Cells

16 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

Viewed by 610

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

Viewed by 472

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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15 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

Viewed by 410

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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19 pages, 1500 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

Viewed by 708

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)

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23 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

Cited by 1 | Viewed by 1399

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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19 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

Viewed by 415

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, 1116 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

Viewed by 575

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

Viewed by 567

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

Viewed by 401

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

Viewed by 721

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

Viewed by 2709

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

Viewed by 633

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

Cited by 2 | Viewed by 856

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

Viewed by 560

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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40 pages, 2306 KB

Open AccessReview

Enamel Maturation as a Systems Physiology: Ion Transport and Pi Flux

by Mehrnaz Zarinfar, Marziyeh Aghazadeh, Rucha Arun Bapat, Yanbin Ji and Michael L. Paine

Cells 2025, 14(22), 1821; https://doi.org/10.3390/cells14221821 - 20 Nov 2025

Viewed by 845

Abstract

Dental enamel, the final product of amelogenesis, is a highly mineralized bioceramic that becomes acellular and non-regenerating after tooth eruption. This paper reviews literature that explores inorganic phosphate (Pi) transport during the process of enamel formation or amelogenesis. Evidence from transcriptomics, immunolocalization, and [...] Read more.

Dental enamel, the final product of amelogenesis, is a highly mineralized bioceramic that becomes acellular and non-regenerating after tooth eruption. This paper reviews literature that explores inorganic phosphate (Pi) transport during the process of enamel formation or amelogenesis. Evidence from transcriptomics, immunolocalization, and physiology implicates ameloblast-specific sodium-dependent Pi uptake by type III sodium–phosphate cotransporters SLC20A1 (PiT1) and SLC20A2 (PiT2), and by type IIb sodium–phosphate cotransporter SLC34A2 (NaPi-IIb) with stage-specific basal (proximal) or apical (distal) enrichment, and pH-dependent expression. Controlled Pi efflux to the enamel space has been partly attributed to xenotropic and polytropic retrovirus receptor (XPR1) mediated Pi export during maturation-stage amelogenesis. These amelogenesis-specific Pi fluxes operate within a polarized cellular framework in which Ca²⁺ delivery and extrusion, together with bicarbonate-based buffering regulated by cystic fibrosis transmembrane conductance regulator (CFTR), Solute carrier family 26 (SLC26) exchangers, anion exchanger 2 (AE2), and electrogenic sodium bicarbonate cotransporter 1 (NBCe1), at-least partially contribute to cellular Pi activity, and neutralize protons generated as the extracellular hydroxyapatite-based enamel matures. Disruption of phosphate handling reduces crystal growth and final mineral content of enamel, and produces hypomineralized or hypomature enamel with opacities, post-eruptive breakdown, and greater caries susceptibility. This review integrates multi-modal findings to appraise established features of ameloblast Pi handling, define constraints imposed by pH control and Ca²⁺ transport, and identify gaps in ion transporter topology and trafficking dynamics. Full article

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26 pages, 1876 KB

Open AccessReview

The m⁶A Modification in Neurodegenerative Disease: A Cellular Perspective

by Shuowei Wang, Ziming Feng, Hongjin Wu, Shen Wang, Suping Qin, Xiaotian Wang, Feng Zhou, Kuiyang Zheng, Xufeng Huang and Xiaomei Liu

Cells 2025, 14(22), 1820; https://doi.org/10.3390/cells14221820 - 20 Nov 2025

Viewed by 1011

Abstract

N6-methyladenosine (m⁶A) is the most abundant internal RNA modification in eukaryotes and plays a critical role in gene expression regulation by influencing RNA stability, splicing, nuclear export, and translation. Emerging evidence suggests that dysregulation of m⁶A contributes to neuroinflammation, [...] Read more.

