Cells

39 pages, 2145 KB

Open AccessEditor’s ChoiceReview

NLRP3 Inflammasome and Inflammatory Response in Aging Disorders: The Entanglement of Redox Modulation in Different Outcomes

by Bhavana Chhunchha, Eri Kubo, Deepali Lehri and Dhirendra P. Singh

Cells 2025, 14(13), 994; https://doi.org/10.3390/cells14130994 - 29 Jun 2025

Cited by 6 | Viewed by 6379

Abstract

Increasing evidence reveals that the deregulation of cellular antioxidant response with advancing age, resulting in the continuing amplification of oxidative stress-induced inflammatory response, is a pre-eminent cause for the onset of aging-related disease states, including blinding diseases. However, several safeguards, like an antioxidant [...] Read more.

Increasing evidence reveals that the deregulation of cellular antioxidant response with advancing age, resulting in the continuing amplification of oxidative stress-induced inflammatory response, is a pre-eminent cause for the onset of aging-related disease states, including blinding diseases. However, several safeguards, like an antioxidant defense system, are genetically in place to maintain redox homeostasis. Nonetheless, if the homeostatic capacity of such systems fails (like in aging), an inflammatory pathway elicited by excessive oxidative stress-evoked aberrant NLRP3 (NOD, LRR- and pyrin domain-containing protein 3) inflammasome activation can become pathogenic and lead to disease states. Among all known inflammasomes, NLRP3 is the most studied and acts as an intracellular sensor to detect danger(s). Upon activation, NLRP3 recruits apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization and facilitates the recruitment of activated Caspase-1 (Cas-1), which results in the release of inflammatory cytokines, IL-1β and IL-18 and the activation of GasderminD, an executor of pyroptosis. NLRP3 inflammasome is tightly regulated in favor of cell health. However, when and how the activation of NLRP3 and its inflammatory components goes awry, leading to cellular derangement, and what regulatory factors are involved in the normal physiological and aging/oxidative conditions will be included in this review. Also, we address the latest findings to highlight the connection between oxidative stress, antioxidants, and NLRP3 activation as this begets aging diseases and explore the cellular pathways that are in place to regulate oxidative-induced inflammations and the pathobiological consequences of dysregulated inflammatory responses and vice versa. Full article

(This article belongs to the Special Issue New Insights into Inflammasome: Mechanisms of Activation, Cell Death, and Diseases)

► Show Figures

Graphical abstract

23 pages, 8906 KB

Open AccessEditor’s ChoiceArticle

9-cis-Retinoic Acid Improves Disease Modelling in iPSC-Derived Liver Organoids

by Mina Kazemzadeh Dastjerd, Vincent Merens, Ayla Smout, Rebeca De Wolf, Christophe Chesné, Catherine Verfaillie, Stefaan Verhulst and Leo A. van Grunsven

Cells 2025, 14(13), 983; https://doi.org/10.3390/cells14130983 - 26 Jun 2025

Cited by 2 | Viewed by 2290

Abstract

Liver fibrosis majorly impacts global health, necessitating the development of in vitro models to study disease mechanisms and develop drug therapies. Relevant models should at least include hepatocytes and hepatic stellate cells (HSCs) and ideally use three-dimensional cultures to mimic in vivo conditions. [...] Read more.

Liver fibrosis majorly impacts global health, necessitating the development of in vitro models to study disease mechanisms and develop drug therapies. Relevant models should at least include hepatocytes and hepatic stellate cells (HSCs) and ideally use three-dimensional cultures to mimic in vivo conditions. Induced pluripotent stem cells (iPSCs) allow for patient-specific liver modelling, but current models based on iPSC-derived hepatocytes (iHepatocytes) and HSCs (iHSCs) still lack key functions. We developed organoids of iHepatocytes and iHSCs and compared them to HepaRG and primary HSC organoids. RNA sequencing analysis comparison of these cultures identified a potential role for the transcription factor RXRA in hepatocyte differentiation and HSC quiescence. Treating cells with the RXRA ligand 9-cis-retinoic acid (9CRA) promoted iHepatocyte metabolism and iHSC quiescence. In organoids, 9CRA enhanced fibrotic response to TGF-β and acetaminophen, highlighting its potential for refining iPSC-based liver fibrosis models to more faithfully replicate human drug-induced liver injury and fibrotic conditions. Full article

(This article belongs to the Special Issue Organoids as an Experimental Tool)

► Show Figures

Graphical abstract

25 pages, 2485 KB

Open AccessEditor’s ChoiceArticle

Epigenetic Changes Regulating Epithelial–Mesenchymal Plasticity in Human Trophoblast Differentiation

by William E. Ackerman IV, Mauricio M. Rigo, Sonia C. DaSilva-Arnold, Catherine Do, Mariam Tariq, Martha Salas, Angelica Castano, Stacy Zamudio, Benjamin Tycko and Nicholas P. Illsley

Cells 2025, 14(13), 970; https://doi.org/10.3390/cells14130970 - 24 Jun 2025

Viewed by 2135

Abstract

The phenotype of human placental extravillous trophoblast (EVT) at the end of pregnancy reflects both differentiation from villous cytotrophoblast (CTB) and later gestational changes, including loss of proliferative and invasive capacity. Invasion abnormalities are central to major obstetric pathologies, including placenta accreta spectrum, [...] Read more.

The phenotype of human placental extravillous trophoblast (EVT) at the end of pregnancy reflects both differentiation from villous cytotrophoblast (CTB) and later gestational changes, including loss of proliferative and invasive capacity. Invasion abnormalities are central to major obstetric pathologies, including placenta accreta spectrum, early onset preeclampsia, and fetal growth restriction. Characterization of the normal differentiation processes is, thus, essential for the analysis of these pathologies. Our gene expression analysis, employing purified human CTB and EVT cells, demonstrates a mechanism similar to the epithelial–mesenchymal transition (EMT), which underlies CTB–EVT differentiation. In parallel, DNA methylation profiling shows that CTB cells, already hypomethylated relative to non-trophoblast cell lineages, show further genome-wide hypomethylation in the transition to EVT. A small subgroup of genes undergoes gains of methylation (GOM), associated with differential gene expression (DE). Prominent in this GOM-DE group are genes involved in epithelial–mesenchymal plasticity (EMP). An exemplar is the transcription factor RUNX1, for which we demonstrate a functional role in regulating the migratory and invasive capacities of trophoblast cells. This analysis highlights epigenetically regulated genes acting to underpin the epithelial–mesenchymal plasticity characteristic of human trophoblast differentiation. Identification of these elements provides important information for the obstetric disorders in which these processes are dysregulated. Full article

(This article belongs to the Special Issue Select Topics in Molecular and Cellular Mechanisms of Mammalian Reproduction)

► Show Figures

Figure 1

21 pages, 4336 KB

Open AccessEditor’s ChoiceArticle

Humanized scFv Molecule Specific to an Extracellular Epitope of P2X4R as Therapy for Chronic Pain Management

by Adinarayana Kunamneni and Karin N. Westlund

Cells 2025, 14(13), 953; https://doi.org/10.3390/cells14130953 - 22 Jun 2025

Cited by 2 | Viewed by 1423

Abstract

Chronic pain affects a significant portion of the population, with fewer than 30% achieving adequate relief from existing treatments. This study describes the humanization methodology and characterization of an effective non-opioid single-chain fragment variable (scFv) biologic that reverses pain-related behaviors, in this case [...] Read more.

Chronic pain affects a significant portion of the population, with fewer than 30% achieving adequate relief from existing treatments. This study describes the humanization methodology and characterization of an effective non-opioid single-chain fragment variable (scFv) biologic that reverses pain-related behaviors, in this case by targeting P2X4. After nerve injury, ATP release activates/upregulates P2X4 receptors (P2X4R) sequestered in late endosomes, triggering a cascade of chronic pain-related events. Nine humanized scFv (hscFv) variants targeting a specific extracellular 13-amino-acid peptide fragment of human P2X4R were generated via CDR grafting. ELISA analysis revealed nanomolar binding affinities, with most humanized molecules exhibiting comparable or superior affinity compared to the original murine antibody. Octet measurements confirmed that the lead, HC3-LC3, exhibited nanomolar binding kinetics (KD = 2.5 × 10⁻⁹ M). In vivo functional validation with P2X4R hscFv reversed nerve injury-induced chronic pain-related behaviors with a single dose (0.4 mg/kg, intraperitoneal) within two weeks. The return to naïve baseline remained durably reduced > 100 days. In independent confirmation, the spared nerve injury (SNI) model was similarly reduced. This constitutes an original method whereby durable reversals of chronic nerve injury pain, anxiety and depression measures are accomplished. Full article

(This article belongs to the Special Issue Mechanisms and Therapies in Chronic Pain)

► Show Figures

Figure 1

25 pages, 1161 KB

Open AccessEditor’s ChoiceReview

Biological Aging and Uterine Fibrosis in Cattle: Reproductive Trade-Offs from Enhanced Productivity

by Yuta Matsuno and Kazuhiko Imakawa

Cells 2025, 14(13), 955; https://doi.org/10.3390/cells14130955 - 22 Jun 2025

Cited by 2 | Viewed by 2656

Abstract

Reproductive efficiency in cattle remains sub-optimal, with pregnancy rates often below 50%, despite fertilization rates approaching 100%, indicating that implantation failure and/or early embryonic loss are major limiting factors. This disparity highlights the need to understand the biological and physiological mechanisms underlying implantation [...] Read more.

Reproductive efficiency in cattle remains sub-optimal, with pregnancy rates often below 50%, despite fertilization rates approaching 100%, indicating that implantation failure and/or early embryonic loss are major limiting factors. This disparity highlights the need to understand the biological and physiological mechanisms underlying implantation failure. This review elucidates the cellular and molecular mechanisms underlying reduced pregnancy rates, with a particular focus on biological aging and fibrosis in the reproductive organs as emerging contributors to uterine dysfunction. Accumulated evidence suggests that metabolic demands associated with intensive breeding strategies aimed at maximizing meat and milk productivity may induce multiple forms of stress, including oxidative stress, metabolic stress, and inflammation, which accelerate biological aging and fibrosis in the female reproductive tract. However, the direct molecular mechanisms remain poorly characterized. We hypothesize that biological aging and fibrosis are interconnected mechanisms contributing to impaired uterine function, resulting in reduced implantation rates. By summarizing recent findings and adopting a comparative perspective, this review explores the extent to which insights from human and mouse models can be applied to cattle, considering species-specific reproductive physiology and metabolic adaptations. It explores their relevance to reproductive inefficiencies and discusses potential strategies to enhance fertility and extend bovine reproductive longevity. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Gynecological Disorders)

► Show Figures

Figure 1

22 pages, 3229 KB

Open AccessEditor’s ChoiceArticle

Tyrosine 67 Phosphorylation Controls Respiration and Limits the Apoptotic Functions of Cytochrome c

by Junmei Wan, Paul T. Morse, Matthew P. Zurek, Alice A. Turner, Asmita Vaishnav, Arthur R. Salomon, Brian F. P. Edwards, Tasnim Arroum and Maik Hüttemann

Cells 2025, 14(13), 951; https://doi.org/10.3390/cells14130951 - 21 Jun 2025

Viewed by 1201

Abstract

Cytochrome c (Cytc) is a multifunctional protein, essential for respiration and intrinsic apoptosis. Post-translational modifications of Cytc have been linked to physiological and pathophysiologic conditions, including cancer. Cytc tyrosine 67 (Y67) is a conserved residue that is important to [...] Read more.

Cytochrome c (Cytc) is a multifunctional protein, essential for respiration and intrinsic apoptosis. Post-translational modifications of Cytc have been linked to physiological and pathophysiologic conditions, including cancer. Cytc tyrosine 67 (Y67) is a conserved residue that is important to the structure and function of Cytc. We here report the phosphorylation of Y67 of Cytc purified from bovine heart mapped by mass spectrometry. We characterized the functional effects of Y67 Cytc modification using in vitro and cell culture models. Y67 was mutated to the phosphomimetic glutamate (Y67E) and to phenylalanyl (Y67F) as a control. The phosphomimetic Y67E Cytc inhibited cytochrome c oxidase (COX) activity, redirecting energy metabolism toward glycolysis, and decreased the pro-apoptotic capabilities of Cytc. The phosphomimetic Y67E Cytc showed a significantly impaired rate of superoxide scavenging and a reduced rate of oxidation by hydrogen peroxide, suggesting a lower ability to transfer electrons and scavenge reactive oxygen species (ROS). Phosphomimetic Y67E replacement led to an almost complete loss of cardiolipin peroxidase activity, pointing to a central role of Y67 for this catalytic function of Cytc. In intact cells, phosphomimetic replacement leads to a reduction in cell respiration, mitochondrial membrane potential, and ROS levels. We propose that Y67 phosphorylation is cardioprotective and promotes cell survival. Full article

► Show Figures

Graphical abstract

16 pages, 76646 KB

Open AccessEditor’s ChoiceArticle

Cytokinesis in Suspension: A Distinctive Trait of Mesenchymal Stem Cells

by Bhavna Rani, Hong Qian and Staffan Johansson

Cells 2025, 14(12), 932; https://doi.org/10.3390/cells14120932 - 19 Jun 2025

Cited by 1 | Viewed by 1081

Abstract

Mesenchymal stem cells (MSCs) have a broad clinical potential, but their selection and expansion on plastic cause unknown purity and phenotypic alterations, reducing therapy efficiency. Furthermore, their behavior in non-adherent conditions during systemic transplantation remains poorly understood. The sphere formation from single cells [...] Read more.

