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Cells, Volume 14, Issue 16 (August-2 2025) – 75 articles

Cover Story (view full-size image): Cells (ISSN 2073-4409) is an international, peer-reviewed, open access journal which provides an advanced forum for studies related to cell biology, molecular biology and biophysics. It publishes reviews, research articles, communications and technical notes. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. The Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH) and Society for Regenerative Medicine (Russian Federation) (RPO) are affiliated with Cells and their members receive discounts on the article processing charges.
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23 pages, 2321 KB  
Article
Selective Anticancer Activity and Safety Profile of Chlorochalcones: Impact on Breast Cancer, Blood, and Endothelial Cells
by Sylwia Cyboran-Mikołajczyk, Karolina Matczak, Teresa Kaźmierczak, Natalia Trochanowska-Pauk, Tomasz Walski, Raghvendra Bohara, Karol Bukowski, Agnieszka Krawczyk-Łebek and Edyta Kostrzewa-Susłow
Cells 2025, 14(16), 1299; https://doi.org/10.3390/cells14161299 - 21 Aug 2025
Viewed by 314
Abstract
In the pursuit of novel anticancer therapies, assessing their selectivity and safety profile towards healthy cells is crucial. This study investigated chlorochalcones, derivatives of 2′-hydroxychalcone containing a chlorine atom, for their impact on human breast cancer cells (MCF-7 and MDA-MB-231), healthy blood cells [...] Read more.
In the pursuit of novel anticancer therapies, assessing their selectivity and safety profile towards healthy cells is crucial. This study investigated chlorochalcones, derivatives of 2′-hydroxychalcone containing a chlorine atom, for their impact on human breast cancer cells (MCF-7 and MDA-MB-231), healthy blood cells (erythrocytes, peripheral blood mononuclear cells (PBMCs), platelets), and microvascular endothelial cells (HMEC-1). Our findings demonstrated that chlorochalcones did not detrimentally affect erythrocytes, showing no hemolysis or preserving osmotic resistance and transmembrane potential. They also exhibited minimal impact on normal PBMC viability and varying effects on platelet metabolic activity at therapeutic concentrations. Importantly, these derivatives displayed lower toxicity towards HMEC-1 endothelial cells than towards breast cancer cells, indicating a degree of selectivity. Chlorochalcones have high antiproliferative activity against cancer cells, primarily by inducing apoptosis with virtually no significant impact on cell cycle progression. Their mechanism of action involves the modulation of reactive oxygen species (ROS) levels and induction of mitochondrial dysfunction, including membrane depolarization and reduced mitochondrial mass. Biological activity, including toxicity and ROS modulation, is dependent on the position and number of chlorine atoms. In conclusion, this study highlights the ability of chlorochalcones to effectively target malignant cells while sparing normal circulatory and endothelial cells, thus positioning them as a promising class of candidates for further anticancer drug development. Full article
(This article belongs to the Section Cellular Biophysics)
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12 pages, 3596 KB  
Article
A Novel Role of Protecadherin-7 in Regulation of Pydc3 Expression and the IFN-β Response During Osteoclast Differentiation
by Hyunsoo Kim, Noriko Takegahara and Yongwon Choi
Cells 2025, 14(16), 1298; https://doi.org/10.3390/cells14161298 - 21 Aug 2025
Viewed by 836
Abstract
Protocadherin-7 (Pcdh7) is a member of the protocadherin family, a subgroup of the cadherin superfamily. We previously demonstrated that Pcdh7 functions as a signaling receptor in osteoclast differentiation. In this study, we investigated the potential gene regulatory role of Pcdh7 in this process [...] Read more.
Protocadherin-7 (Pcdh7) is a member of the protocadherin family, a subgroup of the cadherin superfamily. We previously demonstrated that Pcdh7 functions as a signaling receptor in osteoclast differentiation. In this study, we investigated the potential gene regulatory role of Pcdh7 in this process and identified Pyrin domain-containing protein 3 (Pydc3) as a key mediator of Pcdh7-mediated regulation of osteoclast differentiation. Differential gene expression analysis comparing wild-type (Pcdh7+/+) and Pcdh7-deficient (Pcdh7−/−) cells revealed a significant upregulation of Pydc3 in Pcdh7−/− cells. RNAi-mediated knockdown of Pydc3 rescued the impaired osteoclast differentiation in Pcdh7−/− cells, whereas overexpression of Pydc3 suppressed osteoclast differentiation in Pcdh7+/+ cells, suggesting that Pydc3 negatively regulates osteoclast differentiation. Additionally, Pcdh7−/− cells showed elevated expression of interferon response genes and increased production of interferon-β (IFN-β). Neutralization of IFN-β signaling using anti-IFN-β and/or anti-interferon alpha and beta receptor 1 (IFNAR1) antibodies significantly restored osteoclast differentiation in Pcdh7−/− cells. Collectively, these findings uncover a novel role for Pcdh7 in osteoclast differentiation through regulation of Pydc3 expression and IFN-β production. Full article
(This article belongs to the Section Cell Signaling)
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17 pages, 1193 KB  
Review
Tissue-Resident Memory T Cells in Cancer Metastasis Control
by Tyler H. Montgomery, Anuj P. Master, Zeng Jin, Qiongyu Shi, Qin Lai, Rohan Desai, Weizhou Zhang, Chandra K. Maharjan and Ryan Kolb
Cells 2025, 14(16), 1297; https://doi.org/10.3390/cells14161297 - 21 Aug 2025
Viewed by 421
Abstract
Tissue-resident memory T (TRM) cells have emerged as critical sentinels in the control of cancer metastasis, yet their precise roles across different tumor types and tissues remain underappreciated. Here, we review current insights into the mechanisms governing TRM cell seeding and retention in [...] Read more.
Tissue-resident memory T (TRM) cells have emerged as critical sentinels in the control of cancer metastasis, yet their precise roles across different tumor types and tissues remain underappreciated. Here, we review current insights into the mechanisms governing TRM cell seeding and retention in pre-metastatic niches, their effector functions in eliminating disseminated tumor cells, and their dynamic crosstalk with local stromal and myeloid populations. Here, we highlight evidence for organ-specific variability in TRM cell-mediated immunity, discuss strategies for therapeutically harnessing these cells—ranging from vaccination and checkpoint modulation to chemokine axis manipulation—and explore their promise as prognostic biomarkers. Finally, we outline key knowledge gaps and future directions aimed at translating TRM cell biology into targeted interventions to prevent and treat metastatic disease. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Immune Regulation)
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15 pages, 1709 KB  
Article
N-Lactoyl Phenylalanine Disrupts Insulin Signaling, Induces Inflammation, and Impairs Mitochondrial Respiration in Cell Models
by Laila Hedaya, Khaled Naja, Shamma Almuraikhy, Najeha Anwardeen, Asma A. Elashi, Maha Al-Asmakh, Susu M. Zughaier, Meritxell Espino-Guarch, Osama Y. Aldirbashi, Gavin P. Davey and Mohamed A. Elrayess
Cells 2025, 14(16), 1296; https://doi.org/10.3390/cells14161296 - 20 Aug 2025
Viewed by 545
Abstract
N-lactoyl amino acids (Lac-AAs) are key players that regulate appetite and body weight. The most prominent and well-studied member is N-lactoyl phenylalanine (Lac-Phe), which can be induced by food intake, exercise and metformin treatment. However, its broader metabolic impact remains insufficiently characterized. This [...] Read more.
