Next Issue
Volume 14, November-1
Previous Issue
Volume 14, October-1
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
10.5
5.2
Journals
Cells
Volume 14
Issue 20
share announcement

Cells, Volume 14, Issue 20 (October-2 2025) – 71 articles

Cover Story (view full-size image): TRIC-A facilitates counter-current ion flow and directly interacts with the ryanodine receptor (RyR) to ensure efficient calcium (Ca2+) release from the sarcoplasmic reticulum (SR). This finely tuned Ca2+ signaling supports essential crosstalk with mitochondria, sustaining healthy metabolic function in the heart. Loss of TRIC-A disrupts this balance, leading to Ca2+ overload in the SR due to impaired RyR function. Under stress conditions, this results in pulsatile, large-scale Ca2+ release, triggering mitochondrial Ca2+ toxicity. These findings highlight the critical role of TRIC-A in orchestrating SR-mitochondrial Ca2+ signaling, with implications for both cardiac physiology and disease. View this paper
  • Issues are regarded as officially published after their release is announced to the table of contents alert mailing list.
  • You may sign up for e-mail alerts to receive table of contents of newly released issues.
  • PDF is the official format for papers published in both, html and pdf forms. To view the papers in pdf format, click on the "PDF Full-text" link, and use the free Adobe Reader to open them.
Order results
Result details
Section
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
13 pages, 2525 KB  
Article
Culture Strategy Determines the Differentiation Status of Sweat Gland Cells
by Henri De Koninck, Karel Ferland, Martin A. Barbier, Danielle Larouche and Lucie Germain
Cells 2025, 14(20), 1643; https://doi.org/10.3390/cells14201643 - 21 Oct 2025
Viewed by 261
Abstract
Reliable methods for the isolation and culture of human eccrine sweat gland cells (SGCs) are essential for studying glandular biology and developing tissue-engineered skin substitutes (TESs) that restore full skin function. However, maintaining the glandular phenotype of SGCs in vitro remains a major [...] Read more.
Reliable methods for the isolation and culture of human eccrine sweat gland cells (SGCs) are essential for studying glandular biology and developing tissue-engineered skin substitutes (TESs) that restore full skin function. However, maintaining the glandular phenotype of SGCs in vitro remains a major challenge. In this study, we present an optimized isolation protocol combining enzymatic digestion with mechanical separation to improve SGC yield and purity, while also enabling keratinocyte isolation from a single human skin biopsy. We then evaluated two culture strategies, 2D monolayers and 3D spheroids, to determine their impact on SGC identity and proliferation. While 2D culture supported cell expansion, SGCs and keratinocytes exhibited highly similar marker expression profiles, with the absence of functional SGC markers (AQP5, α-SMA) reflecting a shift toward less differentiated phenotypes. In contrast, SGCs cultured in 3D spheroids preserved the expression of SGC-specific markers (AQP5, K18, α-SMA), distinguishing them from keratinocytes; however, their growth and structural organization were suboptimal under these 3D conditions. Moreover, SGCs expanded in 2D did not regain their glandular features when reintroduced into 3D culture, suggesting potential limitations in phenotype recovery. These results highlight the need for improved culture systems that maintain SGC identity while supporting expansion. Advancing such methods is a critical step toward integrating functional sweat glands into TESs and achieving complete skin regeneration for clinical applications. Full article
►▼ Show Figures

Figure 1

32 pages, 5809 KB  
Article
Vascular Endothelial Growth Factor B Modulates Cardiac Functions via Ferroptosis Pathways in Post-Myocardial Infarction
by Sai Manasa Varanasi, Ankit Sabharwal, Shreyartha Mukherjee, Huzaifa Muhammad, Riya Kar, Carter Magnano, Anya Dorairaj, Enfeng Wang, Shamit Dutta, Pritam Das, Stephen C. Ekker, Ying Wang, Debabrata Mukhopadhyay and Ramcharan Singh Angom
Cells 2025, 14(20), 1642; https://doi.org/10.3390/cells14201642 - 21 Oct 2025
Viewed by 479
Abstract
Myocardial infarction (MI) remains a leading cause of mortality worldwide, yet effective cardioprotective strategies remain limited in clinical settings. Vascular endothelial growth factor B (VEGFB) has emerged as a promising therapeutic candidate in MI, but the role of its co-receptor, Neuropilin-1 (NRP1 [...] Read more.
Myocardial infarction (MI) remains a leading cause of mortality worldwide, yet effective cardioprotective strategies remain limited in clinical settings. Vascular endothelial growth factor B (VEGFB) has emerged as a promising therapeutic candidate in MI, but the role of its co-receptor, Neuropilin-1 (NRP1), in cardiomyocyte (CM) survival under ischemic stress remains poorly understood. Here, we investigated VEGFB-NRP1 signaling using an in vivo zebrafish model of cardiac injury as well as in vitro hypoxia models in CMs. We demonstrated that VEGFB overexpression conferred protection against ischemic injury and enhanced cardiac regeneration in the zebrafish heart. Mechanistically, we showed that VEGFB treatment enhances CM viability through reducing reactive oxygen species (ROS), ferroptosis activation, and preserving mitochondrial integrity. We also demonstrated that NRP1 knockdown in the CMs abolished the VEGFB-mediated protective effects, indicating the significant role of NRP1 signaling in VEGFB-induced cardioprotective effects in MI. Lastly, using transcriptome analysis, we confirmed that VEGFB induces anti-apoptotic and anti-ferroptosis gene programs in CMs in response to hypoxic stress. Collectively, our findings provide mechanistic insight into cell death activation pathways, including ferroptosis, in response to ischemic stress and further validate the therapeutic potential of VEGFB in promoting CM survival in ischemic heart disease. Full article
(This article belongs to the Section Cellular Pathology)
►▼ Show Figures

Figure 1

23 pages, 3965 KB  
Article
C-Kit Is Essential for Vascular Smooth Muscle Cell Phenotypic Switch In Vitro and In Vivo After Injury
by Chiara Siracusa, Giovanni Canino, Mariangela Scalise, Fabiola Marino, Loredana Pagano, Gianluca Santamaria, Annalaura Torella, Salvatore De Rosa, Daniele Torella and Eleonora Cianflone
Cells 2025, 14(20), 1641; https://doi.org/10.3390/cells14201641 - 21 Oct 2025
Viewed by 330
Abstract
Pathological vascular remodeling—central to restenosis, atherosclerosis, and vasculo-proliferative diseases—depends on the phenotypic switching of vascular smooth muscle cells (VSMCs) from a quiescent, contractile state to a synthetic, proliferative program. Although the receptor tyrosine kinase c-Kit is implicated in proliferation, migration, and tissue repair, [...] Read more.
Pathological vascular remodeling—central to restenosis, atherosclerosis, and vasculo-proliferative diseases—depends on the phenotypic switching of vascular smooth muscle cells (VSMCs) from a quiescent, contractile state to a synthetic, proliferative program. Although the receptor tyrosine kinase c-Kit is implicated in proliferation, migration, and tissue repair, its role in VSMC plasticity has yet to be fully understood. Using c-Kit haploinsufficient mice subjected to right carotid artery ligation (CAL) and primary aortic VSMC cultures, we show that c-Kit is required for the contractile-to-synthetic transition. In vitro, c-Kit haploinsufficiency halved c-Kit expression, reduced 5-bromo-2′-deoxyuridine (BrdU) incorporation, and blunted platelet-derived growth factor BB (PDGF-BB)-induced repression of contractile genes. c-Kit–deficient VSMCs exhibited a senescence program with increased p16INK4a/p21 expression and upregulated senescence-associated secretory phenotype (SASP) mediators. RNA-Seq of carotid arteries 7 days post-ligation revealed that wild-type arteries activated cell-cycle pathways and suppressed contractile signatures, whereas c-Kit-deficient carotid arteries failed to fully engage proliferative programs and instead maintained contractile gene expression. At 28 days post CAL in vivo, c-Kit haploinsufficiency produced markedly reduced neointima, fewer Ki67+ VSMCs, more p16INK4a+ cells, and impaired re-endothelialization. Because progenitor-to-VSMC differentiation contributes to remodeling, we tested adult cardiac stem/progenitor cells (CSCs) as a model system of adult progenitor differentiation. Wild-type CSCs efficiently generated induced VSMCs (iVSMCs) with appropriate smooth-muscle gene upregulation; c-Kit–deficient rarely did so. Restoring c-Kit with a BAC transgene rescued both the smooth-muscle differentiation and proliferative competence of c-Kit-deficient iVSMCs. Collectively, our data identified c-Kit as a gatekeeper of reparative VSMC plasticity. Adequate c-Kit enables progenitor-to-VSMC commitment and the expansion of newly formed VSMCs while permitting injury-induced proliferation and matrix synthesis; reduced c-Kit locks cells in a hypercontractile, senescence-prone state and limits neointima formation. Modulating the c-Kit axis may therefore offer a strategy to fine-tune vascular repair while mitigating pathological remodeling. Full article
(This article belongs to the Special Issue Emerging Topics in Smooth Muscle Cell Fate and Plasticity in Atherosclerosis)
►▼ Show Figures

