Cells

17 pages, 896 KiB

Open AccessArticle

RacGAP1 Plays an Oncogenic Role in Lung Adenocarcinoma by Regulating the Wnt/β-Catenin Pathway

by Nicola Mosca, Mariaceleste Pezzullo, Ilenia De Leo, Anna Truda, Giovanna Marchese, Aniello Russo and Nicoletta Potenza

Cells 2025, 14(11), 773; https://doi.org/10.3390/cells14110773 - 23 May 2025

Abstract

Lung cancer is the most diagnosed cancer and the primary cause of cancer-related mortality worldwide, with lung adenocarcinoma (LUAD) becoming the prevalent histological subtype. Rac GTPase activating protein 1 (RacGAP1) has been found to be upregulated in several cancers, where it acts as [...] Read more.

Lung cancer is the most diagnosed cancer and the primary cause of cancer-related mortality worldwide, with lung adenocarcinoma (LUAD) becoming the prevalent histological subtype. Rac GTPase activating protein 1 (RacGAP1) has been found to be upregulated in several cancers, where it acts as an oncogene; nevertheless, its role in lung adenocarcinoma is largely unknown. The present study investigated the clinical relevance, the oncogenic function and the underlying molecular mechanisms of RacGAP1 in LUAD. Analyses of five patient cohorts’ datasets revealed that RacGAP1 was upregulated in adenocarcinoma tissues compared to normal lung tissues, and its overexpression was associated with unfavorable prognostic factors and poor survival; intriguingly, RacGAP1 expression was related to tobacco smoke, a well-known risk factor for LUAD. Then, experimental analyses demonstrated that RacGAP1 knockdown inhibited cell proliferation, migration and invasion, thus highlighting its role in promoting LUAD. Finally, the finding of significant correlations between RacGAP1 and Wnt-altered status or β-catenin in patients led to experiments demonstrating that silencing of RacGAP1 reduced β-catenin transcriptional activity, thereby downregulating the expression of Wnt-related genes, i.e., LGR5, Wnt2B and Wnt5A. Overall, our findings indicate that RacGAP1 plays an oncogenic role in adenocarcinoma, contributing to the abnormal activation of the Wnt/β-catenin signaling pathway. These findings may pave the way for innovative therapeutic strategies and the development of advanced diagnostic panels. Full article

(This article belongs to the Special Issue Ras Family of Genes and Proteins: Structure, Function and Regulation)

21 pages, 3367 KiB

Open AccessArticle

Targeting the Cargo Receptor TMED9 as a Therapeutic Strategy Against Brain Tumors

by Alaa Daoud Sarsour, Sara Kinstlinger, Rephael Nizar, Naama Amos, Narkis Arbeli, Gila Kazimirsky, Irena Bronshtein-Berger, Iris Fried, Ron Unger, Chaya Brodie and Moran Dvela-Levitt

Cells 2025, 14(11), 772; https://doi.org/10.3390/cells14110772 - 23 May 2025

Abstract

Glioblastoma is one of the most aggressive and lethal forms of brain cancer, with limited therapeutic options and poor patient prognosis. Recent research has identified the TMED family of proteins as key regulators of tumor progression and aggressiveness across multiple cancer types. TMED [...] Read more.

Glioblastoma is one of the most aggressive and lethal forms of brain cancer, with limited therapeutic options and poor patient prognosis. Recent research has identified the TMED family of proteins as key regulators of tumor progression and aggressiveness across multiple cancer types. TMED members are cargo receptors expressed within the early secretory pathway and involved in bidirectional traffic of various proteins including EGFR, TGF-ɑ and WNT. In this study, we explored the therapeutic potential of genetic and pharmacologic inhibition of the cargo receptor TMED9 in glial tumor models. Our findings demonstrate that TMED9 expression is upregulated in glioma and that this upregulation is associated with poor patient survival. Using patient-derived glioma tumor cells, we demonstrate that TMED9 is highly expressed in the cancer stem cell population and that this upregulation promotes the cells’ self-renewal and migration. This is the first time, to the best of our knowledge, that TMED9 has been shown to play a major role in the function and tumorigenesis of brain tumor cancer stem cells. BRD4780, a small molecule that targets TMED9, effectively reduced TMED9 abundance, resulting in decreased viability, migration and stemness of patient-derived glioma stem cells. Moreover, BRD4780 mitigated the proliferation and migration of differentiated glioma tumor cells. When applied together with temozolomide, an established glioblastoma treatment, BRD4780 elicited an enhanced anti-tumor response. Lastly, to demonstrate the broad applicability of our findings, we targeted TMED9 in pediatric glioma cells and showed efficient inhibition of various oncogenic functions. Collectively, our study identifies TMED9 inhibition as a promising therapeutic approach that impairs the tumorigenesis and aggressiveness of brain tumors, with high efficacy against the tumor stem cell population. The effectiveness of TMED9 targeting in different tumor cell populations, the potential of combining this strategy with established therapies and the broad applicability of this approach to multiple cancer types highlight the significance of these findings. Full article