N-lactoyl amino acids (Lac-AAs) are key players that regulate appetite and body weight. The most prominent and well-studied member is N-lactoyl phenylalanine (Lac-Phe), which can be induced by food intake, exercise and metformin treatment. However, its broader metabolic impact remains insufficiently characterized. This study investigates the effects of Lac-Phe on insulin signaling, inflammation, and mitochondrial respiration using HepG2 and differentiated C2C12 cell models, as well as isolated rat brain mitochondria and synaptosomes. Our results demonstrate that Lac-Phe significantly impairs insulin-stimulated phosphorylation of key proteins in the insulin signaling pathway, particularly in skeletal muscle cells, indicating disrupted insulin signaling. Additionally, Lac-Phe exposure increases the secretion of pro-inflammatory cytokines in C2C12 skeletal muscle cells and markedly impairs mitochondrial respiration in HepG2 liver cells and rat brain-derived synaptosomes, but not in isolated mitochondria. These findings highlight potential adverse metabolic effects of Lac-Phe, especially when administered at high concentrations, and underscore the necessity of conducting a comprehensive risk assessment and dose optimization before considering Lac-Phe or related Lac-AAs as therapeutic agents. Our work provides important insights into the molecular liabilities associated with Lac-Phe and calls for further studies to balance its therapeutic promise against possible metabolic risks. Full article
(This article belongs to the Special Issue Biomarkers and Therapeutic Targets in Insulin Resistance)
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20 pages, 4840 KB  
Article
The Function of Transforming Growth Factor 2 in Facilitating Inflammasome Activation to Enhance the Development of Myopia via Complement System
by Sheng-Chun Lin, Yu-An Hsu, Chi-Fong Lin, Chih-Sheng Chen, Peng-Tai Tien, Yao-Chien Wang, Ching-Yao Chang, En-Shyh Lin, Jamie Jiin-Yi Chen, Ming-Yen Wu, Hui-Ju Lin and Lei Wan
Cells 2025, 14(16), 1295; https://doi.org/10.3390/cells14161295 - 20 Aug 2025
Viewed by 383
Abstract
Myopia is one of the major public health conditions with significant complications. This study investigates the role of transforming growth factor (TGF)-β2, complement activation, and inflammasome pathways in myopia progression using a Brown Norway rat model. Myopia was induced, and complement regulation was [...] Read more.
Myopia is one of the major public health conditions with significant complications. This study investigates the role of transforming growth factor (TGF)-β2, complement activation, and inflammasome pathways in myopia progression using a Brown Norway rat model. Myopia was induced, and complement regulation was manipulated using gene therapy via adeno-associated virus (AAV) vectors delivering CD55 or CD55 siRNA. Results showed that TGF-β2 exacerbated myopia by upregulating complement components C3 and C5, suppressing CD55, and activating inflammasome pathways through nuclear factor (NF)-κB signaling, leading to axial elongation and increased refractive errors. Overexpression of CD55 via AAV gene therapy effectively counteracted these effects, reducing axial length elongation and inflammation by suppressing inflammasome markers interleukin (IL)-1β and NLR family pyrin domain containing 3 (NLRP3), as confirmed by real-time quantitative PCR and immunofluorescence analyses. Conversely, silencing CD55 intensified TGF-β2-induced effects, further promoting axial elongation and inflammation. These findings highlight the critical role of CD55 in modulating TGF-β2-driven complement and inflammasome activation during myopia progression. The study suggests that gene therapy targeting CD55 could serve as a novel therapeutic strategy to mitigate myopia and related inflammatory processes, offering a promising avenue for managing this significant public health challenge. Full article
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22 pages, 6193 KB  
Article
Cilastatin Modulates DPEP1- and IQGAP1-Associated Neuro-Glio-Vascular Inflammation in Oxaliplatin-Induced Peripheral Neurotoxicity
by Rita Martín-Ramírez, María Ángeles González-Nicolás, Karen Álvarez-Tosco, Félix Machín, Julio Ávila, Manuel Morales, Alberto Lázaro and Pablo Martín-Vasallo
Cells 2025, 14(16), 1294; https://doi.org/10.3390/cells14161294 - 20 Aug 2025
Viewed by 435
Abstract
Oxaliplatin-induced peripheral neurotoxicity (OIPN) represents a major challenge in cancer therapy, characterized by dorsal root ganglia (DRG) inflammation and disruption of neuro-glio-vascular unit function. In this study, we investigated the involvement of the scaffold protein IQ Motif Containing GTPase Activating Protein 1 (IQGAP1) [...] Read more.
Oxaliplatin-induced peripheral neurotoxicity (OIPN) represents a major challenge in cancer therapy, characterized by dorsal root ganglia (DRG) inflammation and disruption of neuro-glio-vascular unit function. In this study, we investigated the involvement of the scaffold protein IQ Motif Containing GTPase Activating Protein 1 (IQGAP1) and dehydropeptidase-1 (DPEP1) in the DRG response to oxaliplatin (OxPt) and the modulatory effect of cilastatin. Behavioral assessment showed a robust nocifensive response to cold stimuli in OxPt-treated rats, attenuated by cilastatin co-treatment. Our confocal study revealed different cellular and subcellular expression patterns of IQGAP1 and DPEP1 in neurons, glia, and endothelial cells, where both signals overlap approximately one-third. OxPt enhanced cytosolic aggregation of IQGAP1 in neurons and upregulation of signal in glia, accompanied by co-expression of TNFα and IL-6, indicating involvement in the inflammatory process. DPEP1 showed altered subcellular distribution in OxPt-treated animals, suggesting a potential role in the inflammatory cascade. Notably, IQGAP1 expression was diminished in endothelial membranes under OxPt, while cilastatin preserved endothelial IQGAP1-CD31 colocalization, suggesting partial restoration of blood-nerve barrier integrity. These findings identify IQGAP1 and DPEP1 as key players in DRG inflammation and position cilastatin as a promising modulator of OIPN through neuro-glio-vascular stabilization. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Neuropathic Pain)
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25 pages, 2729 KB  
Article
Therapeutic Effects of Neuro-Cells on Amyloid Pathology, BDNF Levels, and Insulin Signalling in APPswe/PSd1E9 Mice
by Johannes P. J. M. de Munter, Andrey Tsoy, Kseniia Sitdikova, Erik Ch. Wolters, Kirill Chaprov, Konstantin B. Yenkoyan, Hamlet Torosyan, Sholpan Askarova, Daniel C. Anthony and Tatyana Strekalova
Cells 2025, 14(16), 1293; https://doi.org/10.3390/cells14161293 - 20 Aug 2025
Viewed by 442
Abstract
Stem cell therapies, including mesenchymal (MSCs) and haematopoietic stem cells (HSCs), have shown promise in neurodegenerative diseases. Here, we investigated the therapeutic effects of a defined combination of unmanipulated MSCs and CD34+ HSCs, termed Neuro-Cells (NC), in a murine model of Alzheimer’s [...] Read more.
Stem cell therapies, including mesenchymal (MSCs) and haematopoietic stem cells (HSCs), have shown promise in neurodegenerative diseases. Here, we investigated the therapeutic effects of a defined combination of unmanipulated MSCs and CD34+ HSCs, termed Neuro-Cells (NC), in a murine model of Alzheimer’s disease (AD), the APPswe/PS1dE9 mouse. At 12 months of age, mice received intracisternal injections of NC (1.39 × 106 MSCs + 5 × 105 HSCs) or vehicle. After 45 days, behavioural testing, immunohistochemical analyses of amyloid plaque density (APD), and cortical gene expression profiling were conducted. NC-treated APP/PS1 mice exhibited preserved object recognition memory and reduced anxiety-like behaviours, contrasting with deficits observed in untreated transgenic controls. Histologically, NC treatment significantly reduced the density of small amyloid plaques (<50 μm2) in the hippocampus and thalamus, and total plaque burden in the thalamus. Gene expression analysis revealed that NC treatment normalised or reversed disease-associated changes in insulin receptor (IR) signalling and neurotrophic pathways. Specifically, NC increased expression of Bdnf, Irs2, and Pgc-1α, while attenuating aberrant upregulation of Insr, Igf1r, and markers of ageing and AD-related pathology (Sirt1, Gdf15, Arc, Egr1, Cldn5). These findings indicate that NC therapy mitigates behavioural and molecular hallmarks of AD, potentially via restoration of BDNF and insulin receptor-mediated signalling. Full article
(This article belongs to the Section Cells of the Nervous System)
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21 pages, 2581 KB  
Review
Post-Translational Modifications in Mammalian Folliculogenesis and Ovarian Pathologies
by Dake Chen, Yue Feng, Junjing Wu, Jiawei Zhou, Zipeng Li, Mu Qiao, Tong Chen, Zhong Xu, Xianwen Peng and Shuqi Mei
Cells 2025, 14(16), 1292; https://doi.org/10.3390/cells14161292 - 20 Aug 2025
Viewed by 411
Abstract
Post-translational modifications (PTMs) of proteins, as the core mechanism for dynamically regulating follicular development, affect the maintenance of mammalian fertility by precisely coordinating granulosa cell–oocyte interaction, metabolic reprogramming, and epigenetic remodeling. Dysregulation of these modifications directly contributes to major reproductive diseases, including polycystic [...] Read more.
