International Journal of Molecular Sciences

7 pages, 209 KiB

Open AccessEditorial

Transient Receptor Potential Channels in Physiology and Pathophysiology: Special Issue

by Mohammad Shahidullah and Paul J. Donaldson

Int. J. Mol. Sci. 2025, 26(10), 4960; https://doi.org/10.3390/ijms26104960 - 21 May 2025

Abstract

Since the discovery of the first family member by Cosens and Mannings over 50 years ago [...] Full article

(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology)

14 pages, 1794 KiB

Open AccessArticle

Activating Transcription Factor 3 (ATF3) Regulates Cellular Senescence and Osteoclastogenesis via STAT3/ERK and p65/AP-1 Pathways in Human Periodontal Ligament Cells

by Won-Jung Bae and Sang-Im Lee

Int. J. Mol. Sci. 2025, 26(10), 4959; https://doi.org/10.3390/ijms26104959 - 21 May 2025

Abstract

Oral cellular aging plays a critical role in the pathogenesis of chronic periodontitis and alveolar bone resorption. Although activating transcription factor 3 (ATF3) has been implicated as a senescence-associated factor, its specific role in periodontal ligament cell (PDLC) senescence remains unclear. Human PDLCs [...] Read more.

Oral cellular aging plays a critical role in the pathogenesis of chronic periodontitis and alveolar bone resorption. Although activating transcription factor 3 (ATF3) has been implicated as a senescence-associated factor, its specific role in periodontal ligament cell (PDLC) senescence remains unclear. Human PDLCs were exposed to lipopolysaccharide (LPS, 1 μg/mL) and nicotine (5 mM) for 3 days to induce senescence. ATF3 expression was silenced using siRNA. The expression of senescence-associated secretory phenotype (SASP) factors (IFNγ, IL6, IL8, TNFα, and IL1β) and the secretion of nitric oxide (NO) and prostaglandin E₂ (PGE₂) were assessed by RT-PCR and immunoassay. Conditioned media (CM) from these cells were applied to mouse bone marrow macrophages (BMMs) to evaluate osteoclast differentiation and bone resorption. In addition, key signaling pathways, including STAT3, ERK, NF-κB (p65), and AP-1, were investigated by Western blotting and immunofluorescence. ATF3 knockdown markedly reduced the LPS/nicotine-induced expression of SASP factors and decreased NO and PGE₂ levels. CM from ATF3-silenced PDLCs markedly inhibited osteoclast differentiation, as evidenced by reduced tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells and diminished bone resorption. Moreover, ATF3 inhibition led to a decreased RANKL/OPG ratio and attenuated the phosphorylation of STAT3 and ERK, along with the reduced nuclear translocation of p65 and AP-1 components. These findings suggest that ATF3 plays a critical role in mediating cellular senescence and osteoclastogenesis in PDLCs. Targeting ATF3 may represent a novel therapeutic strategy for managing age-related oral diseases, such as chronic periodontitis. Full article

(This article belongs to the Section Molecular Endocrinology and Metabolism)

19 pages, 6542 KiB

Open AccessArticle

Hydrochar from Carbon Quantum Dots (CQDs) Synthesis for Photocatalytic and Decontamination Applications in Presence of TiO₂

by Daniel López, Karol Zapata, Lilian D. Ramírez-Valencia, Esther Bailón-García, Francisco Carrasco-Marín, Agustín F. Pérez-Cadenas, Camilo A. Franco and Farid B. Cortés

Int. J. Mol. Sci. 2025, 26(10), 4958; https://doi.org/10.3390/ijms26104958 - 21 May 2025

Abstract

This research aimed to co-produce CQDs and hydrochar from natural sources to improve the photocatalytic properties of TiO₂. Juice extract from Citrus lemon fruits from south-eastern Spain was used as the carbon precursor. The synthesis strategy of the CQDs and hydrochar [...] Read more.

This research aimed to co-produce CQDs and hydrochar from natural sources to improve the photocatalytic properties of TiO₂. Juice extract from Citrus lemon fruits from south-eastern Spain was used as the carbon precursor. The synthesis strategy of the CQDs and hydrochar (Hc) was divided into different stages aimed at figuring out the role of the temperature (180, 220, 250 °C), the addition of TiO₂ nanoparticles, and the presence of N-/P-donor compounds (ethylenediamine and orto-phosphoric acid) in the photocatalytic properties of final composites. The results revealed that at 250 °C, using agro-carbon materials as Hc, and the addition of N-donor compounds, improved the photocatalytic activity and photodegradation rate of TiO₂ over methyl orange (MO) under blue light by 1000% and 2700%, respectively, with the parallel reduction of TiO₂ bandgap from 3.5 eV (Uv light) to 3.00 eV (visible light). These results are related to the ability of the carbon materials (electronegative) to enhance the formation of a Ti³⁺-active state. This study provides a landscape for a one-step method for the production of agro-carbon/TiO₂ photocatalysts with high activity under visible light as an efficient and sustainable strategy for applications such as energy generation and water purification under sunlight. Full article

(This article belongs to the Special Issue Recent Research of Nanomaterials in Molecular Science: 2nd Edition)