Figure 1

31 pages, 3420 KB  
Systematic Review
From Adhesion to Invasion: Integrins, Focal Adhesion Signaling, and Actin Binding Proteins in Cervical Cancer Progression—A Scoping Review
by Marta Hałas-Wiśniewska, Patryk Zawadka, Wioletta Arendt and Magdalena Izdebska
Cells 2025, 14(20), 1640; https://doi.org/10.3390/cells14201640 - 21 Oct 2025
Viewed by 622
Abstract
Background: Cervical cancer (CC) is one of the most common malignancies in women worldwide. Its progression involves a cascade of processes, including proliferation, migration, invasion, and metastasis. Each stage is regulated by specific signaling pathways. Objective: This scoping review aimed to map current [...] Read more.
Background: Cervical cancer (CC) is one of the most common malignancies in women worldwide. Its progression involves a cascade of processes, including proliferation, migration, invasion, and metastasis. Each stage is regulated by specific signaling pathways. Objective: This scoping review aimed to map current evidence on the role of cell adhesion-related molecules, including integrins, focal adhesion (FA) proteins, and actin-binding proteins (ABPs), in CC progression. These protein groups act in a coordinated manner—integrins perceive and transmit extracellular matrix (ECM) signals, FA proteins mediate intracellular signaling, and ABPs reorganize the cytoskeleton, ensuring the continuity of adhesion and motility processes. Methods: A structured literature search was conducted for studies published between 2015 and 2025. Eligible articles described the role of adhesion-related proteins in migration, invasion, or EMT in CC. Data were synthesized thematically according to protein families. Results: The evidence highlights integrins, FA/FAK, and ABPs as interconnected regulators coordinating ECM signaling and cytoskeletal remodeling during CC progression. Their dysregulation is associated with enhanced migration, EMT induction, angiogenesis, and therapy resistance. Conclusions: This review provides a unique, integrated perspective linking adhesion molecules with invasion mechanisms in CC progression, providing new insights into their interplay. Understanding the interaction between these proteins is therefore a crucial step in the treatment of CC and may facilitate the discovery of biomarkers and support the development of targeted therapies. Full article
►▼ Show Figures

Figure 1

20 pages, 1731 KB  
Review
Alcohol Consumption and Cervical Carcinogenesis: Time to Draw Conclusions
by Vivek K. Kashyap, Divya B. Kenchappa, Ajay K. Singh, Bhupesh Singh, Murali M. Yallapu, Everardo Cobos and Subhash C. Chauhan
Cells 2025, 14(20), 1639; https://doi.org/10.3390/cells14201639 - 21 Oct 2025
Viewed by 525
Abstract
Cervical cancer is the fourth most common cancer among women worldwide and remains a significant cause of cancer-related mortality. Alcohol consumption is linked to an increased risk of several cancers and is a controversial risk factor for developing cervical cancer. This review updates [...] Read more.
Cervical cancer is the fourth most common cancer among women worldwide and remains a significant cause of cancer-related mortality. Alcohol consumption is linked to an increased risk of several cancers and is a controversial risk factor for developing cervical cancer. This review updates existing information on the correlation between alcohol consumption and the risk of developing cervical cancer. Several comprehensive studies from different geographical regions have shown that moderate and heavy drinking is positively correlated with the development of cervical cancer. There is a synergistic relationship between human papillomavirus (HPV) viral load and alcohol use among drinkers with a high HPV viral load. Excessive alcohol consumption and exposure to second-hand smoke may elevate the risk of persistent HPV infection. Furthermore, high-risk behaviors associated with Human immunodeficiency virus (HIV)/HPV co-infection are more common among binge drinkers. However, several observations failed to establish a relationship between these factors. Despite some inconsistency in the literature, evidence suggests a modest association between alcohol consumption and increased risk of persistent HPV infection, causing cervical cancer. Full article
(This article belongs to the Special Issue The Cellular and Molecular Basis of Lifestyle Factors in Cancer Progression and Prevention)
►▼ Show Figures

Figure 1

17 pages, 7407 KB  
Article
Phospho-Tau Signature During Mitosis: AT8, p-T217 and p-S422 as Key Phospho-Epitopes
by Marion Goussard, Kelly Zarka, Morgane Denus, Thomas Curel, Sylvie Claeysen, Bruno Lefebvre, Malika Hamdane, Philippe Marin, Julien Villeneuve and Marie-Laure Parmentier
Cells 2025, 14(20), 1638; https://doi.org/10.3390/cells14201638 - 21 Oct 2025
Viewed by 402
Abstract
Tau was initially identified as a microtubule-binding protein critical for microtubule stabilization. It is also a pathological hallmark of tauopathies, a group of neurodegenerative diseases that include Alzheimer’s disease. Under pathological conditions, Tau becomes hyperphosphorylated at numerous sites and aggregates into filamentous deposits, [...] Read more.
Tau was initially identified as a microtubule-binding protein critical for microtubule stabilization. It is also a pathological hallmark of tauopathies, a group of neurodegenerative diseases that include Alzheimer’s disease. Under pathological conditions, Tau becomes hyperphosphorylated at numerous sites and aggregates into filamentous deposits, contributing to neuronal cell death and disease progression. While significant research has focused on Tau phosphorylation dynamics and their consequences in pathological contexts, comparatively few studies have investigated Tau phosphorylation during physiological processes, despite the potential relevance to the early onset of pathology. Previous findings have suggested similarities between mitotic Tau phosphorylation and hyperphosphorylation observed in tauopathies, particularly at sites such as AT8, PHF1, S214, and S422. In this study, we quantified the relative levels of phosphorylation at 12 Tau phospho-epitopes during interphase and mitosis in vitro to establish a preliminary mitotic phospho-Tau signature, which was subsequently validated in vivo. Our results demonstrated pronounced phosphorylation of Tau at AT8, p-T217, and p-S422 epitopes during mitosis, both in vitro and in vivo. These findings provide new insights into the physiological phosphorylation of Tau and its potential links to pathological processes. Full article
(This article belongs to the Collection Molecular Insights into Neurodegenerative Diseases)
►▼ Show Figures

Figure 1

23 pages, 1851 KB  
Review
Biological Nanoparticles for Enhancing Chronic Wound Regeneration
by Daniil Zotikov, Natalia Ponomareva, Sergey Brezgin, Anastasiia Kostyusheva, Anastasiya Frolova, Vladimir Chulanov, Alexander Lukashev, Peter Timashev and Dmitry Kostyushev
Cells 2025, 14(20), 1637; https://doi.org/10.3390/cells14201637 - 21 Oct 2025
Viewed by 605
Abstract
Chronic wounds (CWs) represent a growing global health concern with profound clinical and socioeconomic implications. Studies indicate that approximately 15% of CWs remain unhealed one year after the initial treatment. At the same time, it is assumed that from 1% to 2% of [...] Read more.
Chronic wounds (CWs) represent a growing global health concern with profound clinical and socioeconomic implications. Studies indicate that approximately 15% of CWs remain unhealed one year after the initial treatment. At the same time, it is assumed that from 1% to 2% of the population of developed countries will suffer from chronic wounds during their lifetime. CWs severely impair patients’ quality of life. Current therapies (compression bandages, antibiotics, hyperbaric oxygen, and skin grafts) face limitations, including toxicity, contraindications, inefficacy in patients with comorbidities like diabetes, and high cost. Biological nanoparticles (BNPs), particularly extracellular vesicles (EVs), emerge as transformative solutions due to their innate biocompatibility, targeted biodistribution, and multifunctional regenerative properties. This review examines the mechanisms by which BNPs promote CW healing and drug delivery. Innovative BNP delivery platforms (chitosan hydrogels, alginate films) are evaluated, enabling sustained release and responsiveness to the wound microenvironment. Clinical advances, including exosome-laden hydrogels that accelerate healing in diabetic ulcers, underscore BNPs’ potential to overcome conventional therapy limitations. By addressing the challenges of both pathophysiological complexity and healthcare system burden, BNPs demonstrate the potential to improve patient outcomes in the management of chronic wounds. Full article
►▼ Show Figures