N6-methyladenosine (m⁶A) is the most abundant internal RNA modification in eukaryotes and plays a critical role in gene expression regulation by influencing RNA stability, splicing, nuclear export, and translation. Emerging evidence suggests that dysregulation of m⁶A contributes to neuroinflammation, neurotoxicity, and synaptic dysfunction—key features of neurodegenerative diseases. This review aims to examine the role of m6A modification in neurodegenerative diseases from a cell-type-specific perspective. We systematically reviewed recent studies investigating m⁶A modifications in neurons and glial cells. Data from transcriptomic, epitranscriptomic, and functional studies were analyzed to understand how m⁶A dynamics influence disease-related processes. Findings indicate that m⁶A modifications regulate neuroinflammation and immune responses in microglia, modulate astrocytic support functions, affect myelination through oligodendrocytes, and alter m⁶A patterns in neurons, impacting synaptic plasticity, stress responses, and neuronal survival. These cell-type-specific roles of m⁶A contribute to the progression of neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Amyotrophic lateral sclerosis (ALS). Understanding m⁶A-modulated mechanisms in specific neural cell types may facilitate the development of targeted interventions for neurodegenerative diseases. Full article

(This article belongs to the Section Cellular Neuroscience)

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14 pages, 37937 KB

Open AccessCommunication

Unlocking the Tumor Microenvironment: Innovations in Multiplex Immunohistochemistry

by Bipin Gupta, George Yang and Marc Key

Cells 2025, 14(22), 1819; https://doi.org/10.3390/cells14221819 - 20 Nov 2025

Viewed by 713

Abstract

The immune control of cancer growth is an area of active investigation. In this study, we demonstrated the feasibility of using standard immunohistochemistry methods in conjunction with a set of newly developed chromogens to demonstrate immune cell markers in a multiplex staining system. [...] Read more.

The immune control of cancer growth is an area of active investigation. In this study, we demonstrated the feasibility of using standard immunohistochemistry methods in conjunction with a set of newly developed chromogens to demonstrate immune cell markers in a multiplex staining system. Immune infiltrating cells in breast cancer were identified using antibodies to CD20 (B-cells), CD3 (T-cells), and CD163 (macrophages). Additionally, the tumor compartment was identified using cytokeratin (AE1/AE3), and Ki67 was used to determine the proliferation index. These stains showed a significant immune cell infiltrate surrounding and within the tumors. B-cells, T-cells, and macrophages were abundant at the tumor periphery, particularly in areas where tertiary lymphoid structures were also present. In contrast, B-cells were significantly reduced within the tumor interior compared to an abundant infiltrate of T-cells and macrophages. Patterns of B-cell, T-cell, and macrophage infiltration were identified. Depending upon the particular set of markers chosen for analysis, a simple visual examination, without the aid of computer-assisted imaging systems, was sufficient to differentiate up to five different markers. Full article

(This article belongs to the Special Issue Spatial Biology: Decoding Cellular Complexity in Tissues)

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20 pages, 10240 KB

Open AccessArticle

GV1001, an hTERT-Derived Peptide, Prevents Cisplatin-Induced Nephrotoxicity by Preserving Mitochondrial Function

by Wei Chen, Cheyenne Beheshtian, Seojin Kim, Reuben Kim, Sangjae Kim and No-Hee Park

Cells 2025, 14(22), 1818; https://doi.org/10.3390/cells14221818 - 19 Nov 2025

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Abstract

GV1001, a multifunctional peptide, has shown numerous biomedical activities, including antioxidant, anti-inflammatory, anti-Alzheimer’s, and anti-atherosclerotic effects, and protects mitochondria from cytotoxic agents. Cisplatin is a widely used chemotherapeutic agent against cancers, but its clinical utility is limited by nephrotoxicity driven by mitochondrial dysfunction [...] Read more.

GV1001, a multifunctional peptide, has shown numerous biomedical activities, including antioxidant, anti-inflammatory, anti-Alzheimer’s, and anti-atherosclerotic effects, and protects mitochondria from cytotoxic agents. Cisplatin is a widely used chemotherapeutic agent against cancers, but its clinical utility is limited by nephrotoxicity driven by mitochondrial dysfunction in renal epithelial cells. Here, we investigated whether GV1001 protected against cisplatin-induced nephrotoxicity (CIN) in vivo and preserved mitochondrial integrity in human renal epithelial cells in vitro. In mice, GV1001 substantially mitigated CIN by significantly reducing histological damage, kidney injury marker expression, macrophage infiltration, endothelial-to-mesenchymal transition, inflammation, and apoptosis. In cultured renal epithelial cells, GV1001 maintained mitochondrial membrane potential, preserved ATP production, and prevented mitochondrial membrane peroxidation possibly by binding to cardiolipin. GV1001 also reduced the level of reactive oxygen species (ROS), suppressed cytochrome c release into the cytosol, and inhibited activation of apoptosis-related pathways elicited by cisplatin. Collectively, these findings demonstrated that GV1001 might protect kidney from cisplatin through maintaining mitochondrial structure and function and suppressing downstream injury cascades in renal epithelial cells. By directly targeting the mitochondrial mechanisms underlying cisplatin toxicity, GV1001 represents as a promising therapeutic strategy to mitigate CIN and improve the safety of cisplatin-based chemotherapy. Full article