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16 pages, 1772 KiB

Open AccessArticle

Single Cell RNA Sequencing of Papillary Cancer Mesenchymal Stem/Stromal Cells Reveals a Transcriptional Profile That Supports a Role for These Cells in Cancer Progression

by Danny Jandu, Nani Latar, Artida Bajrami, Rachel Queen, Megan Hasoon, Matthew Teasdale, Rafiqul Hussain, Jonathan Coxhead, Sebastian Aspinall and Annette Meeson

Int. J. Mol. Sci. 2025, 26(10), 4957; https://doi.org/10.3390/ijms26104957 - 21 May 2025

Abstract

Papillary thyroid cancer (PTC) contains mesenchymal stem/stromal cells (MSCs), but their contribution to PTC progression is not clear. In this study, we compared the transcriptional signatures of normal thyroid (NT) and PTC-derived MSCs with the aim of determining if these have distinct transcriptomes [...] Read more.

Papillary thyroid cancer (PTC) contains mesenchymal stem/stromal cells (MSCs), but their contribution to PTC progression is not clear. In this study, we compared the transcriptional signatures of normal thyroid (NT) and PTC-derived MSCs with the aim of determining if these have distinct transcriptomes that might influence PTC progression. We used flow cytometry in combination with a panel of MSC clusters of differentiation (CD) markers and showed that both thyroid MSC populations expressed MSC markers and lacked expression of markers not normally expressed by MSCs. In addition, we determined that both MSC populations could differentiate to adipocytes and osteocytes. Analysis of single cell RNA sequencing data from both MSC populations revealed, regardless of tissue of origin, that both contained similar numbers of subpopulations. Cluster analysis revealed similarity in expression of both MSC populations for stromal markers, the vascular marker VEGFA and the smooth muscle marker CALD1, while smaller subpopulations expressed markers of more lineage-committed thyroid cells. PTC MSCs also showed upregulated expression of 28 genes, many of which are known to be involved in epithelial–mesenchymal transition (EMT) and/or disease progression in several types of cancers, including but not limited to breast cancer, gastric cancer, cervical carcinoma, bladder cancer and thyroid cancer. This included several members of the S100 and IGFBP gene families. Taken together, these data support a role for PTC MSCs in PTC progression. Full article

(This article belongs to the Special Issue Stem Cell Research: Discovering the Mechanistic Understanding for Therapeutic Application)

19 pages, 1973 KiB

Open AccessArticle

Characterization of Novel and Known Activators of Cannabinoid Receptor Subtype 2 Reveals Mixed Pharmacology That Differentiates Mycophenolate Mofetil and GW-842,166X from MDA7

by Alice L. Rodriguez, Aidong Qi, Allie Han, Haley E. Kling, Marc C. Quitalig, Aaron M. Bender, Lisa Barbaro, David Whomble, Craig W. Lindsley and Colleen M. Niswender

Int. J. Mol. Sci. 2025, 26(10), 4956; https://doi.org/10.3390/ijms26104956 - 21 May 2025

Abstract

CB₁ and CB₂ cannabinoid receptors are members of the GPCR superfamily that modulate the effects of endocannabinoids. CB₁ is the most abundant CB receptor in the central nervous system, while CB₂ is present both peripherally and in the brain. [...] Read more.

CB₁ and CB₂ cannabinoid receptors are members of the GPCR superfamily that modulate the effects of endocannabinoids. CB₁ is the most abundant CB receptor in the central nervous system, while CB₂ is present both peripherally and in the brain. CB₂ plays a role in inflammation, as well as neurodegenerative and psychiatric disorders. To identify new ligands for CB₂, we screened a library of FDA-approved drugs for activity at the receptor using a thallium flux assay, resulting in the discovery of the immunosuppressant mycophenolate mofetil as a potent, selective activator of CB₂. Further characterization of the compound confirmed agonist activity in a variety of complementary assays, including PI hydrolysis, cAMP inhibition, and β-arrestin recruitment. Radioligand binding assays established a non-competitive interaction with the site occupied by [³H]CP55,940. CB₂ agonists GW-842,166X and MDA7 were also profiled, revealing that GW-842,166X exhibits a similar activity profile to mycophenolate mofetil, whereas MDA7 presents a distinct profile. These differences provide insight into the complex CB₂ pharmacology impacting preclinical and clinical studies, and ultimately, new treatment strategies for brain disorders. Full article

(This article belongs to the Special Issue Molecular Advances on Cannabinoid and Endocannabinoid Research 2.0)

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26 pages, 571 KiB

Open AccessReview

RNA Modifications in Osteoarthritis: Epitranscriptomic Insights into Pathogenesis and Therapeutic Targets

by Shabnam Radbakhsh, Mehdi Najar, Makram Merimi, Mohamed Benderdour, Julio C. Fernandes, Johanne Martel-Pelletier, Jean-Pierre Pelletier and Hassan Fahmi

Int. J. Mol. Sci. 2025, 26(10), 4955; https://doi.org/10.3390/ijms26104955 - 21 May 2025

Abstract

Osteoarthritis (OA) is a chronic joint disorder characterized by progressive degeneration of articular cartilage, pain, synovial inflammation, and bone remodeling. Post-transcriptional RNA modifications, known as epitranscriptome, are a group of biochemical alterations in the primary RNA transcript that might influence RNA structure, stability, [...] Read more.

