, for which deficiency underlies numerous neurological disorders. Full article

(This article belongs to the Section Cells of the Nervous System)

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2 pages, 182 KiB

Open AccessCorrection

Correction: Podolska et al. Graphene Oxide Nanosheets for Localized Hyperthermia—Physicochemical Characterization, Biocompatibility, and Induction of Tumor Cell Death. Cells 2020, 9, 776

by Malgorzata J. Podolska, Alexandre Barras, Christoph Alexiou, Benjamin Frey, Udo Gaipl, Rabah Boukherroub, Sabine Szunerits, Christina Janko and Luis E. Muñoz

Cells 2024, 13(23), 1927; https://doi.org/10.3390/cells13231927 - 21 Nov 2024

Abstract

Add New References [...] Full article

(This article belongs to the Special Issue The Interaction of Biomedical Nanoparticles with the Immune System)

21 pages, 5940 KiB

Open AccessArticle

Distinct Molecular Profiles Underpin Mild-To-Moderate Equine Asthma Cytological Profiles

by Anna E. Karagianni, Eric A. Richard, Marie-Pierre Toquet, Erika S. Hue, Anne Courouce-Malblanc, Bruce McGorum, Dominic Kurian, Judit Aguilar, Stella Mazeri, Thomas M. Wishart and Robert Scott Pirie

Cells 2024, 13(22), 1926; https://doi.org/10.3390/cells13221926 - 20 Nov 2024

Abstract

A state-of-the-art multi-omics approach was applied to improve our understanding of the aetio-pathogenesis of a highly prevalent, performance-limiting disorder of racehorses: mild-to-moderate equine asthma (MMEA). This is a prerequisite to improving prophylactic, management, and therapeutic options for this condition. Although a number of [...] Read more.

A state-of-the-art multi-omics approach was applied to improve our understanding of the aetio-pathogenesis of a highly prevalent, performance-limiting disorder of racehorses: mild-to-moderate equine asthma (MMEA). This is a prerequisite to improving prophylactic, management, and therapeutic options for this condition. Although a number of risk factors have been identified, options for intervention are limited. This study applied a multi-omic approach to reveal key inflammatory pathways involved in inflammatory cell recruitment to the lower airways and highlight distinct MMEA inflammatory profiles. We compared bronchoalveolar lavage fluid (BALF) cell gene and protein expression data from horses with non-inflammatory BALF cytology with those isolated from horses with neutrophilic, mastocytic, mixed neutrophilic/mastocytic, and eosinophilic/mastocytic inflammation. The analyses on transcriptomic/proteomic data derived from BALF from horses with neutrophilic cytology showed enrichment in classical inflammatory pathways, and horses with mastocytic inflammation showed enrichment in pathways involved in hypersensitivity reactions related to nonclassical inflammation potentially mimicking a Th2-immune response. The mixed eosinophilic/mastocytic group also presented with a nonclassical inflammatory profile, whereas the mixed neutrophilic/mastocytic group revealed profiles consistent with both neutrophilic inflammation and hypersensitivity. Our adopted multi-omics approach provided a holistic assessment of the immunological status of the lower airways associated with the different cytological profiles of equine asthma. Full article

(This article belongs to the Special Issue The Role of Secretory RNases and Extracellular RNAs in the Regulation of Inflammation and Organ Injury)

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19 pages, 2532 KiB

Open AccessArticle

Cell Cycle Dynamics in the Microalga Tisochrysis lutea: Influence of Light Duration and Drugs

by Laura Pageault, Aurélie Charrier, Bruno Saint-Jean, Gaël Bougaran, Francis Mairet and Sabine Stachowski-Haberkorn

Cells 2024, 13(22), 1925; https://doi.org/10.3390/cells13221925 - 20 Nov 2024

Abstract

Our investigation into Tisochrysis lutea’s cell cycle regulation involved natural and chemical synchronization methods to maximize their proportion at the division phase (G_2/M). Hence, cultures were grown under different light/dark cycles (24:0, 12:12, and 8:16 h) to assess the impact [...] Read more.

Our investigation into Tisochrysis lutea’s cell cycle regulation involved natural and chemical synchronization methods to maximize their proportion at the division phase (G_2/M). Hence, cultures were grown under different light/dark cycles (24:0, 12:12, and 8:16 h) to assess the impact of extended dark periods on cell division. Flow cytometry analyses of the cell cycle revealed that extending the dark phase resulted in a higher number of cells entering G_2/M. However, this remained a minority within the overall culture (peaking at 19.36% ± 0.17 under an 8:16 h L/D cycle). To further enhance synchronization, chemical agents (nocodazole, hydroxyurea, and aphidicolin) were tested for their efficacy in blocking specific cell cycle stages. Only aphidicolin successfully induced significant G_2/M accumulation (>90%). The commitment point for cell division was examined by exposing cultures to varying light durations (0 to 8 h) and measuring cell concentration and size distribution every 4 h. Our findings identified a critical minimum cell size (“sizer”) of approximately 56.2 ± 0.6 µm³ and a required minimal light exposure (“timer”) of 4 h to reliably trigger cell division. These findings highlight key conditions needed for optimal division of Tisochrysis lutea, offering more controlled and efficient cultivation strategies for future biotechnological applications. Full article

(This article belongs to the Section Plant, Algae and Fungi Cell Biology)

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22 pages, 3365 KiB

Open AccessReview

Emerging Role of Extracellular pH in Tumor Microenvironment as a Therapeutic Target for Cancer Immunotherapy

by Md Ataur Rahman, Mahesh Kumar Yadab and Meser M. Ali

Cells 2024, 13(22), 1924; https://doi.org/10.3390/cells13221924 - 20 Nov 2024

Abstract

Identifying definitive biomarkers that predict clinical response and resistance to immunotherapy remains a critical challenge. One emerging factor is extracellular acidosis in the tumor microenvironment (TME), which significantly impairs immune cell function and contributes to immunotherapy failure. However, acidic conditions in the TME [...] Read more.

Identifying definitive biomarkers that predict clinical response and resistance to immunotherapy remains a critical challenge. One emerging factor is extracellular acidosis in the tumor microenvironment (TME), which significantly impairs immune cell function and contributes to immunotherapy failure. However, acidic conditions in the TME disrupt the interaction between cancer and immune cells, driving tumor-infiltrating T cells and NK cells into an inactivated, anergic state. Simultaneously, acidosis promotes the recruitment and activation of immunosuppressive cells, such as myeloid-derived suppressor cells and regulatory T cells (Tregs). Notably, tumor acidity enhances exosome release from Tregs, further amplifying immunosuppression. Tumor acidity thus acts as a “protective shield,” neutralizing anti-tumor immune responses and transforming immune cells into pro-tumor allies. Therefore, targeting lactate metabolism has emerged as a promising strategy to overcome this barrier, with approaches including buffer agents to neutralize acidic pH and inhibitors to block lactate production or transport, thereby restoring immune cell efficacy in the TME. Recent discoveries have identified genes involved in extracellular pH (pHe) regulation, presenting new therapeutic targets. Moreover, ongoing research aims to elucidate the molecular mechanisms driving extracellular acidification and to develop treatments that modulate pH levels to enhance immunotherapy outcomes. Additionally, future clinical studies are crucial to validate the safety and efficacy of pHe-targeted therapies in cancer patients. Thus, this review explores the regulation of pHe in the TME and its potential role in improving cancer immunotherapy. Full article

(This article belongs to the Special Issue Progress in Cancer Immunotherapies)

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