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33 pages, 10815 KB

Open AccessArticle

Lipid Metabolic Changes and Mitochondrial Stress in Ethanol-Treated Alveolar Type II Epithelial Cells: Initial Events Leading to Alcoholic Chronic Lung Disease

by Mukund Srinivasan and Bhupendra S. Kaphalia

Cells 2025, 14(22), 1817; https://doi.org/10.3390/cells14221817 - 19 Nov 2025

Viewed by 555

Abstract

Alcohol use disorder (AUD) predisposes individuals to pneumonia, acute respiratory distress syndrome, and chronic obstructive pulmonary disease, yet the mechanisms underlying alcohol-related lung disease (ARLD) remain unclear. Alveolar type II (AT2) epithelial cells play a central role in ethanol (EtOH) metabolism, surfactant production, [...] Read more.

Alcohol use disorder (AUD) predisposes individuals to pneumonia, acute respiratory distress syndrome, and chronic obstructive pulmonary disease, yet the mechanisms underlying alcohol-related lung disease (ARLD) remain unclear. Alveolar type II (AT2) epithelial cells play a central role in ethanol (EtOH) metabolism, surfactant production, alveolar repair, and pulmonary innate immunity. To examine EtOH-mediated effects, immortalized human AT2 cells were treated with 22–130 mM EtOH for 6 h (concentration-dependent) and 65 mM EtOH for 6–72 h (time-dependent). Cytotoxicity, inflammation, surfactant lipid/protein dysregulation, fatty acid ethyl ester (FAEE) formation, cellular stress responses, AMP-activated protein kinase (AMPKα) signaling, and mitochondrial function were analyzed. EtOH disrupted surfactant homeostasis by reducing dipalmitoylphosphatidylcholine and surfactant protein C (SP-C). Importantly, EtOH inactivated AMPKα, downregulated CPT1A (involved in β-oxidation of fatty acids), and upregulated lipogenic proteins ACC1 and FAS, accompanied by increased ER stress markers (GRP78, p-eIF2α, and CHOP). Expression of carboxyl ester lipase (FAEE-synthesizing enzyme) and FAEE levels increased with EtOH exposure, further exacerbating oxidative and ER stress, impairing mitochondrial energetics, ATP production, and AT2 cell function. These findings suggest that EtOH-induced FAEE formation, dysregulation of AMPKα-CPT1A signaling, and surfactant contribute to AT2 cell dysfunction and play a critical role in the pathogenesis of ARLD. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Alcohol-Induced Cellular/Organ Injury and Regeneration)

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18 pages, 3942 KB

Open AccessArticle

Cortical Bone Loss and Fragility in a 2-Month Triple Transgenic Mouse Model of Alzheimer’s Disease

by Giuseppina Storlino, Francesca Posa, Teresa Stefania Dell'Endice, Federica Piccolo, Graziana Colaianni, Tommaso Cassano, Maria Grano and Giorgio Mori

Cells 2025, 14(22), 1816; https://doi.org/10.3390/cells14221816 - 19 Nov 2025

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Abstract

Alzheimer’s disease (AD) and osteoporosis frequently co-occur in the elderly; however, the pathophysiological link between these two diseases remains unclear. This study investigates skeletal alterations in a triple transgenic 3xTg-AD mouse model of AD (3xTg-AD), which harbors mutations in β-amyloid precursor protein (βAPP [...] Read more.