Osteoarthritis (OA) is a chronic joint disorder characterized by progressive degeneration of articular cartilage, pain, synovial inflammation, and bone remodeling. Post-transcriptional RNA modifications, known as epitranscriptome, are a group of biochemical alterations in the primary RNA transcript that might influence RNA structure, stability, and function. Different kinds of RNA modifications have been recognized, such as methylation, acetylation, pseudouridylation, and phosphorylation. N6-methyladenosine (m6A), 5-methylcytosine (m5C), N7-methylguanosine (m7G), 2′-O-ribose methylation (2′-O-Me), and pseudouridylation (Ψ) are the most prevalent RNA modifications. Recent studies have shown that disruption in these modifications can interfere with gene expression and protein function. Here, we will review all types of RNA modifications and how they contribute to the onset and progression of OA. To the best of our knowledge, this is the first review comprehensively addressing all epitranscriptomic modifications in OA. Full article

(This article belongs to the Special Issue Highlights in Pathophysiology of the Musculoskeletal System, 2nd Edition)

16 pages, 3224 KiB

Open AccessArticle

The OsNAC25 Transcription Factor Enhances Drought Tolerance in Rice

by Aohuan Yang, Qiong Luo, Lei Liu, Meihe Jiang, Fankai Zhao, Yingjiang Li and Bohan Liu

Int. J. Mol. Sci. 2025, 26(10), 4954; https://doi.org/10.3390/ijms26104954 - 21 May 2025

Abstract

Drought represents a prevalent abiotic stress in terrestrial plants, frequently impairing crop growth and yield. In this paper, we characterized the functional role of OsNAC25, a member of the NAC transcription factor family, in drought tolerance. OsNAC25 was predominantly localized in both [...] Read more.

Drought represents a prevalent abiotic stress in terrestrial plants, frequently impairing crop growth and yield. In this paper, we characterized the functional role of OsNAC25, a member of the NAC transcription factor family, in drought tolerance. OsNAC25 was predominantly localized in both the cytoplasm and nucleus, with its expression being markedly induced under drought conditions. Under severe drought stress, the overexpression of OsNAC25 rice exhibited decreased malondialdehyde (MDA) levels, attenuated oxidative damage, and improved survival rate during the vegetative growth stage. The transcriptome analysis revealed that OsNAC25 coordinates drought response through key pathways associated with phenylpropanoid biosynthesis, plant hormone signal transduction, and diterpenoid biosynthesis. Collectively, our findings highlight OsNAC25 as a pivotal transcriptional regulator governing drought resistance in rice. This study not only provides a candidate gene for improving drought tolerance in rice but also offers valuable insights into the molecular mechanisms underlying drought adaptation in cereal crops. Full article

(This article belongs to the Special Issue Emerging Insights into Phytohormone Signaling in Plants)

23 pages, 4852 KiB

Open AccessArticle

Integrative Analysis of Immune- and Metabolism-Related Genes Identifies Robust Prognostic Signature and PYCR1 as a Carcinogenic Regulator in Clear Cell Renal Cell Carcinoma

by Guo Zhao, Jiatong Ding, Jiaxiu Ma, Yale Jiang, Yuning Wang, Shuhang Wang and Ning Li

Int. J. Mol. Sci. 2025, 26(10), 4953; https://doi.org/10.3390/ijms26104953 - 21 May 2025

Abstract

Clear cell renal cell carcinoma (ccRCC) is distinguished by metabolic irregularities and unique immunological profiles. Nevertheless, the comprehensive examination of immune and metabolic attributes within the tumor microenvironment of ccRCC remains inadequately elucidated. In this study, we identified two distinct molecular subtypes (C1 [...] Read more.

Clear cell renal cell carcinoma (ccRCC) is distinguished by metabolic irregularities and unique immunological profiles. Nevertheless, the comprehensive examination of immune and metabolic attributes within the tumor microenvironment of ccRCC remains inadequately elucidated. In this study, we identified two distinct molecular subtypes (C1 and C2) of ccRCC using the non-negative matrix factorization (NMF) algorithm. Utilizing univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analyses, we developed a prognostic signature comprising eight immune- and metabolism-related genes (IMRGs) associated with the tumor microenvironment. The validation of this signature was performed using both testing and entire datasets. A nomogram was developed using IMRGs prognostic signature and various clinical parameters, including age and TNM stage. We also performed the in vitro experiments to validate the carcinogenic role of PYCR1 in ccRCC cells. Subtype C1 exhibited a more favorable prognosis and higher levels of immune cell infiltration compared to subtype C2. The AUCs of the nomogram at 1-, 3-, and 5-year intervals (AUC = 0.874, 0.820, and 0.794) were slightly higher than those of the IMRGs signature alone (AUC = 0.773, 0.755, and 0.764). The association between risk score and immune checkpoint expressions, immunophenoscore (IPS), and microsatellite instability (MSI) collectively predicted treatment efficacy accurately. Additionally, in vitro experiments confirmed the involvement of PYCR1 in promoting the aggressive behaviors of ccRCC cells, as evidenced by reduced proliferation, invasion, and enhanced apoptosis upon PYCR1 knockdown. In conclusion, the IMRGs signature shows promise in predicting prognostic risk, assessing the effectiveness of immunotherapy, and tailoring treatment for ccRCC patients. Full article

