Cells

22 pages, 4199 KB

Open AccessArticle

Neuroserpin: A Potential Neuroprotective Agent in Mild Neonatal Hypoxic–Ischaemic Encephalopathy

by Eri Kawashita, Yumi Fukuzaki, Jan Fischer, Lei Shi, Yumei Liao, Lancelot Jamie Millar, Peiyun Zhong, Anna Hoerder-Suabedissen, Luana Campos Soares and Zoltán Molnár

Cells 2025, 14(23), 1840; https://doi.org/10.3390/cells14231840 - 21 Nov 2025

Abstract

Neonatal hypoxic–ischaemic encephalopathy (HIE) remains a leading cause of infant morbidity and mortality worldwide, with therapeutic hypothermia being the only clinically approved treatment. This study investigates the cortical expression pattern of neuroserpin during postnatal brain development and evaluates its neuroprotective potential in hypoxia–ischaemia [...] Read more.

Neonatal hypoxic–ischaemic encephalopathy (HIE) remains a leading cause of infant morbidity and mortality worldwide, with therapeutic hypothermia being the only clinically approved treatment. This study investigates the cortical expression pattern of neuroserpin during postnatal brain development and evaluates its neuroprotective potential in hypoxia–ischaemia (HI)-induced brain damage using a modified Rice–Vannucci model. Experiments were conducted in both male and female neuroserpin knockout (KO) mice and through administration of exogenous neuroserpin into the brain. Between postnatal day 4 to 14 (P4–P14), neuroserpin-immunoreactive cell density peaked at P8–P10 in cortical layers 5 and 6b, with a gradual increase in layers 2/3 and minimal changes in layers 4 and 6a. Despite comparable levels of ischaemic brain damage between the KO and wild-type (WT) mice, exogenous neuroserpin administration suppressed the HI-induced oxidative stress. Additionally, it reduced microglial activation and reactive astrogliosis in the cortex in mild HIE, mitigating cortical thinning and preserving neuronal distribution. These findings suggest that endogenous neuroserpin alone is insufficient for neuroprotection against HI-induced damage, but exogenous neuroserpin shows promise as a pharmacological intervention for mild neonatal HIE. Full article

(This article belongs to the Special Issue Perinatal Brain Injury—from Pathophysiology to Therapy)

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18 pages, 2976 KB

Open AccessArticle

Fascin Drives Breast Cancer Cell Proliferation Partly by Modulating the Cell Cycle Checkpoint Regulators of the G1-S Phase

by Hazem Ghebeh, Huda K. Al-Nasrallah, Marwa Elfoly, Alanoud Aldossry, Asma Tulbah, Taher Al-Tweigeri and Monther Al-Alwan

Cells 2025, 14(23), 1839; https://doi.org/10.3390/cells14231839 - 21 Nov 2025

Abstract

Breast cancer (BC) is the most frequently diagnosed malignancy in women worldwide. Despite therapeutic advances, disease relapse and metastasis remain major challenges and drivers of mortality. Fascin, an actin-bundling protein, promotes BC progression by enhancing drug resistance. However, the role of fascin in [...] Read more.

Breast cancer (BC) is the most frequently diagnosed malignancy in women worldwide. Despite therapeutic advances, disease relapse and metastasis remain major challenges and drivers of mortality. Fascin, an actin-bundling protein, promotes BC progression by enhancing drug resistance. However, the role of fascin in proliferation, a hallmark of cancer, and the underlying mechanism remain poorly elucidated. In this study, bioinformatics analysis of publicly available BC datasets, gene manipulation (gain and loss of function) in BC cell lines, flow cytometry, Western blots, and a real-time cell analyzer (RTCA) were employed to assess the role of fascin in proliferation. The clinical relevance of bioinformatics data and in vitro findings was assessed in BC patient samples using immunohistochemistry. FSCN1 expression exhibited a significant correlation with proliferation signature scores in BC datasets. Ectopic expression of fascin in fascin-negative SK-BR-3 and its silencing in fascin-positive MDA-MB-231 BC cell lines demonstrated its direct role in driving proliferation. In-depth bioinformatics analyses revealed a significant correlation between FSCN1 and the cell cycle signature score, particularly the G1-S signature score gene set. Indeed, fascin accelerated the cell cycle progression of synchronized cells from the G to S phase. Mechanistically, fascin upregulated nuclear SKP2 levels and reduced p27 expression—important G1-S cell cycle checkpoint regulators. Immunohistochemistry in samples from 68 patients demonstrated significant correlations between fascin and Ki-67 expression, in addition to SKP2 overexpression and p27 downregulation. Collectively, these data demonstrate the role of fascin as a driver of the G1-S-phase transition during cell cycle proliferation, thereby revealing new opportunities for targeted therapeutic intervention. Full article

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

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20 pages, 831 KB

Open AccessReview

Advancements in Cellular Therapeutics in Corneal Diseases

by Elizabeth Woo, Daniel Henick and Maryam Tahvildari

Cells 2025, 14(23), 1838; https://doi.org/10.3390/cells14231838 - 21 Nov 2025

Abstract

Disorders of the cornea are responsible for a significant portion of preventable blindness worldwide. Various types of corneal transplantation procedures have successfully restored vision in many individuals; however, they carry the risk of graft failure due to immune rejection, endothelial cell dysfunction, infections [...] Read more.

