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Volume 26
Issue 19
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Int. J. Mol. Sci., Volume 26, Issue 19 (October-1 2025) – 576 articles

Cover Story (view full-size image): Recent investigations have highlighted the therapeutic potential of curcumin, a polyphenolic compound from Curcuma longa, in acute myeloid leukemia (AML). Curcumin exerts anti-tumor effects by modulating key signaling pathways, including NF-κB, STAT3, and MAPK, leading to apoptosis induction, inhibition of proliferation, and regulation of angiogenesis. Despite its promise as an adjunctive agent in AML treatment, curcumin’s clinical utility is hindered by poor bioavailability—a limitation currently being addressed through advanced nanoformulation strategies aimed at improving its stability and absorption. View this paper
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10 pages, 1722 KB  
Communication
Antiproliferative and Proapoptotic Effects of Chetomin in Human Melanoma Cells
by Laura Jonderko and Anna Choromańska
Int. J. Mol. Sci. 2025, 26(19), 9835; https://doi.org/10.3390/ijms26199835 - 9 Oct 2025
Viewed by 485
Abstract
Melanoma is an aggressive malignancy with poor prognosis in advanced stages, and current therapeutic options provide only limited benefits, highlighting the need for novel treatments. Chetomin, a fungal metabolite isolated from Chaetomium cochliodes, has been reported to exhibit diverse biological activities, yet [...] Read more.
Melanoma is an aggressive malignancy with poor prognosis in advanced stages, and current therapeutic options provide only limited benefits, highlighting the need for novel treatments. Chetomin, a fungal metabolite isolated from Chaetomium cochliodes, has been reported to exhibit diverse biological activities, yet its effects on melanoma cells remain poorly understood. In this study, we evaluated the antitumor potential of chetomin using the human A375 melanoma cell line. Cell viability was assessed with MTT and CellTiter-Glo® assays, which revealed a significant dose- and time-dependent reduction in proliferation following chetomin exposure. Apoptotic effects were confirmed through Annexin V staining, and immunocytochemical analysis demonstrated a concentration-dependent increase in cleaved PARP1, indicating activation of programmed cell death pathways. Collectively, these findings demonstrate that chetomin effectively inhibits melanoma cell growth and promotes apoptosis. The results suggest that chetomin represents a promising lead compound for melanoma therapy, warranting further investigation into its precise molecular mechanisms. Full article
(This article belongs to the Special Issue Innovative Strategies in the Design and Development of Anticancer Agents)
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13 pages, 1238 KB  
Article
CTCF Mediates the Cis-Regulatory Hubs in Mouse Hearts
by Mick Lee, Loïc Mangnier, Cory C. Padilla, Dominic Paul Lee, Wilson Tan, Wen Hao Zheng, Louis Hanqiang Gan, Ching Kit Chen, Yee Phong Lim, Rina Miao Qin Wang, Peter Yiqing Li, Yonglin Zhu, Steve Bilodeau, Alexandre Bureau, Roger Sik-Yin Foo and Chukwuemeka George Anene-Nzelu
Int. J. Mol. Sci. 2025, 26(19), 9834; https://doi.org/10.3390/ijms26199834 - 9 Oct 2025
Viewed by 525
Abstract
The 3D chromatin architecture establishes a complex network of genes and regulatory elements necessary for transcriptomic regulation in development and disease. This network can be modeled by cis-regulatory hubs (CRH), which underscore the local functional interactions between enhancers and promoter regions and differ [...] Read more.
The 3D chromatin architecture establishes a complex network of genes and regulatory elements necessary for transcriptomic regulation in development and disease. This network can be modeled by cis-regulatory hubs (CRH), which underscore the local functional interactions between enhancers and promoter regions and differ from other higher-order chromatin structures such as topologically associated domains (TAD). The activity-by-contact (ABC) model of enhancer–promoter regulation has been recently used in the identification of these CRHs, but little is known about the role of transcription factor CCTC binding factor (CTCF) on ABC scores and their consequent impact on CRHs. Here, we show that the loss of CTCF leads to a reorganization of the ABC-derived rankings of putative enhancers in the mouse heart, a global reduction in the total number of CRHs and an increase in the size of CRHs. Furthermore, CTCF loss leads to a higher percentage of CRHs that cross TAD boundaries. These results provide additional evidence to support the importance of CTCF in forming the regulatory networks necessary for gene regulation. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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14 pages, 4041 KB  
Article
Comparative Analysis of Crystal Violet-Binding Aptamers as Potential Cores for Binary Sensors
by Gleb A. Bobkov, Gleb S. Yushkov, Andrei D. Kuzmin, Tatiana D. Popysheva, Elena I. Stepchenkova and Maria S. Rubel
Int. J. Mol. Sci. 2025, 26(19), 9833; https://doi.org/10.3390/ijms26199833 - 9 Oct 2025
Viewed by 495
Abstract
‘Light-up’ aptamers are short oligonucleotides that can induce fluorescence of certain organic compounds upon binding. In this study, we compared three crystal violet (CV) aptamers—CV30S, parallel G-quadruplex (G4), and antiparallel G4—regarding their absolute fluorescence intensity, signal-to-background ratio (S/B), and potential as a core [...] Read more.