(This article belongs to the Special Issue A Molecular Perspective on the Genetics of Kidney Diseases)

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17 pages, 3477 KiB

Open AccessArticle

A Combination of Resveratrol and Quercetin Prevents Sarcopenic Obesity: Its Role as a Signaling Inhibitor of Myostatin/ActRIIA and ActRIIB/Smad and as an Enhancer of Insulin Actions

by Agustina Cano-Martínez, Jimena Alejandra Méndez-Castro, Viviana Estefanía García-Vázquez, Elizabeth Carreón-Torres, Eulises Díaz-Díaz, María Sánchez-Aguilar, Vicente Castrejón-Téllez and María Esther Rubio-Ruíz

Int. J. Mol. Sci. 2025, 26(10), 4952; https://doi.org/10.3390/ijms26104952 - 21 May 2025

Abstract

Sarcopenic obesity (SO), characterized by an excess of fat and a decrease in muscle strength or mass, is a global public health concern and is linked to metabolic conditions such as metabolic syndrome (MetS). Different mechanisms contribute to SO, such as inflammation, fatty [...] Read more.

Sarcopenic obesity (SO), characterized by an excess of fat and a decrease in muscle strength or mass, is a global public health concern and is linked to metabolic conditions such as metabolic syndrome (MetS). Different mechanisms contribute to SO, such as inflammation, fatty acid infiltration, and insulin resistance (IR). Recently, myostatin (MYOST), an inhibitory factor for skeletal muscle tissue, was proposed as an aimed compound for the treatment of conditions of muscular metabolic imbalance mass and MetS. On the other hand, a therapy with natural compounds such as resveratrol (R) and quercetin (Q) is effective for the treatment of MetS, but its effect on the MYOST pathway has been poorly explored. The control group received water, and the MetS group received 30% commercial sugar in the drinking water for 6 months. Polyphenol mix (R at a dose of 50 mg/kg/day and Q at 0.95 mg/kg/day) was administered for 1 month. MetS rats present SO linked to an increase in the expression of MYOST/ActRIIA and ActRIIB (p < 0.0001). R+Q treatment prevented SO by lowering the expression of MYOST and its receptors and increased the expression of Smad 7 in MetS rats (p < 0.0001). Moreover, the polyphenol treatment reverted IR by increasing Akt phosphorylation, leading to an increase in muscle mass. It decreased lipid stores, restored glycogen accumulation, and increased myosin expression (p < 0.0001). The results of this work indicate that R+Q supplementation could be a promising therapeutic agent to prevent SO and sarcopenia derived from other metabolic alterations. Full article

(This article belongs to the Special Issue The Structures, Syntheses of Natural Products, and Their Biological Effects)

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18 pages, 2479 KiB

Open AccessArticle

Controlled Exit from the G2/M Checkpoint in RPE-1 Cells Using RO3306: Enrichment of Phase-Specific Cell Populations for In-Depth Analyses of Mitotic Events

by Teresa Anglada, Núria Pulido-Artola, Marina Rodriguez-Muñoz and Anna Genesca

Int. J. Mol. Sci. 2025, 26(10), 4951; https://doi.org/10.3390/ijms26104951 - 21 May 2025

Abstract

Studying the cell cycle is essential for understanding the molecular mechanisms that regulate cell division, growth, and differentiation in living organisms. However, mitosis constitutes only a brief phase of the overall cell cycle, making its analysis challenging in asynchronous cell populations due to [...] Read more.

Studying the cell cycle is essential for understanding the molecular mechanisms that regulate cell division, growth, and differentiation in living organisms. However, mitosis constitutes only a brief phase of the overall cell cycle, making its analysis challenging in asynchronous cell populations due to its transient and dynamic nature. Cell synchronization methods help to enrich populations at specific cell cycle stages, including mitosis, typically by using chemical inhibitors to arrest cells at defined checkpoints. However, many existing protocols rely on combinations of inhibitors that interfere with normal mitotic progression, disrupting dynamics and causing side effects such as chromosome non-disjunction or lagging chromosomes, which limit their applicability. In this study, we present an RO3306 block-and-release strategy to selectively enrich cell populations at defined mitotic stages without compromising cell viability or disrupting their progression to mitotic exit. This approach provides a reliable method for studying mitotic events with high temporal resolution. Furthermore, by preserving mitotic integrity, it offers a valuable framework for investigating the molecular mechanisms of cell division and the processes driving genomic instability in human cells. Full article

(This article belongs to the Special Issue Cell Division: A Focus on Molecular Mechanisms)

17 pages, 601 KiB

Open AccessArticle

Disease Activity-Dependent Siglec-1 Expression on Monocyte Subsets of Patients with Idiopathic Inflammatory Myopathies

by Sándor Baráth, Melinda Nagy-Vincze, Zsuzsanna Kun, Dorottya Szinay, Zoltán Griger, Jr., Tibor Gábor Béldi, Katalin Szabó, Marianna Száraz-Széles, Zsuzsanna Hevessy and Zoltán Griger

Int. J. Mol. Sci. 2025, 26(10), 4950; https://doi.org/10.3390/ijms26104950 - 21 May 2025

Abstract

Interferon signature is one of the key pathogenic pathways in idiopathic inflammatory myopathies (IIMs), particularly in dermatomyositis (DM). The aim of this study was to analyze Siglec-1, an interferon-inducible receptor, on different monocyte subsets in IIM subtypes and investigate its association with disease [...] Read more.