Disorders of the cornea are responsible for a significant portion of preventable blindness worldwide. Various types of corneal transplantation procedures have successfully restored vision in many individuals; however, they carry the risk of graft failure due to immune rejection, endothelial cell dysfunction, infections and limbal stem cell deficiency. Thus, regenerative therapies of the cornea serve as promising alternatives or adjunct therapies. With improved understanding of limbal stem cell function and advancement in limbal stem cell culture technologies, major progress has been made in the in vivo and ex vivo cell-based therapies for treatment of corneal diseases. In this review, we summarize the recent developments achieved in cell-based therapeutics to target corneal epithelial, stromal, and endothelial cell disorders. Full article

(This article belongs to the Special Issue Cell Therapeutics for Corneal Diseases)

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28 pages, 1773 KB

Open AccessReview

Heat Shock Protein Chaperome Is a Multi-Faceted Vector for Tumor Cell Migratory Activity, Invasion, and Metastasis

by Viacheslav Fedorov, Andrey Kurkin, Georgii Fofanov, Vitaliya Kaneva, Anna Kondratenko, Stephanie E. Combs and Maxim Shevtsov

Cells 2025, 14(23), 1837; https://doi.org/10.3390/cells14231837 - 21 Nov 2025

Abstract

Heat shock proteins (HSPs), in particular, representatives of the HSP70 and HSP90 families, are the folding centers of cell proteins and have been proven to be overexpressed in various types of solid and hematological malignancies. With their involvement in a number of cellular [...] Read more.

Heat shock proteins (HSPs), in particular, representatives of the HSP70 and HSP90 families, are the folding centers of cell proteins and have been proven to be overexpressed in various types of solid and hematological malignancies. With their involvement in a number of cellular functions (e.g., protection from various stresses including radiochemotherapy, transport regulation, apoptotic signal inhibition, etc.), these chaperones are a valuable target for cancer progression research. However, recent focus has shifted to the HSP interaction network, which includes many molecules involved in cell migration and invasion pathways. Investigating the interplay between different co-chaperones and their effect on cell motility may help with establishing a palette of available diagnostic and therapeutic targets for highly invasive cancer types. In this review, we describe current models of the HSP functional cycle and recent studies proving links between these cycle regulators and contributions to cell migration. Based on detailed studies of various co-chaperones’ involvement in cancer progression, the network approach gives much necessary molecular context to previously established HSP functions. Full article

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19 pages, 880 KB

Open AccessReview

Lipid–Protein Interplay in the Regulation of Receptor Tyrosine Kinases

by Mattia Domenichini, Anna Gogna, Camilla Maggi, Elisa Moreschi, Anna Ventura, Martina Codibue, Elisabetta Grillo, Michela Corsini and Stefania Mitola

Cells 2025, 14(23), 1836; https://doi.org/10.3390/cells14231836 - 21 Nov 2025

Abstract

Receptor tyrosine kinases (RTKs), a class of membrane proteins involved in several physiological processes such as growth, survival, angiogenesis, and differentiation, are profoundly influenced by the microenvironment, particularly by surrounding lipids. Lipids coordinate RTK life cycle at multiple steps. First, receptor lipidation is [...] Read more.

Receptor tyrosine kinases (RTKs), a class of membrane proteins involved in several physiological processes such as growth, survival, angiogenesis, and differentiation, are profoundly influenced by the microenvironment, particularly by surrounding lipids. Lipids coordinate RTK life cycle at multiple steps. First, receptor lipidation is a key post-translational modification for receptor-targeting localization. Then, RTK dimerization and activation are regulated by membrane-enriched lipids like phosphatidylserine and phosphoinositides, gangliosides, and Cholesterol, which directly engage RTK juxtamembrane domain or cytoplasmic tail. Eventually, lipids spatially organize RTK signaling within Cholesterol- and sphingolipid-enriched membrane microdomains. These membrane rafts act as dynamic “signalosomes” coordinating receptor clustering, endocytosis, and recycling. Perturbations in lipid composition remodel raft architecture and alter RTK behavior, contributing to pathological conditions such as cancer, metabolic, and neurodegenerative disorders. Emerging lipid-targeted therapies offer a promising way to enhance RTK-directed therapies. This review aims to explore how specific lipid species and membrane domains modulate RTK activation, clustering, and endocytic recycling. By bridging biochemical and pathological perspectives, we discuss how membrane lipid composition reshapes RTK signaling in physiology and pathology, pointing to emerging opportunities for lipid-focused therapeutic modulation. Full article