(This article belongs to the Section Cell Proliferation and Division)

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23 pages, 973 KiB

Open AccessReview

PDE3A as a Therapeutic Target for the Modulation of Compartmentalised Cyclic Nucleotide-Dependent Signalling

by Swaroop Ranjan Pati, Anastasiia Sholokh and Enno Klussmann

Cells 2025, 14(11), 771; https://doi.org/10.3390/cells14110771 - 23 May 2025

Abstract

Phosphodiesterase 3A (PDE3A) hydrolyses cAMP, adjusting cAMP signalling pathways with temporal and spatial accuracy. PDE3A contributes to the control of cAMP in several cellular compartments, including the plasma membrane, the cytosol, or membrane-limited organelles such as the nucleus and the sarcoplasmic reticulum. Through [...] Read more.

Phosphodiesterase 3A (PDE3A) hydrolyses cAMP, adjusting cAMP signalling pathways with temporal and spatial accuracy. PDE3A contributes to the control of cAMP in several cellular compartments, including the plasma membrane, the cytosol, or membrane-limited organelles such as the nucleus and the sarcoplasmic reticulum. Through this ability and its expression in various cell types, it regulates a variety of cellular processes like contractility of muscle cells, gene expression, differentiation and proliferation. Dysregulated cAMP signalling causes or is associated with diseases. The therapeutic potential of PDE3A is, however, limited by the lack of specific modulators. Emerging approaches to targeting PDE3A centre on specifically addressing its catalytic domain or its cellular localisation. This review highlights the growing knowledge of PDE3A’s functions in cellular signalling and therapeutic opportunities, opening the door to more fully utilise its potential for the treatment of disease. Full article

(This article belongs to the Special Issue Phosphodiesterases (PDEs): Therapeutic Targets in Human Health and Disease)

21 pages, 1180 KiB

Open AccessReview

Understanding Atherosclerotic Plaque Cellular Composition: Recent Advances Driven by Single Cell Omics

by Esra Cetin and Anne-Catherine Raby

Cells 2025, 14(11), 770; https://doi.org/10.3390/cells14110770 - 23 May 2025

Abstract

Atherosclerosis, a chronic inflammatory condition of the arterial cell wall, is the leading cause of cardiovascular disease (CVD) and death. It is characterised by the accumulation of lipid and immune cell-rich plaques in the arterial intima, which is driven by a dysregulated immune [...] Read more.

Atherosclerosis, a chronic inflammatory condition of the arterial cell wall, is the leading cause of cardiovascular disease (CVD) and death. It is characterised by the accumulation of lipid and immune cell-rich plaques in the arterial intima, which is driven by a dysregulated immune response to cholesterol-containing lipoproteins at the lesion site. Initially thought to be driven by passive lipid accumulation, atherosclerosis is now recognised as a complex process encompassing a multitude of inflammatory and remodelling mechanisms, driven by both immune cells (e.g., macrophages, T-cells, B-cells, antigen-presenting cells) and non-immune cells (smooth muscle cells, endothelial cells). With the development of single-cell transcriptomic and proteomic technologies, a previously inconceivable wealth of data has been generated in an attempt to better understand the pathophysiology of the disease and identify novel avenues for the development of targeted therapeutic interventions. This review provides an overview of the latest findings in the field obtained using single-cell technologies, with a focus on the major cell types present at the atherosclerotic plaque site, their suggested repartition in subsets, as well as their predicted function(s) within the complex processes that interplay to drive atherosclerotic disease. We conclude by highlighting the discrepancies and areas of consensus brought about by these studies and briefly discuss the likely future advances that will come from the continuous development and improvement of single-cell omics technologies. Full article

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

30 pages, 5339 KiB

Open AccessArticle

VPAC1 and VPAC2 Receptor Heterozygosity Confers Distinct Biological Properties to BV2 Microglial Cells

by Xin Ying Rachel Song, Margo Iris Jansen, Rubina Marzagalli, Giuseppe Musumeci, Velia D’Agata and Alessandro Castorina

Cells 2025, 14(11), 769; https://doi.org/10.3390/cells14110769 - 23 May 2025

Abstract

Microglial cells, the resident immune cells of the central nervous system (CNS), are essential for maintaining CNS homeostasis. Dysregulation of microglial function is implicated in the pathogenesis of various neurodegenerative diseases. Vasoactive intestinal polypeptide receptors 1 and 2 (VPAC1 and VPAC2) are G-protein-coupled [...] Read more.