‘Light-up’ aptamers are short oligonucleotides that can induce fluorescence of certain organic compounds upon binding. In this study, we compared three crystal violet (CV) aptamers—CV30S, parallel G-quadruplex (G4), and antiparallel G4—regarding their absolute fluorescence intensity, signal-to-background ratio (S/B), and potential as a core component in binary sensors for nucleic acid detection. The G4 antiparallel aptamer exhibited the highest fluorescence intensity and a robust S/B ratio, indicating its effectiveness in stabilizing the CV binding and enhancing fluorescence. In contrast, the G4 parallel aptamer demonstrated poorer performance, suggesting that its structural topology is less suitable for interactions with CV. The CV30S aptamer showed distinct advantages in binary sensor configurations, achieving the best limit of detection at 6 nM. Full article
(This article belongs to the Special Issue Advances in Structural and Functional Properties of G-Quadruplexes and Aptamers)
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15 pages, 2254 KB  
Article
Metformin Induces Changes in Sphingosine-1-Phosphate-Related Signaling in Diabetic Mice Brain
by Przemysław Leonard Wencel, Kinga Czubowicz, Magdalena Gewartowska, Małgorzata Frontczak-Baniewicz and Robert Piotr Strosznajder
Int. J. Mol. Sci. 2025, 26(19), 9832; https://doi.org/10.3390/ijms26199832 - 9 Oct 2025
Viewed by 537
Abstract
Type 2 diabetes mellitus (T2DM) is a chronic disease that has become a serious health problem worldwide. Moreover, increased systemic and cerebrovascular inflammation is one of the major pathophysiological features of T2DM, and a growing body of evidence emphasizes T2DM with memory and [...] Read more.
Type 2 diabetes mellitus (T2DM) is a chronic disease that has become a serious health problem worldwide. Moreover, increased systemic and cerebrovascular inflammation is one of the major pathophysiological features of T2DM, and a growing body of evidence emphasizes T2DM with memory and executive function decline. Bioactive sphingolipids regulate a cell’s survival, inflammatory response, as well as glucose and insulin signaling/metabolism. Moreover, current research on the role of sphingosine kinases (SPHKs) and sphingosine-1-phosphate receptors (S1PRs) in T2DM is not fully understood, and the results obtained often differ. The aim of the present study was to evaluate the effect of metformin (anti-diabetic agent, MET) on the brain’s sphingosine-1-phosphate-related signaling and ultrastructure in diabetic mice. Our results revealed elevated mRNA levels of genes encoding sphingosine kinase 2 (SPHK2) and sphingosine-1-phosphate receptor 3 (S1PR3), which was accompanied by downregulation of sphingosine-1-phosphate receptor 1 (S1PR1) in the hippocampus of diabetic mice. Simultaneously, upregulation of genes encoding pro-inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) was observed. Administration of MET significantly reversed changes in mRNA levels in the hippocampus and reduced Sphk2, Il6, and Tnf, with concomitant upregulation of S1pr1 gene expression. Ultrastructural analysis of diabetic mice hippocampus revealed morphological alterations in neurons, neuropil, and capillaries that were manifested as mitochondria swelling, blurred synaptic structure, and thickened basal membrane of capillaries. The use of MET partially reversed those changes. Our research emphasizes the important role of insulin sensitivity modulation by metformin in the regulation of SPHKs and S1PRs and inflammatory gene expression in a murine model of T2DM. Full article
(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Health and Diseases)
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37 pages, 2704 KB  
Review
Viral Metagenomic Next-Generation Sequencing for One Health Discovery and Surveillance of (Re)Emerging Viruses: A Deep Review
by Tristan Russell, Elisa Formiconi, Mícheál Casey, Maíre McElroy, Patrick W. G. Mallon and Virginie W. Gautier
Int. J. Mol. Sci. 2025, 26(19), 9831; https://doi.org/10.3390/ijms26199831 - 9 Oct 2025
Viewed by 1427
Abstract
Viral metagenomic next-generation sequencing (vmNGS) has transformed our capacity for the untargeted detection and characterisation of (re)emerging zoonotic viruses, surpassing the limitations of traditional targeted diagnostics. In this review, we critically evaluate the current landscape of vmNGS, highlighting its integration within the One [...] Read more.