Interferon signature is one of the key pathogenic pathways in idiopathic inflammatory myopathies (IIMs), particularly in dermatomyositis (DM). The aim of this study was to analyze Siglec-1, an interferon-inducible receptor, on different monocyte subsets in IIM subtypes and investigate its association with disease activity measures. Siglec-1 expression was measured by 8-color flow cytometry in 62 IIM patients and 10 healthy controls (HC). Disease activity was assessed using the International Myositis Assessment and Clinical Studies (IMACS) core set measures. Active DM patients exhibited significantly higher Siglec-1 mean fluorescence intensity (MFI) compared to inactive subgroups and HCs in every monocyte subset. Intermediate monocytes displayed the highest Siglec-1 expression across all groups and the strongest associations between disease activity markers. Siglec-1 expression on monocyte subsets was strongly associated with global, extramuscular global, constitutional, cutaneous, muscular, and gastrointestinal activity measures, but not with pulmonary, skeletal, and cardiac activities in the DM population. The best indicator of DM global disease activity among the examined biomarkers was Siglec-1 MFI on intermediate monocytes. Siglec-1 on intermediate monocytes correlates strongly with organ-specific clinical and biochemical markers of disease activity; therefore, it is a candidate biomarker for monitoring IIM disease activity. Siglec-1 could be useful in patient selection for interferon-targeted treatments. Full article

(This article belongs to the Special Issue Highlights in Pathophysiology of the Musculoskeletal System, 2nd Edition)

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23 pages, 3751 KiB

Open AccessArticle

Biopolymers of Polycaprolactone Loaded with Caffeic Acid and Trametes versicolor Extract Induced Proliferation in Human Coronary Artery Endothelial Cells and Inhibited Platelet Activity

by Diego Fernando Gualtero, Diana Marcela Buitrago, Ana Delia Pinzón-García, Willy Fernando Cely Veloza, Leydy Tatiana Figueroa-Ariza, Santiago Torres-Morales, Juan David Rodriguez-Navarrete, Victor Junior Jimenez and Gloria Inés Lafaurie

Int. J. Mol. Sci. 2025, 26(10), 4949; https://doi.org/10.3390/ijms26104949 (registering DOI) - 21 May 2025

Abstract

In atherosclerosis, the proliferation and migration of endothelial and smooth muscle cells (SMCs) and platelet activation alter endothelial function. Naturally occurring substances, such as caffeic acid (CA) and Trametes versicolor extract (TvE), have medicinal properties and are traditionally used for their antiproliferative, antioxidant, [...] Read more.

In atherosclerosis, the proliferation and migration of endothelial and smooth muscle cells (SMCs) and platelet activation alter endothelial function. Naturally occurring substances, such as caffeic acid (CA) and Trametes versicolor extract (TvE), have medicinal properties and are traditionally used for their antiproliferative, antioxidant, and anti-inflammatory effects. Electrospun 5% and 8% polycaprolactone-loaded CA or TvE was developed as a delivery system. Cytocompatibility was evaluated using human coronary artery endothelial cells (HCAECs), coronary artery SMCs (CASMCs), and platelets. Three types of systems (µF-CA, µF-TvE, and µF-CA/TvE) were developed and microscopically characterized. Analysis with scanning electron microscopy showed multidirectional fibers with diameters of 2–4.5 μm. The µF systems were hydrophobic and low cellular adhesion. The viability of CASMCs decreased with microfibers of 8% PCL and high CA concentration. However, the viability of CASMCs and HCAECs improved with 5% PCL and low CA concentration. Treatment with µF-TvE and µF-CA/TvE increased cell viability. HCAEC proliferation was affected by µF-CA, but incorporating TvE improved it. Platelet viability was unaffected by any µF system, but µF-CA and µF-CA/TvE inhibited the activation and adhesion of platelets. The results suggest that microfibers loaded with CA and TvE play a dual role in modifying HCAEC proliferation and blocking human platelet activation and adhesion. These findings have the potential to mitigate the atherosclerotic process. Full article

(This article belongs to the Special Issue Research on Bio-Scaffold for Tissue Engineering)

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28 pages, 13126 KiB

Open AccessArticle

CoupleMDA: Metapath-Induced Structural-Semantic Coupling Network for miRNA-Disease Association Prediction

by Zhuojian Li, Guanxing Chen, Guang Tan and Calvin Yu-Chian Chen

Int. J. Mol. Sci. 2025, 26(10), 4948; https://doi.org/10.3390/ijms26104948 - 21 May 2025

Abstract

The prediction of microRNA-disease associations (MDAs) is crucial for understanding disease mechanisms and biomarker discovery. While graph neural networks have emerged as promising tools for MDA prediction, existing methods face critical limitations: (1) data leakage caused by improper use of Gaussian interaction profile [...] Read more.