Microglial cells, the resident immune cells of the central nervous system (CNS), are essential for maintaining CNS homeostasis. Dysregulation of microglial function is implicated in the pathogenesis of various neurodegenerative diseases. Vasoactive intestinal polypeptide receptors 1 and 2 (VPAC1 and VPAC2) are G-protein-coupled receptors (GPCRs) expressed by microglia, with their primary ligands being pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP). However, the specific roles of VPAC-type receptors in microglial regulation remain poorly understood. In this study, we generated VPAC1^+/− and VPAC2^+/− BV2 microglial cell lines using CRISPR-Cas9 gene editing and conducted a series of biological and molecular assays to elucidate the functions of these receptors. Our findings demonstrated that both mutant cell lines exhibited a polarized phenotype and increased migratory activity. VPAC1^+/− cells showed enhanced survivability and baseline activation of the unfolded protein response (UPR), a protective mechanism triggered by endoplasmic reticulum (ER) stress, whereas this response appeared impaired in VPAC2^+/− cells. In contrast, under lipopolysaccharide (LPS)-induced inflammatory conditions, UPR activation was impaired in VPAC1^+/− cells but restored in VPAC2^+/− cells, resulting in improved survival of VPAC2^+/− cells, whereas VPAC1^+/− cells exhibited reduced resilience. Overall, our findings suggest that VPAC1 and VPAC2 receptors play distinct yet complementary roles in BV2 microglia. VPAC2 is critical for regulating survival, ER stress responses, and polarization under basal conditions, while VPAC1 is essential for adaptive responses to inflammatory stimuli such as LPS. These insights advance our understanding of microglial receptor signaling and may inform therapeutic strategies targeting microglial dysfunction in neurodegenerative diseases. Full article

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

10 pages, 3865 KiB

Open AccessCommunication

Defective Mitochondrial Respiration in Hereditary Thoracic Aneurysms

by Daniel Marcos-Ríos, Antonio Rochano-Ortiz, Nerea Méndez-Barbero and Jorge Oller

Cells 2025, 14(11), 768; https://doi.org/10.3390/cells14110768 - 23 May 2025

Abstract

Thoracic aortic aneurysms are life-threatening vascular conditions linked to inherited disorders such as Marfan syndrome, Loeys–Dietz syndrome, vascular Ehlers–Danlos syndrome, and familial thoracic aortic aneurysms and dissections. While traditionally associated with the extracellular matrix and contractile defects in vascular smooth muscle cells, emerging [...] Read more.

Thoracic aortic aneurysms are life-threatening vascular conditions linked to inherited disorders such as Marfan syndrome, Loeys–Dietz syndrome, vascular Ehlers–Danlos syndrome, and familial thoracic aortic aneurysms and dissections. While traditionally associated with the extracellular matrix and contractile defects in vascular smooth muscle cells, emerging evidence suggests the key role of mitochondrial dysfunction. Here, we show that the overexpression of ACTA2^R179H and TGFBR2^G357W in murine aortic VSMCs reduces Mitochondrial Transcription Factor A (Tfam) expression, decreases mitochondrial DNA (mtDNA) content, and impairs oxidative phosphorylation, shifting metabolism toward glycolysis. Notably, nicotinamide riboside, a NAD⁺ precursor, restores mitochondrial respiration, increases Tfam and mtDNA levels, and promotes a contractile phenotype by enhancing actin polymerization and reducing matrix metalloproteinase activity. These findings identify mitochondrial dysfunction as a shared feature in hereditary thoracic aortic aneurysm, not only in Marfan syndrome, but also in other genetic forms, and highlight mitochondrial boosters as a potential therapeutic strategy. Full article

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

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20 pages, 16331 KiB

Open AccessReview

Vasohibins in Health and Disease: From Angiogenesis to Tumorigenesis, Multiorgan Dysfunction, and Brain–Heart Remodeling

by Ghulam Abbas, Annet Kirabo, Usama Ahmed, Jie Liu and Jidong Chen

Cells 2025, 14(11), 767; https://doi.org/10.3390/cells14110767 - 23 May 2025

Abstract

Vasohibins (VASHs), comprising VASH-1 and VASH-2, were initially identified as regulators of angiogenesis. Recent studies, however, have unveiled their novel role in fibrosis and microtubule detyrosination. The dysregulated expression of VASHs is associated with several pathological processes, such as angiogenesis dysfunction, microtubule detyrosination, [...] Read more.