Viral metagenomic next-generation sequencing (vmNGS) has transformed our capacity for the untargeted detection and characterisation of (re)emerging zoonotic viruses, surpassing the limitations of traditional targeted diagnostics. In this review, we critically evaluate the current landscape of vmNGS, highlighting its integration within the One Health paradigm and its application to the surveillance and discovery of (re)emerging viruses at the human–animal–environment interface. We provide a detailed overview of vmNGS workflows including sample selection, nucleic acid extraction, host depletion, virus enrichment, sequencing platforms, and bioinformatic pipelines, all tailored to maximise sensitivity and specificity for diverse sample types. Through selected case studies, including SARS-CoV-2, mpox, Zika virus, and a novel henipavirus, we illustrate the impact of vmNGS in outbreak detection, genomic surveillance, molecular epidemiology, and the development of diagnostics and vaccines. The review further examines the relative strengths and limitations of vmNGS in both passive and active surveillance, addressing barriers such as cost, infrastructure requirements, and the need for interdisciplinary collaboration. By integrating molecular, ecological, and public health perspectives, vmNGS stands as a central tool for early warning, comprehensive monitoring, and informed intervention against (re)emerging viral threats, underscoring its critical role in global pandemic preparedness and zoonotic disease control. Full article
(This article belongs to the Special Issue Molecular Insights into Zoonotic Diseases)
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36 pages, 1854 KB  
Review
Molecular Signatures of Schizophrenia and Insights into Potential Biological Convergence
by Malak Saada and Shani Stern
Int. J. Mol. Sci. 2025, 26(19), 9830; https://doi.org/10.3390/ijms26199830 - 9 Oct 2025
Viewed by 747
Abstract
Schizophrenia is a highly polygenic and clinically heterogeneous disorder. In this paper, we first review layer-specific evidence across genetics, epigenetics, transcriptomics, proteomics, and patient-derived induced pluripotent stem cell (iPSC) models, then integrate cross-layer findings. Genetics research identifies widespread risk architecture. Hundreds of loci [...] Read more.
Schizophrenia is a highly polygenic and clinically heterogeneous disorder. In this paper, we first review layer-specific evidence across genetics, epigenetics, transcriptomics, proteomics, and patient-derived induced pluripotent stem cell (iPSC) models, then integrate cross-layer findings. Genetics research identifies widespread risk architecture. Hundreds of loci from common, rare, and CNV analyses. Epigenetics reveals disease-associated DNA methylation and histone-mark changes. These occur at neuronally active enhancers and promoters, together with chromatin contacts that link non-coding risk to target genes. Transcriptomics show broad differential expression, isoform-level dysregulation, and disrupted co-expression modules. These alterations span synaptic signaling, mitochondrial bioenergetics, and immune programs. Proteomics demonstrates coordinated decreases in postsynaptic scaffold and mitochondrial respiratory-chain proteins in cortex, with complementary inflammatory signatures in serum/plasma. iPSC models recapitulate disease-relevant phenotypes: including fewer synaptic puncta and excitatory postsynaptic currents, electrophysiological immaturity, oxidative stress, and progenitor vulnerability. These same models show partial rescue under targeted perturbations. Integration across layers highlights convergent pathways repeatedly supported by ≥3 independent data types: synaptic signaling, immune/complement regulation, mitochondrial/energetic function, neurodevelopmental programs and cell-adhesion complexes. Within these axes, several cross-layer convergence genes/proteins (e.g., DLG4/PSD-95, C4A, RELN, NRXN1/NLGN1, OXPHOS subunits, POU3F2/BRN2, PTN) recur across cohorts and modalities. Framing results through cross-layer and shared-pathway convergence organizes heterogeneous evidence and prioritizes targets for mechanistic dissection, biomarker development, and translational follow-up. Full article
(This article belongs to the Special Issue Molecular Underpinnings of Schizophrenia Spectrum Disorders, 2nd Edition)
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30 pages, 2176 KB  
Review
Methods for Assessing MAGL Enzymatic Activity: An Extensive Review of Past and Emerging Approaches
by Giulia Bononi, Eva Landucci, Miriana Di Stefano, Lisa Piazza, Simone Bertini, Marco Macchia and Carlotta Granchi
Int. J. Mol. Sci. 2025, 26(19), 9829; https://doi.org/10.3390/ijms26199829 - 9 Oct 2025
Viewed by 722
Abstract
Monoacylglycerol lipase (MAGL) is a key serine hydrolase involved in lipid metabolism, catalyzing the hydrolysis of monoacylglycerols into free fatty acids and glycerol. MAGL plays a central role in regulating endocannabinoid signaling and lipid homeostasis, processes often dysregulated in cancer and other pathological [...] Read more.