The prediction of microRNA-disease associations (MDAs) is crucial for understanding disease mechanisms and biomarker discovery. While graph neural networks have emerged as promising tools for MDA prediction, existing methods face critical limitations: (1) data leakage caused by improper use of Gaussian interaction profile (GIP) kernel similarity during feature construction, (2) self-validation loops in calculating miRNA functional similarity using known MDA data, and (3) information bottlenecks in conventional graph neural network (GNN) architectures that flatten heterogeneous relationships and employ over-simplified decoders. To address these challenges, we propose CoupleMDA, a metapath-guided heterogeneous graph learning framework coupling structural and semantic features. The model constructs a biological heterogeneous network using independent data sources to eliminate feature-target space coupling. Our framework implements a two-stage encoding strategy: (1) relational graph convolutional networks (RGCN) for pre-encoding and (2) metapath-guided semantic aggregation for secondary encoding. During decoding, common metapaths between node pairs structurally guide feature pooling, mitigating information bottlenecks. The comprehensive evaluation shows that CoupleMDA achieves a 2–5% performance improvement over the current state-of-the-art baseline methods in the heterogeneous graph link prediction task. Ablation studies confirm the necessity of each proposed component, while case analyses reveal the framework’s capability to recover cancer-related miRNA-disease associations through biologically interpretable metapaths. Full article

(This article belongs to the Section Molecular Informatics)

22 pages, 5577 KiB

Open AccessArticle

Activation of the NALP3-CASP1-IL-1 β Inflammatory Pathway by Pesticide Exposure in Human Umbilical Vein Endothelial Cells

by Antonella Mazzone, Ylenia Della Rocca, Federica Flamminii, Simone Guarnieri, Dainelys Guadarrama Bello, Antonio Nanci, Oriana Trubiani, Francesca Diomede and Jacopo Pizzicannella

Int. J. Mol. Sci. 2025, 26(10), 4947; https://doi.org/10.3390/ijms26104947 - 21 May 2025

Abstract

Barrier function regulation, angiogenic potential, and immune response modulation are only a few of the many roles of the vascular system that nowadays represent one of the main targets for environmental pollutants, in particular, pesticides. We have used human umbilical vein endothelial cells [...] Read more.

Barrier function regulation, angiogenic potential, and immune response modulation are only a few of the many roles of the vascular system that nowadays represent one of the main targets for environmental pollutants, in particular, pesticides. We have used human umbilical vein endothelial cells (HUVECs) as an in vitro model to investigate the effects of pesticides on the activation of the NALP3-CASP1-IL-1β inflammatory pathway using real time PCR (RT-PCR) and immunofluorescence investigations, reactive oxygen species (ROS) generation, and morphological alterations with scanning electron microscopy (SEM) analysis. Our findings offer a comprehensive evaluation of the cellular and molecular damage induced by pesticide exposure and show strong inflammasome activation. They indicate that these chemicals may initiate necroptosis and drive prolonged inflammation in endothelial cells. This study provides crucial insights into how pesticides contribute to endothelial dysfunction, highlighting the need for further investigation into their inflammatory and immune-modulatory effects on vascular health. Full article

(This article belongs to the Special Issue Pesticide Exposure and Toxicity: 2nd Edition)

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23 pages, 2481 KiB

Open AccessArticle

A New Method of Canine CD4⁺ T Lymphocyte Differentiation Towards the Th17 Phenotype with Analysis of Properties and Mitochondrial Activity

by Iwona Monika Szopa, Kinga Majchrzak-Kuligowska, Rafał Pingwara, Marek Kulka, Monika Taşdemir and Małgorzata Gajewska

Int. J. Mol. Sci. 2025, 26(10), 4946; https://doi.org/10.3390/ijms26104946 - 21 May 2025

Abstract

Th17 lymphocytes are a distinct subpopulation of T cells that are characterized by the production of interleukins IL-17, IL-21, IL-22, and IL-26, and high expression of RORγt. These cells play an important role in inflammation and autoimmune diseases. Recent studies using rodent and [...] Read more.

Th17 lymphocytes are a distinct subpopulation of T cells that are characterized by the production of interleukins IL-17, IL-21, IL-22, and IL-26, and high expression of RORγt. These cells play an important role in inflammation and autoimmune diseases. Recent studies using rodent and human models have also highlighted their promising properties as agents in cellular immunotherapy for cancer. However, much less is known about the properties of canine Th17 lymphocytes, despite the domestic dog being an important model used in comparative medicine. In this study, we developed methods of activation and differentiation of canine CD4⁺ T lymphocytes towards the Th17 phenotype. Additionally, we targeted the Wnt/β-catenin signaling pathway to modulate the efficiency of Th17 cells differentiation. CD4⁺ T cells were successfully activated with magnetic EpoxyBeads, and in combination with the appropriate programming medium, they acquired the Th17 phenotype. Furthermore, indomethacin, an inhibitor of the Wnt/β-catenin pathway, significantly increased the efficiency of differentiation, causing elevated production of IL-17 and changed T cell metabolism by promoting oxidative phosphorylation. The protocol elaborated in our study provides an efficient method of canine Th17 lymphocyte differentiation. Our findings also suggested that the modification of the Wnt/β-catenin signaling pathway could be a valuable strategy for optimizing canine Th17 cell differentiation and advancing cell-based immunotherapy. Full article

(This article belongs to the Special Issue Regulation and Activation of Immune Cells through the Mitochondria)