(This article belongs to the Special Issue Biochemical Interaction and Supramolecular Complexes of Receptors in Cell Membranes)

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17 pages, 3518 KB

Open AccessArticle

Chemically Defined, Efficient Megakaryocyte Production from Human Pluripotent Stem Cells

by Jae Eun Kim, Yeonmi Lee, Yonghee Kim, Sae-Byeok Hwang, Yoo Bin Choi, Jongsuk Han, Juyeol Jung, Jae-woo Song, Je-Gun Joung, Jeong-Jae Ko and Eunju Kang

Cells 2025, 14(22), 1835; https://doi.org/10.3390/cells14221835 - 20 Nov 2025

Abstract

Platelet shortage poses a significant barrier to research and transfusion therapies because native megakaryocytes (MKs) are scarce in blood. To overcome this limitation, pluripotent stem cell–derived MKs (PSC-MKs) offer a standardized, donor-independent platform for research and therapeutic development, including disease modeling and ex [...] Read more.

Platelet shortage poses a significant barrier to research and transfusion therapies because native megakaryocytes (MKs) are scarce in blood. To overcome this limitation, pluripotent stem cell–derived MKs (PSC-MKs) offer a standardized, donor-independent platform for research and therapeutic development, including disease modeling and ex vivo platelet production. Here, we report a chemically defined, feeder-free protocol to generate MKs from human pluripotent stem cells (hPSCs). The protocol combines the small molecule MPL agonist Butyzamide, macrophage colony-stimulating factor (M-CSF), and three-dimensional (3D) suspension culture, achieving high efficiency and reproducibility. Butyzamide replaced recombinant thrombopoietin (TPO), yielding comparable CD41⁺/CD42b⁺ populations and enhanced polyploidization. M-CSF accelerated nuclear lobulation and induced 4N MKs, while 3D culture increased yield, cell size, and substrate detachment. Multiple independent assays confirmed mature MK hallmarks, multi-nuclei, demarcation membranes, granules, and elevated mitochondrial respiration. Single-cell RNA sequencing outlined a continuous trajectory from early progenitors to functionally specialized MK subsets. This platform enables reliable MK supply for mechanistic studies and in vitro platelet production, advancing both basic research and therapeutic development. Full article

(This article belongs to the Special Issue Immune Cells from Pluripotent Stem Cells)

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19 pages, 1655 KB

Open AccessArticle

Knocking Out Rap1a Attenuates Cardiac Remodeling and Fibrosis in a Male Murine Model of Angiotensin II-Induced Hypertension

by Cody S. Porter, Larissa T. Brown, Can’Torrius Lacey, Mason T. Hickel and James A. Stewart, Jr.

Cells 2025, 14(22), 1834; https://doi.org/10.3390/cells14221834 - 20 Nov 2025

Abstract

Hypertension is a leading risk factor for cardiovascular disease and is associated with maladaptive cardiac remodeling, including hypertrophy and fibrosis. The roles of the receptor for advanced glycation end-products (RAGE) and the small GTPase Rap1a in angiotensin II (AngII)-induced remodeling remain unclear. This [...] Read more.

Hypertension is a leading risk factor for cardiovascular disease and is associated with maladaptive cardiac remodeling, including hypertrophy and fibrosis. The roles of the receptor for advanced glycation end-products (RAGE) and the small GTPase Rap1a in angiotensin II (AngII)-induced remodeling remain unclear. This study examined how RAGE and Rap1a influence cardiac responses to AngII using wild-type (WT), RAGE knockout (RAGE KO), and Rap1a knockout (RapKO) mice. Cardiac structure and function were evaluated following AngII infusion. RapKO mice were protected from AngII-induced hypertrophy, whereas RAGE KO mice exhibited altered remodeling patterns. AngII consistently increased left ventricular wall thickness across all genotypes, indicating that structural remodeling is primarily treatment-driven. Measures of cardiac output and stroke volume also changed significantly with AngII, suggesting hemodynamic load as a key driver of functional adaptation. In contrast, diastolic functional parameters were genotype-dependent and remained stable with AngII exposure, demonstrating an intrinsic influence of RAGE and Rap1a on myocardial relaxation. These findings highlight distinct roles for RAGE and Rap1a in modulating hypertensive cardiac remodeling and may parallel human hypertensive heart disease, where increased RAGE and Rap1a expression associate with fibrosis and impaired relaxation. Targeting the crosstalk between the RAGE-AT1R axis and the cAMP-EPAC-Rap1a pathway may offer therapeutic potential to reduce adverse cardiac remodeling in hypertension. Full article

(This article belongs to the Special Issue The Roles of the Extracellular Matrix in Cardiac Structure and Function: A Commemorative Issue in Honor of Dr. Thomas K. Borg)

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16 pages, 4944 KB

Open AccessArticle

Reduced RhoGDI2 Expression Disrupts Centrosome Functions and Promotes Mitotic Errors

by Mudrika Tripathi, Nancy Garbacki, Jérôme Willems, Gaël Cobraiville, Marianne Fillet, Alain Colige and Christophe F. Deroanne

Cells 2025, 14(22), 1833; https://doi.org/10.3390/cells14221833 - 20 Nov 2025

Abstract

RhoGDI2 is a RhoGTPase regulator that has roles in cytoskeleton organization and cell survival, amongst others. It is differentially expressed in many cell types and tissues, including several human cancers, where its expression has been correlated with either good or bad prognosis. To [...] Read more.