Post-translational modifications (PTMs) of proteins, as the core mechanism for dynamically regulating follicular development, affect the maintenance of mammalian fertility by precisely coordinating granulosa cell–oocyte interaction, metabolic reprogramming, and epigenetic remodeling. Dysregulation of these modifications directly contributes to major reproductive diseases, including polycystic ovary syndrome (PCOS) and premature ovarian insufficiency (POI). Post-translational modifications regulate follicular development through intricate mechanisms. Thus, this review systematically synthesizes recent advances in PTMs, encompassing traditional ones such as phosphorylation, ubiquitination, and acetylation, alongside emerging modifications including lactylation, SUMOylation, and ISGylation, thereby constructing a more comprehensive PTM landscape of follicular development. Furthermore, this study dissects the molecular interaction networks of these PTMs during follicular activation, maturation, and ovulation, and uncovers the common mechanisms through which PTM dysregulation contributes to pathological conditions, including hyperandrogenism in PCOS and follicular depletion in POI. Finally, this review ultimately provides a theoretical basis for improving livestock reproductive efficiency and precise intervention in clinical ovarian diseases. Full article
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20 pages, 4459 KB  
Article
Substrate Stiffness Modulates Hypertrophic Chondrocyte Reversion and Chondrogenic Phenotype Restoration
by Da-Long Dong and Guang-Zhen Jin
Cells 2025, 14(16), 1291; https://doi.org/10.3390/cells14161291 - 20 Aug 2025
Viewed by 392
Abstract
The stiffness of the extracellular matrix (ECM) plays a pivotal role in the progression of osteoarthritis (OA), particularly by promoting hypertrophic differentiation of chondrocytes, which hinders cartilage regeneration and accelerates pathological ossification. This study aimed to investigate how substrate stiffness modulates hypertrophic chondrocyte [...] Read more.
The stiffness of the extracellular matrix (ECM) plays a pivotal role in the progression of osteoarthritis (OA), particularly by promoting hypertrophic differentiation of chondrocytes, which hinders cartilage regeneration and accelerates pathological ossification. This study aimed to investigate how substrate stiffness modulates hypertrophic chondrocyte behavior and whether it can reverse their phenotype towards a more stable, chondrogenic state. A series of tunable polydimethylsiloxane (PDMS) substrates with stiffnesses ranging from 78 to 508 kPa were fabricated to simulate varying mechanical microenvironments. Hypertrophic chondrocytes were cultured on these substrates, and their morphology, nuclear architecture, gene/protein expression, and mechanotransductive signaling pathways were systematically evaluated. After 7 to 21 days of culture, the chondrocytes on stiffer matrices exhibited enlarged nuclei, increased cytoskeletal tension, and enhanced focal adhesion signaling. This corresponded with the upregulation of osteogenic and hypertrophic markers such as RUNX2, COL10A1, and COL1A1. In contrast, cells on softer substrates (78 kPa) displayed reduced nuclear YAP localization, higher levels of phosphorylated YAP, and significantly increased expression of COL2A1 and SOX9, indicating reversion to a chondrogenic phenotype. Furthermore, differential activation of Smad1/5/8 and Smad2/3 pathways was observed depending on matrix stiffness, contributing to the phenotype shift. Matrix stiffness exerts a significant regulatory effect on hypertrophic chondrocytes via YAP-mediated mechanotransduction. Soft substrates promote phenotype reversion and cartilage-specific gene expression, offering a promising biomechanical strategy for cartilage tissue engineering and OA intervention. Full article
(This article belongs to the Special Issue Targeting Cellular Microenvironment in Aging and Disease)
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25 pages, 706 KB  
Review
The Roles of Non-Coding RNAs in the Pathogenesis of Uterine Fibroids
by Drake Boos, Tsai-Der Chuang and Omid Khorram
Cells 2025, 14(16), 1290; https://doi.org/10.3390/cells14161290 - 20 Aug 2025
Viewed by 472
Abstract
Uterine fibroids are benign smooth muscle tumors that affect ~70% of women, with Black women being affected at a disproportionate rate. The growth of these tumors is driven by estrogen and progesterone. Driver mutations in genes such as MED12, HMGA2, and FH also [...] Read more.
Uterine fibroids are benign smooth muscle tumors that affect ~70% of women, with Black women being affected at a disproportionate rate. The growth of these tumors is driven by estrogen and progesterone. Driver mutations in genes such as MED12, HMGA2, and FH also play roles in the development and growth of fibroids. Despite their high prevalence, the pathogenesis of fibroids remains largely unknown, leading to a lack of effective therapeutic options. Non-coding RNAs (ncRNAs), including miRNAs (e.g., miR-21, miR-29, miR-200), lncRNAs (e.g., H19, MIAT, XIST), and circRNAs, are important regulatory RNAs that are becoming increasingly implicated in the aberrant expression of protein-coding genes functionally associated with ECM production, cell proliferation, apoptosis, and inflammation in fibroids. Race/ethnicity, MED12 mutations, and ovarian steroids influence the expression of ncRNA expression, further implicating their relevance to fibroid pathogenesis. Therapeutic targeting of these dysregulated ncRNAs in fibroids could enable more precise and individualized non-hormonal-based treatment for this common gynecologic tumor. Full article
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19 pages, 3702 KB  
Article
Kisspeptin Mitigates Hepatic De Novo Lipogenesis in Metabolic Dysfunction-Associated Steatotic Liver Disease
by Kimberly Izarraras, Ankit Shah, Kavita Prasad, Helena Tan, Zhongren Zhou and Moshmi Bhattacharya
Cells 2025, 14(16), 1289; https://doi.org/10.3390/cells14161289 - 20 Aug 2025
Viewed by 618
Abstract
The peptide hormone kisspeptin, signaling via its receptor, KISS1R, decreases hepatic steatosis and protects against metabolic dysfunction-associated steatotic liver disease (MASLD). Enhanced de novo lipogenesis (DNL) contributes to MASLD. Here, we investigated whether kisspeptin treatment in obese, diabetic mice directly attenuates DNL. DNL [...] Read more.