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12 pages, 1212 KiB

Open AccessArticle

Human Herpes Virus Genotype and Immunological Gene Expression Profile in Prostate Cancer with Prominent Inflammation

by Elena Todorova, Anita Kavrakova, Goran Derimachkovski, Bilyana Georgieva, Feodor Odzhakov, Svitlana Bachurska, Ivan Terziev, Maria-Elena Boyadzhieva, Trifon Valkov, Elenko Popov, Chavdar Slavov, Ivan Tourtourikov, Vanyo Mitev and Albena Todorova

Int. J. Mol. Sci. 2025, 26(10), 4945; https://doi.org/10.3390/ijms26104945 - 21 May 2025

Abstract

We aim to investigate the role of the Herpesviridae family (HHV) in the onset and progression of prostate cancer (PCa) and to profile the local PCa immunological status. A total of 116 “tru-cut” biopsies (58 PCa and 58 benign prostatic hyperplasia [...] Read more.

We aim to investigate the role of the Herpesviridae family (HHV) in the onset and progression of prostate cancer (PCa) and to profile the local PCa immunological status. A total of 116 “tru-cut” biopsies (58 PCa and 58 benign prostatic hyperplasia [BPH]) and 49 formalin-fixed paraffin-embedded (FFPE) instances of PCa were analysed using real-time qPCR and histological examination. Infection with CMV, EBV, HHV6, and HHV7 was detected in 11.5% of the “tru-cut” biopsies (25.9% in BPH and 6.9% in the PCa group). In the formalin-fixed paraffin-embedded (FFPE) samples, infection was detected in 69.4% of the patients, with individual rates of EBV (47%), HHV6 (38%), HHV7 (41%), CMV (2.9%), HSV2 (2.9%), and VZV (5.8%). In the HHV-infected PCa cases, the histopathological landscape included intratumor lymphocyte infiltration with fibrosis and necrosis, periductal chronic inflammatory reaction and granulomatous lesions with foci of abscesses and necrosis, as well as inflammatory infiltration, chronic lymphadenitis, prostatic intraepithelial atrophy (PIA), and high-grade prostatic intraepithelial neoplasia (HGPIN). The majority of HHV-infected PCa patients were predominantly classified as grade G3/G4/G5 tumours, exhibiting perineural, perivascular, and lymphovascular invasion, seminal vesicle invasion, senile vesicle amyloidosis, and lymph node metastasis. Statistical analysis demonstrated a significant association between HHV infection and PCa (χ² ≈ 20.3, df = 1, p < 0.0001; Fisher’s exact test, p < 0.0001) with an odds ratio of 6.50 (95% CI: 2.80–15.12). These findings suggest that long-term HHV infection could contribute to a complicated and potentially altered immune PCa tumour environment due to inflammation. This may serve as a predictor of aggressive disease progression. Full article

(This article belongs to the Special Issue Molecular Diagnostic and Treatment Methods in Socially Significant Diseases in Urology)

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30 pages, 2611 KiB

Open AccessArticle

Cannabidiolic Acid Rescues Deficits in Hippocampal Long-Term Potentiation in Models of Alzheimer’s Disease: An Electrophysiological and Proteomic Analysis

by Beatriz Gil, Mairead Sullivan, Caitriona Scaife, Jeffrey C. Glennon and Caroline Herron

Int. J. Mol. Sci. 2025, 26(10), 4944; https://doi.org/10.3390/ijms26104944 - 21 May 2025

Abstract

In this study, we have examined the neuroprotective effects of cannabidiolic acid (CBDA) in models of Alzheimer’s disease (AD). We used in vitro electrophysiological recording in hippocampal slices and performed proteomic analysis of cortical tissue from APP_swe/PS1dE9 (APP/PS1) mice. In wild-type [...] Read more.

In this study, we have examined the neuroprotective effects of cannabidiolic acid (CBDA) in models of Alzheimer’s disease (AD). We used in vitro electrophysiological recording in hippocampal slices and performed proteomic analysis of cortical tissue from APP_swe/PS1dE9 (APP/PS1) mice. In wild-type (WT) slices from C57BL6 mice, acute treatment with CBDA (10 mM) did not alter levels of hippocampal long-term potentiation (LTP); however, it did reverse the attenuation of LTP produced by acute beta amyloid peptide (Aβ₄₂). We also examined the effects of CBDA or vehicle in APP/PS1 mice and WT littermates over a 5-week period at 8 months. LTP levels recorded in slices from WT mice treated with CBDA at 1, 10, or 30 mg/kg (IP) or vehicle were similar. LTP was attenuated in slices from vehicle-treated APP/PS1 compared to vehicle-treated WT mice, while treatment of APP/PS1 mice with all doses of CBDA reversed the deficits in LTP. There was also a deficit in paired-pulse facilitation (PPF) in vehicle-treated APP/PS1 compared to WT, indicating altered synaptic function and transmitter release; this was reversed in slices from CBDA-treated APP/PS1 mice. Levels of cortical soluble Aβ₄₂ were similar across CBDA- and vehicle-treated groups; however, the level of aggregated Aβ₄₂ was decreased in the CBDA-treated group. Proteomic analysis of cortical tissue from APP/PS1 cortex compared to WT revealed alterations in protein expression, with pathway enrichment analyses suggesting implicated canonical pathways, including mitochondrial dysfunction, protein sorting, and synaptogenesis; all were significantly improved by CBDA treatment. These changes likely facilitate the improvement in synaptic transmission and LTP we observed following CBDA treatment in APP/PS1 mice. This research suggests that CBDA should be considered a novel therapy for AD. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Alzheimer’s Disease)