Alzheimer’s disease (AD) and osteoporosis frequently co-occur in the elderly; however, the pathophysiological link between these two diseases remains unclear. This study investigates skeletal alterations in a triple transgenic 3xTg-AD mouse model of AD (3xTg-AD), which harbors mutations in β-amyloid precursor protein (βAPP_Swe), presenilin-1 (PS1_M146V), and tau_P301L, and recapitulates key aspects of AD pathology, including age-dependent β-amyloid plaque accumulation and cognitive decline. To assess early skeletal changes, we analyzed femurs and tibiae of 2-month-old male non-Tg and 3xTg-AD mice (n = 9/group) using micro-CT. Despite the absence of β-amyloid plaques at this stage, 3xTg-AD mice showed significant cortical bone loss, with reduced bone surface, periosteal and endosteal perimeters, total and cortical cross-sectional area, and polar moment of inertia. The 3-point-bending test confirmed compromised mechanical properties, including reduced maximum load-to-fracture and stiffness. Histological analyses highlighted an increased number of Empty Osteocyte Lacunae, reduced TRAP⁺ osteocytes, and an elevated number of osteoclasts; such evidence indicates impaired osteocyte function and increased bone resorption. These findings indicate that cortical bone loss and compromised mechanical properties occur before detectable neuropathological hallmarks in this AD model. Full article

(This article belongs to the Special Issue Osteoblasts, Osteoclasts and Bone Diseases: Cellular Crosstalk and Therapeutic Opportunities)

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29 pages, 2779 KB

Open AccessReview

The Two-Way Role of Jagged1 in Cancer: A Focus on CRC

by Sabrina Zema, Francesca Di Fazio, Rocco Palermo, Claudio Talora and Diana Bellavia

Cells 2025, 14(22), 1815; https://doi.org/10.3390/cells14221815 - 19 Nov 2025

Viewed by 766

Abstract

Colorectal cancer (CRC) remains one of the most prevalent and lethal malignancies. Accumulating genetic evidence supports a multistep model of tumor progression, in which early APC loss leads to chromosomal instability and adenoma formation, followed by activating mutations in KRAS that synergize with [...] Read more.

Colorectal cancer (CRC) remains one of the most prevalent and lethal malignancies. Accumulating genetic evidence supports a multistep model of tumor progression, in which early APC loss leads to chromosomal instability and adenoma formation, followed by activating mutations in KRAS that synergize with β-catenin signaling to promote tumor growth and invasion. Among the downstream effectors of these pathways, the Notch ligand Jagged1 has emerged as a critical mediator of CRC progression and chemoresistance. Jagged1 is not only a transcriptional target of the Wnt/β-catenin axis but also undergoes proteolytic cleavage via the KRAS/ERK/ADAM17 signaling cascade, generating a nuclear Jagged1 intracellular domain (Jag1-ICD) that drives reverse signaling. This dual functionality, activating canonical Notch signaling and initiating reverse nuclear signaling, positions Jagged1 as a key oncogenic driver in CRC. In this review, we first summarize the role of Jagged1 as an integral part of canonical Notch signaling. We then focus on the non-canonical Jagged1 reverse signaling function in cancer, with a particular emphasis on CRC. We underscore the dual role of Jagged1 in tumor biology and propose that it functions as a novel oncogene within the adenoma-to-carcinoma sequence, supporting CRC development and drug resistance via non-canonical mechanisms. Full article

(This article belongs to the Special Issue Gastrointestinal Cancer: From Cellular and Molecular Mechanisms to Therapeutic Opportunities)

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36 pages, 2919 KB

Open AccessReview

Viewing Inflammation and Immunoregulation Under the Calpain System Lens

by Vijay Kumar and John H. Stewart IV

Cells 2025, 14(22), 1814; https://doi.org/10.3390/cells14221814 - 19 Nov 2025

Viewed by 892

Abstract

The controlled pro-inflammatory immune response is critical for fighting against external and endogenous threats, such as microbes/pathogens, allergens, xenobiotics, various antigens, and dying host cells and their mediators (DNA, RNA, and nuclear proteins) released into the circulation and cytosol (PAMPs, MAMPs, and DAMPs). [...] Read more.

The controlled pro-inflammatory immune response is critical for fighting against external and endogenous threats, such as microbes/pathogens, allergens, xenobiotics, various antigens, and dying host cells and their mediators (DNA, RNA, and nuclear proteins) released into the circulation and cytosol (PAMPs, MAMPs, and DAMPs). Several pattern recognition receptors (PRRs) and their downstream adaptor molecules, expressed by innate and adaptive immune cells, are critical in generating the inflammatory immune response by recognizing PAMPs, MAMPs, and DAMPs. However, their dysregulation may predispose the host to develop inflammation-associated organ damage, neurodegeneration, autoimmunity, cancer, and even death due to the absence of the inflammation resolution phase. The cytosolic calcium (Ca²⁺) level regulates the survival, proliferation, and immunological functions of immune cells. Cysteine-rich proteases, specifically calpains, are Ca²⁺-dependent proteases that become activated during inflammatory conditions, playing a critical role in the inflammatory process and associated organ damage. Therefore, this article discusses the expression and function of calpain-1 and calpain-2 (ubiquitous calpains) in various innate (epithelial, endothelial, dendritic, mast, and NK cells, as well as macrophages) and adaptive (T and B cells) immune cells, affecting inflammation and immune regulation. As inflammatory diseases are on the rise due to several factors, such as environment, lifestyle, and an aging population, we must not just investigate but strive for a deeper understanding of the inflammation and immunoregulation under the calpain system (calpain-1 and calpain-2 and their endogenous negative regulator calpastatin) lens, which is ubiquitous and senses cytosolic Ca²⁺ changes to impact immune response. Full article