RhoGDI2 is a RhoGTPase regulator that has roles in cytoskeleton organization and cell survival, amongst others. It is differentially expressed in many cell types and tissues, including several human cancers, where its expression has been correlated with either good or bad prognosis. To identify the underlying mechanisms, we knocked down its expression in human cancer cell lines. We observed that repression of RhoGDI2 expression, but not that of the closely related RhoGDI1, significantly reduces their proliferation rate. In parallel, RhoGDI2 suppression induces supernumerary centrosomes and inhibits ciliogenesis. As RhoGDIs are regulators of GTPases, we checked whether key RhoGTPases are involved in these effects. We found that silencing RhoA partially rescued the induction of supernumerary centrosomes and ciliary defects observed upon RhoGDI2 silencing. It was previously shown that RhoGDI2 is strongly expressed in immune cells and that there are striking similarities between primary cilia and immune synapses. Based on this knowledge, we silenced RhoGDI2 in NK cells and could demonstrate that this strongly affects their immune synapse-related cancer cell-killing activity. Altogether, these data suggest novel roles for RhoGDI2 in centrosome functions in human cancer and immune synapses in immune cells, which provides an explanation for its reported dual role in cancer. Full article

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20 pages, 932 KB

Open AccessReview

Integrin αvβ3 as a Non-Genomic Estrogen Receptor in Breast Cancer for Signaling Pathways and Crosstalk

by Kuan Wang, Zi-Lin Li, Lin-Yi Huang, Chih-Jung Yao, Dana R. Crawford, Chih-Yang Wang, Ju-Ku Mo, Ya-Jung Shih, Hung-Yun Lin and Jacqueline Whang-Peng

Cells 2025, 14(22), 1832; https://doi.org/10.3390/cells14221832 - 20 Nov 2025

Abstract

Integrin αvβ3, a key member of the integrin family, plays a crucial role in cell localization, mobilization, and signal transduction through collaborating with extracellular proteins. Its unique expression and activation in tumor cells and rapidly dividing endothelial cells suggest its potential role in [...] Read more.

Integrin αvβ3, a key member of the integrin family, plays a crucial role in cell localization, mobilization, and signal transduction through collaborating with extracellular proteins. Its unique expression and activation in tumor cells and rapidly dividing endothelial cells suggest its potential role in cancer cell growth and metastasis, making it a promising therapeutic target. In genomic pathways, estrogen binds to its receptors to form transcription complexes that bind to the promoters of steroid hormone-receptive genes. Conversely, G protein-coupled estrogen receptor 1 (GPER) and integrin αvβ3 have been shown to play oles in non-genomic actions that contribute to estrogen-induced cancer growth. The molecular mechanisms of these non-genomic functions involve signal transduction via focal activated kinase (FAK), mitogen-activated protein kinase (ERK1/2), and phosphatidylinositol 3-kinase (PI3K), as well as the differential expression of multiple genes associated with various cellular processes. As a hormone receptor, integrin αvβ3, collaborating with ER-α and GPER, exhibits a wide range of cellular effects relevant to cancer biology. Full article

(This article belongs to the Special Issue Hormone Receptors in Cancers: From Molecular Insights to Clinical Applications)

24 pages, 1045 KB

Open AccessReview

From Senescent Cells to Systemic Inflammation: The Role of Inflammaging in Age-Related Diseases and Kidney Dysfunction

by Federica De Luca, Valentina Camporeale, Giorgia Leccese, Roberto Cuttano, Dario Troise, Barbara Infante, Giovanni Stallone, Giuseppe Stefano Netti and Elena Ranieri

Cells 2025, 14(22), 1831; https://doi.org/10.3390/cells14221831 - 20 Nov 2025

Abstract

Aging is characterized by a chronic, low-grade inflammatory state known as inflammaging, which closely interacts with immunosenescence—the gradual deterioration of immune function. Together, these processes contribute to tissue dysfunction and the development of age-related diseases. This review explores the cellular and molecular mechanisms [...] Read more.