Figure 1

19 pages, 1585 KB  
Article
Circulating CD16-Positive Monocyte-like Myeloid-Derived Suppressor Cells and Intermediate Monocytes Associated with Clinical and Immunological Complications in Pars Planitis Patients
by Agata Kosmaczewska, Joanna Przeździecka-Dołyk, Lidia Ciszak, Zofia Rojek-Gajda, Irena Frydecka, Anna Turno-Kręcicka, Marta Misiuk-Hojło and Edyta Pawlak
Cells 2025, 14(20), 1636; https://doi.org/10.3390/cells14201636 - 21 Oct 2025
Viewed by 331
Abstract
Recently, we observed that pars planitis (PP) patients present alterations in peripheral blood (PB) Th17/Treg associated with dysregulation in the Th1 response. Yet, little is known about the systemic distribution of myeloid cells, which drive the recruitment and differentiation of the adaptive effectors [...] Read more.
Recently, we observed that pars planitis (PP) patients present alterations in peripheral blood (PB) Th17/Treg associated with dysregulation in the Th1 response. Yet, little is known about the systemic distribution of myeloid cells, which drive the recruitment and differentiation of the adaptive effectors toward pathogenic inflammatory Th1 and Th17 as well as regulatory lymphocytes in PP. Although myeloid populations in patients with uveitis have previously been addressed, the data did not provide an exact description of PP patients. Using flow cytometry, we evaluated monocyte and IDO-expressing monocyte-like myeloid-derived suppressor cell (MDSC) subpopulations in PB samples from 15 patients with different courses of PP (cystoid macular edema and non-macular edema subgroups; CME and nCME, respectively) and 17 healthy controls (HCs) in relation to the Th1, Th17, and immunoregulatory subsets. We observed that only PP patients from the CME subgroup presented a significantly higher fraction of CD16+ IDO-expressing MDSCs and intermediate CD14highCD16+ monocytes compared to the HCs; this corresponded with relative up-regulation of Th1 and Th17, and down-regulation of Treg. In addition, alongside the increased percentage of IDO-expressing CD16+ MDSCs, the MDSC compartment displayed an inappropriate level of IDO (more pronounced in the CD16− subset) only in CME patients. At the same time, the fraction of CD16− myeloid cells did not differ significantly among the patient cohorts and healthy participants. Our study is the first to evaluate subpopulations of circulating myeloid cells in PP patients and indicates that an increased fraction of CD16+ myeloid cells might reflect the immunological and clinical severity of PP. Full article
►▼ Show Figures

Figure 1

12 pages, 6093 KB  
Communication
RAGE Cytosolic Partner Diaph1 Does Not Play an Essential Role in Diabetic Peripheral Neuropathy Progression
by Kamila Zglejc-Waszak, Bernard Kordas, Agnieszka Korytko, Andrzej Pomianowski, Bogdan Lewczuk, Joanna Wojtkiewicz, Krzysztof Wąsowicz, Izabella Babińska, Konark Mukherjee and Judyta Juranek
Cells 2025, 14(20), 1635; https://doi.org/10.3390/cells14201635 - 21 Oct 2025
Viewed by 386
Abstract
Receptor for advanced glycation end-products (RAGE) activation by hyperglycemia-induced AGE (advanced glycation end-products) accumulation is likely to play a crucial role in the development of complications such as diabetic peripheral neuropathy (DPN). RAGE signaling is mediated via its cytosolic tail. Through its cytosolic [...] Read more.
Receptor for advanced glycation end-products (RAGE) activation by hyperglycemia-induced AGE (advanced glycation end-products) accumulation is likely to play a crucial role in the development of complications such as diabetic peripheral neuropathy (DPN). RAGE signaling is mediated via its cytosolic tail. Through its cytosolic tail, RAGE recruits diaphanous-related formin 1 (Diaph1), a protein involved in actin filament organization. Disruption of RAGE–Diaph1 interactions using small molecules alleviates diabetic complications in mice; however, the role of Diaph1 in DPN progression has not been rigorously tested. In this study, we employed a Diaph1 knockout mouse (DKO) to investigate the role of Diaph1 in DPN progression. Herein, we demonstrate that, at the systemic level, CRISPR deletion of Diaph1 fails to ameliorate diabetes-induced weight loss in mice. Within the sciatic nerve (SCN), the lack of Diaph1 failed to prevent hyperglycemia-induced loss of β-actin in the nerve fibers. At a morphological level, the lack of Diaph1 leads to a partial rescue in DPN. While we observed improvements in axonal and fiber diameters in diabetic DKO mice, the g-ratio (an indicator of myelination) and myelin invaginations displayed incomplete rescue. Furthermore, the lack of Diaph1 failed to rescue motor or sensory nerve conduction defects resulting from hyperglycemia over 6 months. Overall, our data thus indicate that the complete loss of Diaph1 is insufficient to halt the progression of DPN. However, across a range of parameters including blood glucose levels, body weight measurements, axon and fiber diameters, and nerve conduction velocity, DKO diabetic mice show improvement when compared to wild-type diabetic mice. Full article
►▼ Show Figures

Graphical abstract

23 pages, 1461 KB  
Review
RNA Degradation in Pluripotent Stem Cells: Mechanisms, Crosstalk, and Fate Regulation
by Seunghwa Jeong, Myunggeun Oh, Jaeil Han and Seung-Kyoon Kim
Cells 2025, 14(20), 1634; https://doi.org/10.3390/cells14201634 - 20 Oct 2025
Viewed by 634
Abstract
Pluripotent stem cells (PSCs) exhibit remarkable self-renewal capacity and differentiation potential, necessitating tight regulation of gene expression at both transcriptional and post-transcriptional levels. Among post-transcriptional mechanisms, RNA turnover and degradation together play pivotal roles in maintaining transcriptome homeostasis and controlling RNA stability. RNA [...] Read more.
Pluripotent stem cells (PSCs) exhibit remarkable self-renewal capacity and differentiation potential, necessitating tight regulation of gene expression at both transcriptional and post-transcriptional levels. Among post-transcriptional mechanisms, RNA turnover and degradation together play pivotal roles in maintaining transcriptome homeostasis and controlling RNA stability. RNA degradation plays a pivotal role in determining transcript stability for both messenger RNAs (mRNAs) and non-coding RNAs (ncRNAs), thereby influencing cell identity and fate transitions. The core RNA decay machinery, which includes exonucleases, decapping complexes, RNA helicases, and the RNA exosome, ensures timely and selective decay of transcripts. In addition, RNA modifications such as 5′ capping and N6-methyladenosine (m6A) further modulate RNA stability, contributing to the fine-tuning of gene regulatory networks essential for maintaining PSC states. Recent single-cell and multi-omics studies have revealed that RNA degradation exhibits heterogeneous and dynamic kinetics during cell fate transitions, highlighting its role in preserving transcriptome homeostasis. Conversely, disruption of RNA decay pathways has been implicated in developmental defects and disease, underscoring their potential as therapeutic targets. Collectively, RNA degradation emerges as a central regulator of PSC biology, integrating the decay of both mRNAs and ncRNAs to orchestrate pluripotency maintenance, lineage commitment, and disease susceptibility. Full article
(This article belongs to the Special Issue Advances and Breakthroughs in Stem Cell Research)
►▼ Show Figures

Figure 1

16 pages, 2501 KB  
Article
SIRT3 Mediates Coordination Between Energy Metabolism and SOD Activity in Melatonin-Enhanced Boar Sperm Motility
by Naisheng Lu, Hulong Lei, Xueyuan Jiang, Peng Jia, Bushe Li and Dong Xia
Cells 2025, 14(20), 1633; https://doi.org/10.3390/cells14201633 - 20 Oct 2025
Viewed by 368
Abstract
Previous studies have demonstrated that melatonin (MLT) enhances boar sperm motility by modulating energy metabolism status, yet the underlying mechanisms remain incompletely understood. This study aims to investigate whether sirtuin 3 (SIRT3), a key mitochondrial deacetylase, mediates MLT’s effects. Herein, the semen of [...] Read more.
Previous studies have demonstrated that melatonin (MLT) enhances boar sperm motility by modulating energy metabolism status, yet the underlying mechanisms remain incompletely understood. This study aims to investigate whether sirtuin 3 (SIRT3), a key mitochondrial deacetylase, mediates MLT’s effects. Herein, the semen of six Landrace boars (16–18 months of age) was treated with 1.0 μM MLT with/without the SIRT3 inhibitor 3-TYP, preserved at 17 °C for 3 days, and subsequently maintained at 37 °C for a duration of 10 min. We demonstrated that MLT upregulated SIRT3 protein expression and reduced the acetylation level in mitochondrial proteins. MLT significantly increased glucose uptake and suppressed lactate release in the sperm, while elevating levels of pyruvate and acetyl-CoA, the substrates of pyruvate dehydrogenase (PDH) and the tricarboxylic acid (TCA) cycle, respectively, and the protein expression of PDH, indicating enhanced metabolic flux. Notably, inhibition of SIRT3 reversed MLT’s effects: it blocked the increases in SIRT3 expression, glucose consumption, PDH expression, complex I activity, ATP content, and superoxide dismutase (SOD) activity, and prevented the decreases in the levels of acetylation and lactate, as well as pyruvate kinase (PK) activity, confirming the essential role of SIRT3. Functionally, the MLT-induced improvements in sperm motility parameters (total, progressive, fast motility, immotile) were also reversed by 3-TYP. Collectively, these findings demonstrate that the SIRT3-mediated pathway is essential for MLT to enhance boar sperm energy metabolism and antioxidant defense, thereby increasing ATP production and enhancing sperm motility. Targeting SIRT3 represents a promising therapeutic strategy for improving boar fertility and may also provide insights for research into human male infertility. Full article
(This article belongs to the Collection Research Advances in Cellular Metabolism)
►▼ Show Figures