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16 pages, 1267 KB

Open AccessFeature PaperReview

The Role of Microbiota in Ovarian Cancer: Implications for Treatment Response and Therapeutic Strategies

by Jose-Ramon Blanco, Rosa del Campo, José Avendaño-Ortiz, Mariano Laguna-Olmos and Amancio Carnero

Cells 2025, 14(22), 1813; https://doi.org/10.3390/cells14221813 - 19 Nov 2025

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Abstract

Cancer remains a global health challenge (18.1 million new cases in 2020), with incidence projected to reach 28 million within two decades. Ovarian cancer (OC) is the deadliest gynecologic malignancy, usually diagnosed at advanced stages and with poorly understood etiology. Emerging evidence implicates [...] Read more.

Cancer remains a global health challenge (18.1 million new cases in 2020), with incidence projected to reach 28 million within two decades. Ovarian cancer (OC) is the deadliest gynecologic malignancy, usually diagnosed at advanced stages and with poorly understood etiology. Emerging evidence implicates reproductive tract and gut microbiota in OC biology. Microbiota shape carcinogenesis via turnover, immunity, and metabolism; dysbiosis promotes DNA damage, inflammation, and carcinogenic metabolites, engaging multiple hallmarks of cancer. In OC, microbes may reach tumors by local ascent, translocation, or hematogenous spread, originating from vagina, upper reproductive tract, peritoneal fluid, or gut. Lactobacillus-dominant vaginal communities support mucosal integrity, whereas anaerobes disrupt barriers, increase inflammation, and correlate with OC risk; mouse models show vaginal dysbiosis accelerates tumor progression. Distinct microbial profiles in upper reproductive sites and peritoneal fluid associated with immune remodeling. Gut dysbiosis drives barrier loss, immune imbalance, and estrogen reactivation. Microbial metabolites (lipopolysaccharides, short-chain fatty acids) modulate oncogenic pathways, altering epithelial–mesenchymal transition, immune evasion, and drug resistance. Across cohorts, OC tissues and fluids show Pseudomonadota/Bacteroidota enrichment and Akkermansia depletion; fecal microbiota from OC patients accelerates tumor growth in mice, whereas Akkermansia supplementation restores antitumor immunity. Antibiotic exposure and platinum resistance associate with reduced diversity and expansion of lactate-producing taxa. Microbiome-informed interventions–diet, probiotics/postbiotics, fecal microbiota transfer, and selective antibiotics–may augment chemotherapy and immunotherapy. Overall, the microbiome is a modifiable determinant of OC risk, progression, and treatment response, warranting rigorous, standardized, multi-omics studies. Full article

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14 pages, 439 KB

Open AccessArticle

Impact of SARS-CoV-2 Infection and Vaccination on Pregnancy Outcome and Passive Neonatal Immunity

by Gina Marie Uehre, Valeriia Grabar, Evelin Grage-Griebenow, Oliver Klemens, Laura Scholz, Nils Hoymann, Suzan Alboradi, Atanas Ignatov, Svetlana Tchaikovski and Mandy Busse

Cells 2025, 14(22), 1812; https://doi.org/10.3390/cells14221812 - 19 Nov 2025

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Abstract

Background: During the SARS-CoV-2 pandemic, many women were infected or received vaccinations against the virus before or during their pregnancy. Little is known about the possible consequences of vaccination or infection on obstetric outcomes, as well as antibody levels against other infectious [...] Read more.