The peptide hormone kisspeptin, signaling via its receptor, KISS1R, decreases hepatic steatosis and protects against metabolic dysfunction-associated steatotic liver disease (MASLD). Enhanced de novo lipogenesis (DNL) contributes to MASLD. Here, we investigated whether kisspeptin treatment in obese, diabetic mice directly attenuates DNL. DNL was assessed in kisspeptin-treated mouse livers, using a mouse model of MASLD, (DIAMOND mice), employing 2H2O-enriched water, mass spectrometry analysis, and transcriptomic profiling. Gene and protein expression were evaluated in primary hepatocytes and livers. Additionally, hepatic Kiss1r expression was increased in DIAMOND mice, following which various biochemical and metabolic assessments were employed. Metabolic tracing in kisspeptin-treated steatotic livers demonstrated a decrease in the DNL of free fatty acids (FFAs), known to be associated with diabetes, steatosis, and hepatocellular carcinoma. Transcriptomic profiling of kisspeptin-treated livers identified disruption of key metabolic pathways, the most prominent being a decrease in fatty acid metabolism, and downregulation of Cidea, a key regulator of lipid droplet formation. Kisspeptin treatment of FFA-loaded primary mouse hepatocytes significantly decreased Cidea expression. Mechanistically, we found that kisspeptin administration decreased levels of transcription factor SREBP-1c, a crucial regulator of DNL, and CIDEA. Thus, enhanced KISS1R signaling limits hepatic DNL, suggesting a crucial role in restricting MASLD. Full article
(This article belongs to the Section Cellular Metabolism)
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24 pages, 3831 KB  
Review
Therapeutic Strategies Targeting Aerobic Glycolysis in Cancer and Dynamic Monitoring of Associated Metabolites
by Mengjie Hu, Kaijie Zheng, Lijiao Zhang, Yue Kan, Jiaqian Zhao and Dajing Chen
Cells 2025, 14(16), 1288; https://doi.org/10.3390/cells14161288 - 19 Aug 2025
Viewed by 336
Abstract
Cancer cells predominantly utilize aerobic glycolysis for energy production, preferentially converting glucose (Glu) to pyruvate (PA) and subsequently to lactate (LA). This metabolic reprogramming results in extracellular LA accumulation, acidifying the tumor microenvironment (TME) and facilitating tumor invasion and metastasis. The dynamics of [...] Read more.
Cancer cells predominantly utilize aerobic glycolysis for energy production, preferentially converting glucose (Glu) to pyruvate (PA) and subsequently to lactate (LA). This metabolic reprogramming results in extracellular LA accumulation, acidifying the tumor microenvironment (TME) and facilitating tumor invasion and metastasis. The dynamics of Glu, PA, and LA are pivotal to tumor initiation and progression. This review comprehensively discussed therapeutic strategies targeting these key metabolites and systematically evaluates electrochemical and fluorescence-based techniques for their dynamic monitoring. We highlight the critical role of these monitoring approaches in advancing early cancer diagnosis, enabling personalized treatment, and accelerating anticancer drug development. Full article
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15 pages, 2208 KB  
Article
Cell Culture in a Hyperbaric Chamber: A Research Model to Study the Effects of Hyperbarism (Hyperbaric Pressure) on Bone Cell Culture
by Alessia Mariano, Valerio Consalvi, Enrico Marchetti, Angelo Rodio, Anna Scotto d’Abusco and Luigi Fattorini
Cells 2025, 14(16), 1287; https://doi.org/10.3390/cells14161287 - 19 Aug 2025
Viewed by 330
Abstract
The hyperbaric environment, to which many categories of workers are exposed, can provoke injuries that can lead to various types of disorders. A major part of the studies aiming to explore the causes/effects leading to these injuries are conducted in vivo. In the [...] Read more.
The hyperbaric environment, to which many categories of workers are exposed, can provoke injuries that can lead to various types of disorders. A major part of the studies aiming to explore the causes/effects leading to these injuries are conducted in vivo. In the present manuscript, we describe the effects on osteoblast cell cultures stressed in a hyperbaric purpose-built chamber, using an in vitro model to analyze the affected pathways. A hyperbaric chamber for cell cultures was constructed by adapting a pressurized test chamber originally designed for technical use. The MG-63 cell line and human primary osteoblasts were placed into this chamber at different atm and exposure times, at 37 °C. After treatment, the chamber was depressurized by performing controlled decompression stops. Then, the pro-inflammatory cytokines and bone tissue biomarker expression were analyzed. The stress conditions induced the overexpression of pro-inflammatory cytokines, such as IL-6, IL-1β, and TNF-α, along with reactive oxygen species release. Moreover, the alteration of bone tissue marker production was observed. In particular, the increase in Receptor Activator of NF-κB Ligand (RANKL) and the decrease in Osteoprotegerin (OPG) were detected. Further modulation was observed regarding other biomarkers, Alkaline phosphatase, Osteocalcin, Bone Morphogenetic Protein-2, and mainly Collagen type I, all of which were downregulated by treatment. Taken together, these findings account for certain illnesses, such as dysbaric osteonecrosis, diagnosed in workers exposed to a hyperbaric environment. Inflammation induced by this kind of stress affects several factors involved in bone tissue homeostasis, leading to bone injuries, which are among the typical disorders observed in divers. Full article
(This article belongs to the Special Issue Cellular and Molecular Players in Bone Homeostasis)
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30 pages, 6716 KB  
Article
Mutation of MeCP2 at T158M Leads to Distinct Molecular and Phenotypic Abnormalities in Male and Female Mice
by Chris-Tiann Roberts, Ashraf Kadar Shahib, Khatereh Saei Arezoumand, Ghanan Bin Akhtar, Kazem Nejati-Koshki, Jessica S. Jarmasz, Seyyed Mohyeddin Ziaee, Marjorie Buist, Nicole Raabe, Abbas Rezaeian Mehrabadi, Carl O. Olson and Mojgan Rastegar
Cells 2025, 14(16), 1286; https://doi.org/10.3390/cells14161286 - 19 Aug 2025
Viewed by 428
Abstract
Methyl CpG-binding protein 2 (MeCP2) is an epigenetic reader of DNA methylation with high abundance in the brain. While genetic mutations occur across different protein domains of MeCP2, the T158M mutation is amongst the most frequent MeCP2 mutations. MeCP2 is encoded by the [...] Read more.
Methyl CpG-binding protein 2 (MeCP2) is an epigenetic reader of DNA methylation with high abundance in the brain. While genetic mutations occur across different protein domains of MeCP2, the T158M mutation is amongst the most frequent MeCP2 mutations. MeCP2 is encoded by the MECP2/Mecp2 gene located on the X chromosome. In humans, MECP2 mutations cause Rett Syndrome, a debilitating neurodevelopmental disorder in females, with very rare cases presenting in males. Despite the generation of different transgenic mouse lines with MeCP2 mutations, the sex-dependent phenotypic and molecular impact of common MeCP2 mutations in mouse models of disease remains largely unexplored. Here, we focus on the MeCP2 T158M mutation using Mecp2tm4.1Bird/J transgenic mice (referred to as Mecp2T158M), and report that Mecp2T158M mutant mice display sex-specific molecular, behavioural, and phenotypic characteristics when compared to wild-type controls. Our data indicates sex- and brain-region-dependent impacts on the expression of MeCP2, synaptic proteins, cytoskeletal markers, and autophagy factors. Our findings demonstrate that the phenotypic and molecular characteristics of this mouse model may relate to the clinical manifestation in human patients with Rett Syndrome. Full article
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16 pages, 682 KB  
Review
Claudin18.2 as a Promising Therapeutic Target in Gastric Cancer
by Agata Poniewierska-Baran, Paulina Plewa, Zuzanna Żabicka and Andrzej Pawlik
Cells 2025, 14(16), 1285; https://doi.org/10.3390/cells14161285 - 19 Aug 2025
Viewed by 549
Abstract
Claudin-18.2 (CLDN18.2) is an isoform of a tight junction protein and has emerged as a promising therapeutic target in gastric cancer (GC). CLDN18.2 is responsible for gastric homeostasis and protects epithelial cells from low pH conditions. Interestingly, CLDN18.2 expression is strictly restricted to [...] Read more.