Graphical abstract

25 pages, 5974 KB  
Article
Identification of Regulatory RNA-Binding Genes in Spermatogonial Stem Cell Reprogramming to ES-like Cells Using Machine Learning–Integrated Transcriptomic and Network Analysis
by Ali Shakeri Abroudi, Hossein Azizi, Hewa Khalid Abdullah, Marwa Fadhil Alsaffar and Thomas Skutella
Cells 2025, 14(20), 1632; https://doi.org/10.3390/cells14201632 - 20 Oct 2025
Viewed by 482
Abstract
Spermatogonial stem cells (SSCs) are unipotent germline cells with emerging pluripotent potential under specific in vitro conditions. Understanding their capacity for reprogramming and the molecular mechanisms involved offers valuable insights into regenerative medicine and fertility preservation. SSCs were isolated from Oct4-GFP C57BL/6 transgenic [...] Read more.
Spermatogonial stem cells (SSCs) are unipotent germline cells with emerging pluripotent potential under specific in vitro conditions. Understanding their capacity for reprogramming and the molecular mechanisms involved offers valuable insights into regenerative medicine and fertility preservation. SSCs were isolated from Oct4-GFP C57BL/6 transgenic mice using enzymatic digestion and cultured in defined media. Under these conditions, ES-like colonies emerged expressing pluripotency markers. These cells were characterized by immunocytochemistry, teratoma assays, and transcriptomic analyses using bulk and single-cell RNA sequencing datasets. Gene expression profiles were compared with ESCs and SSCs using datasets from GEO (GSE43850, GSE38776, GSE149512). Protein–protein interaction (PPI) networks and co-expression modules were explored through STRING, Cytoscape, and WGCNA. ES-like cells derived from SSCs exhibited strong expression of OCT4, DAZL, and VASA. Transcriptomic analysis revealed key differentially expressed genes and shared regulatory networks with ESCs. WGCNA identified key co-expression modules and hub regulatory RNA binding genes (Ctdsp1, Rest, and Stra8) potentially responsible for the reprogramming process. Teratoma assays confirmed pluripotency, and single-cell RNA-seq validated expression of critical markers in cultured SSCs. This study demonstrates that SSCs can acquire pluripotency features and be reprogrammed into ES-like cells. The integration of transcriptomic and network-based analyses reveals novel insights into the molecular drivers of SSC reprogramming, highlighting their potential utility in stem cell-based therapies and male fertility preservation. Full article
►▼ Show Figures

Figure 1

15 pages, 2133 KB  
Article
BelloStage™-3000 Bioreactor Versus Conventional Cultivation of Recombinant Capripoxvirus Expressing Brucella Antigens in Vero Cells: A Step Towards the Development of a New Human Brucellosis Vaccine
by Zhanat Amanova, Zhanna Sametova, Olga Chervyakova, Sholpan Turyskeldi, Alina Kurmasheva, Ruslan Abitayev, Abdurakhman Ussembay, Zhanat Kondibayeva, Dariya Toktyrova, Dana Mazbayeva and Yerbol Bulatov
Cells 2025, 14(20), 1631; https://doi.org/10.3390/cells14201631 - 20 Oct 2025
Viewed by 771
Abstract
Brucellosis remains one of the most significant zoonotic diseases, posing a serious threat to both human health and livestock. This issue is particularly relevant for Kazakhstan, which is among the countries endemic for brucellosis with a high incidence rate. Such circumstances highlight the [...] Read more.
Brucellosis remains one of the most significant zoonotic diseases, posing a serious threat to both human health and livestock. This issue is particularly relevant for Kazakhstan, which is among the countries endemic for brucellosis with a high incidence rate. Such circumstances highlight the urgent need for the development and implementation of effective preventive measures, including modern vaccine platforms capable of providing reliable protection for the population and reducing the economic impact on the agricultural sector. Recombinant capripoxviruses are considered promising vector platforms for vaccine development, as they ensure high expression of target antigens, elicit strong immune responses, and are safe for humans. In this study, the replication of recombinant capripoxviruses expressing Brucella antigens (SPPV (TK-) OMP19/SODC and SPPV (TK-) OMP25) was evaluated in Vero cells using the BelloStage™-3000 bioreactor system in combination with BioNOC II® macrocarriers. Application of the bioreactor resulted in nearly a 100-fold increase in Vero cell density compared with static cultures and provided optimal conditions for cell adhesion, growth, and metabolic activity. Consequently, a significant increase in viral titers was observed: for SPPV (TK-) OMP19/SODC, mean titers reached 7.50 log10 TCID50/mL versus 4.50 in static culture (p < 0.0001), while SPPV (TK-) OMP25 achieved 7.08 log10 TCID50/mL versus 4.33 (p < 0.001). These findings confirm the reliability, reproducibility, and scalability of this bioreactor-based approach, demonstrating clear advantages over conventional cultivation methods. Overall, the study highlights the high potential of the BelloStage™-3000 system with BioNOC II® macrocarriers for the industrial production of recombinant capripoxvirus-based vaccines against brucellosis and for the broader development of other recombinant viral vaccines. Full article
(This article belongs to the Special Issue 3D Cultures and Organ-on-a-Chip in Cell and Tissue Cultures)
►▼ Show Figures

Figure 1

14 pages, 3033 KB  
Article
MK3 Gene Upregulates Granulosa Cell Apoptosis Through the TNF/P38 MAPK Pathway in Chicken
by Li Chen, Jia Liu, Ying Zhang, Jinsong Pi and Yan Wu
Cells 2025, 14(20), 1630; https://doi.org/10.3390/cells14201630 - 20 Oct 2025
Viewed by 320
Abstract
In poultry production, the laying rate is a critical economic trait, as high egg production significantly enhances profitability. Mitogen-activated protein kinase-activated protein kinase 3 (MK3) is a member of the mitogen-activated protein kinase (MAPK) family, which plays an important role in [...] Read more.
In poultry production, the laying rate is a critical economic trait, as high egg production significantly enhances profitability. Mitogen-activated protein kinase-activated protein kinase 3 (MK3) is a member of the mitogen-activated protein kinase (MAPK) family, which plays an important role in follicular development. Our previous RNA-seq analysis revealed that MK3 expression was significantly altered in the ovaries of laying hens exposed to normal versus light-deprivation conditions. Based on previous RNA-seq analysis of chicken ovaries, this study focused on the MK3 gene to explore its role in regulating apoptosis of follicular granulosa cells in laying hens. The results demonstrated that MK3 overexpression induced granulosa cell apoptosis by modulating the expression of key proliferation- and apoptosis-related genes, including FAS, Caspase3, BCL2, and C-myc. These findings were further validated using specific siRNA-mediated knockdown of MK3. Flow cytometry, CCK-8, and EdU assays consistently showed that MK3 facilitated apoptosis and inhibited granulosa cell proliferation. Additionally, dual-luciferase reporter assays revealed that the transcription factor WT1 bound to the MK3 promoter and enhanced its transcriptional activity. Mechanistically, MK3 regulated granulosa cell apoptosis through the TNF/P38 MAPK pathway. This conclusion was corroborated by treatment with the P38 inhibitor GS-444217 and specific siRNA targeting components of the pathway. In summary, MK3 promotes granulosa cell apoptosis in the follicles of laying hens, is transcriptionally regulated by WT1, and exerts its pro-apoptotic effects via the TNF/P38 MAPK pathway. Full article
(This article belongs to the Special Issue Focus on Machinery of Cell Death)
►▼ Show Figures