Aging is characterized by a chronic, low-grade inflammatory state known as inflammaging, which closely interacts with immunosenescence—the gradual deterioration of immune function. Together, these processes contribute to tissue dysfunction and the development of age-related diseases. This review explores the cellular and molecular mechanisms underlying inflammaging, including mitochondrial dysfunction, telomere attrition, impaired autophagy, and gut microbiota dysbiosis. A particular emphasis is given to the senescence-associated secretory phenotype (SASP), which sustains a pro-inflammatory microenvironment and exacerbates tissue damage. We further discuss the impact of inflammaging on major age-related pathologies, with a focus on the kidney as a paradigmatic model of age-related decline, where inflammaging and cellular senescence contribute to chronic kidney disease (CKD) and impaired regeneration. Finally, we summarize emerging therapeutic strategies such as senolytics, senomorphics, immunomodulation, and lifestyle interventions, aimed at reducing the burden of senescent cells, mitigating inflammaging and extending healthspan. Full article

(This article belongs to the Special Issue The Role of Cellular Senescence in Health, Disease, and Aging)

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20 pages, 6092 KB

Open AccessArticle

Region-Specific Roles of TGF-β2 and Angiotensin II in Fibrotic and Inflammatory Remodeling of the Optic Nerve Head

by Si-Eun Oh, Jie-Hyun Kim, Se-Eun Park, Chan-Kee Park and Hae-Young Lopilly Park

Cells 2025, 14(22), 1830; https://doi.org/10.3390/cells14221830 - 20 Nov 2025

Abstract

This study investigated the region-specific roles of transforming growth factor-β2 (TGF-β2) and angiotensin II (AngII) in extracellular matrix (ECM) remodeling and inflammatory responses within scleral tissues surrounding the optic nerve head (ONH), using primary human fibroblasts from posterior sclera, peripapillary sclera (ppScl), and [...] Read more.

This study investigated the region-specific roles of transforming growth factor-β2 (TGF-β2) and angiotensin II (AngII) in extracellular matrix (ECM) remodeling and inflammatory responses within scleral tissues surrounding the optic nerve head (ONH), using primary human fibroblasts from posterior sclera, peripapillary sclera (ppScl), and fibroblast-like cells from lamina cribrosa (LC). In vivo validation was performed in a chronic ocular hypertension rat model. Fibrotic and inflammatory markers were analyzed by Western blotting, quantitative PCR, and immunocytochemistry following TGF-β2 or AngII stimulation, and in vivo effects were assessed after subtenon injection of pathway-specific inhibitors. TGF-β2 induced robust upregulation of α-smooth muscle actin, collagen type I, and fibronectin across all scleral regions, whereas AngII elicited regionally confined pro-inflammatory responses, particularly in the LC and ppScl, characterized by increased cyclooxygenase-2 expression. Inhibition of either pathway reduced ECM deposition in vivo, but only AngII blockade significantly attenuated glial activation and preserved retinal ganglion cells. These findings demonstrate that TGF-β2 predominantly drives fibrosis, while AngII promotes region-specific neuroinflammation, and that inflammation, rather than fibrosis alone, plays a critical role in glaucomatous neurodegeneration. Targeting both fibrotic and inflammatory mechanisms in a region-specific manner may offer improved neuroprotection in glaucoma. Full article

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18 pages, 1115 KB

Open AccessPerspective

The Crosstalk Between Mycobacterium abscessus and Immune Cells: Exploring Novel Interaction Modalities

by Ilse Mendoza-Trujillo, Patricia Diez-Echave, Chiara Tontini and Silvia Bulfone-Paus

Cells 2025, 14(22), 1829; https://doi.org/10.3390/cells14221829 - 20 Nov 2025

Abstract

Mycobacterium abscessus (Mab) is a rapidly growing, non-tuberculous mycobacterium and opportunistic pathogen that causes lung and skin infections in immunocompromised individuals. In recent years, Mab has gained attention due to its resistance to multiple antibiotics and its ability to evade the [...] Read more.

Mycobacterium abscessus (Mab) is a rapidly growing, non-tuberculous mycobacterium and opportunistic pathogen that causes lung and skin infections in immunocompromised individuals. In recent years, Mab has gained attention due to its resistance to multiple antibiotics and its ability to evade the immune response by transitioning into different morphotypes. Macrophages and neutrophils play key roles during the acute phase of infection and granuloma formation, utilising clearance mechanisms that affect the smooth and rough morphotypes differently. Despite considerable research, the inflammatory response elicited by Mab and its impact on disease outcomes remain not well understood. This perspective examines the interactions between Mab and immune cells, proposing potential receptors that may mediate Mab-driven immune communication. By drawing insights from immune evasion and signalling strategies employed by other mycobacterial species, it aims to deepen our understanding of Mab pathogenicity and to outline innovative approaches for infection control. Full article

(This article belongs to the Special Issue Host–Pathogen Interactions and Immune Responses)

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17 pages, 5800 KB

Open AccessArticle

FGF12 Enhances Prostate Cancer Cell Survival via the YB1-lncRNA Axis

by Zechao Huang, Sonia H. Y. Kung, Hans Adomat, Htoo Zarni Oo, Connor Forbes, Faraz Hach and Xuesen Dong

Cells 2025, 14(22), 1828; https://doi.org/10.3390/cells14221828 - 20 Nov 2025

Abstract

Treatment-induced neuroendocrine prostate cancer (t-NEPC) is a highly aggressive and therapy-resistant subtype of prostate cancer characterized by lineage plasticity and poor response to standard chemotherapy and androgen deprivation therapy. Although transcriptional mechanisms driving t-NEPC have been extensively studied, the contribution of post-transcriptional regulation [...] Read more.