Claudin-18.2 (CLDN18.2) is an isoform of a tight junction protein and has emerged as a promising therapeutic target in gastric cancer (GC). CLDN18.2 is responsible for gastric homeostasis and protects epithelial cells from low pH conditions. Interestingly, CLDN18.2 expression is strictly restricted to the stomach, making it an ideal tumor marker. This narrative review presents the characterization and role of claudin 18.2 (CLDN18.2) as a promising biomarker in GC and a target for clinical therapies, more specifically CLDN18.2-targeted drugs and therapies including mABs (e.g., Zolbetuximab, Osemitamab, ZL-1211), bsAB, and CAR-T cell-based immunotherapies. We also summarize numerous ongoing worldwide clinical trials that are evaluating CLDN18.2 as a target for GC treatment. What seems to be crucial is that preclinical and clinical data indicate their high efficacy and safety. Full article
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21 pages, 1777 KB  
Article
Decoding ADGRE5: How Proteolytic Cleavage and Mechanical Forces Unleash Cellular Signals
by Ana L. Moreno-Salinas, Arturo Mancini, Samya Aouad, Herthana Kandasamy, Sandra Morissette, Arhamatoulaye Maiga, Michel Bouvier, Richard Leduc and Laurent Sabbagh
Cells 2025, 14(16), 1284; https://doi.org/10.3390/cells14161284 - 19 Aug 2025
Viewed by 411
Abstract
The adhesion G protein-coupled receptor ADGRE5/CD97 is upregulated in many cancers, representing a potential drug target in oncology/immuno-oncology. Yet, ADGRE5′s activation and signaling mechanisms remain poorly understood. Here, we used enhanced bystander bioluminescence resonance energy transfer (ebBRET)-based biosensors and three strategies to characterize [...] Read more.
The adhesion G protein-coupled receptor ADGRE5/CD97 is upregulated in many cancers, representing a potential drug target in oncology/immuno-oncology. Yet, ADGRE5′s activation and signaling mechanisms remain poorly understood. Here, we used enhanced bystander bioluminescence resonance energy transfer (ebBRET)-based biosensors and three strategies to characterize human (h) ADGRE5 signaling. First, a synthetic tobacco etch virus (TEV) protease-cleavable receptor chimera enabling controlled tethered agonist (TA) exposure at the GPCR proteolysis site (GPS) revealed signaling through Gα12 and Gα13, along with the recruitment of β-Arrestins 1/2 (β-Arrs). Second, we investigated WT hADGRE5 signaling elicited by Gingipain K (Kgp), an endopeptidase that cleaves hADGRE5 upstream of the GAIN domain. Kgp mirrored TEV-induced signaling but also promoted Gαz and Gα11 activity. The abolition of hADGRE5′s GPS did not block Kgp-induced receptor activation, revealing a GPS cleavage-independent mechanism of action. Finally, we developed an assay to study hADGRE5 mechanical stimulation (MS) using β-Arr2 as a readout. MS promoted β-Arr2 recruitment in hADGRE5-expressing cells, and this response was lost upon abolition of the GPS. A neutralizing antibody to the hADGRE5 ligand CD55 significantly dampened MS-induced β-Arr2 engagement. Overall, this study advances our understanding of hADGRE5′s signaling and highlights the receptor’s plasticity in activating pathways via both GPS cleavage-dependent and -independent mechanisms. Full article
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18 pages, 1357 KB  
Review
Nonsense-Mediated mRNA Decay: Mechanisms and Recent Implications in Cardiovascular Diseases
by Fasilat Oluwakemi Hassan, Md Monirul Hoque, Abdul Majid, Joy Olaoluwa Gbadegoye, Amr Raafat and Djamel Lebeche
Cells 2025, 14(16), 1283; https://doi.org/10.3390/cells14161283 - 19 Aug 2025
Viewed by 595
Abstract
This review highlights the emerging functional implications of nonsense-mediated mRNA decay (NMD) in human diseases, with a focus on its therapeutic potential for cardiovascular disease. NMD, conserved from yeast to humans, is involved in apoptosis, autophagy, cellular differentiation, and gene expression regulation. NMD [...] Read more.
This review highlights the emerging functional implications of nonsense-mediated mRNA decay (NMD) in human diseases, with a focus on its therapeutic potential for cardiovascular disease. NMD, conserved from yeast to humans, is involved in apoptosis, autophagy, cellular differentiation, and gene expression regulation. NMD is a highly conserved surveillance mechanism that degrades mRNAs containing premature termination codons (PTCs) located upstream of the final exon-exon junction. NMD serves to prevent the translation of aberrant mRNA and prevents the formation of defective protein products that could result in diseases. Key players in this pathway include up-frameshift proteins (UPFs), nonsense-mediated mRNA decay associated with p13K-related kinases (SMGs), and eukaryotic release factors (eRFs), among others. Dysregulation of NMD has been linked to numerous pathological conditions such as dilated cardiomyopathy, cancer, viral infections, and various neurodevelopmental and genetic disorders. This review will examine the regulatory mechanisms by which NMD regulation or dysregulation may contribute to disease mitigation or progression and its potential for cardiovascular disease therapy. We will further explore how modulating NMD could prevent the outcomes of mutations underlying genetically induced cardiovascular conditions and its applications in personalized medicine due to its role in gene regulation. While recent advances have provided valuable insights into NMD machinery and its therapeutic potential, further studies are needed to clarify the precise roles of key NMD components in cardiovascular disease prevention and treatment. Full article
(This article belongs to the Section Cells of the Cardiovascular System)
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20 pages, 744 KB  
Review
HER2/neu as a Signaling and Therapeutic Marker in Uterine Serous Carcinoma
by Victoria M. Ettorre, Luca Palmieri, Valentino Clemente and Alessandro D. Santin
Cells 2025, 14(16), 1282; https://doi.org/10.3390/cells14161282 - 19 Aug 2025
Viewed by 568
Abstract
Research into aggressive gynecologic cancers such as uterine serous carcinoma (USC) has recently evolved from chemotherapy to the development of drugs targeting specific biomarkers differentially expressed/active in tumor cells. One such target is HER2/neu, which plays an important role in the coordination of [...] Read more.
Research into aggressive gynecologic cancers such as uterine serous carcinoma (USC) has recently evolved from chemotherapy to the development of drugs targeting specific biomarkers differentially expressed/active in tumor cells. One such target is HER2/neu, which plays an important role in the coordination of cell growth and differentiation. Importantly, when overexpressed and/or amplified in tumor cells, the downstream tyrosine kinase of HER2/neu becomes constitutively activated, causing dysregulated gene transcription. In breast cancer patients, HER2/neu has been successfully utilized for many years as a target for multiple monoclonal antibodies and more recently antibody–drug conjugates (ADCs). Use in gynecologic malignancies has been slower, however, due to recently identified unique characteristics of HER2/neu protein expression and gene amplification in biologically aggressive tumors such as USC including its major heterogeneity and lack of apical staining when compared to breast cancer. Accordingly, the use of optimal testing algorithms for HER2/neu status in patients with USC may have important implications for the development of novel, effective, and targeted treatment modalities against this lethal variant of endometrial cancer. In this review, we discuss HER2/neu gene expression in USC, evaluate the efficacy of HER2/neu-directed therapies in both preclinical and clinical settings, and discuss possible mechanisms of resistance to HER2/neu targeting agents. Full article
(This article belongs to the Special Issue Signaling Pathways in Endometrial Cancer Cells)
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21 pages, 321 KB  
Review
Lipid-Laden Microglia: Characterization and Roles in Diseases
by Jiani Xing, Takese McKenzie and Jian Hu
Cells 2025, 14(16), 1281; https://doi.org/10.3390/cells14161281 - 19 Aug 2025
Viewed by 583
Abstract
Microglia are resident phagocytes of the central nervous system that play an essential role in brain development and homeostasis. When the intracellular lipid content exceeds the metabolic capacity of microglia, lipid droplets accumulate, giving rise to a distinct population termed lipid-laden microglia (LLMs). [...] Read more.