Figure 1

13 pages, 1437 KB  
Review
HPV Oncoproteins and Mitochondrial Reprogramming: The Central Role of ROMO1 in Oxidative Stress and Metabolic Shifts
by Eva Tsoneva and Angel Yordanov
Cells 2025, 14(20), 1629; https://doi.org/10.3390/cells14201629 - 19 Oct 2025
Viewed by 899
Abstract
High-risk human papillomaviruses (HPVs), particularly types 16 and 18, drive carcinogenesis by rewiring host metabolism and mitochondrial function. The oncoproteins E5, E6, and E7 collectively induce mitochondrial fragmentation, increase reactive oxygen species (ROS), and promote a metabolic shift from oxidative phosphorylation (OXPHOS) to [...] Read more.
High-risk human papillomaviruses (HPVs), particularly types 16 and 18, drive carcinogenesis by rewiring host metabolism and mitochondrial function. The oncoproteins E5, E6, and E7 collectively induce mitochondrial fragmentation, increase reactive oxygen species (ROS), and promote a metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis (the Warburg effect). A redox-sensitive mitochondrial protein, Reactive Oxygen Species Modulator 1 (ROMO1), has emerged as a key mediator of these processes. ROMO1 contributes to mitochondrial morphology, regulates ROS homeostasis, and interacts with key stress-response pathways. While ROMO1 is overexpressed in many cancers and correlates with poor prognosis, recent data suggest that HPV-associated cervical lesions exhibit a unique biphasic expression pattern, with high ROMO1 levels in early stages and reduced expression in advanced tumors. The underlying molecular mechanisms remain unclear, but may involve HPV genome integration, NF-κB suppression, or epigenetic silencing. Key mechanisms such as how HPV modulates ROMO1 expression and how this contributes to stage-dependent metabolic vulnerability remain incompletely understood. This review highlights the current understanding of how HPV oncoproteins impact mitochondrial structure and function, emphasizes the role of ROMO1 in this context, and compares findings with other cancer types. Although no ROMO1-targeted therapies currently exist, the protein may serve as a redox-sensitive biomarker and potential vulnerability in HPV-driven tumors. We propose that targeting mitochondrial fragmentation, ROS signaling, or metabolic reprogramming may offer new avenues for therapeutic intervention. Further research is needed to clarify ROMO1’s dual role in early vs. late-stage disease and to validate its relevance as a clinical target. Our review fills a gap in the current literature by being the first to systematically explore ROMO1’s contribution to HPV-induced mitochondrial dysfunction and metabolic rewiring, and we outline research priorities for future studies. Full article
(This article belongs to the Special Issue From Energy Metabolism to Disease: The Multifaceted Roles of Mitochondria)
►▼ Show Figures

Figure 1

36 pages, 15614 KB  
Article
Non-Competitive AMPA Receptor Antagonist Perampanel Inhibits Ischemia-Induced Neurodegeneration and Behavioral Deficits in Focal Cortical Pial Vessel Disruption Stroke Model
by Michael G. Zaki, Mohamed Taha Moutaoufik, Mahboubeh Pordeli, Mohan Babu, Changiz Taghibiglou and Francisco S. Cayabyab
Cells 2025, 14(20), 1628; https://doi.org/10.3390/cells14201628 - 19 Oct 2025
Viewed by 974
Abstract
Glutamate receptors represent a potential target for neuroprotection in neurodegenerative neurological conditions. Perampanel, a non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR) antagonist, is clinically approved for the management of epilepsy. Perampanel’s neuroprotective effects have been reported in global and focal cerebral ischemia models, but the [...] Read more.
Glutamate receptors represent a potential target for neuroprotection in neurodegenerative neurological conditions. Perampanel, a non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR) antagonist, is clinically approved for the management of epilepsy. Perampanel’s neuroprotective effects have been reported in global and focal cerebral ischemia models, but the cellular mechanisms remain incompletely understood. Therefore, we studied the potential neuroprotective effects of perampanel in rats using the pial vessel disruption (PVD) stroke model, an established focal cortical non-reperfusion ischemic stroke model. Perampanel was given once intraperitoneally (3 mg/kg body weight) 1 h after PVD surgery and repeated on days 2–3 post-surgery. On the fourth day post PVD, animal behavioral assays and imaging, biochemical, and electrophysiological analyses were performed. Compared to vehicle control, perampanel in PVD-treated rats significantly inhibited hippocampal neurodegeneration and long-term potentiation deficits. Perampanel also attenuated PVD-induced motor deficits, depressive/anxiety-like behaviors, and hippocampal-dependent cognitive impairment. In addition, perampanel prevented the PVD-induced downregulation of surface-expressed GluA1 and GluA2 AMPARs and increased phosphorylation of GluA1 at S831 and S845. Molecular docking analysis revealed perampanel binding to transmembrane regions M1, M3 and M4 of GluA1 and GluA2 subunits. Together, our results show that perampanel attenuated PVD-induced neurodegeneration and behavioral deficits by blocking AMPARs and decreasing GluA1 and GluA2 internalization. In addition, this study shows the neuroprotective potential of perampanel through the inhibition of neuroinflammation mediated by activated microglia and astrocytes following cerebral ischemia. This study is the first to evaluate perampanel in the pial vessel disruption model of ischemia without reperfusion, a clinically relevant stroke paradigm that differs fundamentally from middle cerebral carotid artery occlusion and photothrombosis stroke models. Full article
(This article belongs to the Topic Application of Animal Models: From Physiology to Pathology)
►▼ Show Figures

Figure 1

22 pages, 1061 KB  
Review
Heat Shock Proteins in Pancreatic Cancer: Pathogenic Mechanisms and Clinical Implications
by Jacek Kabut, Jakub Sokołowski, Wiktoria Żelazna, Mateusz Stępień, Marta Strauchman, Natalia Jaworska, Jakub Wnuk, Anita Gorzelak-Magiera, Łukasz Michalecki and Iwona Gisterek-Grocholska
Cells 2025, 14(20), 1627; https://doi.org/10.3390/cells14201627 - 18 Oct 2025
Viewed by 563
Abstract
Heat shock proteins (HSPs) are highly conserved molecular chaperones that play a key role in maintaining protein homeostasis, or proteostasis, especially under stressful environmental conditions such as hyperthermia, hypoxia, or the presence of reactive oxygen species. In pancreatic cancer, the expression of many [...] Read more.
Heat shock proteins (HSPs) are highly conserved molecular chaperones that play a key role in maintaining protein homeostasis, or proteostasis, especially under stressful environmental conditions such as hyperthermia, hypoxia, or the presence of reactive oxygen species. In pancreatic cancer, the expression of many HSP isoforms is dysregulated, contributing to the activation of mechanisms that promote tumor development, including proliferation, invasion, angiogenesis, treatment resistance, and cancer cachexia syndrome. HSPs are significant diagnostic and prognostic biomarkers. Some of them, such as HSP27, HSP70, and HSP90, have been shown to correlate with treatment response and patient survival. Others, including HSPA2 and HSPB6, may indicate an increased risk of disease recurrence. These proteins also represent promising therapeutic targets. Preclinical and clinical studies suggest that inhibiting HSP activity and associated signaling pathways may inhibit tumor growth and increase treatment efficacy. These therapeutic effects include inducing apoptosis, autophagy, and ferroptosis, as well as sensitizing cancer cells to chemotherapy and immunotherapy. This article summarizes the current knowledge about the role of HSPs in pancreatic cancer biology, their significance as biomarkers, and their potential therapeutic applications in treating pancreatic ductal adenocarcinoma (PDAC). Most studies conducted so far have been preclinical, and due to the promising results, further clinical investigation is warranted. Full article
(This article belongs to the Special Issue Heat Shock Proteins and Human Cancers)
►▼ Show Figures

Figure 1

13 pages, 2281 KB  
Article
Generating a Preclinical Model for PITPNM3 and Evaluating Genotype–Phenotype Concordance: Insights from a Mouse Model
by Aykut Demirkol, Joanne Li and Stephen H. Tsang
Cells 2025, 14(20), 1626; https://doi.org/10.3390/cells14201626 - 18 Oct 2025
Viewed by 472
Abstract
PITPNM3 has been identified as a crucial gene associated with various phenotypes of retinal disease in humans; however, detailed mechanisms through which PITPNM3 mutations result in these conditions are not fully understood. In this study, we aimed to generate such a preclinical mouse [...] Read more.
PITPNM3 has been identified as a crucial gene associated with various phenotypes of retinal disease in humans; however, detailed mechanisms through which PITPNM3 mutations result in these conditions are not fully understood. In this study, we aimed to generate such a preclinical mouse model and evaluate its relevance to human PITPNM3-related conditions. Heterozygous mice were bred to obtain a homozygous genotype, aiming to mimic the human genetic condition. Subsequent phenotyping and genetic segregation analyses were conducted along with electrophysiological studies and histological examinations. Full-field electroretinogram analysis revealed a reduced cone response although the severity was not as pronounced as observed in humans with PITPNM3-related conditions. Histologically, the retinal structure appeared largely unchanged, indicating a discordance between functional impairment and morphological changes. In our preclinical mouse model, the observed phenotypic changes were not as severe as those found in humans with PITPNM3-related conditions and this discrepancy points to a potentially different disease progression trajectory in the mouse model. These findings highlight the importance of longer follow-up periods in such studies and the need for further research to elucidate the genotype–phenotype relationship in PITPNM3. Full article
►▼ Show Figures