Treatment-induced neuroendocrine prostate cancer (t-NEPC) is a highly aggressive and therapy-resistant subtype of prostate cancer characterized by lineage plasticity and poor response to standard chemotherapy and androgen deprivation therapy. Although transcriptional mechanisms driving t-NEPC have been extensively studied, the contribution of post-transcriptional regulation remains less defined. Here, we report fibroblast growth factor 12 (FGF12) as a critical post-transcriptional regulator of t-NEPC progression. Transcriptomic analyses of patient biopsies, patient-derived xenografts, and prostate cancer cell models consistently demonstrated elevated FGF12 expression in t-NEPC, which was further validated by immunohistochemistry in archival specimens. Functional assays revealed that FGF12 expression conferred survival of cancer cells to chemotherapeutic agents, including etoposide and camptothecin. Integrative RNA sequencing and affinity purification–mass spectrometry showed that FGF12 mediates these functions mainly through interaction with the RNA-binding protein YB1, leading to stabilization of oncogenic long noncoding RNAs, including NEAT1 and MALAT1, whereas RNA silencing of YB1 abrogated the ability of FGF12 to upregulate these transcripts. Collectively, these findings uncover a previously unrecognized FGF12-YB1-lncRNA signaling axis that drives t-NEPC progression. Targeting this pathway may provide new therapeutic opportunities for patients with this aggressive disease. Full article

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20 pages, 5208 KB

Open AccessArticle

Multifaceted Effects of Thymoquinone on Platelet Calcium Homeostasis

by Natalia Rukoyatkina, Igor Mindukshev, Diana M. Mikhailova, Mikhail A. Panteleev and Stepan Gambaryan

Cells 2025, 14(22), 1827; https://doi.org/10.3390/cells14221827 - 20 Nov 2025

Abstract

Thymoquinone (TQ), the main bioactive ingredient of Nigella sativa, exhibits numerous pharmacological activities and is used for the prevention of many diseases including hypertension and cancer. However, information concerning the effects of TQ on platelets is limited. In this study, we used [...] Read more.

Thymoquinone (TQ), the main bioactive ingredient of Nigella sativa, exhibits numerous pharmacological activities and is used for the prevention of many diseases including hypertension and cancer. However, information concerning the effects of TQ on platelets is limited. In this study, we used the upgraded laser microparticle analyzer LaSca-TMF for simultaneous analysis of platelet shape change, aggregation, and changes in [Ca²⁺]_i. We showed that TQ acutely inhibited platelet aggregation induced by ADP, Trap-6, and CRP; however, the rise of [Ca²⁺]_i was inhibited only in CRP-stimulated platelets, but not in ADP- or Trap-6-stimulated ones. DTT, a thiol-reducing agent, prevented TQ-induced effects in platelets, indicating that protein disulfide isomerases could be involved in the regulation of TQ effects on platelets. Our results, for the first time, demonstrated acute inhibitory effects of TQ on platelet activation induced by GPCRs and ITAM-containing receptors, which were independent of PKA and caspase-3 activation. To the best of our knowledge, this is the first example in which complete inhibition of ADP- and Trap-6-, but not CRP-induced, aggregation is accompanied by high [Ca²⁺]_i levels. Additional experimental approaches are required to explain some effects of TQ on calcium homeostasis and TQ could be a valuable molecule for the analysis of calcium homeostasis in platelets and other cells. Full article

(This article belongs to the Special Issue Molecular and Cellular Insights into Platelet Function, 2nd Edition)

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24 pages, 2412 KB

Open AccessReview

Innate Immune Pairing: Eosinophils as Hidden Architects of T Cell Immunity

by Kriti Gupta, Natalie A. Falta and Lisa A. Spencer

Cells 2025, 14(22), 1826; https://doi.org/10.3390/cells14221826 - 20 Nov 2025

Abstract

Eosinophils, once primarily considered strictly end-stage effector cells in parasitic infections and allergic inflammation, are now emerging as vital immunoregulatory cells. This review focuses on eosinophil contributions to cell-mediated adaptive immunity by exploring the multifaceted interactions between eosinophils and T cells that underlie [...] Read more.