Background: During the SARS-CoV-2 pandemic, many women were infected or received vaccinations against the virus before or during their pregnancy. Little is known about the possible consequences of vaccination or infection on obstetric outcomes, as well as antibody levels against other infectious agents, such as the TORCH pathogens. Methods: A total of 136 pregnant women were included in our study between March 2022 and February 2024. The concentrations of antibodies against nucleocapsid (NCP), the spike protein of SARS-CoV-2, as well as IgG and IgM antibodies against TORCH, were assessed in the maternal and umbilical cord blood. Results: The patients were grouped into the following categories according to responses given in the questionnaire and antibody titer: controls (neither infected nor vaccinated; N = 17), infected only (N = 35), vaccinated only (N = 21), acutely infected (N = 15), and both vaccinated and experienced a COVID-19 infection (N = 47). No differences between the groups in terms of pregnancy outcomes were found. The presence of IgG antibodies against NCP or spike protein in maternal blood was dependent on the patient’s vaccination status or previous infection, correlating with that in cord blood. The level of maternal IgG against spike protein correlated negatively with TORCH antibodies. Conclusions: The present study demonstrates the infection- and vaccination-dependent formation of SARS-CoV-2-specific antibodies in the mother and their transfer to the unborn child. Further studies are necessary to investigate the interaction between SARS-CoV-2-specific antibodies and antibodies formed by infection (e.g., CMV) or vaccination against other pathogens in the mother and transmitted transplacentally to the unborn child. Full article

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19 pages, 3412 KB

Open AccessArticle

AICAR Inhibits Insulin-Stimulated Glucose Uptake in 3T3-L1 Adipocytes via an AMPK-Independent, ZMP-Dependent Mechanism

by Yazeed Alshuweishi, Fatmah Binzomah Alghamdi, Kieran Patrick and Ian P. Salt

Cells 2025, 14(22), 1811; https://doi.org/10.3390/cells14221811 - 18 Nov 2025

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Abstract

AMP-activated protein kinase (AMPK) is activated by reduced cellular energy charge and mimics the action of insulin in muscle by stimulating increased trafficking of GLUT4 to the plasma membrane. In contrast, we have previously reported that short-term activation of AMPK in adipocytes has [...] Read more.

AMP-activated protein kinase (AMPK) is activated by reduced cellular energy charge and mimics the action of insulin in muscle by stimulating increased trafficking of GLUT4 to the plasma membrane. In contrast, we have previously reported that short-term activation of AMPK in adipocytes has no effect on glucose uptake. Whether prolonged AMPK activation influences adipocyte glucose uptake remains poorly characterised. To investigate the effect of sustained AMPK activation on glucose uptake in adipocytes, glucose uptake and insulin signalling were assessed in 3T3-L1 adipocytes stimulated with AICAR and 991, which activate AMPK by different mechanisms, for 24 h. Furthermore, glucose uptake and GLUT4 levels were assessed in adipocytes or adipose tissue from mice lacking AMPKα1 as a model of prolonged AMPK downregulation. AICAR, but not 991, markedly inhibited insulin-stimulated glucose uptake in 3T3-L1 adipocytes. This effect of AICAR was associated with impaired trafficking of GLUT4 to the plasma membrane but did not alter cellular GLUT4 levels or insulin signalling via AKT. The effect of AICAR did, however, require phosphorylation to the nucleotide ZMP and was associated with altered insulin-stimulated MEK1/2-ERK1/2 phosphorylation. Sustained AMPK downregulation had no effect on adipocyte glucose uptake or GLUT4 levels. Taken together, these data demonstrate that sustained changes in AMPK activity do not alter adipocyte glucose uptake. Furthermore, AICAR reduces insulin-stimulated GLUT4 translocation and glucose uptake in adipocytes by a mechanism that is independent of AMPK but requires phosphorylation of AICAR to ZMP. Full article

(This article belongs to the Special Issue AMPK: From Mechanisms to New Therapies)

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1 pages, 135 KB

Open AccessEditorial

Editorial for Special Issue “Islet Transplantation”

by Shinichi Matsumoto

Cells 2025, 14(22), 1810; https://doi.org/10.3390/cells14221810 - 18 Nov 2025

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Abstract

Islet cell transplantation is revolutionary [...] Full article

(This article belongs to the Special Issue Islet Transplantation)

19 pages, 1916 KB

Open AccessReview

Brucella Immune Escape: TLR Subversion, Antigen Presentation Destruction and T Cell Disorder

by Hanwei Jiao, Gengxu Zhou, Shengping Wu, Chi Meng, Lingjie Wang, Cailiang Fan, Jixiang Li and Yuefeng Chu

Cells 2025, 14(22), 1809; https://doi.org/10.3390/cells14221809 - 18 Nov 2025

Viewed by 717

Abstract

Brucellosis is a severe zoonotic disease caused by Brucella infection, which remains prevalent in several regions worldwide and poses a significant public health challenge. The host deploys complex immune mechanisms to combat the pathogen, including the recognition of pathogenic signals, secretion of inflammatory [...] Read more.