Monoacylglycerol lipase (MAGL) is a key serine hydrolase involved in lipid metabolism, catalyzing the hydrolysis of monoacylglycerols into free fatty acids and glycerol. MAGL plays a central role in regulating endocannabinoid signaling and lipid homeostasis, processes often dysregulated in cancer and other pathological conditions. In recent years, MAGL has emerged as a promising therapeutic target, particularly in oncology, where its inhibition has shown potential to impair tumor growth, metastasis, and inflammation-driven processes. Alongside the development of selective MAGL inhibitors, several biochemical methods have been established to measure MAGL enzymatic activity, providing essential tools for target validation and inhibitor characterization. In this review, we provide a comprehensive and critical overview of the main approaches developed for MAGL activity evaluation, including radiometric, chromatographic, colorimetric, fluorescence-based, bioluminescence-based, and activity-based protein profiling (ABPP) assays. For each method, we discuss principles, advantages, and limitations. This review aims to support researchers in the selection of the most appropriate assay strategy for their experimental needs, ultimately fostering the rapid and accurate development of novel MAGL inhibitors with potential applications in cancer therapy and metabolic disease management. Full article
(This article belongs to the Special Issue Role of Cell Metabolism in Cancer Biology)
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38 pages, 8212 KB  
Article
Immunoinformatic Prediction of HIV-1 Glycoprotein gp120 and Nef Epitopes Conjugated to HBsAg-Binding Protein (SBP) to Induce the Humoral and Cellular Immune Response
by Arslan Habib, Xinyi Xu, Jun Xie and Naishuo Zhu
Int. J. Mol. Sci. 2025, 26(19), 9828; https://doi.org/10.3390/ijms26199828 - 9 Oct 2025
Viewed by 665
Abstract
Acquired Immunodeficiency Syndrome (AIDS) is caused by Human Immunodeficiency Virus (HIV), and continues to be responsible for a substantial number of deaths worldwide each year. Development of a robust and efficient HIV-1 vaccine remains a critical priority. Structural analysis of viral proteins provides [...] Read more.
Acquired Immunodeficiency Syndrome (AIDS) is caused by Human Immunodeficiency Virus (HIV), and continues to be responsible for a substantial number of deaths worldwide each year. Development of a robust and efficient HIV-1 vaccine remains a critical priority. Structural analysis of viral proteins provides a foundational approach to designing peptide-based immunogenic vaccines. In the current experiment, we used computational prediction approaches alongside molecular docking and molecular dynamics (MD) simulations to identify potential epitopes within gp120 and Nef proteins. The selected co-epitopes were fused with the HBsAg-binding protein (SBP), a 344-amino acid protein previously identified in our laboratory through screening of a human liver cDNA expression library against HBsAg, to facilitate efficient delivery to and uptake by dendritic cells (DCs), thereby enhancing antigen (Ag) presentation. Flexible linkers are used to connect B cells, Helper T Lymphocytes (HTLs), and Cytotoxic T Lymphocytes (CTLs) in a sequential manner. The assembled vaccine construct comprises 757 amino acids, corresponding to a recombinant protein of 83.64 kDa molecular weight. Structural analysis through docking studies, MD simulations, and 3D structure validation revealed that the designed protein exhibits high structural stability and potential for interaction with Toll-like receptors (TLRs). These findings support the vaccine’s ability to enhance cellular and humoral feedback, including the stimulation of T and B cells and induction of antibody (Ab) production. The results underscore the promise of this in silico designed co-epitope vaccine as a viable candidate for HIV-1 prevention and suggest that such constructs may serve as effective immunogens in future HIV-1 vaccine strategies. Full article
(This article belongs to the Section Molecular Informatics)
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18 pages, 4937 KB  
Article
An Innovative Immunotoxin Design Against Allergy Based on the IL-33 Cytokine and the Ribotoxin α-Sarcin
by Javier Narbona, Rodrigo Lázaro-Gorines, Adrián Gutiérrez-Carmona, Juan Carlos López-Rodríguez, Mayte Villalba and Javier Lacadena
Int. J. Mol. Sci. 2025, 26(19), 9827; https://doi.org/10.3390/ijms26199827 - 9 Oct 2025
Viewed by 464
Abstract
Allergies constitute one of the major health problems worldwide, increasing their prevalence in developed countries. To overcome this multifactorial disease, immunotherapy and the use of immune molecules, such as immunotoxins, have arisen as promising therapeutic tools. We have designed, produced, and characterized a [...] Read more.