Eosinophils, once primarily considered strictly end-stage effector cells in parasitic infections and allergic inflammation, are now emerging as vital immunoregulatory cells. This review focuses on eosinophil contributions to cell-mediated adaptive immunity by exploring the multifaceted interactions between eosinophils and T cells that underlie their unique contributions to immune modulation in allergic diseases. We begin by reviewing key features of eosinophil immunobiology within the context of their relevance to the development, differentiation, and function of CD4⁺ and CD8⁺ T cells in homeostasis and immunity. Building on this framework, we review recent literature revealing new roles for eosinophils in homeostatic immunosuppression, adaptive immune initiation, and immunomodulation within the context of an active immune response. We further explore the significance of eosinophil functionality impacting the structure and function of primary and secondary lymphoid organs, including thymic involution and regeneration, on cell-mediated immunity. This review presents an evolving paradigm that positions eosinophils as essential players in shaping multiple layers of the immune landscape in allergic diseases and beyond. Full article

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

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35 pages, 3906 KB

Open AccessReview

A Comprehensive Review of Modern Cancer Therapies Utilizing Oncolytic Viruses

by Michał Sułek and Agnieszka Szuster-Ciesielska

Cells 2025, 14(22), 1825; https://doi.org/10.3390/cells14221825 - 20 Nov 2025

Abstract

Oncolytic viruses (OVs) are gaining traction as advanced tools in cancer therapy. They are distinguished by their ability to destroy malignant cells while sparing normal tissue specifically. In addition to their direct tumor-lysing properties, an essential benefit of oncolytic virus therapy is its [...] Read more.

Oncolytic viruses (OVs) are gaining traction as advanced tools in cancer therapy. They are distinguished by their ability to destroy malignant cells while sparing normal tissue specifically. In addition to their direct tumor-lysing properties, an essential benefit of oncolytic virus therapy is its capacity to activate both the innate and adaptive immune systems. To enhance these therapeutic actions, many OVs have been genetically engineered to encode immune-modulating factors that reestablish or strengthen antitumor immune responses. Recent studies show that combining OVs with other forms of immunotherapy—such as immune checkpoint inhibitors, CAR-T cells, specific T-cell receptor therapies, or autologous tumor-infiltrating lymphocytes—offers significant advances in cancer treatment. This article reviews how OVs work, discusses strategies to enhance their immunogenicity further, and presents the latest rational combinations of oncolytic viruses with other immunotherapies based on current preclinical and clinical research. Full article

(This article belongs to the Special Issue How Can We Optimise Cancer Therapy? Tumour Microenvironment and Immune Evasion Strategies)

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21 pages, 1331 KB

Open AccessArticle

Osteopontin Preconditioning Improves the Regenerative Effects of Mesenchymal Stem Cells In Vitro but Not Their Therapeutic Efficacy Following Hypoxia-Ischemia in Mice

by Sara T. De Palma, Celine N. van Wijk-Eeftink, Lisanne M. Baak, Cora H. A. Nijboer and Caroline G. M. de Theije

Cells 2025, 14(22), 1824; https://doi.org/10.3390/cells14221824 - 20 Nov 2025

Abstract

Hypoxic-ischemic (HI) brain injury is associated with high mortality and severe long-term neurodevelopmental impairments in term newborns. Intranasal mesenchymal stem cell (MSC) therapy is a promising strategy to boost neurorepair after injury, and optimization strategies to further enhance its therapeutic potential are under [...] Read more.

Hypoxic-ischemic (HI) brain injury is associated with high mortality and severe long-term neurodevelopmental impairments in term newborns. Intranasal mesenchymal stem cell (MSC) therapy is a promising strategy to boost neurorepair after injury, and optimization strategies to further enhance its therapeutic potential are under development. In this study, we explored whether 24 h preconditioning of MSCs with 1000 ng/mL of osteopontin (OPN) could enhance MSC properties in vitro and in vivo. OPN-preconditioned MSCs (OPN-MSCs) showed increased activation of the ERK transcription pathway at 1 h during preconditioning and enhanced migration compared to naïve-MSCs. OPN preconditioning also altered gene expression of neurotrophic and immunomodulatory factors in MSCs. In vitro assessment of MSC potency showed that while OPN-MSCs were as effective as naïve-MSCs in reducing microglia activation, OPN preconditioning enhanced the potency of MSCs to boost neural stem cell differentiation into more complex neurons. However, in vivo, OPN-MSCs were not superior to naïve-MSCs in reducing lesion size in mice when applied at 3 days post-HI. Altogether, OPN preconditioning enhanced the migratory and neurotrophic properties of MSCs in vitro but not in vivo, highlighting its potential to optimize MSC function while underscoring the need for further research to refine in vivo translation and to evaluate functional outcomes for therapeutic efficacy. Full article

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21 pages, 983 KB

Open AccessReview

Valeric Acid: A Gut-Derived Metabolite as a Potential Epigenetic Modulator of Neuroinflammation in the Gut–Brain Axis

by Chiara Paciolla, Michele Manganelli, Mariagiovanna Di Chiano, Francesca Montenegro, Anna Gallone, Fabio Sallustio and Gabriella Guida

Cells 2025, 14(22), 1823; https://doi.org/10.3390/cells14221823 - 20 Nov 2025

Abstract

The gut–brain axis (GBA) is a critical area of research for understanding the pathogenesis of neuroinflammatory and neurodegenerative diseases. Metabolites produced by the gut microbiota, particularly short-chain fatty acids (SCFAs), act as key mediators in this bidirectional communication. While the roles of acetate, [...] Read more.