Vasohibins (VASHs), comprising VASH-1 and VASH-2, were initially identified as regulators of angiogenesis. Recent studies, however, have unveiled their novel role in fibrosis and microtubule detyrosination. The dysregulated expression of VASHs is associated with several pathological processes, such as angiogenesis dysfunction, microtubule detyrosination, and fibrosis, contributing to various diseases. These findings suggest the pleiotropic effects of VASHs in multiple organs and systems beyond angiogenesis. This review explores the molecular properties of VASHs and their emerging functions in tubulin carboxyl activity and microtubule detyrosination—key to brain and cardiac remodeling. We also discuss the potential therapeutic applications of their interference in diseases such as tumorigenesis, as well as renal-, reproductive-, and liver-related diseases. Full article

(This article belongs to the Special Issue New Insights into Vascular Biology in Health and Disease)

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28 pages, 1697 KiB

Open AccessReview

IL-6 as a Mediator of Platelet Hyper-Responsiveness

by Connor Elliot Webb, Jordan Vautrinot and Ingeborg Hers

Cells 2025, 14(11), 766; https://doi.org/10.3390/cells14110766 - 22 May 2025

Abstract

Interleukin-6 (IL-6) is a pleiotropic cytokine with critical roles in immune regulation, inflammation, and haematopoiesis. While its functions in host defence and tissue repair are well established, accumulating evidence suggests that IL-6 also can directly and indirectly modulate megakaryocyte and platelet biology. This [...] Read more.

Interleukin-6 (IL-6) is a pleiotropic cytokine with critical roles in immune regulation, inflammation, and haematopoiesis. While its functions in host defence and tissue repair are well established, accumulating evidence suggests that IL-6 also can directly and indirectly modulate megakaryocyte and platelet biology. This review examines the mechanistic basis supporting IL-6-mediated platelet hyper-responsiveness, in addition to its effect on megakaryopoiesis and thrombopoiesis in thromboinflammatory disease states. We discuss how IL-6-mediated trans-signalling may sensitizes platelets to activation, and that this may be exclusive to glycoprotein VI (GPVI) stimulation due to Janus kinase (JAK)–signal transducer 2 crosstalk, in addition to other mechanisms that may contribute to priming platelets. We further highlight clinical evidence linking IL-6 to thrombotic complications in cardiovascular disease and infection (e.g., COVID-19 and sepsis). Given the emerging interest in IL-6-targeting therapies as anti-inflammatory and anti-thrombotic agents, a thorough understanding of how IL-6 can drive platelet responsiveness is crucial. Full article

(This article belongs to the Special Issue Molecular and Cellular Insights into Platelet Function)

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21 pages, 5109 KiB

Open AccessArticle

P53-Induced Autophagy Degradation of NKX3-2 Improves Ovarian Cancer Prognosis

by Alessandra Ferraresi, Ian Ghezzi, Amreen Salwa, Chiara Lualdi, Danny N. Dhanasekaran and Ciro Isidoro

Cells 2025, 14(11), 765; https://doi.org/10.3390/cells14110765 - 22 May 2025

Abstract

NKX3-2, a transcriptional repressor factor belonging to the NK family of homeobox-containing proteins, has been widely studied for its role in promoting chondrogenic differentiation and homeostasis. NKX3-2 is upregulated in chemoresistant ovarian tumors and metastatic gastric cancer cells; however, its prognostic role and [...] Read more.

NKX3-2, a transcriptional repressor factor belonging to the NK family of homeobox-containing proteins, has been widely studied for its role in promoting chondrogenic differentiation and homeostasis. NKX3-2 is upregulated in chemoresistant ovarian tumors and metastatic gastric cancer cells; however, its prognostic role and mechanistic involvement in cancer cell biology remain to be elucidated. By interrogating the TCGA database, we found that cancer patients with high NKX3-2 expression had a shorter overall survival rate than patients with low expression. In ovarian cancer patients, NKX3-2 negatively correlates with P53. Given the prominent role of the latter oncosuppressor in controlling DNA repair and cell death, here we investigate the molecular mechanism involved in this negative correlation in several ovarian cancer cell lines expressing different levels of the two proteins. We found that the high expression of endogenous or ectopic P53 reduced NKX3-2 protein expression, while its knockdown increased it. In contrast, the genetic manipulation of NKX3-2 expression did not affect P53 expression. Mechanistically, P53-mediated downregulation of NKX3-2 does not entail transcriptional activity or proteasomal clearance but occurs via P53–NKX3-2 protein–protein interaction, which in turn results in P53-induced NKX3-2 degradation via the autophagy–lysosome pathway. Remarkably, patients bearing a tumor characterized by low NKX3-2 and high MAP1LC3B expression (indicative of active autophagy) display a better prognosis. Taken together, our data indicate that NKX3-2 represents a negative prognostic factor under P53 control in ovarian cancer. From a translational point of view, identifying this novel mechanism may represent a new molecular signature capable of predicting the clinical outcome of patients, a crucial aspect of developing personalized therapeutic approaches. Full article

(This article belongs to the Special Issue Ovarian Cancer and Endometriosis)

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18 pages, 1724 KiB

Open AccessReview

The Diversity of Fibrillin Functions: Lessons from the Periodontal Ligament

by Elisabeth Genot, Tala Al Tabosh, Sylvain Catros, Florian Alonso and Damien Le Nihouannen

Cells 2025, 14(11), 764; https://doi.org/10.3390/cells14110764 - 22 May 2025

Abstract

Marfan syndrome is caused by a mutation in the FBN1 gene encoding fibrillin-1. This extracellular matrix glycoprotein, which assembles into microfibrils, is best known for its scaffolding role in the production of elastic fibers responsible for connective tissue elasticity and tensile strength. Research [...] Read more.