Figure 1

23 pages, 6946 KB  
Article
Ginsenoside Derivative AD-1 Suppresses Pathogenic Phenotypes of Rheumatoid Arthritis Fibroblast-like Synoviocytes by Modulating the PI3K/Akt Signaling Pathway
by Yuan Fu, Fangfang Li, Biao Cui, Zhongyu Zhou, Xizhu Fang, Shengnan Huang, Xingguo Quan, Yuqing Zhao and Dan Jin
Cells 2025, 14(20), 1625; https://doi.org/10.3390/cells14201625 - 18 Oct 2025
Viewed by 397
Abstract
Rheumatoid arthritis (RA) is a systemic autoimmune disorder marked by chronic inflammation of small synovial joints, with frequent extra-articular involvement of the skin and eyes. Prolonged methotrexate therapy for RA is often accompanied by serious side effects. Therefore, new drugs with less toxicity [...] Read more.
Rheumatoid arthritis (RA) is a systemic autoimmune disorder marked by chronic inflammation of small synovial joints, with frequent extra-articular involvement of the skin and eyes. Prolonged methotrexate therapy for RA is often accompanied by serious side effects. Therefore, new drugs with less toxicity and greater effectiveness need to be developed. The ginsenoside 20(R)-25-methoxyl-dammarane-3β,12β,20-triol (AD-1), purified from Panax ginseng berry, exhibits potent anti-inflammatory and anti-cancer activities. However, the pharmacological mechanism of AD-1 in RA remains unclear. This study explored the potential anti-RA effects of AD-1 using an integrative strategy that combined network pharmacology, molecular docking, molecular dynamics simulation, and in vitro pharmacological validation. Enrichment analyses of KEGG and GO terms based on network pharmacology pointed to the PI3K/Akt signaling axis as a key regulatory pathway modulated by AD-1. Molecular docking and dynamics simulations revealed that AD-1 may have a close interaction with PIK3R1 and AKT1, demonstrating a stabilizing effect. Then, after experimental verification using human rheumatoid arthritis fibroblasts (MH7A), it was found that AD-1 suppressed cell proliferation, migration, and invasion and promoted apoptosis. Subsequent analysis of the RABC databases revealed that PIK3R1 and AKT1 were upregulated in RA, while AD-1 reduces phosphorylation of PI3K and Akt. In conclusion, these findings indicate that AD-1 exerts its anti-RA action, at least in part, through modulation of the PI3K/Akt signaling pathway and induction of apoptosis in synovial cells. This study provides a basis and new strategies for the role of ginsenosides in the treatment of RA. Full article
(This article belongs to the Special Issue Study on Immune Activity of Natural Products)
►▼ Show Figures

Graphical abstract

18 pages, 14672 KB  
Article
Propiconazole-Induced Testis Damage and MAPK-Mediated Apoptosis and Autophagy in Germ Cells
by Won-Young Lee, Ran Lee, Hyeon Woo Sim and Hyun-Jung Park
Cells 2025, 14(20), 1624; https://doi.org/10.3390/cells14201624 - 17 Oct 2025
Viewed by 300
Abstract
Propiconazole (PRO), a triazole fungicide, controls fungal diseases by disrupting ergosterol production in fungal cells. It is used in crops such as cereals and fruits. However, there are concerns regarding its potential to disrupt the endocrine system and cause reproductive toxicity. This study [...] Read more.
Propiconazole (PRO), a triazole fungicide, controls fungal diseases by disrupting ergosterol production in fungal cells. It is used in crops such as cereals and fruits. However, there are concerns regarding its potential to disrupt the endocrine system and cause reproductive toxicity. This study examined the effects of PRO on mouse testes, germ cells, and GC-1 spermatogonia. After eight weeks, PRO reduced testicular diameter and downregulated key germ cell genes (Sall4, Piwil, Nanos2, and Dazl). A histological examination revealed smaller seminiferous tubules and fewer SALL4+ cells. PRO also impaired steroidogenesis by downregulating genes (StAR, Cyp11a1, 3β-HSD1) and reducing sperm motility, with a decline in Velocity Straight Line (VSL), Linearity (LIN), Straightness (STR), and motile sperm. PRO caused dose-dependent cytotoxicity in GC-1 spermatogonia, decreased proliferation, and increased apoptosis, marked by cleaved caspase-3 and BAX. PRO also induced autophagy, as presented by elevated levels of autophagy-related genes (LC3 and ATG12) and proteins (ATG5 and LC3A/B). 3-Methyladenine (3-MA), an autophagy inhibitor, downregulates levels of autophagy- and apoptosis-related proteins when 3-MA and PRO are simultaneously treated in vitro. This suggests that both apoptosis and autophagy contribute to PRO-induced testicular cytotoxicity. This study is the first to detail that PRO affects sperm motility in mice and induces autophagy-mediated apoptosis in GC-1 spg. Full article
►▼ Show Figures

Graphical abstract

19 pages, 2243 KB  
Review
Pyruvate Kinase M2 Role in Cardiovascular Repair
by Mohd Rihan, Lior Zangi and Ajit Magadum
Cells 2025, 14(20), 1623; https://doi.org/10.3390/cells14201623 - 17 Oct 2025
Viewed by 531
Abstract
Adult cardiomyocytes (CMs) lose their proliferative capacity shortly after birth, posing a major challenge for cardiac repair following injury such as myocardial infarction (MI). Despite significant advances over the past decade, many strategies for promoting cardiac regeneration have faced limitations, underscoring the need [...] Read more.
Adult cardiomyocytes (CMs) lose their proliferative capacity shortly after birth, posing a major challenge for cardiac repair following injury such as myocardial infarction (MI). Despite significant advances over the past decade, many strategies for promoting cardiac regeneration have faced limitations, underscoring the need to identify novel molecular pathways and targets. Pyruvate kinase muscle isoform 2 (PKM2), a key metabolic enzyme, has emerged as a compelling candidate in this context due to its multifaceted roles in cellular metabolism, proliferation, redox balance, angiogenesis, and master gene regulator in repair. Recent studies highlight the critical function of PKM2 in cardiac repair and regeneration. PKM2 not only promotes the proliferation of CMs but also protects the heart from oxidative stress by redirecting glycolytic intermediates toward the pentose phosphate pathway (PPP), thereby increasing nicotinamide adenine dinucleotide phosphate (NADPH) levels, reducing reactive oxygen species (ROS), and minimizing DNA damage. Moreover, PKM2 interacts with key signaling molecules, including β-catenin, hypoxia-inducible factor 1α (HIF-1a), and checkpoint kinase 1 (CHK1), to promote CM cell cycle reentry, angiogenesis, and enhanced cell survival. Collectively, these multifaceted actions highlight PKM2 as both a metabolic and signaling hub in cardiac repair by promoting myocardial remuscularization, protection, and revascularization and position PKM2 as a promising therapeutic. This review explores the diverse roles of PKM2 in myocardial repair and discusses its potential as a novel avenue for advancing regenerative therapies in cardiovascular medicine. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Heart Diseases)
►▼ Show Figures

Figure 1

30 pages, 20757 KB  
Article
Protective Immune Signatures Associated with Latent TB Infection in PLHIV—Insights from an Integrative Prospective Immune Monitoring Study
by Shilpa Bhowmick, Pratik Devadiga, Sapna Yadav, Nandan Mohite, Pranay Gurav, Tejaswini Pandey, Varsha Padwal, Namrata Neman, Aarya Suryawanshi, Satyajit Musale, Amit Kumar Singh, Sharad Bhagat, Snehal Kaginkar, Harsha Palav, Shantanu Birje, Shilpa Kerkar, Susan Idicula-Thomas, Vidya Nagar, Priya Patil, Sachee Agrawal, Sushma Gaikwad, Jayanthi Shastri, Nupur Mukherjee, Kiran Munne, Vikrant M. Bhor, Taruna Madan and Vainav Pateladd Show full author list remove Hide full author list
Cells 2025, 14(20), 1622; https://doi.org/10.3390/cells14201622 - 17 Oct 2025
Viewed by 533
Abstract
Understanding how HIV-1 pathogenesis affects systemic and TB specific immunity in the setting of latent (LTBI+) compared to active TB infection could provide actionable insights for the prevention of reactivation. Fifty HIV-seronegative and 112 HIV-1-positive anti-retroviral therapy (ART)-naïve participants were stratified as LTBI+ [...] Read more.
Understanding how HIV-1 pathogenesis affects systemic and TB specific immunity in the setting of latent (LTBI+) compared to active TB infection could provide actionable insights for the prevention of reactivation. Fifty HIV-seronegative and 112 HIV-1-positive anti-retroviral therapy (ART)-naïve participants were stratified as LTBI+ (n = 35), active TB+ (n = 22) and non-coinfected (n = 55) based on an interferon gamma release assay (IGRA) and clinical confirmation prior to receiving TB therapy. Systemic and TB-specific (DosR and Rpf) immune monitoring of cellular subsets, together with multi-analyte plasma analysis, was carried out. Pursuant to isoniazid prophylaxis therapy (IPT) and ART initiation, HIV-1-positive LTBI+ participants (HLTBI+) were followed for up to two years. Before ART initiation, HLTBI+ individuals exhibited the lowest levels of circulating intermediate monocytes, T-cell activation and PD-1 expression, with a decreased frequency of T-regulatory cells and higher circulating IL-10 and IL-17A. PD-1 expression on CD4+ T cell memory subsets, together with opposing anamnestic TNF-α responses to DosR and Rpf, was a discriminatory signature for the HLTBI+ group, as was preserved (following ART) TB-specific TNF-α production, which positively correlated with the CD4/CD8 ratio. Our results highlight an immunomodulatory phenotype conferred by latent TB infection in PLHIV, whose preservation may provide strategies to mitigate TB reactivation. Full article
(This article belongs to the Special Issue Flow Cytometry in Immunology Research)
►▼ Show Figures