Microglia are resident phagocytes of the central nervous system that play an essential role in brain development and homeostasis. When the intracellular lipid content exceeds the metabolic capacity of microglia, lipid droplets accumulate, giving rise to a distinct population termed lipid-laden microglia (LLMs). LLMs have been implicated in various neuroinflammatory and neurodegenerative diseases, functioning as both regulators/indicators of inflammation and potential therapeutic targets. This review summarizes the current research on LLMs, focusing on disease-specific regulators and functions, protective roles, interactions with neighboring cells, and advances in diagnostic and analytical tools. We also discuss the blurred distinction between LLMs and macrophages, inconsistent terminology, and major knowledge gaps across different disease contexts. Deciphering the composition, formation, and dynamics of lipid droplets in microglia is critical for uncovering how microglial states shift under diverse pathological stimuli. A clearer view of these mechanisms may reveal novel roles of LLMs and open new avenues for therapeutic intervention. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Immune Regulation)
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27 pages, 1862 KB  
Review
The Yin and Yang of Heartbeats: Magnesium–Calcium Antagonism Is Essential for Cardiac Excitation–Contraction Coupling
by Chiara Marabelli, Demetrio J. Santiago and Silvia G. Priori
Cells 2025, 14(16), 1280; https://doi.org/10.3390/cells14161280 - 18 Aug 2025
Viewed by 657
Abstract
While calcium (Ca2+) is a universal cellular messenger, the ionic properties of magnesium (Mg2+) make it less suited for rapid signaling and more for structural integrity. Still, besides being a passive player, Mg2+ is the only active Ca [...] Read more.
While calcium (Ca2+) is a universal cellular messenger, the ionic properties of magnesium (Mg2+) make it less suited for rapid signaling and more for structural integrity. Still, besides being a passive player, Mg2+ is the only active Ca2+ antagonist, essential for tuning the efficacy of Ca2+-dependent cardiac excitation–contraction coupling (ECC) and for ensuring cardiac function robustness and stability. This review aims to provide a comprehensive framework to link the structural and molecular mechanisms of Mg2+/Ca2+ antagonistic binding across key proteins of the cardiac ECC machinery to their physiopathological relevance. The pervasive “dampening” effect of Mg2+ on ECC activity is exerted across various players and mechanisms, and lies in the ions’ physiological competition for multiple, flexible binding protein motifs across multiple compartments. Mg2+ profoundly modulates the cardiac action potential waveform by inhibiting the L-type Ca2+ channel Cav1.2, i.e., the key trigger of cardiac ryanodine receptor (RyR2) opening. Cytosolic Mg2+ favors RyR2 closed or inactive conformations not only through physical binding at specific sites, but also indirectly through modulation of RyR2 phosphorylation by Camk2d and PKA. RyR2 is also potently inhibited by luminal Mg2+, a vital mechanism in the cardiac setting for preventing excessive Ca2+ release during diastole. This mechanism, able to distinguish between Ca2+ and Mg2+, is mediated by luminal partners Calsequestrin 2 (CASQ2) and Triadin (TRDN). In addition, Mg2+ favors a rearrangement of the RyR2 cluster configuration that is associated with lower Ca2+ spark frequencies. Full article
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22 pages, 1840 KB  
Article
A miR-30 Guided Molecular Profiling of Canine Osteosarcoma and Extraskeletal Osteosarcoma Reveals Non-Seed Regulatory Divergence
by Gabriella Guelfi, Petronela Munteanu, Camilla Capaccia, Ilaria Porcellato, Elisabetta Manuali, Margherita Maranesi and Leonardo Leonardi
Cells 2025, 14(16), 1279; https://doi.org/10.3390/cells14161279 - 18 Aug 2025
Viewed by 374
Abstract
Osteosarcoma (OS) and extraskeletal osteosarcoma (EOS) in dogs exhibit histological similarities but differ in anatomical origin, which poses a challenge to diagnostic accuracy. We adopted a marker-first strategy to enhance molecular classification by selecting RUNX2, KPNA2, and SATB2, three validated immunohistochemical (IHC) markers, [...] Read more.
Osteosarcoma (OS) and extraskeletal osteosarcoma (EOS) in dogs exhibit histological similarities but differ in anatomical origin, which poses a challenge to diagnostic accuracy. We adopted a marker-first strategy to enhance molecular classification by selecting RUNX2, KPNA2, and SATB2, three validated immunohistochemical (IHC) markers, as primary targets. Bioinformatic screening identified the miR-30 family as the only miRNA group predicted to coordinately regulate RUNX2, KPNA2, and SATB2, justifying its prioritization for expression analysis. RT-qPCR on FFPE tissues from 14 OS, 19 EOS, and 10 healthy controls revealed that miR-30a was significantly downregulated in OS and inversely correlated with RUNX2 nuclear expression, confirmed by IHC. MiR-30e also showed high diagnostic accuracy, while miR-30b and miR-30c distinguished EOS from OS. Non-seed interaction modeling (i.e., outside the canonical “seed” region, spanning nucleotides 2–8 of the miRNA) suggested divergent regulatory affinities within the PI3K/AKT/RUNX2 axis among miR-30 family members. MiR-30a and miR-30e exhibited the highest diagnostic power (LR+ 7.7 and 6.8, respectively), supporting their role as biomarkers. These results highlight a miR–30–centered regulatory axis with relevance for diagnosis and molecular stratification of canine osteogenic tumors. Full article
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23 pages, 1044 KB  
Review
Cellular Models of Aging and Senescence
by Byunggik Kim, Dong I. Lee, Nathan Basisty and Dao-Fu Dai
Cells 2025, 14(16), 1278; https://doi.org/10.3390/cells14161278 - 18 Aug 2025
Viewed by 749
Abstract
Aging, a state of progressive decline in physiological function, is an important risk factor for chronic diseases, ranging from cancer and musculoskeletal frailty to cardiovascular and neurodegenerative diseases. Understanding its cellular basis is critical for developing interventions to extend human health span. This [...] Read more.
Aging, a state of progressive decline in physiological function, is an important risk factor for chronic diseases, ranging from cancer and musculoskeletal frailty to cardiovascular and neurodegenerative diseases. Understanding its cellular basis is critical for developing interventions to extend human health span. This review highlights the crucial role of in vitro models, discussing foundational discoveries like the Hayflick limit and the senescence-associated secretory phenotype (SASP), the utility of immortalized cell lines, and transformative human induced pluripotent stem cells (iPSCs) for aging and disease modeling and rejuvenation studies. We also examine methods to induce senescence and discuss the distinction between chronological time and biological clock, with examples of applying cells from progeroid syndromes and mitochondrial diseases to recapitulate some signaling mechanisms in aging. Although no in vitro model can perfectly recapitulate organismal aging, well-chosen models are invaluable for addressing specific mechanistic questions. We focus on experimental strategies to manipulate cellular aging: from “steering” cells toward resilience to “reversing” age-related phenotypes via senolytics, partial epigenetic reprogramming, and targeted modulation of proteostasis and mitochondrial health. This review ultimately underscores the value of in vitro systems for discovery and therapeutic testing while acknowledging the challenge of translating insights from cell studies into effective, organism-wide strategies to promote healthy aging. Full article
(This article belongs to the Special Issue Experimental Systems to Model Aging Processes)
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24 pages, 1526 KB  
Review
p38α MAPK Regulation of Energy Metabolism in Skeletal Muscle Offers a Therapeutic Path for Type 2 Diabetes
by Eyal Bengal and Sharon Aviram
Cells 2025, 14(16), 1277; https://doi.org/10.3390/cells14161277 - 18 Aug 2025
Viewed by 810
Abstract
Type 2 diabetes (T2D), a growing global health concern, is closely linked to obesity and sedentary behavior. Central to its development are insulin resistance and impaired glucose metabolism in peripheral tissues, particularly skeletal muscle, which plays a key role in energy expenditure, glucose [...] Read more.