Brucellosis is a severe zoonotic disease caused by Brucella infection, which remains prevalent in several regions worldwide and poses a significant public health challenge. The host deploys complex immune mechanisms to combat the pathogen, including the recognition of pathogenic signals, secretion of inflammatory factors, and activation of innate and adaptive immune responses. Brucella, as a facultative intracellular pathogen, replicates within host cells and establishes chronic infections through diverse immune evasion strategies. These include subversion of Toll-like receptor (TLR) signaling, disruption of antigen presentation, and interference with T cell responses. This review focuses on Brucella species with significant human infectivity, such as B. melitensis and B. abortus, summarizing their interactions with the host immune system. Recent studies have highlighted TLR pathway inhibition, antigen presentation impairment, and T cell dysregulation as key mechanisms of immune evasion. Understanding these processes is crucial for elucidating Brucella pathogenesis and developing novel therapeutic and vaccine strategies against brucellosis. Full article

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20 pages, 9583 KB

Open AccessArticle

Long Non-Coding RNA Analysis of Vitrified Porcine Immature Oocytes During Maturation and Early Parthenogenetic Embryo Development

by De-Cai Xiang, Zhen He, Shi-Qi Pu, De-Meng Mu, Jing Fu, Wen-Juan Chen, Jun-Yu Jiang, Xue-Mei Li, Bao-Yu Jia and Guo-Quan Wu

Cells 2025, 14(22), 1808; https://doi.org/10.3390/cells14221808 - 18 Nov 2025

Viewed by 521

Abstract

The preservation of porcine oocytes is critically important for advancing superior breeds and conserving genetic resources in pig production. Vitrification has gained traction as a preferred alternative to slow freezing for porcine oocytes because of its effectiveness in reducing ice crystal formation, yet [...] Read more.

The preservation of porcine oocytes is critically important for advancing superior breeds and conserving genetic resources in pig production. Vitrification has gained traction as a preferred alternative to slow freezing for porcine oocytes because of its effectiveness in reducing ice crystal formation, yet it can still negatively affect oocyte quality, compromising their in vitro maturation (IVM) and later embryonic development. Long non-coding RNAs (lncRNAs) have proven to be key players in numerous biological processes, such as oocyte growth, maturation, and early embryogenesis. Despite this, the effects of vitrified porcine germinal vesicle (GV) oocytes, particularly regarding IVM and the dynamic expression patterns of lncRNAs during embryonic development, remain largely unclear. To address this gap, this study conducted lncRNA sequencing at the metaphase II (MII), parthenogenetic 4-cell embryo, and parthenogenetic blastocyst stages sourced from both fresh and vitrified GV oocytes. This method enabled us to ascertain the impact of vitrification on lncRNA expression throughout oocyte maturation and embryonic development. Results identified 773 differentially expressed lncRNAs (DELs) at the MII stage, 1973 at the parthenogenetic 4-cell, and 1192 at the parthenogenetic blastocyst. Enrichment analysis of forecasted target genes revealed their involvement in key regulatory pathways associated with the cell cycle, meiosis, stress response, and metabolic activity. Overall, this study provides a comprehensive overview of lncRNA expression during oocyte maturation and embryonic development following porcine GV oocyte vitrification, thereby shedding light on the molecular mechanisms behind vitrification-induced damage. Full article

(This article belongs to the Section Reproductive Cells and Development)

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18 pages, 5640 KB

Open AccessArticle

Single-Cell Cloning and Transcriptomic Analysis Support a Myogenic Origin of Bovine Intramuscular Adipocytes

by Zhendong Tan, Binod Pokhrel and Honglin Jiang

Cells 2025, 14(22), 1807; https://doi.org/10.3390/cells14221807 - 18 Nov 2025

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Abstract

Intramuscular fat (IMF) refers to the adipose tissue located between muscle fibers and is a major determinant of meat quality in cattle. The cellular origin of bovine intramuscular adipocytes remains unclear. Therefore, the objective of this study was to investigate this origin. We [...] Read more.