Mesenchymal stem cells (MSCs) have a broad clinical potential, but their selection and expansion on plastic cause unknown purity and phenotypic alterations, reducing therapy efficiency. Furthermore, their behavior in non-adherent conditions during systemic transplantation remains poorly understood. The sphere formation from single cells is commonly used to assess stemness, but MSCs lack this ability, raising questions about their anchorage dependence for proliferation. We investigated whether bone marrow-derived MSCs can complete cytokinesis in non-adherent environments. Primary human and mouse bone marrow-derived MSCs were synchronized in early mitosis using nocodazole and were cultured on soft, rigid, or non-adherent surfaces. Both human and mouse MSCs displayed an ALIX (abscission licensor) recruitment to the midbody 40–90 min post-nocodazole release, regardless of the substrate adherence. Cells maintained for 4hr in the suspension remained viable, and daughter cells rapidly migrated apart upon the re-adhesion to fibronectin-coated surfaces, demonstrating cytokinesis completion in suspension. These findings distinguish MSCs from fibroblasts (which require adhesion for division), provide a more general stemness feature, and suggest that adhesion-independent cytokinesis is a trait relevant to the post-transplantation survival and tissue homing. This property may offer strategies to expand MSCs with an improved purity and functionality and to enhance engraftment by leveraging cell cycle manipulation to promote an early extracellular matrix deposition at target sites. Full article

(This article belongs to the Section Stem Cells)

► Show Figures

Figure 1

31 pages, 12256 KB

Open AccessEditor’s ChoiceArticle

Inter-Relationship Between Melanoma Vemurafenib Tolerance Thresholds and Metabolic Pathway Choice

by Pratima Nangia-Makker, Madison Ahrens, Neeraja Purandare, Siddhesh Aras, Jing Li, Katherine Gurdziel, Hyejeong Jang, Seongho Kim and Malathy P Shekhar

Cells 2025, 14(12), 923; https://doi.org/10.3390/cells14120923 - 18 Jun 2025

Viewed by 1701

Abstract

Melanomas quickly acquire resistance to vemurafenib, an important therapeutic for BRAFV600 mutant melanomas. Although combating vemurafenib resistance (VemR) to counter mitochondrial metabolic shift using mitochondria-targeting therapies has promise, no studies have analyzed the relationship between vemurafenib tolerance levels and metabolic plasticity. To determine [...] Read more.

Melanomas quickly acquire resistance to vemurafenib, an important therapeutic for BRAFV600 mutant melanomas. Although combating vemurafenib resistance (VemR) to counter mitochondrial metabolic shift using mitochondria-targeting therapies has promise, no studies have analyzed the relationship between vemurafenib tolerance levels and metabolic plasticity. To determine how vemurafenib endurance levels drive metabolic plasticity, we developed isogenic BRAFV600E VemR melanoma models with variant vemurafenib tolerances and performed an integrative analysis of metabolomic and transcriptome alterations using metabolome, Mitoplate-S1, Seahorse, and RNA-seq assays. Regardless of drug tolerance differences, both VemR models display resistance to MEK inhibitor and sensitivity to Wnt/β-catenin inhibitor, ICG-001. β-catenin, MITF, and ABCB5 levels are upregulated in both VemR models, and ICG-001 treatment restored vemurafenib sensitivity with reductions in MITF, ABCB5, phospho-ERK1/2, and mitochondrial respiration. Whereas β-catenin signaling induced TCA cycle and OXPHOS in highly drug tolerant A2058VemR cells, it activated pentose phosphate pathway in M14VemR cells with low vemurafenib tolerance, both of which are inhibited by ICG-001. These data implicate an important role for Wnt/β-catenin signaling in VemR-induced metabolic plasticity. Our data demonstrate that drug tolerance thresholds play a direct role in driving metabolic shifts towards specific routes, thus providing a new basis for delineating VemR melanomas for metabolism-targeting therapies. Full article

(This article belongs to the Collection Pathometabolism: Understanding Disease through Metabolism)

► Show Figures

Graphical abstract

19 pages, 6474 KB

Open AccessEditor’s ChoiceArticle

Transcriptomic Profiling of iPS Cell-Derived Hepatocyte-like Cells Reveals Their Close Similarity to Primary Liver Hepatocytes

by Saqlain Suleman, Sharmin Alhaque, Andrew Guo, Aaron Zhang, Serena Fawaz, Stefany Perera, Mohammad S. Khalifa, Hassan Rashidi, David C. Hay and Michael Themis

Cells 2025, 14(12), 925; https://doi.org/10.3390/cells14120925 - 18 Jun 2025

Cited by 2 | Viewed by 1484

Abstract

Human-induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (HLCs) have been shown to be useful for the development of cell-based regenerative strategies and for modelling drug discovery. However, stem cell-derived HLCs are not identical in nature to primary human hepatocytes (PHHs), which could affect [...] Read more.

Human-induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (HLCs) have been shown to be useful for the development of cell-based regenerative strategies and for modelling drug discovery. However, stem cell-derived HLCs are not identical in nature to primary human hepatocytes (PHHs), which could affect the cell phenotype and, potentially, model reliability. Therefore, we employed the in-depth gene expression profiling of HLCs and other important and relevant cell types, which led to the identification of clear similarities and differences between them at the transcriptional level. Through gene set enrichment analysis, we identified that genes that are critical for immune signalling pathways become downregulated upon HLC differentiation. Our analysis also found that TAV.HLCs exhibit a mild gene signature characteristic of acute lymphoblastic leukaemia, but not other selected cancers. Importantly, HLCs present significant similarity to PHHs, making them genuinely valuable for modelling human liver biology in vitro and for the development of prototype cell-based therapies for pre-clinical testing. Full article

(This article belongs to the Section Tissues and Organs)

► Show Figures

Figure 1

20 pages, 2299 KB

Open AccessEditor’s ChoiceArticle

Downregulated ALDH2 Contributes to Tumor Progression and Targeted Therapy Resistance in Human Metastatic Melanoma Cells

by Zili Zhai, Takeshi Yamauchi, Karenna Sandoval, Kira Villarreal, Man Wai Charlotte Kwong, Emily J. Swanson, Aik Choon Tan and Mayumi Fujita

Cells 2025, 14(12), 913; https://doi.org/10.3390/cells14120913 - 17 Jun 2025

Cited by 2 | Viewed by 2175

Abstract

Aldehyde dehydrogenase 2 (ALDH2) is a crucial detoxifying enzyme that eliminates toxic aldehydes. ALDH2 deficiency has been linked to various human diseases, including certain cancers. We have previously reported ALDH2 downregulation in human melanoma tissues. Here, we further investigated the biological significance of [...] Read more.

Aldehyde dehydrogenase 2 (ALDH2) is a crucial detoxifying enzyme that eliminates toxic aldehydes. ALDH2 deficiency has been linked to various human diseases, including certain cancers. We have previously reported ALDH2 downregulation in human melanoma tissues. Here, we further investigated the biological significance of ALDH2 downregulation in this malignancy. Analysis of TCGA dataset revealed that low ALDH2 expression correlates with poorer survival in metastatic melanoma. Examination of human metastatic melanoma cell lines confirmed that most had ALDH2 downregulation (ALDH2-low) compared to primary melanocytes. In contrast, a small subset of metastatic melanoma cell lines exhibited normal ALDH2 levels (ALDH2-normal). CRISPR/Cas9-mediated ALDH2 knockout in ALDH2-normal A375 cells promoted tumor growth and MAPK/ERK activation. Given the pivotal role of MAPK/ERK signaling in melanoma and cellular response to acetaldehyde, we compared A375 with ALDH2-low SK-MEL-28 and 1205Lu cells. ALDH2-low cells were intrinsically resistant to BRAF and MEK inhibitors, whereas A375 cells were not. However, A375 cells acquired resistance upon ALDH2 knockout. Furthermore, melanoma cells with acquired resistance to these inhibitors displayed further ALDH2 downregulation. Our findings indicate that ALDH2 downregulation contributes to melanoma progression and therapy resistance in BRAF-mutated human metastatic melanoma cells, highlighting ALDH2 as a potential prognostic marker and therapeutic target in metastatic melanoma. Full article

(This article belongs to the Special Issue Melanoma: From Molecular Mechanisms to Therapeutic Opportunities—3rd Edition)

► Show Figures

Figure 1

14 pages, 3107 KB

Open AccessEditor’s ChoiceArticle

The Pro-Angiogenic Potential of Periodontal Ligament Stem Cells and Dental Pulp Stem Cells: A Comparative Analysis

by Ilaria Roato, Clarissa Orrico, Sara Meinardi, Riccardo Pedraza, Alessandro Mosca Balma, Giacomo Baima, Tullio Genova, Mario Aimetti and Federico Mussano

Cells 2025, 14(12), 864; https://doi.org/10.3390/cells14120864 - 8 Jun 2025

Cited by 2 | Viewed by 1439

Abstract

The role of periodontal ligament stem cells (PDLSCs) and dental pulp stem cells (DPSCs) in stimulating angiogenesis has been reported, but their angiogenetic potential has not been directly compared. In this work, paired PDLSCs and DPSCs, i.e., derived from the same donor, were [...] Read more.

The role of periodontal ligament stem cells (PDLSCs) and dental pulp stem cells (DPSCs) in stimulating angiogenesis has been reported, but their angiogenetic potential has not been directly compared. In this work, paired PDLSCs and DPSCs, i.e., derived from the same donor, were tested for their immunophenotype and multi-differentiation capabilities, with particular emphasis on their pro-angiogenic activity. Flow cytometry was utilized to study the expression of mesenchymal stem cell, pericyte, and endothelial markers, while gene expression was evaluated through real-time PCR. The angiogenic potential was assessed recurring to tubulogenesis assay, co-cultures with Human Microvascular Endothelial Cell (HMEC-1), and VEGF-A quantification. The immunophenotype of DPSCs and PDLSCs was different in CD146+ and CD31+ cell subsets, but both cell types promoted HMEC-1 tubulogenesis in vitro. Consistently, VEGF-A gene expression level and its quantification in cell-conditioned media of PDLSCs and DPSCs was comparable between them, and both promoted the formation of vessel-like structures, when co-cultured with HMEC-1 cells. All together, these results showed the heterogeneity of PDLSCs and DPSCs, which are constituted of different cellular subsets, likely modulated by the microenvironmental cues. PDLSCs and DPSCs showed comparable pro-angiogenic activity, enhanced by the contemporary expression of angiogenic and chemotactic factors. Full article

► Show Figures

Graphical abstract

32 pages, 4653 KB

Open AccessEditor’s ChoiceReview

Molecular Mechanisms of Cellular Senescence in Age-Related Endometrial Dysfunction

by Hiroshi Kobayashi, Mai Umetani, Miki Nishio, Hiroshi Shigetomi, Shogo Imanaka and Hiratsugu Hashimoto

Cells 2025, 14(12), 858; https://doi.org/10.3390/cells14120858 - 6 Jun 2025

Cited by 6 | Viewed by 3128

Abstract

The endometrium is essential for reproductive function, supporting implantation and pregnancy through mechanisms such as hormonal responsiveness, immune regulation, and tissue regeneration. Aging disrupts these processes, with cellular senescence—marked by irreversible cell cycle arrest due to DNA damage and oxidative stress—being a key [...] Read more.

The endometrium is essential for reproductive function, supporting implantation and pregnancy through mechanisms such as hormonal responsiveness, immune regulation, and tissue regeneration. Aging disrupts these processes, with cellular senescence—marked by irreversible cell cycle arrest due to DNA damage and oxidative stress—being a key contributor. While senescence aids in tumor suppression and tissue repair, its dysregulation impairs endometrial function. Central to this regulation are p53, AMPK, and mTOR, which coordinate stress responses, metabolic regulation, and proliferation control. p53 activates AMPK and inhibits mTOR, promoting energy conservation and limiting senescence. AMPK also suppresses mTOR, reducing age-related dysfunction. This p53–AMPK–mTOR axis, along with autophagy, governs cell fate in response to stress and nutrient status. Although moderate senescence supports endometrial function, excessive accumulation can hinder fertility. Understanding these molecular interactions may advance fertility treatments and strategies to counteract reproductive aging. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Gynecological Disorders)

► Show Figures

Figure 1

17 pages, 995 KB

Open AccessEditor’s ChoiceReview

Broken Balance: Emerging Cross-Talk Between Proteostasis and Lipostasis in Neurodegenerative Diseases

by Jessica Tittelmeier and Carmen Nussbaum-Krammer

Cells 2025, 14(11), 845; https://doi.org/10.3390/cells14110845 - 4 Jun 2025

Cited by 1 | Viewed by 2187

Abstract

Neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, are characterized by progressive neuronal loss, leading to cognitive and motor impairments. Although these diseases have distinct clinical manifestations, they share pathological hallmarks such as protein aggregation and lysosomal dysfunction. The lysosome plays a vital [...] Read more.

Neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, are characterized by progressive neuronal loss, leading to cognitive and motor impairments. Although these diseases have distinct clinical manifestations, they share pathological hallmarks such as protein aggregation and lysosomal dysfunction. The lysosome plays a vital role in maintaining cellular homeostasis by mediating the degradation and recycling of proteins, lipids, and other macromolecules. As such, it serves as a central hub for both proteostasis and lipostasis. This review outlines genetic and mechanistic parallels between rare lysosomal lipid storage diseases, such as Gaucher disease and Niemann–Pick disease, and more prevalent neurodegenerative diseases. We discuss how impaired lysosomal sphingolipid metabolism compromises lysosomal integrity, disrupts proteostasis, and contributes to neurodegeneration. Furthermore, we describe how age-related decline in lysosomal function may similarly drive neurodegeneration in the absence of overt genetic mutations. Taken together, this review highlights the lysosome as a central integrator of protein and lipid homeostasis and emphasizes the bidirectional relationship between lipostasis and proteostasis, whereby disruption of one adversely affects the other in the pathogenesis of multiple neurodegenerative diseases. Full article

(This article belongs to the Special Issue Protein Misfolding Diseases: From Experimental Approaches to Therapeutic Opportunities)

► Show Figures

Figure 1

30 pages, 1307 KB

Open AccessEditor’s ChoiceReview

Electrical Stimulation of Oral Tissue-Derived Stem Cells: Unlocking New Potential for Dental and Periodontal Regeneration

by Rúben S. Pires, Mafalda S. Santos, Filipe Miguel, Cláudia L. da Silva and João Carlos Silva

Cells 2025, 14(11), 840; https://doi.org/10.3390/cells14110840 - 4 Jun 2025

Cited by 5 | Viewed by 3233

Abstract

The tooth and its supporting periodontium are essential structures of the oral cavity, frequently compromised by conditions such as dental defects, aries, and periodontal diseases, which, if poorly treated, often lead to tooth loss. These conditions, affecting billions of people worldwide, remain significant [...] Read more.

The tooth and its supporting periodontium are essential structures of the oral cavity, frequently compromised by conditions such as dental defects, aries, and periodontal diseases, which, if poorly treated, often lead to tooth loss. These conditions, affecting billions of people worldwide, remain significant healthcare and socio-economic challenges. Regenerative dentistry has emerged as a possible therapeutic option, leveraging advances in tissue engineering (TE), stem cell biology, and biophysical stimulation. Oral tissue-derived mesenchymal stem/stromal cells (OMSCs) hold great potential for dental and periodontal regeneration. Electrical stimulation (ES), a biophysical cue known to regulate key cellular behaviors such as migration, proliferation, and differentiation, has gained increasing attention for enhancing the therapeutic capacities of OMSCs. This review explores the biological properties of OMSCs under ES, its role in regenerative dentistry, and recent breakthroughs in ES-based dental and periodontal TE strategies. Furthermore, the current challenges and future directions for translating these innovative approaches into clinical practice are discussed. Full article

(This article belongs to the Special Issue Oral Tissue Stem Cells in Regenerative Dentistry)

► Show Figures

Graphical abstract

18 pages, 2226 KB

Open AccessEditor’s ChoiceArticle

Short- and Long-Term Endothelial Inflammation Have Distinct Effects and Overlap with Signatures of Cellular Senescence

by Barbora Belakova, José Basílio, Manuel Campos-Medina, Anna F. P. Sommer, Adrianna Gielecińska, Ulrike Resch and Johannes A. Schmid

Cells 2025, 14(11), 806; https://doi.org/10.3390/cells14110806 - 30 May 2025

Cited by 1 | Viewed by 2300

Abstract

This study investigates the interplay between cellular senescence and inflammation in human umbilical vein endothelial cells (HUVECs). We employed RNA sequencing to analyze gene expression changes in HUVECs subjected to replicative- or radiation-stress-induced senescence, and we compared these profiles with those of cells [...] Read more.

This study investigates the interplay between cellular senescence and inflammation in human umbilical vein endothelial cells (HUVECs). We employed RNA sequencing to analyze gene expression changes in HUVECs subjected to replicative- or radiation-stress-induced senescence, and we compared these profiles with those of cells under acute or chronic TNFα-mediated inflammation. Our findings reveal that both senescence types exhibited significant upregulation of genes associated with epithelial- (or endothelial) mesenchymal transition (EMT) and inflammatory pathways, indicating a shared molecular response. Notably, chronic inflammation led to a pronounced EMT signature, while acute inflammation primarily activated classical inflammatory responses. Experimental validation confirmed reduced proliferation and increased secretion of pro-inflammatory cytokines (IL-6 and IL-8) in senescent and chronically inflamed cells and substantiated the upregulation of EMT marker genes. Additionally, we observed impaired wound healing capacity in senescent and chronically inflamed cells, highlighting the functional consequences of these cellular states. Our study underscores the critical role of inflammation in exacerbating senescence-related changes, contributing to the understanding of age-related cardiovascular pathologies. These insights may inform future therapeutic strategies aimed at mitigating the effects of aging and inflammation on endothelial function and cardiovascular health. Full article

(This article belongs to the Special Issue Mechanisms Underlying Cardiovascular Aging)

► Show Figures

Graphical abstract

34 pages, 508 KB

Open AccessEditor’s ChoiceSystematic Review

The Whisper of the Follicle: A Systematic Review of Micro Ribonucleic Acids as Predictors of Oocyte Quality and In Vitro Fertilization Outcomes

by Charalampos Voros, Antonia Varthaliti, Diamantis Athanasiou, Despoina Mavrogianni, Anthi-Maria Papahliou, Kyriakos Bananis, Aristotelis-Marios Koulakmanidis, Antonia Athanasiou, Aikaterini Athanasiou, Constantinos G. Zografos, Athanasios Gkirgkinoudis, Maria Anastasia Daskalaki, Dimitris Mazis Kourakos, Dimitrios Vaitsis, Ioannis Papapanagiotou, Marianna Theodora, Panagiotis Antsaklis, Dimitrios Loutradis and Georgios Daskalakis

Cells 2025, 14(11), 787; https://doi.org/10.3390/cells14110787 - 27 May 2025

Cited by 7 | Viewed by 2147

Abstract

Background: MicroRNAs (miRNAs) in follicular fluid (FF) are being recognized as important regulators of ovarian function and biomarkers of reproductive success. This systematic analysis investigates FF-derived miRNAs and their relationship to polycystic ovarian syndrome (PCOS) and in vitro fertilization (IVF) outcomes. Methods: Following [...] Read more.

Background: MicroRNAs (miRNAs) in follicular fluid (FF) are being recognized as important regulators of ovarian function and biomarkers of reproductive success. This systematic analysis investigates FF-derived miRNAs and their relationship to polycystic ovarian syndrome (PCOS) and in vitro fertilization (IVF) outcomes. Methods: Following PRISMA recommendations, 21 original papers were included that looked at miRNA expression in FF or granulosa cells from women undergoing IVF, with or without PCOS. The study design, miRNA profiling methodologies, IVF protocols, and clinical results were gathered and analyzed. Results: Across the investigations, 15 miRNAs were regularly implicated, including miR-132, miR-320, miR-222, miR-224, miR-146a, and miR-93. Downregulation of miR-132 and miR-320 was consistently detected in PCOS and associated with decreased steroidogenesis. Elevated miR-222 and miR-146a were linked to insulin resistance and follicular inflammation. In IVF, miR-202-5p and miR-224 were elevated in high-quality embryos and successful cycles, indicating that they have roles in granulosa cell proliferation and estrogen synthesis. MiRNA dysregulation was linked to critical pathways, such as PI3K/AKT, NF-κB, TGF-β, and WNT. Conclusions: Specific FF miRNAs are consistently linked to PCOS pathogenesis and IVF effectiveness. Their use into noninvasive biomarker panels could improve embryonic selection and personalized reproductive care. Full article

► Show Figures

Figure 1

20 pages, 1228 KB

Open AccessEditor’s ChoiceReview

The cGAS/STING Pathway: Friend or Foe in Regulating Cardiomyopathy

by Weiyue Wang, Yuanxu Gao, Hyun Kyoung Lee, Albert Cheung-Hoi Yu, Markus Kipp, Hannes Kaddatz and Jiangshan Zhan

Cells 2025, 14(11), 778; https://doi.org/10.3390/cells14110778 - 25 May 2025

Cited by 3 | Viewed by 3852

Abstract

Inflammation is a central hallmark of cardiomyopathy, where misdirected immune responses contribute to chronic myocardial dysfunction. Among the emerging molecular mechanisms implicated in this process, the cyclic GMP–AMP synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway has garnered increasing attention. Acting as a [...] Read more.

Inflammation is a central hallmark of cardiomyopathy, where misdirected immune responses contribute to chronic myocardial dysfunction. Among the emerging molecular mechanisms implicated in this process, the cyclic GMP–AMP synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway has garnered increasing attention. Acting as a key cytosolic DNA sensor, the cGAS/STING pathway orchestrates inflammatory responses triggered by microbial infections or endogenous cellular stressors such as autophagy and apoptosis. Despite its pivotal role, the precise molecular mechanisms regulating this pathway and its role in cardiomyopathy-associated inflammation remain poorly understood and subject to ongoing debate. To address this scientific gap, we first reviewed key findings on cGAS/STING signaling in various forms of cardiomyopathy, drawing from in vivo and in vitro studies, as well as clinical samples. In the next step, we explored how the cGAS/STING pathway could be modulated by specific agonists and antagonists in the context of cardiac disease. Finally, by integrating publicly available human single-cell RNA sequencing (scRNA-seq) data and a systematic literature review, we identified existing molecular interventions and highlighted promising therapeutic targets aimed at mitigating cGAS/STING-driven inflammation. This comprehensive approach emphasizes the therapeutic potential of targeting the cGAS/STING pathway and provides a foundation for developing novel interventions aimed at alleviating inflammatory cardiomyopathy and improving patient outcomes. Future studies will be essential to validate these findings and facilitate their translation into clinical practice. Full article

► Show Figures

Figure 1

18 pages, 15168 KB

Open AccessEditor’s ChoiceArticle

Impact of Drp1 Loss on Organelle Interaction, Metabolism, and Inflammation in Mouse Liver

by Lixiang Wang, Seiji Nomura, Nao Hasuzawa, Sadaki Yokota, Ayako Nagayama, Kenji Ashida, Junjiro Rikitake, Yoshinori Moriyama, Masatoshi Nomura and Ken Yamamoto

Cells 2025, 14(10), 679; https://doi.org/10.3390/cells14100679 - 8 May 2025

Cited by 1 | Viewed by 1676

Abstract

Dynamin-related protein 1 (Drp1) is a crucial player in mitochondrial fission and liver function. The interactions between mitochondria, endoplasmic reticulum (ER), and lipid droplets (LDs) are fundamental for lipid metabolism. This study utilized liver-specific Drp1 knockout (Drp1LiKO) mice to investigate the [...] Read more.

Dynamin-related protein 1 (Drp1) is a crucial player in mitochondrial fission and liver function. The interactions between mitochondria, endoplasmic reticulum (ER), and lipid droplets (LDs) are fundamental for lipid metabolism. This study utilized liver-specific Drp1 knockout (Drp1LiKO) mice to investigate the effects of Drp1 deficiency on organelle interactions, metabolism, and inflammation. Our analysis revealed disrupted interactions between mitochondria and LDs, as well as altered interactions among ER, mitochondria, and LDs in Drp1LiKO mice. Through mass spectrometry and microarray analysis, we identified changes in lipid profiles and perturbed expression of lipid metabolism genes in the livers of Drp1LiKO mice. Further in vitro experiments using primary hepatocytes from Drp1LiKO mice confirmed disturbances in lipid metabolism and increased inflammation. These findings highlight the critical involvement of Drp1 in regulating organelle interactions for efficient lipid metabolism and overall liver health. Targeting Drp1-mediated organelle interactions may offer potential for developing therapies for liver diseases associated with disrupted lipid metabolism. Full article

► Show Figures

Graphical abstract

16 pages, 1313 KB

Open AccessEditor’s ChoiceArticle

Bilateral Germ Cell Tumor of the Testis: Biological and Clinical Implications for a Stem Versus Genetic Origin of Cancers

by Jamaal C. Jackson, Darren Sanchez, Aron Y. Joon, Marcos R. Estecio, Andrew C. Johns, Amishi Y. Shah, Matthew Campbell, John F. Ward, Louis L. Pisters, Charles C. Guo, Miao Zhang, Niki M. Zacharias and Shi-Ming Tu

Cells 2025, 14(9), 658; https://doi.org/10.3390/cells14090658 - 30 Apr 2025

Cited by 1 | Viewed by 1914

Abstract

Germ cell tumors of the testis (GCTs) provide an ideal tumor model to investigate the cellular versus genetic origin of cancers. In this single institutional study, we evaluated 38 patients with bilateral GCT, including tumors that occurred simultaneously (synchronous) and those occurring at [...] Read more.