Type 2 diabetes (T2D), a growing global health concern, is closely linked to obesity and sedentary behavior. Central to its development are insulin resistance and impaired glucose metabolism in peripheral tissues, particularly skeletal muscle, which plays a key role in energy expenditure, glucose uptake, and insulin sensitivity. Notably, increased accumulation of lipid metabolites in skeletal muscle is observed both in endurance exercise—associated with improved insulin sensitivity—and in high-fat diets that induce insulin resistance. The review examines the contrasting metabolic adaptations of skeletal muscle to these opposing conditions and highlights the key signaling molecules involved. The focus then shifts to the role of the stress kinase p38α mitogen-activated protein kinase (MAPK) in skeletal muscle adaptation to overnutrition and endurance exercise. p38α enhances mitochondrial oxidative capacity and regulates nutrient utilization, both critical for maintaining metabolic homeostasis. During exercise, it cooperates with AMP-activated protein kinase (AMPK) to boost glucose uptake and fatty acid oxidation, key mechanisms for improving insulin sensitivity. The co-activation of p38α and AMPK in skeletal muscle emerges as a promising therapeutic avenue to combat insulin resistance and T2D. The review explores strategies for selectively enhancing p38α activity in skeletal muscle. In conclusion, it advocates a comprehensive approach to T2D prevention and treatment, combining established caloric intake-reducing therapies, such as GLP-1 receptor agonists, with interventions aimed at increasing energy expenditure via activation of p38α and AMPK signaling pathways. Full article
(This article belongs to the Special Issue Advances in Muscle Research in Health and Disease—2nd Edition)
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15 pages, 2374 KB  
Article
Fibroblasts Attenuate Anti-Tumor Drug Efficacy in Tumor Cells via Paracrine Interactions with Tumor Cells in 3D Plexiform Neurofibroma Cultures
by Kyungmin Ji and George J. Schwenkel
Cells 2025, 14(16), 1276; https://doi.org/10.3390/cells14161276 - 18 Aug 2025
Viewed by 494
Abstract
Plexiform neurofibromas (hereafter called pNF1) are often diagnosed in early childhood and occur in about 30% of neurofibromatosis type 1 (NF1) patients. pNF1 exhibits aggressive growth along a nerve in the body and has substantial potential for progression to malignant peripheral nerve sheath [...] Read more.
Plexiform neurofibromas (hereafter called pNF1) are often diagnosed in early childhood and occur in about 30% of neurofibromatosis type 1 (NF1) patients. pNF1 exhibits aggressive growth along a nerve in the body and has substantial potential for progression to malignant peripheral nerve sheath tumors that are rarely curable. There are two recently FDA-approved drugs, selumetinib and mirdametinib, for pNF1 patients who have symptomatic and inoperable plexiform neurofibromas; however, these treatments achieve only approximately 30% tumor shrinkage. Fibroblasts, the most abundant cell types within the pNF1 tumor microenvironment, are implicated in pNF1 growth and invasion; however, how fibroblasts affect a drug response of pNF1 remains poorly understood. In the present study, we focused on contributions of fibroblasts to the drug resistance in pNF1 via their secretome. We employed our established three-dimensional (3D) culture system incorporating human pNF1 tumor cells (Nf1−/−) and primary fibroblasts (Nf1+/−) grown in our patented microfluidic culture chips for monocultures and parallel cocultures in which 3D pNF1 structures and fibroblasts share their secretome without direct cell-to-cell contact. Three-dimensional pNF1 structures in 3D parallel cocultures with fibroblasts exhibited greater drug resistance than ones in monocultures. We found that pNF1 tumor cells showed increased P-glycoprotein expression when incubated with fibroblast-derived conditioned media or parallel cocultured with fibroblasts, compared to control conditions. Pharmacological inhibition of P-glycoprotein partially restored drug sensitivity. Additionally, fibroblasts showed higher resistance to selumetinib and mirdametinib than pNF1 tumor structures, likely due to elevated P-glycoprotein levels. This study is the first to define precise roles of fibroblasts in pNF1 drug resistance, emphasizing the potential of fibroblast-targeted therapies as a promising approach to improve pNF1 treatment outcomes. Full article
(This article belongs to the Section Cell Microenvironment)
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14 pages, 1757 KB  
Article
Photosynthetic Electron Transport in Winter Wheat: Responses to Low-Temperature and Weak-Light Condition
by Cheng Yang, Minghan Liu, Simeng Du, Deqi Zhang, Xiangdong Li, Liting Wu, Yanhua Shi, Baoting Fang, Ge Yan and Fang Wei
Cells 2025, 14(16), 1275; https://doi.org/10.3390/cells14161275 - 18 Aug 2025
Viewed by 412
Abstract
Spring low temperatures are a serious natural threat to wheat production in the Huang-Huai wheat region, and they are often accompanied by weak light environments during the day. To elucidate the response patterns and adaptation mechanisms of winter wheat leaves to low-temperature and [...] Read more.
Spring low temperatures are a serious natural threat to wheat production in the Huang-Huai wheat region, and they are often accompanied by weak light environments during the day. To elucidate the response patterns and adaptation mechanisms of winter wheat leaves to low-temperature and weak-light environments, we simultaneously measured prompt chlorophyll a fluorescence, delayed chlorophyll a fluorescence, and modulated 820 nm light reflection; moreover, we analyzed the effects of low temperature and weak light treatment for different duration (2 h and 4 h) on the donor-side activity of photosystem II (PSII), the degree of PSII unit dissociation, the efficiency of light energy absorption and capture by PSII, electron transfer to QA and PSI terminal, PSI activity and cyclic electron transport activity in isolated wheat leaves under controlled conditions. The results, which were corroborated using the three methods, revealed that in low-temperature and weak-light environments, the degree of PSII unit dissociation, and the efficiency of light energy absorption, capture, and electron transfer to QA decreased, while the donor-side activity remained unaffected. In contrast, the efficiency of electron transfer to the PSI terminal and the overall performance of photosynthetic electron transport increased. Comprehensive analysis suggests that the increase in the electron receptor pool at the PSI terminal under low-temperature stress is a crucial factor contributing to the enhanced electron transfer efficiency to the PSI terminal and the improved overall performance of the photosynthetic electron transport chain, which is also a crucial factor in the high cold tolerance of winter wheat. Full article
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19 pages, 1067 KB  
Review
The Role of Extracellular Vesicles in Mediating Signaling in Biliary Epithelial Cell Activation and Cholangiopathies
by Sharmila Fagoonee, Marcela Fabiana Bolontrade, Paola Defilippi and Ralf Weiskirchen
Cells 2025, 14(16), 1274; https://doi.org/10.3390/cells14161274 - 18 Aug 2025
Viewed by 452
Abstract
Cholangiopathies, a diverse group of diseases affecting the biliary tract, are characterized by the activation of cholangiocytes, fibrosis, and inflammation. Recent research has identified extracellular vesicles (EVs) as crucial mediators of communication within the hepatobiliary system. This review aims to explore the impact [...] Read more.