Marfan syndrome is caused by a mutation in the FBN1 gene encoding fibrillin-1. This extracellular matrix glycoprotein, which assembles into microfibrils, is best known for its scaffolding role in the production of elastic fibers responsible for connective tissue elasticity and tensile strength. Research into Marfan syndrome mainly focuses on the pathophysiology involved in the degeneration of elastin-rich elastic fibers, which are essential components of the aortic wall. However, fibrillin-1 also exists in elastin-poor (elaunin) or elastin-free (oxytalan) microfibril bundles that were first described in the periodontal ligament (PDL). This dynamic, densely cellular, and highly vascularized tissue anchors teeth in their bone sockets and acts as a protective shock absorber during chewing. Current knowledge suggests that fibrillin microfibrils mechanically support blood vessels in the PDL and ensure their proper functioning. However, many more insights on the roles of fibrillin, especially independently of elastin, can be extracted from this tissue. Here, we review the phenotypic and functional characteristics of the PDL in connection with fibrillin-1, focusing on those related to microvessels. This review aims to shed light on this often-overlooked fibrillin-rich resource as a model for future studies investigating fibrillin functions in health and Marfan disease. Full article

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

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19 pages, 1255 KiB

Open AccessReview

Dynamics of Innate Immunity in SARS-CoV-2 Infections: Exploring the Impact of Natural Killer Cells, Inflammatory Responses, Viral Evasion Strategies, and Severity

by Juan C. Batista, Rodrigo DeAntonio and Sandra López-Vergès

Cells 2025, 14(11), 763; https://doi.org/10.3390/cells14110763 - 22 May 2025

Abstract

The COVID-19 pandemic, caused by SARS-CoV-2, has had a profound impact on global health, with nearly 800 million cases reported in the Americas alone. The clinical presentation of the disease is highly variable, with approximately half of all patients experiencing severe symptoms. This [...] Read more.

The COVID-19 pandemic, caused by SARS-CoV-2, has had a profound impact on global health, with nearly 800 million cases reported in the Americas alone. The clinical presentation of the disease is highly variable, with approximately half of all patients experiencing severe symptoms. This variability confounds the complex interplay between immune responses and disease severity. Severe cases are often characterized by elevated levels of inflammatory cytokines. Over 88% of COVID-19 patients have multiple comorbidities; factors such as age and pre-existing conditions further modulate immune responses and contribute to the severity of the disease. While some studies have reported differences in cytokine profiles between severity groups, larger, well-designed cohorts are needed to clarify these relationships. Natural Killer cells, which are critical for the innate immune response against SARS-CoV-2, are often impaired and contribute to immune exhaustion. In addition, SARS-CoV-2 evades innate immune defenses through accessory proteins that inhibit interferon signaling and exacerbate cytokine storms and inflammation. This integrative review aims to synthesize findings from 2020 onward and provide insights into the innate immune responses induced by SARS-CoV-2 and their contributions to disease pathogenesis. Understanding cytokine dynamics, NK cell behaviors, and viral immune evasion strategies is critical for advancing therapeutic approaches. Full article

(This article belongs to the Special Issue Emerging Insights into Natural Killer Cell Immunity in Infection and Cancer)

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25 pages, 2465 KiB

Open AccessReview

Progranulin’s Protective Mechanisms and Therapeutic Potential in Cardiovascular Disease

by Gan Qiao, Yongxiang Lu, Jianping Wu, Chunyang Ren, Roudian Lin and Chunxiang Zhang

Cells 2025, 14(11), 762; https://doi.org/10.3390/cells14110762 - 22 May 2025

Abstract

Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality globally, prompting the investigation of novel therapeutic targets. Progranulin (PGRN), a glycoprotein initially associated with neurodegenerative disorders, has emerged as a critical protective agent in cardiovascular health. Recent studies indicate that PGRN [...] Read more.

Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality globally, prompting the investigation of novel therapeutic targets. Progranulin (PGRN), a glycoprotein initially associated with neurodegenerative disorders, has emerged as a critical protective agent in cardiovascular health. Recent studies indicate that PGRN exerts its protective effects through various mechanisms, including the modulation of inflammatory pathways, enhancement of mitochondrial function, and promotion of vascular integrity. By engaging with key signaling pathways, such as PI3K/Akt, NF-κB and Wnt/β-catenin, PGRN mitigates oxidative stress and fosters an environment conducive to cardiac repair following ischemic injury. Furthermore, PGRN’s role in lipid metabolism and vascular smooth muscle cell behavior highlights its complexity in influencing atherogenesis and vascular homeostasis. This review synthesizes current knowledge regarding PGRN’s protective mechanisms in CVD, emphasizing its potential as a therapeutic target and paving the way for innovative approaches to prevent and treat cardiovascular diseases, ultimately improving patient outcomes in this critical area of public health. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Cardiovascular Diseases)

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16 pages, 1790 KiB

Open AccessReview

CYR61 as a Potential Biomarker and Target in Cancer Prognosis and Therapies

by Andrew J. Schenker and Greisha L. Ortiz-Hernández

Cells 2025, 14(11), 761; https://doi.org/10.3390/cells14110761 - 22 May 2025

Abstract

Cysteine-rich protein 61 (CYR61) is a matricellular protein in the CCN family that is involved in cellular adhesion, migration, proliferation, and angiogenesis. CYR61 interacts with integrins α6β1, αvβ3, αvβ5, and αIIbβ3 to modulate tumor progression and metastasis while modifying the tumor microenvironment. CYR61 [...] Read more.

Cysteine-rich protein 61 (CYR61) is a matricellular protein in the CCN family that is involved in cellular adhesion, migration, proliferation, and angiogenesis. CYR61 interacts with integrins α6β1, αvβ3, αvβ5, and αIIbβ3 to modulate tumor progression and metastasis while modifying the tumor microenvironment. CYR61 exhibits context-dependent roles in cancer, acting as both a tumor promoter and suppressor. Increased CYR61 expression is linked to extracellular matrix remodeling, immune modulation, and integrin-mediated signaling, making it a potential prognostic biomarker and therapeutic target. Emerging research highlights the utility of CYR61 in liquid biopsies for cancer detection and monitoring. Integrin-targeted therapies, including CYR61-blocking antibodies and CAR-T approaches, offer novel treatment strategies. However, therapy-induced toxicity and resistance remain challenges with these strategies. The further elucidation of the molecular mechanisms of CYR61 may enhance targeted therapeutic interventions and improve patient outcomes. Full article

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29 pages, 9850 KiB

Open AccessArticle

Novel Hyperplastic Expansion of White Adipose Tissue Underlies the Metabolically Healthy Obese Phenotype of Male LFABP Null Mice

by Anastasia Diolintzi, Yinxiu Zhou, Angelina Fomina, Yifei Sun, Seema Husain, Labros S. Sidossis, Susan K. Fried and Judith Storch

Cells 2025, 14(11), 760; https://doi.org/10.3390/cells14110760 - 22 May 2025

Abstract

Obesity is an important risk factor for the development of metabolic syndrome disorders. We previously showed that the liver fatty acid-binding protein null mouse (LFABP^−/−) becomes obese upon high-fat diet (HFD) feeding but remains metabolically healthy. Here, we find that [...] Read more.

Obesity is an important risk factor for the development of metabolic syndrome disorders. We previously showed that the liver fatty acid-binding protein null mouse (LFABP^−/−) becomes obese upon high-fat diet (HFD) feeding but remains metabolically healthy. Here, we find that the obese LFABP^−/− mouse increases subcutaneous adipose tissue (SAT) mass by markedly increasing the number rather than the size of adipocytes, as is typical with HFD. Indeed, while HFD-fed LFABP^−/− mice had almost double the fat mass of WT, SAT adipocyte size was >4-fold smaller and adipocyte number was 5-fold higher in the LFABP^−/−. Transcriptomic analysis of SAT revealed that Lfabp deletion alters the expression of multiple pathways that modulate adipose expansion and function including cholesterol biosynthesis, adipogenesis, and extracellular matrix remodeling. LFABP is expressed in the liver and small intestine but not in adipose tissues; thus, its ablation may promote interorgan crosstalk that drives the hyperplastic expansion of metabolically beneficial SAT, contributing to the healthy obese phenotype of the LFABP^−/− mouse. Full article

(This article belongs to the Special Issue Adipose Tissue Functioning in Health and Diseases)

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12 pages, 1810 KiB

Open AccessArticle

Examining Stromal Cell Interactions in an In Vitro Blood–Brain Barrier Model with Human Umbilical Vein Endothelial Cells

by Andrea Margari, Simon Konig, Vignesh Jayarajan, Silvia Rizzato, Giuseppe Maruccio and Emad Moeendarbary

Cells 2025, 14(11), 759; https://doi.org/10.3390/cells14110759 - 22 May 2025

Abstract

Understanding the function of the blood–brain barrier (BBB) in health and disease, as well as improving drug delivery across the BBB, remains a critical priority in neuroscience research. However, current in vitro models of the BBB have become increasingly complex and challenging to [...] Read more.