Germ cell tumors of the testis (GCTs) provide an ideal tumor model to investigate the cellular versus genetic origin of cancers. In this single institutional study, we evaluated 38 patients with bilateral GCT, including tumors that occurred simultaneously (synchronous) and those occurring at different times (metachronous). For nine of these patients, DNA was isolated from the right and left GCT to determine the genomic and epigenetic differences between tissues using whole-exome sequencing (WES) and reduced representation bisulfite sequencing (RRBS). We found that seminomas and non-seminomas are molecularly distinct based on DNA methylation and not due to synchronous or metachronous disease. In addition, we did not observe conservation of genetic mutations in right and left GCT in either synchronous or metachronous disease. Our data suggest a cellular origin for bilateral GCT. Full article

► Show Figures

Figure 1

32 pages, 15039 KB

Open AccessEditor’s ChoiceArticle

Enhanced Expression of Mitochondrial Magmas Protein in Ovarian Carcinomas: Magmas Inhibition Facilitates Antitumour Effects, Signifying a Novel Approach for Ovarian Cancer Treatment

by Ali Raza, Ashfaqul Hoque, Rodney Luwor, Ruth M. Escalona, Jason Kelly, Revati Sharma, Fadi Charchar, Simon Chu, Mary K. Short, Paul T. Jubinsky, George Kannourakis and Nuzhat Ahmed

Cells 2025, 14(9), 655; https://doi.org/10.3390/cells14090655 - 29 Apr 2025

Cited by 1 | Viewed by 1608

Abstract

Mitochondrial-associated granulocyte macrophage colony-stimulating factor (Magmas) is a unique protein located in the inner membrane of mitochondria, with an active role in scavenging reactive oxygen species (ROS) in cellular systems. Ovarian cancer (OC), one of the deadliest gynaecological cancers, is characterised by genomic [...] Read more.

Mitochondrial-associated granulocyte macrophage colony-stimulating factor (Magmas) is a unique protein located in the inner membrane of mitochondria, with an active role in scavenging reactive oxygen species (ROS) in cellular systems. Ovarian cancer (OC), one of the deadliest gynaecological cancers, is characterised by genomic instability, affected by ROS production in the tumour microenvironment. This manuscript discusses the role of Magmas and efficacy of its novel small molecule inhibitor BT#9 in OC progression, metastasis, and chemoresistance. Magmas expression levels were significantly elevated in high-grade human OC compared to benign tumours by immunohistochemistry. The inhibition of Magmas by BT#9 enhanced ROS production and reduced mitochondrial membrane permeability, basal respiration, mitochondrial ATP production, and cellular functions, such as the proliferation and migration of OC cell lines in vitro. Oral administration of BT#9 in vivo significantly reduced tumour growth and spread and enhanced the survival of mice without having any effect on the peritoneal organs. These data suggest that Magmas is functionally important for OC growth and spread by affecting ROS levels and that the inhibition of Magmas activity by BT#9 may provide novel clinical benefits for patients with this malignancy. Full article

(This article belongs to the Special Issue Mitochondria and Metabolism in Cancer Stem Cells (CSCs))

► Show Figures

Graphical abstract

17 pages, 2551 KB

Open AccessEditor’s ChoiceArticle

Platelet-Derived Soluble CD40L and Its Impact on Immune Modulation and Anti-IL6R Antibody Treatment Outcome in Rheumatoid Arthritis

by Carlos Zamora, Cesar Diaz-Torne, Maria Angels Ortiz, Patricia Moya, Hye Sang Park, Concepció Pitarch, Elisabet Cantó, Ruben Osuna-Gomez, Maria Mulet, Maisa Garcia-Arguinzonis, Diego Collado, Hector Corominas and Silvia Vidal

Cells 2025, 14(9), 625; https://doi.org/10.3390/cells14090625 - 22 Apr 2025

Cited by 2 | Viewed by 1626

Abstract

Background: Platelets (PLTs) from healthy donors (HD) modulate T lymphocyte responses but PLTs from rheumatoid arthritis (RA) patients contribute to persistent systemic inflammation. This suggests that PLTs from RA patients and HD have different immunomodulatory effects. Methods: Using cell culture, flow cytometry, proteomics, [...] Read more.

Background: Platelets (PLTs) from healthy donors (HD) modulate T lymphocyte responses but PLTs from rheumatoid arthritis (RA) patients contribute to persistent systemic inflammation. This suggests that PLTs from RA patients and HD have different immunomodulatory effects. Methods: Using cell culture, flow cytometry, proteomics, and ELISA, we compared PLTs from HD and RA patients and their effects on T lymphocyte activation and cytokine production. Results: HD PLTs suppressed T lymphocyte proliferation and IFNγ and TNF production, while RA PLTs exhibited reduced suppressive capacity. In the presence of RA PLTs, IFNγ levels correlated with T lymphocyte proliferation, greater disease activity, and anti-citrullinated protein antibodies (ACPA). Proteomic analysis revealed that RA PLTs show upregulation of proteins linked to acute-phase response and complement activation. RA PLTs secreted higher levels of soluble CD40L (sCD40L) and PDGF-BB that correlated with enhanced IFNγ production. Seropositive RA patients had higher levels of sCD40L, and these levels were predictive of disease remission in RA patients treated with anti-IL6R. sCD40L was found to enhance T lymphocyte activation and to contribute to increased pro-inflammatory cytokine production. Conclusions: This study highlights the diminished ability of RA PLTs to suppress T lymphocyte activation and that sCD40L can be a potential biomarker and therapeutic target in RA. Full article

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

► Show Figures

Graphical abstract

24 pages, 1421 KB

Open AccessEditor’s ChoiceReview

Mitochondrial Dysfunction: A New Hallmark in Hereditable Thoracic Aortic Aneurysm Development

by Daniel Marcos-Ríos, Antonio Rochano-Ortiz, Irene San Sebastián-Jaraba, María José Fernández-Gómez, Nerea Méndez-Barbero and Jorge Oller

Cells 2025, 14(8), 618; https://doi.org/10.3390/cells14080618 - 21 Apr 2025

Cited by 10 | Viewed by 2947

Abstract

Thoracic aortic aneurysms (TAAs) pose a significant health burden due to their asymptomatic progression, often culminating in life-threatening aortic rupture, and due to the lack of effective pharmacological treatments. Risk factors include elevated hemodynamic stress on the ascending aorta, frequently associated with hypertension [...] Read more.

Thoracic aortic aneurysms (TAAs) pose a significant health burden due to their asymptomatic progression, often culminating in life-threatening aortic rupture, and due to the lack of effective pharmacological treatments. Risk factors include elevated hemodynamic stress on the ascending aorta, frequently associated with hypertension and hereditary genetic mutations. Among the hereditary causes, Marfan syndrome is the most prevalent, characterized as a connective tissue disorder driven by FBN1 mutations that lead to life-threatening thoracic aortic ruptures. Similarly, mutations affecting the TGF-β pathway underlie Loeys–Dietz syndrome, while mutations in genes encoding extracellular or contractile apparatus proteins, such as ACTA2, are linked to non-syndromic familial TAA. Despite differences in genetic origin, these hereditary conditions share central pathophysiological features, including aortic medial degeneration, smooth muscle cell dysfunction, and extracellular remodeling, which collectively weaken the aortic wall. Recent evidence highlights mitochondrial dysfunction as a crucial contributor to aneurysm formation in Marfan syndrome. Disruption of the extracellular matrix–mitochondrial homeostasis axis exacerbates aortic wall remodeling, further promoting aneurysm development. Beyond its structural role in maintaining vascular integrity, the ECM plays a pivotal role in supporting mitochondrial function. This intricate relationship between extracellular matrix integrity and mitochondrial homeostasis reveals a novel dimension of TAA pathophysiology, extending beyond established paradigms of extracellular matrix remodeling and smooth muscle cell dysfunction. This review summarizes mitochondrial dysfunction as a potential unifying mechanism in hereditary TAA and explores how understanding mitochondrial dysfunction, in conjunction with established mechanisms of TAA pathogenesis, opens new avenues for developing targeted treatments to address these life-threatening conditions. Mitochondrial boosters could represent a new clinical opportunity for patients with hereditary TAA. Full article

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

► Show Figures

Figure 1

24 pages, 1380 KB

Open AccessEditor’s ChoiceReview

The Role of Oxidative Stress and Inflammation in the Pathogenesis and Treatment of Vascular Dementia

by Aseel Y. Altahrawi, Antonisamy William James and Zahoor A. Shah

Cells 2025, 14(8), 609; https://doi.org/10.3390/cells14080609 - 17 Apr 2025

Cited by 17 | Viewed by 5069

Abstract

Vascular dementia (VaD) is a heterogeneous group of brain disorders caused by cerebrovascular pathologies and the second most common cause of dementia, accounting for over 20% of cases and posing an important global health concern. VaD can be caused by cerebral infarction or [...] Read more.

Vascular dementia (VaD) is a heterogeneous group of brain disorders caused by cerebrovascular pathologies and the second most common cause of dementia, accounting for over 20% of cases and posing an important global health concern. VaD can be caused by cerebral infarction or injury in critical brain regions, including the speech area of the dominant hemisphere or arcuate fasciculus of the dominant hemisphere, leading to notable cognitive impairment. Although the exact causes of dementia remain multifactorial and complex, oxidative stress (reactive oxygen species), neuroinflammation (TNFα, IL-6, and IL-1β), and inflammasomes are considered central mechanisms in its pathology. These conditions contribute to neuronal damage, synaptic dysfunction, and cognitive decline. Thus, antioxidants and anti-inflammatory agents have emerged as potential therapeutic targets in dementia. Recent studies emphasize that cerebrovascular disease plays a dual role: first, as a primary cause of cognitive impairment and then as a contributor to the manifestation of dementia driven by other factors, such as Alzheimer’s disease and other neurodegenerative conditions. This comprehensive review of VaD focuses on molecular mechanisms and their consequences. We provided up-to-date knowledge about epidemiology, pathophysiological mechanisms, and current therapeutic approaches for VaD. Full article

(This article belongs to the Special Issue Molecular Pathways and Potential Therapeutic Targets of Vascular Dysfunction)

► Show Figures

Figure 1

50 pages, 3293 KB

Open AccessEditor’s ChoiceReview

Circulating Non-Coding RNAs as Indicators of Fibrosis and Heart Failure Severity

by Veronika Boichenko, Victoria Maria Noakes, Benedict Reilly-O’Donnell, Giovanni Battista Luciani, Costanza Emanueli, Fabio Martelli and Julia Gorelik

Cells 2025, 14(7), 553; https://doi.org/10.3390/cells14070553 - 7 Apr 2025

Cited by 9 | Viewed by 3331

Abstract

Heart failure (HF) is a leading cause of morbidity and mortality worldwide, representing a complex clinical syndrome in which the heart’s ability to pump blood efficiently is impaired. HF can be subclassified into heart failure with reduced ejection fraction (HFrEF) and heart failure [...] Read more.

Heart failure (HF) is a leading cause of morbidity and mortality worldwide, representing a complex clinical syndrome in which the heart’s ability to pump blood efficiently is impaired. HF can be subclassified into heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF), each with distinct pathophysiological mechanisms and varying levels of severity. The progression of HF is significantly driven by cardiac fibrosis, a pathological process in which the extracellular matrix undergoes abnormal and uncontrolled remodelling. Cardiac fibrosis is characterized by excessive matrix protein deposition and the activation of myofibroblasts, increasing the stiffness of the heart, thus disrupting its normal structure and function and promoting lethal arrythmia. MicroRNAs, long non-coding RNAs, and circular RNAs, collectively known as non-coding RNAs (ncRNAs), have recently gained significant attention due to a growing body of evidence suggesting their involvement in cardiac remodelling such as fibrosis. ncRNAs can be found in the peripheral blood, indicating their potential as biomarkers for assessing HF severity. In this review, we critically examine recent advancements and findings related to the use of ncRNAs as biomarkers of HF and discuss their implication in fibrosis development. Full article

► Show Figures

Figure 1

40 pages, 2165 KB

Open AccessEditor’s ChoiceReview

Stem Cells in Cancer: From Mechanisms to Therapeutic Strategies

by Laurence Haddadin and Xueqin Sun

Cells 2025, 14(7), 538; https://doi.org/10.3390/cells14070538 - 3 Apr 2025

Cited by 18 | Viewed by 9143

Abstract

Stem cells have emerged as a pivotal area of research in the field of oncology, offering new insights into the mechanisms of cancer initiation, progression, and resistance to therapy. This review provides a comprehensive overview of the role of stem cells in cancer, [...] Read more.

Stem cells have emerged as a pivotal area of research in the field of oncology, offering new insights into the mechanisms of cancer initiation, progression, and resistance to therapy. This review provides a comprehensive overview of the role of stem cells in cancer, focusing on cancer stem cells (CSCs), their characteristics, and their implications for cancer therapy. We discuss the origin and identification of CSCs, their role in tumorigenesis, metastasis, and drug resistance, and the potential therapeutic strategies targeting CSCs. Additionally, we explore the use of normal stem cells in cancer therapy, focusing on their role in tissue regeneration and their use as delivery vehicles for anticancer agents. Finally, we highlight the challenges and future directions in stem cell research in cancer. Full article

(This article belongs to the Special Issue Stem Cells in Cancer)

► Show Figures

Figure 1

41 pages, 3013 KB

Open AccessFeature PaperEditor’s ChoiceReview

Zebrafish as a Versatile Model for Cardiovascular Research: Peering into the Heart of the Matter

by Ramcharan Singh Angom, Meghna Singh, Huzaifa Muhammad, Sai Manasa Varanasi and Debabrata Mukhopadhyay

Cells 2025, 14(7), 531; https://doi.org/10.3390/cells14070531 - 2 Apr 2025

Cited by 5 | Viewed by 5434

Abstract

Cardiovascular diseases (CVDs) are the leading cause of death in the world. A total of 17.5 million people died of CVDs in the year 2012, accounting for 31% of all deaths globally. Vertebrate animal models have been used to understand cardiac disease biology, [...] Read more.