Cholangiopathies, a diverse group of diseases affecting the biliary tract, are characterized by the activation of cholangiocytes, fibrosis, and inflammation. Recent research has identified extracellular vesicles (EVs) as crucial mediators of communication within the hepatobiliary system. This review aims to explore the impact of EVs on cholangiocyte behavior and their role in disease development. EVs originating from cholangiocytes, hepatocytes, and immune cells carry a variety of molecules, including non-coding RNAs, proteins, and lipids, which influence immune responses, fibrosis, and epithelial repair. Specifically, EVs released by activated or senescent cholangiocytes can worsen inflammation and fibrosis by delivering molecules such as lncRNA H19, miR-21, and damage-associated molecular patterns (DAMPs) to hepatic stellate and immune cells. Additionally, the polarity and content of EVs are influenced by specific subcellular domains of cholangiocytes, indicating distinct signaling functions. In conditions such as primary sclerosing cholangitis (PSC), cholangiocarcinoma (CCA), and biliary atresia, EVs play a role in disease progression and offer potential as non-invasive biomarkers and therapeutic targets. This review underscores the importance of in-depth profiling and validation of EVs to fully utilize their diagnostic and therapeutic capabilities. Overall, EV-mediated signaling is a critical mechanism in cholangiopathies, providing a new avenue for understanding disease progression and developing precision medicine approaches. Full article
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26 pages, 3283 KB  
Article
Expression of Toll-like Receptors on Lymphocyte Subpopulations and Their Soluble Forms in Serum and Urine of Women with Endometriosis
by Anna Sobstyl, Paulina Mertowska, Sebastian Mertowski, Rafał Tarkowski, Dominik Dudziński, Michał Kotowski, Krzysztof Bojarski, Bogusława Stelmach, Błażej Chermuła, Maciej Brązert and Ewelina Grywalska
Cells 2025, 14(16), 1273; https://doi.org/10.3390/cells14161273 - 18 Aug 2025
Viewed by 429
Abstract
Introduction: Endometriosis is a chronic inflammatory disease affecting women of reproductive age, often accompanied by chronic pelvic pain and infertility. Despite numerous studies, its pathogenesis remains incompletely understood. Increasing evidence indicates the important role of immunological disorders, especially in the mechanisms of innate [...] Read more.
Introduction: Endometriosis is a chronic inflammatory disease affecting women of reproductive age, often accompanied by chronic pelvic pain and infertility. Despite numerous studies, its pathogenesis remains incompletely understood. Increasing evidence indicates the important role of immunological disorders, especially in the mechanisms of innate immunity and Toll-like receptors (TLRs). Study objective: This study aimed to assess the expression of selected TLRs (TLR2, TLR3, TLR4, TLR7, TLR8, and TLR9) on peripheral blood lymphocyte subpopulations (CD4+, CD8+, and CD19+ cells) in patients diagnosed with endometriosis and to quantify the levels of their soluble forms in serum and urine. This study was conducted on patients who were not undergoing hormonal bridging therapy and were not using any form of hormonal contraception to eliminate potential confounding effects on immune parameters. Methods: Flow cytometric analysis of TLR expression on peripheral blood lymphocytes was performed, and the levels of their soluble forms in serum and urine samples were determined. Additionally, ROC curve analysis was used to evaluate the diagnostic potential of the studied parameters. Results: We found increased expression of TLRs in lymphocyte populations in patients with endometriosis compared to the control group, suggesting their involvement in both local and systemic immune responses. In addition, ROC analysis showed the diagnostic potential of TLR expression in differentiating patients with endometriosis from healthy women, and it may also identify disease subtypes. Conclusions: The findings support the role of TLRs in the immunopathogenesis of endometriosis and highlight their promise as diagnostic biomarkers and therapeutic targets. Further studies on larger patient cohorts and functional signaling analyses are warranted. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Gynecological Disorders)
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13 pages, 292 KB  
Review
Current Status of α-Synuclein Biomarkers and the Need for α-Synuclein PET Tracers
by Sara E. Berman and Andrew D. Siderowf
Cells 2025, 14(16), 1272; https://doi.org/10.3390/cells14161272 - 18 Aug 2025
Viewed by 727
Abstract
Synucleinopathies are neurodegenerative disorders defined by the pathological aggregation of α-synuclein. Several α-synuclein biomarkers have been developed to aid diagnosis and research, such as cerebrospinal fluid (CSF) and blood-based measurements, seed amplification assays (SAAs), and immunohistochemical detection from skin biopsies. While these existing [...] Read more.
Synucleinopathies are neurodegenerative disorders defined by the pathological aggregation of α-synuclein. Several α-synuclein biomarkers have been developed to aid diagnosis and research, such as cerebrospinal fluid (CSF) and blood-based measurements, seed amplification assays (SAAs), and immunohistochemical detection from skin biopsies. While these existing biomarkers have important uses, they face limitations in diagnostic specificity, spatial localization, and the ability to monitor disease progression or response to therapy. The development of α-synuclein PET tracers, which would allow for the direct in vivo imaging of α-synuclein, represents an important unmet need in both research and the clinical care of patients with movement disorders. This review outlines the current landscape of α-synuclein biomarkers and discusses both the scientific and technical challenges in developing α-synuclein PET imaging tracers. Full article
(This article belongs to the Special Issue Development of PET Radiotracers for Imaging Alpha-Synuclein)
18 pages, 6192 KB  
Article
New Approaches to Old Techniques in Cell Handling for Microscopy
by Zhanna Bartosh, Veenu Aishwarya, Wayne W. Hancock and Tatiana Akimova
Cells 2025, 14(16), 1271; https://doi.org/10.3390/cells14161271 - 18 Aug 2025
Viewed by 383
Abstract
Appropriate concentrations of reagents, an absence of significant cell clumps and debris, minimization of artifacts and ensuring satisfactory cell preservation directly affect the quality of data generated and cannot be overestimated. Traditionally, cells in suspension are prepared using a cytospin, which uses centrifugal [...] Read more.
Appropriate concentrations of reagents, an absence of significant cell clumps and debris, minimization of artifacts and ensuring satisfactory cell preservation directly affect the quality of data generated and cannot be overestimated. Traditionally, cells in suspension are prepared using a cytospin, which uses centrifugal force to concentrate and deposit cells onto a glass slide. Adherent cells are traditionally grown on coverslips located on the bottom of the wells of cell culture plates, or using special chamber slide systems. In our laboratory, we developed and tested simplified homemade approaches for both techniques, allowing users to perform large volume cell functional tests followed by microscopy evaluation without a need for a cytospin, special chamber slide systems or the use of round cover slips. We present methods and illustrative examples involving the cellular uptake of self-delivering oligonucleotides in murine splenocytes and in two adherent human tumor cell lines. Full article
(This article belongs to the Section Cell Methods)
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15 pages, 2310 KB  
Article
CELTPLUS Fat Increases the Metabolic Activity as Well as the SVF-Yield Significantly When Compared to CELT Fat, Even After Cryopreservation with DMSO
by Tom Schimanski, Lukas Prantl, Andreas Eigenberger, Oliver Felthaus, Rafael Loucas, Kirsten Utpatel and Kerstin Steer
Cells 2025, 14(16), 1270; https://doi.org/10.3390/cells14161270 - 17 Aug 2025
Viewed by 470
Abstract
Lipofilling has far more applications than cosmetic surgery alone. Due to its high content of stromal vascular fraction (SVF) cells, lipoaspirate can also be used to treat wounds, as its cellular components may accelerate wound healing. Using our CELTPLUS protocol, we can [...] Read more.
Lipofilling has far more applications than cosmetic surgery alone. Due to its high content of stromal vascular fraction (SVF) cells, lipoaspirate can also be used to treat wounds, as its cellular components may accelerate wound healing. Using our CELTPLUS protocol, we can increase the number of SVF cells per volume. Unfortunately, some patients require more than one treatment to achieve an optimal outcome, but would unnecessarily suffer from repeated liposuction. Therefore, our objective was to test whether cryopreserving CELTPLUS fat could offer a solution, potentially avoiding the need for repeated liposuction procedures. DMSO was used as a cryoprotective agent for proof-of-principle testing, although other non-toxic cryoprotective agents should be considered in the future. The rest of our freezing protocol is a clinically friendly attempt to facilitate the translation into clinical practice. We tested the cryopreserved tissue using histological evaluation, metabolism measurement, SVF cell yield estimation, PCRs from both whole tissue and from cultured SVF cells, and Oil Red “O” staining. We found that freezing CELTPLUS fat with DMSO yields better results than without cryoprotection in all evaluated methods. Until non-toxic cryoprotective agents are tested on CELTPLUS fat, we do not recommend initiating animal or human testing. Full article
(This article belongs to the Special Issue Adipose-Derived Stem Cells for Tissue Regeneration)
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