Allergies constitute one of the major health problems worldwide, increasing their prevalence in developed countries. To overcome this multifactorial disease, immunotherapy and the use of immune molecules, such as immunotoxins, have arisen as promising therapeutic tools. We have designed, produced, and characterized a new immunotoxin called IL-33αS, encompassing the murine IL-33 (mIL-33) as the target domain and the ribotoxin α-sarcin as the toxic domain. IL-33 is a widely described alarmin that binds to the ST2 receptor of a variety of immune cells, including ILC2s, leading to Th2-derived inflammatory response, as occurs in allergic reactions. Both IL-33αS and mIL-33 were successfully produced in the methylotrophic yeast Pichia pastoris and purified to homogeneity through affinity chromatography for their characterization. Both IL-33αS and mIL-33 were able to specifically bind to ST2+ Raw 264.7 cells, and IL-33αS kept the ribonucleolytic activity of α-sarcin, allowing IL-33αS to exhibit cytotoxic effects against ST2+-targeted cells. In addition, IL-33αS induced significantly less secretion of the Th2-linked cytokine IL-13 in comparison to mIL-33, suggesting steric interference produced by the presence of the α-sarcin. These results assess the potential therapeutic effect of this new immunotoxin against allergies, causing ST2-targeted cytotoxicity while avoiding the Th2 cytokine secretion. Full article
(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in “Molecular Immunology”)
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27 pages, 2603 KB  
Review
Oxidative Stress, Mitochondrial Quality Control, Autophagy, and Sirtuins in Heart Failure
by Jan Krekora, Marcin Derwich, Jarosław Drożdż, Elzbieta Pawlowska and Janusz Blasiak
Int. J. Mol. Sci. 2025, 26(19), 9826; https://doi.org/10.3390/ijms26199826 - 9 Oct 2025
Viewed by 754
Abstract
Heart failure (HF) has become an emerging problem, especially in regions where life expectancy is increasing. Despite its prevalence, the mechanisms behind HF development are not well understood, which is reflected in the lack of curative therapies. Mitochondria, autophagy, and sirtuins form a [...] Read more.
Heart failure (HF) has become an emerging problem, especially in regions where life expectancy is increasing. Despite its prevalence, the mechanisms behind HF development are not well understood, which is reflected in the lack of curative therapies. Mitochondria, autophagy, and sirtuins form a crucial triad involved in HF pathogenesis, interconnected by oxidative stress. Identifying a common pathway involving these three components could be valuable in developing new treatment strategies. Since HF is the end result of several cardiovascular diseases, this review highlights the main HF precursors and explores the roles of mitochondrial quality control (mtQC), autophagy, and sirtuins in HF development. Dysfunctional mitochondria may play a key role by enhancing oxidative stress and influencing autophagy and sirtuins, both of which possess antioxidant properties. The dual nature of autophagy—its pro-life and pro-death roles—may contribute to different outcomes in HF related to oxidative stress. As mtQC, autophagy, and sirtuins may interact, we present data on their mutual dependencies in HF. However, the specificity of these interactions remains unclear and needs further investigation, which could help identify new therapeutic targets. In conclusion, the interplay between mtQC, autophagy, and sirtuins may be crucial in HF pathogenesis and could be leveraged in developing HF treatments. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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18 pages, 6555 KB  
Article
Bioinformatics Analysis of Tumor-Associated Macrophages in Hepatocellular Carcinoma and Establishment of a Survival Model Based on Transformer
by Zhuo Zeng, Shenghua Rao and Jiemeng Zhang
Int. J. Mol. Sci. 2025, 26(19), 9825; https://doi.org/10.3390/ijms26199825 - 9 Oct 2025
Viewed by 571
Abstract
Hepatocellular carcinoma (HCC) ranks among the most prevalent malignancies globally. Although treatment strategies have improved, the prognosis for patients with advanced HCC remains unfavorable. Tumor-associated macrophages (TAMs) play a dual role, exhibiting both anti-tumor and pro-tumor functions. In this study, we analyzed single-cell [...] Read more.