Intramuscular fat (IMF) refers to the adipose tissue located between muscle fibers and is a major determinant of meat quality in cattle. The cellular origin of bovine intramuscular adipocytes remains unclear. Therefore, the objective of this study was to investigate this origin. We derived single-preadipocyte clones from IMF and subcutaneous fat (SF) of cattle through single-cell cloning and subsequent validation of their potential to differentiate into adipocytes. Transcriptomic analysis of selected single-preadipocyte clones revealed that although both IMF- and SF-derived preadipocyte clones expressed classical preadipocyte markers such as PDGFRA, DLK1, and ZNF423, they differed significantly in global gene expression profile. Notably, many muscle-specific genes (e.g., MYOG, MB, and MYH3) were expressed at high levels in IMF-derived preadipocyte clones while not expressed in SF-derived clones. Functional enrichment analysis of differentially expressed genes between IMF- and SF-derived preadipocyte clones indicated that many muscle-related functions were enriched in the former. Furthermore, high-level expression of muscle-specific genes persisted in mature adipocytes differentiated from IMF-derived preadipocyte clones. We also found that bovine satellite cells, the widely considered progenitor cells of myocytes in postnatal animals, had the ability to form both myocytes and adipocytes under respective differentiation conditions. Based on these findings, we conclude that in cattle, at least some intramuscular adipocytes are derived from satellite cells. Full article

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22 pages, 10255 KB

Open AccessArticle

Targeting PAK1 or PAK4 Uncovers Different Mechanisms of Vascular Reprogramming in Pancreatic Cancer

by Arian Ansardamavandi, Chelsea Dumesny, Sarah Ellis, Ching-Seng Ang, Mehrdad Nikfarjam and Hong He

Cells 2025, 14(22), 1806; https://doi.org/10.3390/cells14221806 - 17 Nov 2025

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Abstract

The tumour microenvironment in pancreatic ductal adenocarcinoma (PDA) regulates vascular function and therapeutic response. P21-activated kinases (PAKs) regulate cytoskeletal dynamics and angiogenesis; however, their roles in vascular reprogramming and chemotherapy responses remain unclear. This study examined the effects of a PAK1 knockdown (PAK1KD) [...] Read more.

The tumour microenvironment in pancreatic ductal adenocarcinoma (PDA) regulates vascular function and therapeutic response. P21-activated kinases (PAKs) regulate cytoskeletal dynamics and angiogenesis; however, their roles in vascular reprogramming and chemotherapy responses remain unclear. This study examined the effects of a PAK1 knockdown (PAK1KD) and a PAK4 knockout (PAK4KO) on vascular remodelling in PDA. Human PANC-1 wild-type (WT), PAK1KD, and PAK4KO cells were injected subcutaneously into the flanks of SCID mice followed gemcitabine treatment. The tumour growth, vascular density, pericyte coverage, adhesion molecules, and hypoxia were determined. A proteomics study was used to identify the molecular changes involved in the vascular pathways. PAK1KD suppressed tumour growth and angiogenesis, promoted vascular normalisation, reduced hypoxia, and increased stromal ICAM-1. PAK4KO inhibited tumour growth, enlarged vessels, enhanced angiogenesis, and reduced hypoxia. PAK4KO did not affect adhesion molecules in the absence of gemcitabine, but markedly upregulated ICAM-1 and VCAM-1 with gemcitabine. Additionally, PAK4KO promoted vascular mimicry (VM) with a compromised integrity in tumour-derived vessels, but enhanced the integrity in endothelial-derived vessels. The proteomics study confirmed the enrichment of molecules in fibronectin and the VEGF pathway in PAK4KO cancer cells, along with the upregulation of EphA2, RhoA, ROCK1, ROCK2, and components of the EPH-ephrin signalling pathway, linking to enhanced VM. Neither PAK1KD nor PAK4KO increased the gemcitabine efficacy. In conclusion, PAK1KD and PAK4KO suppressed tumour growth with distinct vascular effects, but failed to enhance the gemcitabine responses, suggesting that PAK targeting reprograms the PDA vasculature, but offers limited benefit in chemotherapy-resistant models. Full article

(This article belongs to the Special Issue Molecular, Cellular and Biochemical Approaches of Anti-Cancer Drugs)

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