Cardiovascular diseases (CVDs) are the leading cause of death in the world. A total of 17.5 million people died of CVDs in the year 2012, accounting for 31% of all deaths globally. Vertebrate animal models have been used to understand cardiac disease biology, as the cellular, molecular, and physiological aspects of human CVDs can be replicated closely in these organisms. Zebrafish is a popular model organism offering an arsenal of genetic tools that allow the rapid in vivo analysis of vertebrate gene function and disease conditions. It has a short breeding cycle, high fecundity, optically transparent embryos, rapid internal organ development, and easy maintenance. This review aims to give readers an overview of zebrafish cardiac biology and a detailed account of heart development in zebrafish and its comparison with humans and the conserved genetic circuitry. We also discuss the contributions made in CVD research using the zebrafish model. The first part of this review focuses on detailed information on the morphogenetic and differentiation processes in early cardiac development. The overlap and divergence of the human heart’s genetic circuitry, structure, and physiology are emphasized wherever applicable. In the second part of the review, we overview the molecular tools and techniques available to dissect gene function and expression in zebrafish, with special mention of the use of these tools in cardiac biology. Full article

(This article belongs to the Special Issue Advances in Zebrafish Cardiac Disease Models)

► Show Figures

Figure 1

15 pages, 886 KB

Open AccessFeature PaperEditor’s ChoiceArticle

Lipocalin-2, Matrix Metalloproteinase-9, and MMP-9/NGAL Complex in Upper Aerodigestive Tract Carcinomas: A Pilot Study

by Luca Cavalcanti, Silvia Francati, Giampiero Ferraguti, Francesca Fanfarillo, Daniele Peluso, Christian Barbato, Antonio Greco, Antonio Minni and Carla Petrella

Cells 2025, 14(7), 506; https://doi.org/10.3390/cells14070506 - 29 Mar 2025

Cited by 4 | Viewed by 2129

Abstract

Upper aerodigestive tract (UADT) carcinomas have a high and rapidly increasing incidence, particularly in industrialized countries. The identification of diagnostic and prognostic biomarkers remains a key objective in oncological research. However, conflicting data have been reported regarding Lipocalin-2 (LCN-2 or NGAL), Matrix Metalloproteinase-9 [...] Read more.

Upper aerodigestive tract (UADT) carcinomas have a high and rapidly increasing incidence, particularly in industrialized countries. The identification of diagnostic and prognostic biomarkers remains a key objective in oncological research. However, conflicting data have been reported regarding Lipocalin-2 (LCN-2 or NGAL), Matrix Metalloproteinase-9 (MMP-9), and the MMP-9/NGAL complex in UADT carcinomas. For this reason, the primary aim of this study was to investigate the involvement and modulation of the LCN-2 system in UADT cancer by selecting patients at first diagnosis and excluding any pharmacological or interventional treatments that could act as confounding factors. In this clinical retrospective pilot study, we investigated LCN-2 and MMP-9 tissue gene expression, as well as circulating levels of LCN-2, MMP-9, and the MMP-9/NGAL complex. Our findings revealed a downregulation of LCN-2 and an upregulation of MMP-9 gene expression in tumor tissues compared to healthy counterparts. A similar trend was observed in circulating levels, with decreased LCN-2 and increased MMP-9 in cancer patients compared to healthy controls. Additionally, serum levels of the MMP-9/NGAL complex were significantly elevated in UADT cancer patients relative to controls. Our study suggests a potentially distinct role for the free form of LCN-2 and its conjugated form (MMP-9/NGAL complex) in UADT tumors. These findings not only provide new insights into the molecular mechanisms underlying tumor progression but also highlight the potential clinical relevance of these biomarkers. The differential expression patterns observed suggest that the LCN-2 and MMP-9/NGAL complex could serve as valuable tools for improving early diagnosis, monitoring disease progression, and potentially guiding therapeutic strategies. Further research is needed to validate their utility in clinical settings and to explore their prognostic and predictive value in personalized treatment approaches. Full article

(This article belongs to the Special Issue New Trends and Advances in Diagnosis and Prognosis of Head and Neck Cancer from Carcinogenesis to Future Molecular Targeted Therapies: 2nd Edition)

► Show Figures

Graphical abstract

21 pages, 8811 KB

Open AccessEditor’s ChoiceArticle

Empagliflozin Plays Vasoprotective Role in Spontaneously Hypertensive Rats via Activation of the SIRT1/AMPK Pathway

by Monika Kloza, Anna Krzyżewska, Hanna Kozłowska, Sandra Budziak and Marta Baranowska-Kuczko

Cells 2025, 14(7), 507; https://doi.org/10.3390/cells14070507 - 29 Mar 2025

Cited by 4 | Viewed by 2023

Abstract

Empagliflozin (EMPA), a sodium-glucose co-transporter 2 (SGLT2) inhibitor, prevents endothelial dysfunction, but its effects on vascular tone in hypertension remain unclear. This study investigated whether EMPA modulates vasomotor tone via sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK) pathways in spontaneously hypertensive rats [...] Read more.

Empagliflozin (EMPA), a sodium-glucose co-transporter 2 (SGLT2) inhibitor, prevents endothelial dysfunction, but its effects on vascular tone in hypertension remain unclear. This study investigated whether EMPA modulates vasomotor tone via sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK) pathways in spontaneously hypertensive rats (SHR) and controls (Wistar Kyoto rats, WKY). Functional (wire myography, organ bath) and biochemical (Western blot) studies were conducted on the third-order of the superior mesenteric arteries (sMAs) and/or aortas. EMPA induced concentration-dependent relaxation of preconstricted sMAs in both groups. In SHR, EMPA enhanced acetylcholine (Ach)-induced relaxation in sMAs and aortas and reduced constriction induced by phenylephrine (Phe) and U46619 in sMAs. The SIRT1 inhibitor (EX527) abolished EMPA’s effects on Ach-mediated relaxation and U46619-induced vasoconstriction, while AMPK inhibition reduced Ach-mediated relaxation and Phe-induced vasoconstriction. SHR showed increased SGLT2 and SIRT1 expression and decreased pAMPK/AMPK levels in sMAs. In conclusion, EMPA might exert vasoprotective effects in hypertension by enhancing endothelium-dependent relaxation and reducing constriction via AMPK/SIRT1 pathways. These properties could improve vascular health in patients with hypertension and related conditions. Further studies are needed to explore new indications for SGLT2 inhibitors. Full article

► Show Figures

Graphical abstract

32 pages, 1765 KB

Open AccessEditor’s ChoiceReview

Preclinical Models for Studying Fuchs Endothelial Corneal Dystrophy

by Fancheng Sun, Lexie W. Q. Xi, Wesley Luu, Myagmartsend Enkhbat, Dawn Neo, Jodhbir S. Mehta, Gary S. L. Peh and Evelyn K. F. Yim

Cells 2025, 14(7), 505; https://doi.org/10.3390/cells14070505 - 28 Mar 2025

Cited by 6 | Viewed by 4937

Abstract

Fuchs Endothelial Corneal Dystrophy (FECD) is a corneal endothelial disease that causes microenvironment alterations and endothelial cell loss, which leads to vision impairment. It has a high global prevalence, especially in elderly populations. FECD is also one of the leading indications of corneal [...] Read more.

Fuchs Endothelial Corneal Dystrophy (FECD) is a corneal endothelial disease that causes microenvironment alterations and endothelial cell loss, which leads to vision impairment. It has a high global prevalence, especially in elderly populations. FECD is also one of the leading indications of corneal transplantation globally. Currently, there is no clearly defined canonical pathway for this disease, and it has been proposed that the combinatorial effects of genetic mutations and exogenous factors cause FECD. Clinical studies and observations have provided valuable knowledge and understanding of FECD, while preclinical studies are essential for gaining insights into disease progression and mechanisms for the development and testing of regenerative medicine therapies. In this review, we first introduce the proposed genetic and molecular pathologies of FECD. Notably, we discuss the impact of abnormal extracellular matrix deposition (guttata), endothelial-to-mesenchymal transition, cell senescence, and oxidative stress on the pathology and etiology of FECD. We review and summarize the in vitro cell models, ex vivo tissues, and in vivo animal models used to study FECD. The benefits and challenges of each model are also discussed. Full article

► Show Figures

Figure 1

29 pages, 1740 KB

Open AccessEditor’s ChoiceReview

The Role of Inflammation in Cancer: Mechanisms of Tumor Initiation, Progression, and Metastasis

by Atsushi Nishida and Akira Andoh

Cells 2025, 14(7), 488; https://doi.org/10.3390/cells14070488 - 25 Mar 2025

Cited by 103 | Viewed by 15104

Abstract

Inflammation is an essential component of the immune response that protects the host against pathogens and facilitates tissue repair. Chronic inflammation is a critical factor in cancer development and progression. It affects every stage of tumor development, from initiation and promotion to invasion [...] Read more.

Inflammation is an essential component of the immune response that protects the host against pathogens and facilitates tissue repair. Chronic inflammation is a critical factor in cancer development and progression. It affects every stage of tumor development, from initiation and promotion to invasion and metastasis. Tumors often create an inflammatory microenvironment that induces angiogenesis, immune suppression, and malignant growth. Immune cells within the tumor microenvironment interact actively with cancer cells, which drives progression through complex molecular mechanisms. Chronic inflammation is triggered by factors such as infections, obesity, and environmental toxins and is strongly linked to increased cancer risk. However, acute inflammatory responses can sometimes boost antitumor immunity; thus, inflammation presents both challenges and opportunities for therapeutic intervention. This review examines how inflammation contributes to tumor biology, emphasizing its dual role as a critical factor in tumorigenesis and as a potential therapeutic target. Full article

(This article belongs to the Special Issue Pathogenic Mechanisms of Chronic Inflammation-Associated Cancer)

► Show Figures

Figure 1

16 pages, 3864 KB

Open AccessEditor’s ChoiceArticle

Impact of a High-Fat Diet on the Gut Microbiome: A Comprehensive Study of Microbial and Metabolite Shifts During Obesity

by Md Abdullah Al Mamun, Ahmed Rakib, Mousumi Mandal and Udai P. Singh

Cells 2025, 14(6), 463; https://doi.org/10.3390/cells14060463 - 20 Mar 2025

Cited by 22 | Viewed by 9089

Abstract

Over the last few decades, the prevalence of metabolic diseases such as obesity, diabetes, non-alcoholic fatty liver disease, hypertension, and hyperuricemia has surged, primarily due to high-fat diet (HFD). The pathologies of these metabolic diseases show disease-specific alterations in the composition and function [...] Read more.

Over the last few decades, the prevalence of metabolic diseases such as obesity, diabetes, non-alcoholic fatty liver disease, hypertension, and hyperuricemia has surged, primarily due to high-fat diet (HFD). The pathologies of these metabolic diseases show disease-specific alterations in the composition and function of their gut microbiome. How HFD alters the microbiome and its metabolite to mediate adipose tissue (AT) inflammation and obesity is not well known. Thus, this study aimed to identify the changes in the gut microbiome and metabolomic signatures induced by an HFD to alter obesity. To explore the changes in the gut microbiota and metabolites, 16S rRNA gene amplicon sequencing and metabolomic analyses were performed after HFD and normal diet (ND) feeding. We noticed that, at taxonomic levels, the number of operational taxonomic units (OTUs), along with the Chao and Shannon indexes, significantly shifted in HFD-fed mice compared to those fed a ND. Similarly, at the phylum level, an increase in Firmicutes and a decrease in Bacteroidetes were noticed in HFD-fed mice. At the genus level, an increase in Lactobacillus and Ruminococcus was observed, while Allobaculum, Clostridium, and Akkermansia were markedly reduced in the HFD group. Many bacteria from the Ruminococcus genus impair bile acid metabolism and restrict weight loss. Firmicutes are efficient in breaking down complex carbohydrates into short-chain fatty acids (SCFAs) and other metabolites, whereas Bacteroidetes are involved in a more balanced or efficient energy extraction. Thus, an increase in Firmicutes over Bacteroidetes enhances the absorption of more calories from food, which may contribute to obesity. Taken together, the altered gut microbiota and metabolites trigger AT inflammation, which contributes to metabolic dysregulation and disease progression. Thus, this study highlights the potential of the gut microbiome in the development of therapeutic strategies for obesity and related metabolic disorders. Full article

(This article belongs to the Section Cellular Pathology)

► Show Figures

Graphical abstract

15 pages, 1619 KB

Open AccessEditor’s ChoiceArticle

Blockade of HSP70 Improves Vascular Function in a Mouse Model of Type 2 Diabetes

by Valentina Ochoa Mendoza, Amanda Almeida de Oliveira and Kenia Pedrosa Nunes

Cells 2025, 14(6), 424; https://doi.org/10.3390/cells14060424 - 13 Mar 2025

Cited by 1 | Viewed by 1615

Abstract

Type 2 diabetes (T2D) is a chronic disease that damages blood vessels and increases the risk of cardiovascular disease (CVD). Heat-shock protein 70 (HSP70), a family of chaperone proteins, has been recently reported as a key player in vascular reactivity that affects large [...] Read more.