Hepatocellular carcinoma (HCC) ranks among the most prevalent malignancies globally. Although treatment strategies have improved, the prognosis for patients with advanced HCC remains unfavorable. Tumor-associated macrophages (TAMs) play a dual role, exhibiting both anti-tumor and pro-tumor functions. In this study, we analyzed single-cell RNA sequencing data from 10 HCC tumor cores and 8 adjacent non-tumor liver tissues available in the dataset GSE149614. Using dimensionality reduction and clustering approaches, we identified six major cell types and nine distinct TAM subtypes. We employed Monocle2 for cell trajectory analysis, hdWGCNA for co-expression network analysis, and CellChat to investigate functional communication between TAMs and other components of the tumor microenvironment. Furthermore, we estimated TAM abundance in TCGA-LIHC samples using CIBERSORT and observed that the relative proportions of specific TAM subtypes were significantly correlated with patient survival. To identify TAM-related genes influencing patient outcomes, we developed a high-dimensional, gene-based transformer survival model. This model achieved superior concordance index (C-index) values across multiple datasets, including TCGA-LIHC, OEP000321, and GSE14520, outperforming other methods. Our results emphasize the heterogeneity of tumor-associated macrophages in hepatocellular carcinoma and highlight the practicality of our deep learning framework in survival analysis. Full article
(This article belongs to the Section Molecular Informatics)
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17 pages, 3188 KB  
Article
Diverse Members of the Phylum Armatimonadota Promote the Growth of Aquatic Plants, Duckweeds
by Tomoki Iwashita, Ayaka Makino, Ryosuke Nakai, Yasuko Yoneda, Yoichi Kamagata, Tadashi Toyama, Kazuhiro Mori, Yasuhiro Tanaka and Hideyuki Tamaki
Int. J. Mol. Sci. 2025, 26(19), 9824; https://doi.org/10.3390/ijms26199824 - 9 Oct 2025
Viewed by 464
Abstract
Duckweeds are small, fast-growing aquatic plants with high starch and protein content, making them promising candidates for next-generation plant biomass resources. Despite their importance, little is known about their interactions with microorganisms, particularly plant growth-promoting bacteria (PGPB), which play key roles in enhancing [...] Read more.
Duckweeds are small, fast-growing aquatic plants with high starch and protein content, making them promising candidates for next-generation plant biomass resources. Despite their importance, little is known about their interactions with microorganisms, particularly plant growth-promoting bacteria (PGPB), which play key roles in enhancing plant productivity. In this study, we report the plant growth-promoting effects of strain LA-C6, a member of the phylum Armatimonadota, isolated from duckweed fronds. Based on 16S rRNA gene analysis, this strain represents a novel genus-level lineage, and is referred to as Fimbriimonadaceae bacterium strain LA-C6. In axenic co-culture experiments, strain LA-C6 promoted duckweed growth, increasing the frond proliferation of four duckweed species (Lemna minor, Lemna aequinoctialis, Spirodela polyrhiza, and Landoltia punctata) by 1.8- to 4.0-fold compared with uninoculated controls. Importantly, three other phylogenetically distinct Armatimonadota species also exhibited significant plant growth-promoting effects on L. minor, increasing frond number by up to 2.3-fold and dry weight by up to 2.4-fold. This finding highlights the broader potential of diverse Armatimonadota members as PGP bacteria. A survey of the IMNGS database showed that strain LA-C6 and other Armatimonadota species are widely distributed across diverse plant-associated environments. Biochemical assays and gene prediction analyses revealed that strain LA-C6 produces indole-3-acetic acid (IAA) as a representative PGP trait, whereas no additional PGP-associated traits were detected. These results suggest that diverse bacterial lineages within the phylum Armatimonadota exert growth-promoting effects on aquatic plants, potentially through yet-to-be-identified mechanisms. Full article
(This article belongs to the Section Molecular Microbiology)
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20 pages, 3269 KB  
Article
A Novel Approach for the Preparation of Tetrathionate Ionic Liquids and Study of Their Sulfur Dissolution Properties
by Luca Guglielmero, Stefano Becherini, Felicia D’Andrea, Lorenzo Guazzelli, Christian Silvio Pomelli, Alberto Renato de Angelis, Ivan Maffeis, Wallace O’Neil Parker, Jr. and Andrea Mezzetta
Int. J. Mol. Sci. 2025, 26(19), 9823; https://doi.org/10.3390/ijms26199823 - 9 Oct 2025
Viewed by 634
Abstract
A series of sulfur dissolving tetrathionate ionic liquids (ILs), featuring imidazolium and pyridinium cationic heads, have been prepared and characterized along with their chloride IL precursors. A novel synthetic approach for the preparation of the proposed tetrathionate ILs has been introduced and successfully [...] Read more.