The gut–brain axis (GBA) is a critical area of research for understanding the pathogenesis of neuroinflammatory and neurodegenerative diseases. Metabolites produced by the gut microbiota, particularly short-chain fatty acids (SCFAs), act as key mediators in this bidirectional communication. While the roles of acetate, propionate, and butyrate are well-established, valeric acid (VA), a five-carbon SCFA, is poorly understood. This comprehensive review explores VA as a gut-derived physiological epigenetic modulator, examining its microbial biosynthesis and systemic effects. This review discusses how VA acts as a selective histone deacetylase inhibitor (HDACi), particularly targeting Class I HDACs, to modulate gene expression and exert neuroprotective and anti-inflammatory effects. The analysis compares VA with its pharmacological analog, valproic acid (VPA), a well-known but non-selective HDACi. This comparison highlights how VA’s physiological nature may offer a more targeted and safer intervention. In conclusion, elucidating VA’s role as a microbiome-derived epigenetic regulator would open promising avenues for therapeutic strategies that directly connect gut and CNS health within the GBA. Full article

(This article belongs to the Special Issue Molecular and Cellular Advances in Gut-Brain Axis)

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22 pages, 5839 KB

Open AccessArticle

Novel Nitrogen Heterocycle–Hydroxamic Acid Conjugates Demonstrating Potent Anti-Acute Lymphoblastic Leukemia Activity: Induction of Endogenous Apoptosis and G0/G1 Arrest via Regulation of Histone H3 Acetylation and AKT Phosphorylation in Jurkat Cells

by Lingjie Wu, Li Zhao, Liping Wang, Yi Lu, Gaojie Lou, Bin Zhang and Ning Wang

Cells 2025, 14(22), 1822; https://doi.org/10.3390/cells14221822 - 20 Nov 2025

Abstract

Epigenetics garnered significant scientific interest in recent decades, with histone acetylation emerging as the most prevalent epigenetic deregulation process observed in malignancies. The clinical application of histone deacetylase (HDAC) inhibitors faced challenges, including complex therapeutic mechanisms and inconsistent treatment outcomes. In Acute Lymphoblastic [...] Read more.

Epigenetics garnered significant scientific interest in recent decades, with histone acetylation emerging as the most prevalent epigenetic deregulation process observed in malignancies. The clinical application of histone deacetylase (HDAC) inhibitors faced challenges, including complex therapeutic mechanisms and inconsistent treatment outcomes. In Acute Lymphoblastic Leukemia (ALL), the dysregulation of HDAC activity presents a promising therapeutic target. To investigate cellular-level tumor suppression by HDAC inhibitors possessing potent target engagement, we developed two novel azetidine-hydroxamic acid conjugates. Compared to N-hydroxy-4-((quinolin-4-ylamino)methyl)benzamide (NBU-1), N-hydroxy-6-((5-methyl-4-nitro-9-oxo-9,10-dihydroacridin-1-yl)amino)hexanamide (NBU-2) demonstrated enhanced inhibitory activity against HDAC1 (class I) and HDAC6 (class II) with IC₅₀ values of 7.75 nM and 7.34 nM, respectively, consistent with binding mode analysis and docking energy calculations. In vitro evaluation across 12 tumor cell lines revealed NBU-2’s potent antiproliferative effects, particularly against the ALL-derived Jurkat cells (IC₅₀ = 0.86 μM). Subsequent mechanistic studies were therefore conducted in this ALL model. Proteomic profiling indicated its potential involvement in modulating AKT signaling and histone modification pathways in Jurkat cells. Mechanistic investigations demonstrated that NBU-2 elevated histone acetylation while suppressing AKT phosphorylation. This compound altered apoptotic regulators by downregulating Bcl-2 and Bcl-XL expression while upregulating BAX, ultimately activating Caspase-9 and Caspase-3 to induce apoptosis. Cell cycle analysis revealed NBU-2-mediated G0/G1 arrest through reduced expression of Cyclin D1 and CDK4, diminished Rb protein phosphorylation, and increased p21 expression. These findings propose a strategic framework for developing next-generation HDAC inhibitors for ALL treatment and elucidating their mechanism-specific anti-cancer actions. Full article

(This article belongs to the Topic Bioactive Compounds and Therapeutics: Molecular Aspects, Metabolic Profiles, and Omics Studies 2nd Edition)

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