Understanding the function of the blood–brain barrier (BBB) in health and disease, as well as improving drug delivery across the BBB, remains a critical priority in neuroscience research. However, current in vitro models of the BBB have become increasingly complex and challenging to implement. In this study, we present a simplified microfluidic BBB model in which human umbilical vein endothelial cells (HUVECs) are cultured as a monolayer along a fibrin gel containing human pericytes and astrocytes. Remarkably, within just three days, the 3D co-culture significantly enhanced barrier formation and upregulated the expression of tight-junction proteins in HUVECs. These findings demonstrate that HUVECs, which have been extensively used for over 50 years to study vascular endothelium due to their ease of isolation and culture, can adapt their phenotype towards that of BBB endothelial cells under appropriate conditions. This microfluidic BBB model offers a valuable tool for drug development and for advancing our understanding of BBB physiology in both health and disease contexts. Full article

(This article belongs to the Collection Emerging Topics in Vascular Endothelial Cell Biology)

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20 pages, 4340 KiB

Open AccessArticle

Primary Cell Cultures in Neurobiology: Optimized Protocol for Culture of Mouse Fetal Hindbrain Neurons

by Hadrien Glibert, Laure Bridoux, Maëlle Palate, Coralie Piget, Marie-Thérèse Ahn, Roberta Gualdani, Ana Domínguez-Bajo, Frédéric Clotman, Filippo M. Rijli and Françoise Gofflot

Cells 2025, 14(11), 758; https://doi.org/10.3390/cells14110758 - 22 May 2025

Abstract

Primary cultures of neural cells are important key tools for basic and translational neuroscience research. These primary cell cultures are classically generated from the rodent brain hippocampus or cortex and optimized for enrichment in neurons at the expense of glial cells. Importantly, considerable [...] Read more.

Primary cultures of neural cells are important key tools for basic and translational neuroscience research. These primary cell cultures are classically generated from the rodent brain hippocampus or cortex and optimized for enrichment in neurons at the expense of glial cells. Importantly, considerable differences exist in neuronal cell populations and in glial cell contribution between different brain regions. Because many basic and translational research projects aim to identify mechanisms underlying brainstem neuronal networks that affect major vital functions, primary cultures representative of cell populations present in the hindbrain are required. However, the preparation of primary cultures of brainstem/hindbrain neurons is scarcely described in the literature, limiting the possibilities for studying the development and physiology of these brain regions in vitro. The present report describes a reliable protocol to dissociate and culture in vitro embryonic mouse fetal hindbrain neurons in a defined culture medium, while control of astrocytes’ expansion was attained by using a chemically defined, serum-free supplement, namely CultureOne™. The neuronal cells maintained according to this protocol differentiate and, by 10 days in vitro, they develop extensive axonal and dendritic branching. Using immunofluorescence, we further characterized the different cell populations and neuronal subtypes. Patch–clamp recordings demonstrate the excitable nature of these neurons, while colocalization of pre- and postsynaptic neuronal markers showed that neurons form mature synapses, suggesting the establishment of functional networks in vitro. The cultures produced by this method show excellent reproducibility and can be used for molecular, biochemical, and physiological analyses, as illustrated here for tamoxifen-induced Cre recombination in genetically-modified neural cells. Full article

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

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21 pages, 37647 KiB

Open AccessTechnical Note

Human Differentiated Adipocytes as Surrogate Mature Adipocytes for Adipocyte-Derived Extracellular Vesicle Analysis

by Mangesh Dattu Hade, Bradley L. Butsch, Paola Loreto Palacio, Kim Truc Nguyen, Dharti Shantaram, Sabrena F. Noria, Stacy A. Brethauer, Bradley J. Needleman, Willa Hsueh, Eduardo Reátegui and Setty M. Magaña

Cells 2025, 14(11), 757; https://doi.org/10.3390/cells14110757 - 22 May 2025

Abstract

Obesity is a growing global health concern, contributing to diseases such as cancer, autoimmune disorders, and neurodegenerative conditions. Adipose tissue dysfunction, characterized by abnormal adipokine secretion and chronic inflammation, plays a key role in these conditions. Adipose-derived extracellular vesicles (ADEVs) have emerged as [...] Read more.