Type 2 diabetes (T2D) is a chronic disease that damages blood vessels and increases the risk of cardiovascular disease (CVD). Heat-shock protein 70 (HSP70), a family of chaperone proteins, has been recently reported as a key player in vascular reactivity that affects large blood vessels like the aorta. Hyperglycemia, a hallmark of diabetes, correlates with the severity of vascular damage and circulating HSP70 levels. In diabetes, blood vessels often show impaired contractility, contributing to vascular dysfunction. However, HSP70’s specific role in T2D-related vascular contraction remains unclear. We hypothesized that blocking HSP70 would improve vascular function in a widely used diabetic mouse model (db/db). To test this, we measured both vascular intracellular and serum circulating HSP70 levels in control and diabetic male mice using immunofluorescence and Western blotting. We also examined the aorta’s contractile response using a wire myograph system, which measured the force produced in response to phenylephrine (PE), both with and without VER155008, a pharmacological inhibitor that targets the ATPase domain of HSP70, and after removing extracellular calcium. Our findings show that intracellular HSP70 (iHSP70) levels were similar in control and diabetic groups, while circulating HSP70 (eHSP70) levels were higher in the serum of diabetic mice, altering the iHSP70/eHSP70 ratio. Even though VER155008 attenuated both phases of the contractile curve in the diabetic and control groups, enhanced vasoconstriction to PE was only observed in the tonic phase of the curve in the db/db group, which was prevented by iHSP70 inhibition. This effect involved calcium mobilization, as both the maximal and total contraction forces to PE were restored in groups treated with VER155008. Additionally, internal calcium levels in aortic rings treated with VER155008 decreased, as observed in force generation upon calcium reintroduction, which was further corroborated using a biochemical calcium assay. In conclusion, our study demonstrates that blocking HSP70 improves vascular reactivity in the hyperglycemic state of T2D by restoring proper vascular contraction. Full article

(This article belongs to the Special Issue Molecular Pathways and Potential Therapeutic Targets of Vascular Dysfunction)

► Show Figures

Graphical abstract

23 pages, 3082 KB

Open AccessEditor’s ChoiceReview

Metaboloepigenetics: Role in the Regulation of Flow-Mediated Endothelial (Dys)Function and Atherosclerosis

by Francisco Santos, Hashum Sum, Denise Cheuk Lee Yan and Alison C. Brewer

Cells 2025, 14(5), 378; https://doi.org/10.3390/cells14050378 - 5 Mar 2025

Cited by 6 | Viewed by 2925

Abstract

Endothelial dysfunction is the main initiating factor in atherosclerosis. Through mechanotransduction, shear stress regulates endothelial cell function in both homeostatic and diseased states. Accumulating evidence reveals that epigenetic changes play critical roles in the etiology of cardiovascular diseases, including atherosclerosis. The metabolic regulation [...] Read more.

Endothelial dysfunction is the main initiating factor in atherosclerosis. Through mechanotransduction, shear stress regulates endothelial cell function in both homeostatic and diseased states. Accumulating evidence reveals that epigenetic changes play critical roles in the etiology of cardiovascular diseases, including atherosclerosis. The metabolic regulation of epigenetics has emerged as an important factor in the control of gene expression in diseased states, but to the best of our knowledge, this connection remains largely unexplored in endothelial dysfunction and atherosclerosis. In this review, we (1) summarize how shear stress (or flow) regulates endothelial (dys)function; (2) explore the epigenetic alterations that occur in the endothelium in response to disturbed flow; (3) review endothelial cell metabolism under different shear stress conditions; and (4) suggest mechanisms which may link this altered metabolism to the regulation of the endothelial epigenome by modulations in metabolite availability. We believe that metabolic regulation plays an important role in endothelial epigenetic reprogramming and could pave the way for novel metabolism-based therapeutic strategies. Full article

(This article belongs to the Collection Cardiovascular Disease: From Molecular and Cellular Mechanisms to Therapeutic Opportunities)

► Show Figures

Figure 1

15 pages, 746 KB

Open AccessEditor’s ChoiceReview

Diabetic Retinopathy (DR): Mechanisms, Current Therapies, and Emerging Strategies

by Hyewon Seo, Sun-Ji Park and Minsoo Song

Cells 2025, 14(5), 376; https://doi.org/10.3390/cells14050376 - 4 Mar 2025

Cited by 40 | Viewed by 9782

Abstract

Diabetic retinopathy (DR) is one of the most prevalent complications of diabetes, affecting nearly one-third of patients with diabetes mellitus and remaining a leading cause of blindness worldwide. Among the various diabetes-induced complications, DR is of particular importance due to its direct impact [...] Read more.

Diabetic retinopathy (DR) is one of the most prevalent complications of diabetes, affecting nearly one-third of patients with diabetes mellitus and remaining a leading cause of blindness worldwide. Among the various diabetes-induced complications, DR is of particular importance due to its direct impact on vision and the irreversible damage to the retina. DR is characterized by multiple pathological processes, primarily a hyperglycemia-induced inflammatory response and oxidative stress. Current gold standard therapies, such as anti-VEGF injections and photocoagulation, have shown efficacy in slowing disease progression. However, challenges such as drug resistance, partial therapeutic responses, and the reliance on direct eye injections—which often result in low patient compliance—remain unresolved. This review provides a comprehensive overview of the underlying molecular mechanisms in DR, the current therapies, and their unmet needs for DR treatment. Additionally, emerging therapeutic strategies for improving DR treatment outcomes are discussed. Full article

(This article belongs to the Special Issue Diabetes-Induced Organ Damage: Cellular Mechanisms and Therapeutic Opportunities)

► Show Figures

Figure 1

18 pages, 1457 KB

Open AccessEditor’s ChoiceReview

Sex Disparities in P53 Regulation and Functions: Novel Insights for Personalized Cancer Therapies

by Miriana Cardano, Giacomo Buscemi and Laura Zannini

Cells 2025, 14(5), 363; https://doi.org/10.3390/cells14050363 - 28 Feb 2025

Cited by 2 | Viewed by 1708

Abstract

Epidemiological studies have revealed significant sex differences in the incidence of tumors unrelated to reproductive functions, with females demonstrating a lesser risk and a better response to therapy than males. However, the reasons for these disparities are still unknown and cancer therapies are [...] Read more.

Epidemiological studies have revealed significant sex differences in the incidence of tumors unrelated to reproductive functions, with females demonstrating a lesser risk and a better response to therapy than males. However, the reasons for these disparities are still unknown and cancer therapies are generally sex-unbiased. The tumor-suppressor protein p53 is a transcription factor that can activate the expression of multiple target genes mainly involved in the maintenance of genome stability and tumor prevention. It is encoded by TP53, which is the most-frequently mutated gene in human cancers and therefore constitutes an attractive target for therapy. Recently, evidence of sex differences has emerged in both p53 regulations and functions, possibly providing novel opportunities for personalized cancer medicine. Here, we will review and discuss current knowledge about sexual disparities in p53 pathways, their role in tumorigenesis and cancer progression, and their importance in the therapy choice process, finally highlighting the importance of considering sex contribution in both basic research and clinical practice. Full article

(This article belongs to the Section Cell Signaling)

► Show Figures

Graphical abstract

16 pages, 1714 KB

Open AccessEditor’s ChoiceReview

Pro-Fibrotic Macrophage Subtypes: SPP1+ Macrophages as a Key Player and Therapeutic Target in Cardiac Fibrosis?

by Moritz Uhlig, Sebastian Billig, Jan Wienhold and David Schumacher

Cells 2025, 14(5), 345; https://doi.org/10.3390/cells14050345 - 27 Feb 2025

Cited by 7 | Viewed by 6630

Abstract

Cardiac fibrosis is a major driver of heart failure, a leading cause of morbidity and mortality worldwide. Advances in single-cell transcriptomics have revealed the pivotal role of SPP1+ macrophages in the pathogenesis of cardiac fibrosis, positioning them as critical mediators and promising therapeutic [...] Read more.

Cardiac fibrosis is a major driver of heart failure, a leading cause of morbidity and mortality worldwide. Advances in single-cell transcriptomics have revealed the pivotal role of SPP1+ macrophages in the pathogenesis of cardiac fibrosis, positioning them as critical mediators and promising therapeutic targets. SPP1+ macrophages, characterized by elevated expression of secreted phosphoprotein 1 (SPP1) and often co-expressing Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), localize to fibrotic niches in the heart and other organs. These cells interact with activated fibroblasts and myofibroblasts, driving extracellular matrix remodeling and fibrosis progression. Their differentiation is orchestrated by signals such as CXCL4, GM-CSF, and IL-17A, further emphasizing their regulatory complexity. Therapeutic strategies targeting SPP1+ macrophages have shown encouraging preclinical results. Approaches include silencing Spp1 using antibody–siRNA conjugates and modulating key pathways involved in macrophage differentiation. These interventions have effectively reduced fibrosis and improved cardiac function in animal models. The mechanisms underlying SPP1+ macrophage function in cardiac fibrosis provide a foundation for innovative therapies aimed at mitigating pathological remodeling and improving outcomes in patients with heart failure. This emerging field has significant potential to transform the treatment of fibrotic heart disease. Full article

(This article belongs to the Special Issue New Insights into Therapeutic Targets for Cardiovascular Diseases)

► Show Figures

Figure 1

20 pages, 4395 KB

Open AccessEditor’s ChoiceArticle

Sex Differences in Circulating Inflammatory, Immune, and Tissue Growth Markers Associated with Fabry Disease-Related Cardiomyopathy

by Margarita M. Ivanova, Julia Dao, Andrew Friedman, Neil Kasaci and Ozlem Goker-Alpan

Cells 2025, 14(5), 322; https://doi.org/10.3390/cells14050322 - 20 Feb 2025

Cited by 6 | Viewed by 2108

Abstract

Fabry disease (FD) is a lysosomal disorder due to alpha-galactosidase-A enzyme deficiency, accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) which lead to proinflammatory effects. Males develop progressive hypertrophic cardiomyopathy (HCM) followed by fibrosis; females develop nonconcentric hypertrophy and/or early fibrosis. The inflammatory response [...] Read more.

Fabry disease (FD) is a lysosomal disorder due to alpha-galactosidase-A enzyme deficiency, accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) which lead to proinflammatory effects. Males develop progressive hypertrophic cardiomyopathy (HCM) followed by fibrosis; females develop nonconcentric hypertrophy and/or early fibrosis. The inflammatory response to Gb3/lyso-Gb-3 accumulation is one of the suggested pathogenic mechanisms in FD cardiomyopathy when the secretion of inflammatory and transforming growth factors with infiltration of lymphocytes and macrophages into tissue promotes cardiofibrosis. This study aims to evaluate inflammation-driving cytokines and cardio-hypertrophic remodeling biomarkers contributing to sex-specific HCM progression. Biomarkers were studied in 20 healthy subjects and 45 FD patients. IL-2, IL-10, TNF-α, and IFN-γ were elevated in all patients, while IL-1α, MCP-1, and TNFR2 showed sex-specific differences. The increased cytokines were associated with the NF-kB pathway in FD males with HCM, revealing a correlation between MCP-1, IFN-γ, VEGF, GM-CSF, IL-10, and IL-2. In female patients, the impaired TNFα/TNFR2/TGFβ cluster with correlations to MCP-1, VEGF, GM-CSF, and IL-1α was observed. The activation of cytokines and the NF-kB pathway indicates significant inflammation during HCM remodeling in FD males. The TNFα/TNFR2/TGFβ signaling cluster may explain early fibrosis in females with FD cardiomyopathy. Sex-specific inflammatory responses in FD influence the severity and progression of HCM. Full article

(This article belongs to the Special Issue Downstream Pathways in Lysosomal Disorders from Basic Science to Clinical Contexts)

► Show Figures

Figure 1

19 pages, 6384 KB

Open AccessEditor’s ChoiceArticle

A Critical Role of Intracellular PD-L1 in Promoting Ovarian Cancer Progression

by Rui Huang, Brad Nakamura, Rosemary Senguttuvan, Yi-Jia Li, Antons Martincuks, Rania Bakkar, Mihae Song, David K. Ann, Lorna Rodriguez-Rodriguez and Hua Yu

Cells 2025, 14(4), 314; https://doi.org/10.3390/cells14040314 - 19 Feb 2025

Cited by 2 | Viewed by 3189

Abstract

Disrupting the interaction between tumor-cell surface PD-L1 and T cell membrane PD-1 can elicit durable clinical responses. However, only about 10% of ovarian cancer patients respond to PD-1/PD-L1 blockade. Here, we show that PD-L1 expression in ovarian cancer-patient tumors is predominantly intracellular. Notably, [...] Read more.

Disrupting the interaction between tumor-cell surface PD-L1 and T cell membrane PD-1 can elicit durable clinical responses. However, only about 10% of ovarian cancer patients respond to PD-1/PD-L1 blockade. Here, we show that PD-L1 expression in ovarian cancer-patient tumors is predominantly intracellular. Notably, PARP inhibitor treatment highly increased intracellular PD-L1 accumulation in both ovarian cancer-patient tumor samples and cell lines. We investigated whether intracellular PD-L1 might play a critical role in ovarian cancer progression. Mutating the PD-L1 acetylation site in PEO1 and ID8^Brca1−/− ovarian cancer cells significantly decreased PD-L1 levels and impaired colony formation, which was accompanied by cell cycle G2/M arrest and apoptosis induction. PEO1 and ID8^Brca1−/− tumors with PD-L1 acetylation site mutation also exhibited significantly reduced growth in mice. Furthermore, targeting intracellular PD-L1 with a cell-penetrating antibody effectively decreased ovarian tumor-cell intracellular PD-L1 level and induced tumor-cell growth arrest and apoptosis, as well as enhanced DNA damage and STING activation, both in vitro and in vivo. In conclusion, we have shown the critical role of intracellular PD-L1 in ovarian cancer progression. Full article

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

► Show Figures

Figure 1

22 pages, 4264 KB

Open AccessEditor’s ChoiceArticle

Seasonal Influences on Human Placental Transcriptomes Associated with Spontaneous Preterm Birth

by Khondoker M. Akram, Eleanor Dodd and Dilly O. C. Anumba

Cells 2025, 14(4), 303; https://doi.org/10.3390/cells14040303 - 18 Feb 2025

Cited by 1 | Viewed by 2382

Abstract

Demographic studies have revealed a strong association between exposure to high ambient temperatures during pregnancy and increased risks of preterm birth (PTB). The mechanism underlying this association is unclear, but it is plausible that altered placental function may contribute to it. In this [...] Read more.