20 pages, 11718 KiB

Open AccessArticle

Transcriptome Sequencing and Metabolite Analysis Revealed the Single and Combined Effects of Microplastics and Di-(2-ethylhexyl) Phthalate on Mouse Liver

by Jiabin Zhang, Yangcheng Li, Yihan Wang, Zeyu Li, Xiaolei Li, Hongxia Bao, Jiakui Li and Donghai Zhou

Int. J. Mol. Sci. 2025, 26(10), 4943; https://doi.org/10.3390/ijms26104943 - 21 May 2025

Abstract

The widespread use of plastics has led to a substantial increase in plastic waste, resulting in the dissemination of plastic debris throughout ecosystems and posing significant threats to biota. Bis(2-ethylhexyl) phthalate (DEHP), a commonly used plasticizer, enhances plastic flexibility but may also exert [...] Read more.

The widespread use of plastics has led to a substantial increase in plastic waste, resulting in the dissemination of plastic debris throughout ecosystems and posing significant threats to biota. Bis(2-ethylhexyl) phthalate (DEHP), a commonly used plasticizer, enhances plastic flexibility but may also exert subtle toxic effects. This study aimed to investigate the potential toxicological impacts and underlying mechanisms of microplastics (MPs), di-(2-ethylhexyl) phthalate (DEHP), and their combined exposure (MPs + DEHP) on oxidative stress, apoptotic damage, transcriptomic alterations, and metabolic disturbances in mice. The results demonstrated that exposure to MPs, DEHP, and MPs + DEHP impaired the antioxidant defense system and reduced overall antioxidant capacity. Concurrently, all three exposure conditions significantly increased biochemical markers, particularly those associated with liver dysfunction, prompting further analysis of hepatic tissues. Histopathological examination revealed apoptotic damage in hepatocytes. Integrated transcriptomic and metabolomic analyses indicated that exposure to MPs, DEHP, and MPs + DEHP disrupted carbohydrate, amino acid, and lipid metabolism, induced the expression of genes related to hepatocarcinogenesis, and impaired purine metabolism. Moreover, MP and DEHP exposure aggravated hepatic apoptosis and inflammatory responses via activation of the PI3K/AKT signaling pathway, thereby eliciting notable biotoxic effects. These findings provide new scientific evidence regarding the individual and combined toxicological effects of MPs and the plastic additive DEHP on living organisms. Full article

(This article belongs to the Section Molecular Endocrinology and Metabolism)

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19 pages, 2883 KiB

Open AccessArticle

Back to the Wastes: The Potential of Agri-Food Residues for Extracting Valuable Plant Cell Wall Polysaccharides

by Susana Saez-Aguayo, Dayan Sanhueza, Paloma Fuenzalida, María Paz Covarrubias, Michael Handford, Raúl Herrera and María Alejandra Moya-León

Int. J. Mol. Sci. 2025, 26(10), 4942; https://doi.org/10.3390/ijms26104942 - 21 May 2025

Abstract

The agro-industrial sector generates large volumes of fruit waste each year, leading to environmental concerns and sustainability challenges. In this study, we evaluate the potential of fruit residues—apple, pear, blueberry, tomato, papaya, and a mixed fruit juice blend—as alternative sources of high-value polysaccharides, [...] Read more.

The agro-industrial sector generates large volumes of fruit waste each year, leading to environmental concerns and sustainability challenges. In this study, we evaluate the potential of fruit residues—apple, pear, blueberry, tomato, papaya, and a mixed fruit juice blend—as alternative sources of high-value polysaccharides, including pectins, hemicelluloses, and cellulose. Additionally, white strawberry, included as a reference from fresh fruit rather than agro-industrial waste, was analyzed to expand the comparative framework. These biopolymers, naturally derived from the plant cell wall, are renewable and biodegradable, and they possess physicochemical properties suitable for applications in food, pharmaceutical, cosmetic, textile, and bioenergy industries. Using a combination of cell wall fractionation, biochemical characterization, and immunodetection of specific structural domains, we identified significant variability in polysaccharide composition and structure among the samples. Blueberry, pear, and apple residues showed high levels of rhamnogalacturonan-I (RG-I) with extensive branching, while variations in rhamnogalacturonan-II (RG-II) dimerization and the degree of methylesterification of homogalacturonan were also observed. These structural differences are key to determining the gelling properties and functional potential of pectins. In the hemicellulose fractions, xylans and xyloglucans with distinct substitution patterns were especially abundant in apple and pear waste. Our findings demonstrate that fruit processing waste holds significant promise as a sustainable source of structurally diverse polysaccharides. These results support the reintegration of agro-industrial residues into production chains and emphasize the need for environmentally friendly extraction methods to enable industrial recovery and application. Overall, this study contributes to advancing a circular bioeconomy by transforming underutilized plant waste into valuable functional materials. Full article

(This article belongs to the Special Issue The Plant Cell Wall: Structural Dynamics, Functions, and Future Innovations)

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