Obesity is a growing global health concern, contributing to diseases such as cancer, autoimmune disorders, and neurodegenerative conditions. Adipose tissue dysfunction, characterized by abnormal adipokine secretion and chronic inflammation, plays a key role in these conditions. Adipose-derived extracellular vesicles (ADEVs) have emerged as critical mediators in obesity-related diseases. However, the study of mature adipocyte-derived EVs (mAdipo-EVs) is limited due to the short lifespan of mature adipocytes in culture, low EV yields, and the low abundance of these EV subpopulations in the circulation. Additionally, most studies rely on rodent models, which have differences in adipose tissue biology compared to humans. To overcome these challenges, we developed a standardized approach for differentiating human preadipocytes (preAdipos) into mature differentiated adipocytes (difAdipos), which produce high-yield, human adipocyte EVs (Adipo-EVs). Using visceral adipose tissue from bariatric surgical patients, we isolated the stromal vascular fraction (SVF) and differentiated preAdipos into difAdipos. Brightfield microscopy revealed that difAdipos exhibited morphological characteristics comparable to mature adipocytes (mAdipos) directly isolated from visceral adipose tissue, confirming their structural similarity. Additionally, qPCR analysis demonstrated decreased preadipocyte markers and increased mature adipocyte markers, further validating successful differentiation. Functionally, difAdipos exhibited lipolytic activity comparable to mAdipos, supporting their functional resemblance to native adipocytes. We then isolated preAdipo-EVs and difAdipo-EVs using tangential flow filtration and characterized them using bulk and single EV analysis. DifAdipo-EVs displayed classical EV and adipocyte-specific markers, with significant differences in biomarker expression compared to preAdipo-EVs. These findings demonstrate that difAdipos serve as a reliable surrogate for mature adipocytes, offering a consistent and scalable source of adipocyte-derived EVs for studying obesity and its associated disorders. Full article

(This article belongs to the Special Issue Extracellular Vesicles as Biomarkers for Human Disease)

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16 pages, 2271 KiB

Open AccessArticle

Inhibition of GPX4 by Toxoplasma gondii Promotes Ferroptosis and Enhances Its Proliferation in Acute and Chronic Infection

by Yanlong Gu, Zhipeng Niu, Hui-Hong Lu, Si-Ang Li and Dong-Hui Zhou

Cells 2025, 14(10), 756; https://doi.org/10.3390/cells14100756 - 21 May 2025

Abstract

Toxoplasma gondii (T. gondii) is an intracellular parasite that extensively infects warm-blooded animals, causing toxoplasmosis and posing a significant threat to global public health. In this study, we investigated the association between T. gondii infection and ferroptosis in host cells, as [...] Read more.

Toxoplasma gondii (T. gondii) is an intracellular parasite that extensively infects warm-blooded animals, causing toxoplasmosis and posing a significant threat to global public health. In this study, we investigated the association between T. gondii infection and ferroptosis in host cells, as well as the regulatory role of glutathione peroxidase 4 (GPX4). Our findings revealed that mice infected with RH and PRU strains of T. gondii exhibited significantly elevated levels of reactive oxygen species and malondialdehyde in brain and liver tissues. Concurrently, the expression of GPX4, a critical negative regulator of ferroptosis, was downregulated, which correlated with the elevated parasite burden. In Vero cells, T. gondii infection similarly inhibited GPX4 expression, whereas GPX4 overexpression suppressed T. gondii proliferation. These results indicate that T. gondii infection can promote ferroptosis in host cells and that GPX4 plays a pivotal role in regulating infection and proliferation. This study provides novel insights into the pathogenic mechanisms of T. gondii and identifies GPX4 as a regulatory factor that constrains parasite proliferation, offering new approaches for toxoplasmosis prevention and control. Full article

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17 pages, 393 KiB

Open AccessReview

Survivin Interference and SurVaxM as an Adjunct Therapy for Glioblastoma Multiforme

by Willie James Elliott, Nandini Gurramkonda, Maheedhara R. Guda, Andrew J. Tsung and Kiran K. Velpula

Cells 2025, 14(10), 755; https://doi.org/10.3390/cells14100755 - 21 May 2025

Abstract

Glioblastoma, IDH wild-type WHO Grade IV, is a devastating diagnosis in pediatric and adult populations with a poor prognosis and median overall survival of less than two years. Despite the advent of the Stupp protocol and advances in neurosurgical tumor resection techniques, there [...] Read more.

Glioblastoma, IDH wild-type WHO Grade IV, is a devastating diagnosis in pediatric and adult populations with a poor prognosis and median overall survival of less than two years. Despite the advent of the Stupp protocol and advances in neurosurgical tumor resection techniques, there has been minimal change to both the quantity and quality of life in individuals diagnosed. Provided the extensive research on survivin’s association with glioblastoma tumor microenvironment, this review suggests that priming the individual’s immune systems to the tumor-promoting protein may reduce tumor burden through multiple mechanisms, including the arrest of the G2/M phase, microtubule dysfunction, induction of autophagy, and ultimately activation of apoptosis in glioblastoma cells. SurVaxM, a multiple peptide, survivin-specific vaccine, may assist in tumor cell destruction by eliciting the production of cytotoxic T-cells specific to survivin-expression glioblastoma tumors. Although phase I and II clinical trials suggest relatively safe adverse effects and potential efficacy, additional research is necessary to evaluate further how this vaccine may compare to standard treatment. Full article

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