Demographic studies have revealed a strong association between exposure to high ambient temperatures during pregnancy and increased risks of preterm birth (PTB). The mechanism underlying this association is unclear, but it is plausible that altered placental function may contribute to it. In this study, we conducted differential gene expression analysis, gene set enrichment analysis (GSEA), and gene ontology (GO) analysis on bulk RNA-seq data from human placentas delivered at term and preterm during the warmer months compared to placentas delivered at term and preterm during the colder months in the UK. We detected 48 differentially expressed genes in preterm placentas delivered during the warmer months compared to preterm placentas delivered during the colder months, the majority of which were inflammatory cytokines and chemokines, including SERPINA1, IL1B, CCL3, CCL3L3, CCL4, CCL4L2, CCL20, and CXCL8. The GSEA positively enriched 17 signalling pathways, including the NF-κB, IL17, Toll-like receptor, and chemokine signalling pathways in preterm placentas delivered during warmer months. These results were not observed in the placentas delivered at term during the same times of the year. The GO analysis revealed several enhanced biological processes, including neutrophil, granulocyte, monocyte, and lymphocyte chemotaxis, as well as inflammatory and humoral immune responses in preterm placentas, but not in placentas delivered at term in the summer. We conclude that maternal exposure to warm environmental temperatures during pregnancy likely alters the placental transcriptomes towards inflammation and immune regulation, potentially leading to PTB. Full article

(This article belongs to the Special Issue Molecular Insight into the Pathogenesis of Spontaneous Preterm Birth)

► Show Figures

Figure 1

14 pages, 2097 KB

Open AccessEditor’s ChoiceArticle

Angiotensin-(1-7) Provides Potent Long-Term Neurorepair/Neuroregeneration in a Rodent White Matter Stroke Model: Nonarteritic Ischemic Optic Neuropathy (rNAION)

by Kwang Min Woo, Yan Guo, Zara Mehrabian, Thomas Walther, Neil R. Miller and Steven L. Bernstein

Cells 2025, 14(4), 289; https://doi.org/10.3390/cells14040289 - 15 Feb 2025

Cited by 2 | Viewed by 1751

Abstract

Nonarteritic anterior ischemic optic neuropathy (NAION) is an ischemic lesion of the anterior optic nerve (ON), currently untreatable due to the length of time from symptom onset until treatment. We evaluated angiotensin-(1-7) (Ang-(1-7)): the MAS1-receptor ligand, as a possible NAION treatment using the [...] Read more.

Nonarteritic anterior ischemic optic neuropathy (NAION) is an ischemic lesion of the anterior optic nerve (ON), currently untreatable due to the length of time from symptom onset until treatment. We evaluated angiotensin-(1-7) (Ang-(1-7)): the MAS1-receptor ligand, as a possible NAION treatment using the rodent NAION model (rNAION). Long-Evans rats were unilaterally rNAION-induced. One-day post-induction, lesion severity was quantified via optic nerve head (ONH) edema using spectral domain optical coherence tomography. Animals meeting rNAION induction criteria were randomized into (1) Subcutaneous Ang-(1-7) infusion for 28 days and (2) Vehicle. Visual function was assessed using both visual acuity and flash visual evoked potentials (fVEP). Tissues were collected >30d and RGC neurons were quantified by stereology. ONs were histologically examined for inflammation. Ang-(1-7) improved post-rNAION visual function. Ang-(1-7)-treated animals showed improved visual acuity (ANCOVA: p = 0.0084) and improved fVEP amplitudes (ANCOVA: p = 0.0378) vs vehicle controls. The relative degree of improvement correlated with ONH edema severity. Treated animals showed trends towards increased RGC survival, and reduced optic nerve inflammatory cell infiltration. Ang-(1-7) is the first agent effective ≥1 day after rNAION induction. Ang-(1-7) type agonists may be useful in improving long-term function and neuronal survival in clinical NAION and other forms of white matter ischemia. Full article

(This article belongs to the Special Issue Novel and Experimental Strategies for the Treatment of Neurodegenerative Diseases)

► Show Figures

Graphical abstract

28 pages, 2721 KB

Open AccessEditor’s ChoiceReview

Autophagy in Tissue Repair and Regeneration

by Daniel Moreno-Blas, Teresa Adell and Cristina González-Estévez

Cells 2025, 14(4), 282; https://doi.org/10.3390/cells14040282 - 14 Feb 2025

Cited by 10 | Viewed by 8854

Abstract

Autophagy is a cellular recycling system that, through the sequestration and degradation of intracellular components regulates multiple cellular functions to maintain cellular homeostasis and survival. Dysregulation of autophagy is closely associated with the development of physiological alterations and human diseases, including the loss [...] Read more.

Autophagy is a cellular recycling system that, through the sequestration and degradation of intracellular components regulates multiple cellular functions to maintain cellular homeostasis and survival. Dysregulation of autophagy is closely associated with the development of physiological alterations and human diseases, including the loss of regenerative capacity. Tissue regeneration is a highly complex process that relies on the coordinated interplay of several cellular processes, such as injury sensing, defense responses, cell proliferation, differentiation, migration, and cellular senescence. These processes act synergistically to repair or replace damaged tissues and restore their morphology and function. In this review, we examine the evidence supporting the involvement of the autophagy pathway in the different cellular mechanisms comprising the processes of regeneration and repair across different regenerative contexts. Additionally, we explore how modulating autophagy can enhance or accelerate regeneration and repair, highlighting autophagy as a promising therapeutic target in regenerative medicine for the development of autophagy-based treatments for human diseases. Full article

(This article belongs to the Collection Feature Papers in Autophagy)

► Show Figures

Figure 1

19 pages, 3088 KB

Open AccessEditor’s ChoiceArticle

Mitogen-Activated Protein Kinase Phosphatase-2 Deletion Promotes Hyperglycemia and Susceptibility to Streptozotocin-Induced Diabetes in Female Mice In Vivo

by Nabin Ghimire, Morgan Welch, Cassandra Secunda, Alexis Fink and Ahmed Lawan

Cells 2025, 14(4), 261; https://doi.org/10.3390/cells14040261 - 12 Feb 2025

Cited by 3 | Viewed by 1355

Abstract

The development of type 2 diabetes (T2D) is largely dependent on the maintenance of pancreatic islet function and mass. Sexual dimorphism in T2D is evident in many areas, such as pathophysiology, treatment, and prevention. Mitogen-activated protein kinase phosphatase-2 (MKP-2) has a distinct role [...] Read more.

The development of type 2 diabetes (T2D) is largely dependent on the maintenance of pancreatic islet function and mass. Sexual dimorphism in T2D is evident in many areas, such as pathophysiology, treatment, and prevention. Mitogen-activated protein kinase phosphatase-2 (MKP-2) has a distinct role in the regulation of cell proliferation and the development of metabolic disorders. However, whether there is a causal relationship between MKP-2 and diabetes onset is unclear. The aim of this study was to determine the role of MKP-2 in the regulation of whole-body glucose homeostasis and the impact on pancreatic islet function using streptozotocin-induced pancreatic injury. Here, we show that female mice with whole-body deletion of MKP-2 exhibit hyperglycemia in mouse models treated with multiple low doses of streptozotocin (STZ). In comparison, both male MKP-2 wild-type and knockout mice were hyperglycemic. Consistent with the hyperglycemia, female MKP-2-deficient mice exhibited reduced islet size. Under T2D conditions, MKP-2-deficient mice display enhanced pancreatic JNK and ERK phosphorylation that is associated with the downregulation of genes important for pancreatic islet development and function, Pdx-1 and MafA. Furthermore, we found impaired metabolic flux in adipose tissue that is consistent with hyperglycemia and dysfunctional pancreas. MKP-2 deletion results in reduced Akt activation that is associated with increased adiposity and insulin resistance in female MKP-2 KO mice. These studies demonstrate the critical role of MKP-2 in the development of T2D diabetes in vivo. This suggests that MKP-2 may have a gender-specific role in diabetes development. This discovery raises the possibility that postmenopausal prevention of T2D may benefit from the activation of MKP-2 activity in islet cells. Full article

(This article belongs to the Section Cell Signaling)

► Show Figures

Figure 1

20 pages, 5182 KB

Open AccessEditor’s ChoiceArticle

Combinational Inhibition of MEK and AKT Synergistically Induces Melanoma Stem Cell Apoptosis and Blocks NRAS Tumor Growth

by Ryyan Alobaidi, Nusrat Islam, Toni Olkey, Yogameenakshi Haribabu, Mathew Shamo, Peter Sykora, Cynthia M. Simbulan-Rosenthal and Dean S. Rosenthal

Cells 2025, 14(4), 248; https://doi.org/10.3390/cells14040248 - 10 Feb 2025

Cited by 4 | Viewed by 2232

Abstract

Malignant melanoma is a lethal skin cancer containing melanoma-initiating cells (MICs), implicated in tumorigenesis, invasion, and drug resistance, and characterized by an elevated expression of stem cell markers, including CD133. siRNA knockdown of CD133 has been previously shown to enhance apoptosis induced by [...] Read more.

Malignant melanoma is a lethal skin cancer containing melanoma-initiating cells (MICs), implicated in tumorigenesis, invasion, and drug resistance, and characterized by an elevated expression of stem cell markers, including CD133. siRNA knockdown of CD133 has been previously shown to enhance apoptosis induced by the MEK inhibitor trametinib in melanoma cells. This study investigates the underlying mechanisms of CD133’s anti-apoptotic activity in patient-derived BAKP melanoma, harboring the difficult-to-treat NRAS^Q61K driver mutation, after CRISPR-Cas9 CD133 knockout or Doxycycline (Dox)-inducible re-expression of CD133. CD133 knockout in BAKP cells increased trametinib-induced apoptosis by reducing anti-apoptotic p-AKT and p-BAD and increasing pro-apoptotic BAX. Conversely, Dox-induced CD133 expression diminished apoptosis in trametinib-treated cells, coincident with elevated p-AKT, p-BAD, and decreased activation of BAX and caspase-3. However, trametinib in combination with pan-AKT inhibitor capivasertib reduced cell survival as measured by XTT viability assays and apoptosis and colony formation assays, independent of CD133 status. CD133 may therefore activate a survival pathway wherein (1) increased AKT phosphorylation and activation induces (2) BAD phosphorylation and inactivation, which (3) decreases BAX activation, and (4) reduces caspases-3 activity and caspase-mediated PARP cleavage, leading to apoptosis suppression and drug resistance in melanoma. In vivo mouse xenograft studies using Dox-inducible melanoma cells revealed increased rates of tumor growth after induction of CD133 expression in trametinib-treated +Dox mice, an effect which was synergistically suppressed by combination treatment. Targeting nodes of the AKT and MAPK survival pathways with trametinib and capivasertib highlights the potential for combination therapies for NRAS-mutant melanoma stem cells for the development of more effective treatments for patients with high-risk melanoma. Full article

(This article belongs to the Section Cellular Pathology)

► Show Figures

Graphical abstract

13 pages, 9327 KB

Open AccessEditor’s ChoiceArticle

BCL-B Promotes Lung Cancer Invasiveness by Direct Inhibition of BOK

by Palaniappan Ramesh, Amal R. Al Kadi, Gaurav M. Borse, Maximilian Webendörfer, Gregor Zaun, Martin Metzenmacher, Fabian Doerr, Servet Bölükbas, Balazs Hegedüs, Smiths S. Lueong, Joelle Magne, Beiyun Liu, Greisly Nunez, Martin Schuler, Douglas R. Green and Halime Kalkavan

Cells 2025, 14(4), 246; https://doi.org/10.3390/cells14040246 - 9 Feb 2025

Cited by 1 | Viewed by 2294

Abstract

Expression of BCL-B, an anti-apoptotic BCL-2 family member, is correlated with worse survival in lung adenocarcinomas. Here, we show that BCL-B can mitigate cell death initiation through interaction with the effector protein BOK. We found that this interaction can promote sublethal mitochondrial [...] Read more.

Expression of BCL-B, an anti-apoptotic BCL-2 family member, is correlated with worse survival in lung adenocarcinomas. Here, we show that BCL-B can mitigate cell death initiation through interaction with the effector protein BOK. We found that this interaction can promote sublethal mitochondrial outer membrane permeabilization (MOMP) and consequently generate apoptosis-flatliners, which represent a source of drug-tolerant persister cells (DTPs). The engagement of endothelial-mesenchymal-transition (EMT) further promotes cancer cell invasiveness in such DTPs. Our results reveal that BCL-B fosters cancer cell aggressiveness by counteracting complete MOMP. Full article

(This article belongs to the Special Issue Mitophagy, Autophagy, Apoptosis and Senescence—the Roles of These Processes in Invasive Cancer Growth: Second Edition)

► Show Figures

Graphical abstract

15 pages, 1568 KB

Open AccessEditor’s ChoiceArticle

Telomere Length, Oxidative Stress, and Kidney Damage Biomarkers in Fabry Nephropathy

by Tina Levstek, Erazem Bahčič, Bojan Vujkovac, Andreja Cokan Vujkovac, Tine Tesovnik, Žiga Iztok Remec, Vanja Čuk and Katarina Trebušak Podkrajšek

Cells 2025, 14(3), 218; https://doi.org/10.3390/cells14030218 - 4 Feb 2025

Cited by 4 | Viewed by 2419

Abstract

Fabry nephropathy is a life-threatening complication of Fabry disease characterized by complex and incompletely understood pathophysiological processes possibly linked to premature aging. We aimed to investigate leukocyte telomere length (LTL), oxidative stress, and kidney damage biomarkers in relation to kidney function. The study [...] Read more.