Graphical abstract

36 pages, 2323 KB  
Review
Advances in Mitochondrial Dysfunction and Its Role in Cardiovascular Diseases
by Yan Qiu, Shuo Chang, Ye Zeng and Xiaoqi Wang
Cells 2025, 14(20), 1621; https://doi.org/10.3390/cells14201621 - 17 Oct 2025
Viewed by 806
Abstract
Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide and is attributed to complex pathophysiological mechanisms that surpass the traditional risk factors. Emerging evidence indicates that mitochondrial dysfunction plays a central role in CVD progression, linking impaired bioenergetics, oxidative stress [...] Read more.
Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide and is attributed to complex pathophysiological mechanisms that surpass the traditional risk factors. Emerging evidence indicates that mitochondrial dysfunction plays a central role in CVD progression, linking impaired bioenergetics, oxidative stress imbalance, and defective mitochondrial quality control to endothelial dysfunction, myocardial injury, and adverse cardiac remodeling. However, the mechanistic interplay between mitochondrial dysfunction and CVD pathogenesis remains unclear. This review provides a comprehensive synthesis of recent knowledge, focusing on the dysregulation of mitochondrial energy metabolism, alterations in mitochondrial membrane potential, and disruptions in mitochondrial dynamics, including the balance of fusion and fission, mitophagy, and biogenesis. Furthermore, we critically evaluated emerging mitochondria-targeted therapeutic strategies, including pharmacological agents, gene therapies, and regenerative approaches. By bridging fundamental mitochondrial biology with clinical cardiology, this review underscores the critical translational challenges and opportunities in developing mitochondria-focused interventions. A deeper understanding of the mitochondrial mechanisms in CVD pathophysiology will offer novel diagnostic biomarkers and precision-targeted therapeutics, thereby transforming CVD management. Full article
(This article belongs to the Section Cellular Pathology)
►▼ Show Figures

Figure 1

21 pages, 1616 KB  
Review
The Evolution, Current Landscape, and Future Prospects of Oncolytic Virotherapy in Melanoma: Talimogene Laherparepvec and Beyond
by John Smestad, John Rieth, Douglas Laux and Mohammed Milhem
Cells 2025, 14(20), 1620; https://doi.org/10.3390/cells14201620 - 17 Oct 2025
Viewed by 627
Abstract
Oncolytic viruses represent an emerging class of therapeutic agents that have the potential to transform the care of patients with melanoma. In this narrative review, we describe the evolution of oncolytic virus approaches. We begin by describing early investigations using wild type viruses [...] Read more.
Oncolytic viruses represent an emerging class of therapeutic agents that have the potential to transform the care of patients with melanoma. In this narrative review, we describe the evolution of oncolytic virus approaches. We begin by describing early investigations using wild type viruses and then the development of sophisticated Herpes simplex virus 1 (HSV-1) variant constructs such as talimogene laherparepvec (T-VEC) and vusolimogene oderparepvec (Replimune-1, RP1), which incorporate deletions of viral genes and expression of human or synthetic transgenes to promote tumor selectivity, dendritic cell recruitment, antigen presentation, and stimulation of systemic anti-tumor immune responses. We review the status of clinical trials of oncolytic viruses in melanoma, highlight regulatory challenges, and describe important concepts and key remaining questions within the field. While T-VEC remains the only Food and Drug Administration (FDA)-approved oncolytic virus for melanoma treatment, ongoing research focusing on next-generation viral constructs and combination strategies aims to further improve clinical outcomes and expand the applicability of oncolytic virus therapy in melanoma. Full article
(This article belongs to the Special Issue mRNA Vaccines and Therapeutics in Melanoma: From Mechanisms to Cellular Impact)
►▼ Show Figures

Figure 1

25 pages, 7144 KB  
Article
Efficacy of Oncolytic Virus VV-GMCSF-Lact Against Immunocompetent Glioma
by Alisa Ageenko, Natalia Vasileva, Gaukhar Yusubalieva, Aleksandra Sen’kova, Alexander Romashchenko, Ilya Gubskiy, Fedor Zabozlaev, Evgeniy Zavyalov, Maya Dymova, Vladimir Richter and Elena Kuligina
Cells 2025, 14(20), 1619; https://doi.org/10.3390/cells14201619 - 17 Oct 2025
Viewed by 395
Abstract
Virotherapy is a promising method for treating oncological diseases, including such aggressive and difficult-to-treat brain tumors such as glioblastoma. Recombinant vaccinia virus VV-GMCSF-Lact has previously shown high antitumor potential against tumor cells of varying histogenesis, including gliomas, and completed a Phase I clinical [...] Read more.
Virotherapy is a promising method for treating oncological diseases, including such aggressive and difficult-to-treat brain tumors such as glioblastoma. Recombinant vaccinia virus VV-GMCSF-Lact has previously shown high antitumor potential against tumor cells of varying histogenesis, including gliomas, and completed a Phase I clinical trial, demonstrating safety and good tolerability in patients with recurrent/refractory metastatic breast cancer. Investigating two types of VV-GMCSF-Lact delivery, intravenous and intratumoral, into orthotopically transplanted C6 glioma in rats, it was shown that intratumoral injection significantly increases tumor volumes in comparison with intravenous virus delivery and is accompanied by noticeable toxic effects. Extensive areas of necrotic decay of tumor tissue and its significant mixed-cell infiltration and peritumoral edema, affecting the tumor volume, were detected using H&E staining of C6 tumors after intratumoral injection of VV-GMCSF-Lact. However, only with intratumoral administration was a significant decrease in the level of the tumor cell proliferation marker Ki67 demonstrated by immunohistochemical staining. The observed toxic effects of VV-GMCSF-Lact with intratumoral administration revealed the need for dose selection, which was performed on a mouse GL261 glioma model. Results of the study allowed us to determine the viral dose that does not lead to toxic effects and can potentially increase life expectancy of mice. The data obtained show the need for careful selection of both the route of viral drug dose and administration. Full article
(This article belongs to the Special Issue Glioblastoma: What Do We Know?)
►▼ Show Figures

Graphical abstract

20 pages, 3046 KB  
Article
ASMase Activation in Ultrasound-Stimulated Radiation Enhancement Using MRI-Guided Focused Ultrasound
by Tera N. Petchiny, Deepa Sharma, Anoja Giles, Kai Xuan Leong, Wenyi Yang, Lakshmanan Sannachi, David Alberico and Gregory J. Czarnota
Cells 2025, 14(20), 1618; https://doi.org/10.3390/cells14201618 - 17 Oct 2025
Viewed by 352
Abstract
Focused ultrasound-stimulated microbubble (MB + FUS) therapy is a promising radiation enhancement strategy, utilizing vascular disruption to enhance radiation efficacy. However, its mechanistic effects in large tumour volumes and clinical translatability remain insufficiently characterized. This study evaluates the synergistic impact of MB + [...] Read more.
Focused ultrasound-stimulated microbubble (MB + FUS) therapy is a promising radiation enhancement strategy, utilizing vascular disruption to enhance radiation efficacy. However, its mechanistic effects in large tumour volumes and clinical translatability remain insufficiently characterized. This study evaluates the synergistic impact of MB + FUS combined with radiation therapy (XRT) in a large-scale, immunosuppressed rabbit xenograft model using a clinically adaptable, MRI-guided 6144-element focused ultrasound (MRgFUS) system. Tumours were treated with MB + FUS, XRT, or both, with real-time image-guided MB activation and evaluation of treatment effects on vascular integrity, proliferation, and cellular stress responses. Assessments included Power Doppler ultrasound, histology, and immunohistochemistry targeting TUNEL, ASMase, Ki-67, Factor VIII, HIF-1α, and VEGF. Combination therapy induced significant vascular collapse, reduced perfusion, and decreased Factor VIII expression, alongside increased nuclear condensation, TUNEL positivity, and ASMase expression, consistent with ASMase-mediated endothelial apoptosis and vascular disruption. Upregulation of HIF-1α and VEGF indicated hypoxia-driven angiogenic signalling, while Ki-67 suppression reflected sustained tumour growth inhibition. Although immune responses were limited by host immunosuppression, the larger tumour burden provided clinically relevant constraints. The MRgFUS platform enabled precise and reproducible MB activation, reinforcing MB + FUS as a potent radio-enhancement modality. These findings support the continued development of MB + FUS toward clinical translation and highlight its potential as a complementary strategy to radiation therapy. Full article
►▼ Show Figures