Fabry nephropathy is a life-threatening complication of Fabry disease characterized by complex and incompletely understood pathophysiological processes possibly linked to premature aging. We aimed to investigate leukocyte telomere length (LTL), oxidative stress, and kidney damage biomarkers in relation to kidney function. The study included 35 Fabry patients and 35 age and sex-matched control subjects. Based on the estimated slope of the glomerular filtration rate, the patients were divided into two groups. Relative LTL was quantified by qPCR, urinary biomarkers 8-hydroxy-2′-deoxyguanosine (8-OHdG) and malondialdehyde (MDA) by UHPLC-MS/MS, and kidney damage biomarkers by flow cytometry. There was no statistically significant difference in LTL between Fabry patients and controls. However, a significant difference was observed in male patients compared to their matched control subjects (p = 0.013). Oxidative stress biomarkers showed no differences between patients and controls, while significant differences were observed in urinary IGFBP7, EGF, and OPN levels between Fabry patients with stable kidney function and those with progressive nephropathy (FDR = 0.021, 0.002, and 0.013, respectively). Significant differences were also observed in plasma levels of cystatin C, TFF3, and uromodulin between patients with progressive nephropathy and controls (all FDR = 0.039). Along with these biomarkers (FDR = 0.007, 0.017, and 0.010, respectively), NGAL also exhibited a significant difference between the two patient groups (FDR = 0.017). This study indicates accelerated telomere attrition, which may be related to disease burden in males. Furthermore, analyses of urinary oxidative stress markers revealed no notable disparities between the different kidney function groups, indicating their limited utility. However, promising differences were found in some biomarkers of kidney damage in urine and plasma. Full article

(This article belongs to the Special Issue Kidney Injury Biomarkers: From Early Detection to Transition to Chronic Kidney Disease)

► Show Figures

Figure 1

12 pages, 2279 KB

Open AccessEditor’s ChoiceArticle

Lactoferrin-Derived Peptide Chimera Induces Caspase-Independent Cell Death in Multiple Myeloma

by Young-Saeng Jang, Shima Barati Dehkohneh, Jaewon Lim, Jaehui Kim, Donghwan Ahn, Sun Shim Choi and Seung Goo Kang

Cells 2025, 14(3), 217; https://doi.org/10.3390/cells14030217 - 3 Feb 2025

Viewed by 2523

Abstract

Lactoferrin-derived peptide chimera is a synthetic peptide that mimics the functional unit of lactoferrin with antibacterial activity. Although LF has anticancer effects, to the best of our knowledge, its effects on multiple myeloma have not yet been studied. We explored the potential of [...] Read more.

Lactoferrin-derived peptide chimera is a synthetic peptide that mimics the functional unit of lactoferrin with antibacterial activity. Although LF has anticancer effects, to the best of our knowledge, its effects on multiple myeloma have not yet been studied. We explored the potential of a lactoferrin-derived chimera for multiple myeloma treatment, a malignant clonal plasma cell bone marrow disease. The lactoferrin-derived chimera effectively inhibited MM1S, MM1R, and RPMI8226 multiple myeloma cell growth, and induced the early and late phases of apoptosis, but not in normal peripheral blood mononuclear cells. Furthermore, the lactoferrin-derived chimera modulates the relative expression of genes involved in survival, apoptosis, and mitochondrial dysfunction at the transcriptional level. Mitochondrial analysis revealed that lactoferrin-derived chimera triggered oxidative stress in multiple myeloma cells, leading to reactive oxygen species generation and a decline in mitochondrial membrane potential, resulting in mitochondrial dysfunction. Although lactoferrin-derived chimera did not cause caspase-dependent cell death, it induced nuclear translocation of apoptosis-inducing factor and endonuclease G, indicating the initiation of caspase-independent apoptosis. Overall, the lactoferrin-derived chimera induces caspase-independent programmed cell death in multiple myeloma cell lines by increasing the nuclear translocation of apoptosis-inducing factor/endonuclease G. Therefore, it has potential for multiple myeloma cancer therapies. Full article

(This article belongs to the Special Issue Focus on Machinery of Cell Death)

► Show Figures

Figure 1

34 pages, 14955 KB

Open AccessEditor’s ChoiceArticle

Early Synapse-Specific Alterations of Photoreceptor Mitochondria in the EAE Mouse Model of Multiple Sclerosis

by Dalia R. Ibrahim, Karin Schwarz, Shweta Suiwal, Sofia Maragkou and Frank Schmitz

Cells 2025, 14(3), 206; https://doi.org/10.3390/cells14030206 - 30 Jan 2025

Cited by 2 | Viewed by 3217

Abstract

Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system (CNS) linked to many neurological disabilities. The visual system is frequently impaired in MS. In previous studies, we observed early malfunctions of rod photoreceptor ribbon synapses in the EAE mouse [...] Read more.

Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system (CNS) linked to many neurological disabilities. The visual system is frequently impaired in MS. In previous studies, we observed early malfunctions of rod photoreceptor ribbon synapses in the EAE mouse model of MS that included alterations in synaptic vesicle cycling and disturbances of presynaptic Ca²⁺ homeostasis. Since these presynaptic events are highly energy-demanding, we analyzed whether synaptic mitochondria, which play a major role in synaptic energy metabolism, might be involved at that early stage. Rod photoreceptor presynaptic terminals contain a single large mitochondrion next to the synaptic ribbon. In the present study, we analyzed the expression of functionally relevant mitochondrial proteins (MIC60, ATP5B, COX1, PINK1, DRP1) by high-resolution qualitative and quantitative immunofluorescence microscopy, immunogold electron microscopy and quantitative Western blot experiments. We observed a decreased expression of many functionally relevant proteins in the synaptic mitochondria of EAE photoreceptors at an early stage, suggesting that early mitochondrial dysfunctions play an important role in the early synapse pathology. Interestingly, mitochondria in presynaptic photoreceptor terminals were strongly compromised in early EAE, whereas extra-synaptic mitochondria in photoreceptor inner segments remained unchanged, demonstrating a functional heterogeneity of photoreceptor mitochondria. Full article

(This article belongs to the Special Issue Mechanism of Cell Signaling during Eye Development and Diseases)

► Show Figures

Figure 1

18 pages, 3496 KB

Open AccessEditor’s ChoiceArticle

Heme-Oxygenase 1 Mediated Activation of Cyp3A11 Protects Against Non-Steroidal Pain Analgesics Induced Acute Liver Damage in Sickle Cell Disease Mice

by Ravi Vats, Ramakrishna Ungalara, Rikesh K. Dubey, Prithu Sundd and Tirthadipa Pradhan-Sundd

Cells 2025, 14(3), 194; https://doi.org/10.3390/cells14030194 - 28 Jan 2025

Cited by 1 | Viewed by 1847

Abstract

Pain constitutes a significant comorbidity associated with sickle cell disease (SCD). Analgesics serve as the primary method for pain management; however, the long-term effects of these drugs on the liver of SCD patients remain not completely understood. Using real-time intravital imaging, we analyzed [...] Read more.

Pain constitutes a significant comorbidity associated with sickle cell disease (SCD). Analgesics serve as the primary method for pain management; however, the long-term effects of these drugs on the liver of SCD patients remain not completely understood. Using real-time intravital imaging, we analyzed the effect of non-steroidal analgesics (NSA) in the liver of control and SS (SCD) mice. Remarkably, we found completely opposing effects in the liver of control and SS mice post-NSA treatment. Whereas SS mice were able to better tolerate the NSA treatment acutely compared to their littermate controls, in the long term, these mice showed delayed resolution of liver injury and exacerbated fibrosis compared to control mice. Mechanistically, we found that SS mice were protected from cytotoxicity caused by NSA at baseline due to the significant activation of hepatic Kupffer cells, which produced heme-oxygenase 1 (HO-1). HO-1 promoted the activation of the cytoprotective enzyme Cyp3A11, which inhibited hepatic damage caused by NSA. However, in the long term, depletion of hepatic Kupffer cells led to reduced expression of HO-1, which blocked the activation of Cyp3A11, resulting in fibrosis and a delay in the resolution of liver injury and inflammation. These preclinical data provide a strong proof-of-concept for HO-1 as well as Cyp3A11 as cytoprotectors against NSA-induced liver damage in the Townes model of SCD and support further development of these compounds as potential novel therapies for end-organ damage in SCD. Full article

(This article belongs to the Special Issue Sickle Cell Disease: Pathogenesis, Diagnosis and Treatment)

► Show Figures

Figure 1

23 pages, 4274 KB

Open AccessEditor’s ChoiceArticle

Investigation of the Roles of the Adenosine A(2A) and Metabotropic Glutamate Receptor Type 5 (mGlu5) Receptors in Prepulse Inhibition and CREB Signaling in a Heritable Rodent Model of Psychosis

by Anthony M. Cuozzo, Loren D. Peeters, Cristal D. Ahmed, Liza J. Wills, Justin T. Gass and Russell W. Brown

Cells 2025, 14(3), 182; https://doi.org/10.3390/cells14030182 - 24 Jan 2025

Cited by 2 | Viewed by 1574

Abstract

The metabotropic glutamate receptor type 5 (mGlu5) and adenosine A(2A) receptor form a mutually inhibitory heteromer with the dopamine D2 receptor, where the activation of either mGlu5 or A(2A) leads to reduced D2 signaling. This study investigated whether a mGlu5-positive allosteric modulator (PAM) [...] Read more.

The metabotropic glutamate receptor type 5 (mGlu5) and adenosine A(2A) receptor form a mutually inhibitory heteromer with the dopamine D2 receptor, where the activation of either mGlu5 or A(2A) leads to reduced D2 signaling. This study investigated whether a mGlu5-positive allosteric modulator (PAM) or an A(2A) agonist treatment could mitigate sensorimotor gating deficits and alter cyclic AMP response element-binding protein (CREB) levels in a rodent neonatal quinpirole (NQ) model of psychosis. F0 Sprague–Dawley rats were treated with neonatal saline or quinpirole (1 mg/kg) from postnatal day 1 to 21 and bred to produce an F1 generation. F1 offspring underwent prepulse inhibition (PPI) testing from postnatal day 44 to 48 to assess sensorimotor gating. The rats were treated with mGlu5 PAM 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) or A(2A) agonist CGS21680. Rats with at least one NQ-treated parent showed PPI deficits, which were alleviated by both CDPPB and CGS21680. Sex differences were noted across groups, with CGS21680 showing greater efficacy than CDPPB. Additionally, CREB levels were elevated in the nucleus accumbens (NAc), and both CDPPB and CGS21680 reduced CREB expression to control levels. These findings suggest that targeting the adenosinergic and glutamatergic systems alleviates sensorimotor gating deficits and abnormal CREB signaling, both of which are associated with psychosis. Full article

(This article belongs to the Special Issue Biological Mechanisms in the Treatment of Neuropsychiatric Diseases)

► Show Figures

Figure 1

23 pages, 1685 KB

Open AccessEditor’s ChoiceReview

Crosstalk Between Abiotic and Biotic Stresses Responses and the Role of Chloroplast Retrograde Signaling in the Cross-Tolerance Phenomena in Plants

by Muhammad Kamran, Paweł Burdiak and Stanisław Karpiński

Cells 2025, 14(3), 176; https://doi.org/10.3390/cells14030176 - 23 Jan 2025

Cited by 11 | Viewed by 3854

Abstract

In the natural environment, plants are simultaneously exposed to multivariable abiotic and biotic stresses. Typical abiotic stresses are changes in temperature, light intensity and quality, water stress (drought, flood), microelements availability, salinity, air pollutants, and others. Biotic stresses are caused by other organisms, [...] Read more.

In the natural environment, plants are simultaneously exposed to multivariable abiotic and biotic stresses. Typical abiotic stresses are changes in temperature, light intensity and quality, water stress (drought, flood), microelements availability, salinity, air pollutants, and others. Biotic stresses are caused by other organisms, such as pathogenic bacteria and viruses or parasites. This review presents the current state-of-the-art knowledge on programmed cell death in the cross-tolerance phenomena and its conditional molecular and physiological regulators, which simultaneously regulate plant acclimation, defense, and developmental responses. It highlights the role of the absorbed energy in excess and its dissipation as heat in the induction of the chloroplast retrograde phytohormonal, electrical, and reactive oxygen species signaling. It also discusses how systemic- and network-acquired acclimation and acquired systemic resistance are mutually regulated and demonstrates the role of non-photochemical quenching and the dissipation of absorbed energy in excess as heat in the cross-tolerance phenomenon. Finally, new evidence that plants evolved one molecular system to regulate cell death, acclimation, and cross-tolerance are presented and discussed. Full article

(This article belongs to the Section Cell Signaling)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Editor’s Choice Articles

Further Information

Guidelines

MDPI Initiatives

Follow MDPI