Figure 1

15 pages, 621 KB  
Review
The Pathogenesis and Virulence of the Major Enterovirus Pathogens Associated with Severe Clinical Manifestations: A Comprehensive Review
by Yuwei Liu, Maiheliya Maisimu, Zhihang Ge, Suling Xiao and Haoran Wang
Cells 2025, 14(20), 1617; https://doi.org/10.3390/cells14201617 - 17 Oct 2025
Viewed by 527
Abstract
Enteroviruses (EVs), particularly those within the species Enterovirus A and B, represent a significant global public health burden, especially in infants and young children. While often causing self-limiting hand, foot, and mouth disease (HFMD), certain serotypes can lead to severe neurological and cardiopulmonary [...] Read more.
Enteroviruses (EVs), particularly those within the species Enterovirus A and B, represent a significant global public health burden, especially in infants and young children. While often causing self-limiting hand, foot, and mouth disease (HFMD), certain serotypes can lead to severe neurological and cardiopulmonary complications. This comprehensive review focuses on the major pathogenic serotypes, including enterovirus A71 (EV-A71), coxsackievirus A16 (CV-A16), coxsackievirus A6 (CV-A6), coxsackievirus B3 (CV-B3), and enterovirus D68 (EV-D68). We began by reconstructing a phylogenetic tree based on VP1 protein sequences, elucidating the genetic relationships and evolutionary patterns among these serotypes, which underpin their diverse antigenicity and epidemiology. Building upon this genetic foundation, the review then provides a detailed synthesis of their distinct pathogenesis, highlighting the five-phase clinical progression from exanthematous phase to convalescence, and their unique tropisms for target organs such as the central nervous system and heart. Progressing to the molecular mechanisms, a critical component of this work is a systematic summary of the specific host receptors that mediate viral entry, including SCARB2 for EV-A71 and CV-A16, sialic acid and ICAM-5 for EV-D68, and CAR/CD55 for CV-B3, explaining the mechanistic basis for their tissue specificity and pathogenicity. Finally, to translate these insights into clinical applications, we critically evaluate the current landscape of vaccine development, noting the high efficacy (~90%) of inactivated EV-A71 vaccines in Asia and the significant global success of poliovirus vaccines, while also addressing the stark lack of cross-protective or licensed vaccines for other prevalent serotypes like CV-A16, CV-A6, and EV-D68. The review concludes that the high genetic diversity and serotype-specific immunity of enteroviruses pose a major challenge, necessitating a concerted shift towards the development of broad-spectrum vaccines and therapeutics informed by an integrated understanding of viral evolution, receptor usage, and pathogenesis. Full article
(This article belongs to the Special Issue The Cellular and Molecular Mechanisms of Immunity to Infectious Viruses)
►▼ Show Figures

Figure 1

19 pages, 4150 KB  
Article
Cisplatin-Loaded M1 Macrophage-Derived Vesicles Have Anti-Cancer Activity in Osteosarcoma
by Namrata Anand, Joseph Robert McCorkle, David S. Schweer, Lan Li, Kristen S. Hill, Melissa A. Fath, Derek B. Allison, Christopher L. Richards and Jill M. Kolesar
Cells 2025, 14(20), 1616; https://doi.org/10.3390/cells14201616 - 17 Oct 2025
Viewed by 377
Abstract
Osteosarcoma (OS) is a relatively rare bone malignancy that primarily affects children and young adults and is associated with significant morbidity and mortality. Cisplatin is a mainstay of treatment, but its efficacy is limited by off-target toxicities. Immunotherapy is not effective due to [...] Read more.
Osteosarcoma (OS) is a relatively rare bone malignancy that primarily affects children and young adults and is associated with significant morbidity and mortality. Cisplatin is a mainstay of treatment, but its efficacy is limited by off-target toxicities. Immunotherapy is not effective due to a poor antigenic tumor microenvironment. Here, we address these challenges by using manufactured M1 macrophage-derived vesicles (MVs) loaded with cisplatin. Human blood and mouse RAW 264.7 M1 macrophages were used to prepare empty (E-MVs) and cisplatin-loaded MVs (C-MVs). Human OS cell lines were used in vitro and in a tibia xenograft mouse model to evaluate the anti-cancer and immune-stimulating abilities of MVs. C-MVs had lower IC50s but equivalent DNA damage in OS cell lines when compared with free cisplatin. E-MVs and C-MVs were observed to accumulate in the tumor in OS tumor-bearing mice. C-MVs significantly reduced tumor burden and prolonged survival in a mouse model of OS. Animals dosed with free cisplatin experienced weight loss and renal and hepatic toxicity, while equivalent doses of C-MVs did not cause these effects. In addition, both E-MVs and C-MVs showed immunomodulation of the tumor microenvironment with a significant increase in the M1/M2 macrophages ratio (7-fold and 22-fold, respectively) and increased levels of TNF-α in serum (1.8-fold and 2.1-fold, respectively) compared to control mice. Collectively, these experiments support further development of C-MVs for the treatment of OS. Full article
(This article belongs to the Special Issue Advances in Smart and Innovative Nanoparticles for Precision Tumor Therapy: Design, Delivery, Immune Modulation, and Clinical Translation)
►▼ Show Figures

Graphical abstract

17 pages, 1359 KB  
Article
Release of Mast Cell Mediators from Cochlear Tissue Following Short Exposure to Compound 48/80 or Cisplatin, and Their Damage to Cochlear Structure
by Bin Zeng, Stefan Frischbutter, Sherezade Moñino-Romero, Jörg Scheffel, Frank Siebenhaar, Heidi Olze and Agnieszka J. Szczepek
Cells 2025, 14(20), 1615; https://doi.org/10.3390/cells14201615 - 17 Oct 2025
Viewed by 319
Abstract
The cochlea is susceptible to damage from ototoxic agents such as cisplatin, yet the mechanisms underlying cochlear injury remain incompletely understood. Mast cells (MCs), key immune players in allergic and inflammatory responses, have recently been identified in the rodent cochlea and implicated in [...] Read more.
The cochlea is susceptible to damage from ototoxic agents such as cisplatin, yet the mechanisms underlying cochlear injury remain incompletely understood. Mast cells (MCs), key immune players in allergic and inflammatory responses, have recently been identified in the rodent cochlea and implicated in cisplatin-induced ototoxicity. Our study investigated the role of MC degranulation in cochlear damage and evaluated the activation capacity of cochlear-resident MCs. Bone marrow-derived MCs (BMMCs) were cultured and induced to degranulate via IgE-anti-DNP/DNP stimulation, and the supernatants were applied to cochlear explants. Cochlear explants were also treated with Compound 48/80 (CP48/80) or cisplatin to assess MC activation. Morphological changes were assessed and hair cells (HC) quantified via phalloidin staining, while ELISA measured mediator release. Supernatants from degranulated BMMC induced a dose-dependent HC loss and tissue damage. A significant chymase and tryptase release was triggered by CP48/80 from cochlear MCs, with chymase elevation detected even at low concentrations. Cochlear MCs were rapidly activated by cisplatin exposure, elevating chymase and histamine levels, and the effects were attenuated by the MC stabilizer sodium cromolyn. Notably, tryptase remained undetectable post-cisplatin treatment, suggesting tissue-specific MC responses. These findings establish MC degranulation as an early event in cisplatin-induced cochlear injury, mediated by chymase and histamine. Our study highlights MCs as potential therapeutic targets for mitigating ototoxicity and underscores the need to explore MC-driven pathways in hearing loss. Full article
(This article belongs to the Special Issue Mast Cells in Health and Disease: Current Insights and Future Perspectives on Development, Activation, Functional Roles, and Therapeutic Strategies)
►▼ Show Figures

Figure 1

4 pages, 159 KB  
Editorial
First Edition Special Issue on “Cellular and Molecular Mechanisms in Immune Regulation”
by Fabio R. Santori and Natalia B. Ivanova
Cells 2025, 14(20), 1614; https://doi.org/10.3390/cells14201614 - 17 Oct 2025
Viewed by 394
Abstract
In 1974, Niels K [...] Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Immune Regulation)
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-71
Previous Issue
Next Issue
Back to TopTop