A series of sulfur dissolving tetrathionate ionic liquids (ILs), featuring imidazolium and pyridinium cationic heads, have been prepared and characterized along with their chloride IL precursors. A novel synthetic approach for the preparation of the proposed tetrathionate ILs has been introduced and successfully tested in the current work, yielding the desired compounds in quantitative yield and high purity, offering a significant advancement over the traditional Volynskii–Smolyaninov reaction. The presented method addresses key challenges of the traditional approach, solving the issues deriving from the influence of the IL cation on the reaction outcome and the unpredictability of the formed polythionate species. The solubility of elemental sulfur in the considered tetrathionate ILs has been investigated at various temperatures, providing good preliminary evidence of the suitability of these ILs as convenient and effective sulfur solubilizing media readily available on the field in “sour” gas extraction plants. Furthermore, the use of ILs instead of traditional organic solvents in operative conditions represents a noteworthy safety improvement due to their lower flammability and volatility. Finally, interesting results were obtained studying binary mixtures of organic solvents and ILs, with cooperative effects or salting-out effects being observed in relation to the type of solvent used. Full article
(This article belongs to the Section Materials Science)
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44 pages, 2369 KB  
Review
Brain–Bone Axis in Physiological and Pathological Conditions
by Luca Massaccesi, Massimiliano Marco Corsi Romanelli and Emanuela Galliera
Int. J. Mol. Sci. 2025, 26(19), 9822; https://doi.org/10.3390/ijms26199822 - 9 Oct 2025
Viewed by 623
Abstract
The brain–bone axis has garnered increasing attention over the years, leading to numerous studies that have unraveled the intricate bidirectional communication between the central nervous system (CNS) and skeletal metabolism. This review explores this profound relationship, examining the complex mechanisms that regulate it, [...] Read more.
The brain–bone axis has garnered increasing attention over the years, leading to numerous studies that have unraveled the intricate bidirectional communication between the central nervous system (CNS) and skeletal metabolism. This review explores this profound relationship, examining the complex mechanisms that regulate it, the key players involved, and the clinical implications of its dysfunction in various pathological situations affecting the CNS and skeletal system. Ultimately, it emphasizes the potential of ongoing research to develop diagnostic tools, therapeutic interventions, and preventive strategies aimed at enhancing skeletal and neurological health. Full article
(This article belongs to the Special Issue Lipid Metabolism and Biomarkers in Neural and Cardiometabolic Health)
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16 pages, 676 KB  
Article
The NME7 Gene Is Involved in the Kinetics of Glucose Processing
by Daniela Vejražková, Josef Včelák, Markéta Vaňková, Petra Lukášová, Michaela Svojtková, Tereza Grimmichová, Hana Kvasničková, Andrea Tura, Lucie Šedová, Ondřej Šeda, Kateřina Škultéty and Běla Bendlová
Int. J. Mol. Sci. 2025, 26(19), 9821; https://doi.org/10.3390/ijms26199821 - 9 Oct 2025
Viewed by 443
Abstract
Given that type 2 diabetes mellitus is common in several ciliopathies, the NME7 gene (non-metastatic cells 7), encoding a recognized member of the ciliome, was studied in connection with glucose metabolism. The aim was to find out whether the variability in the gene [...] Read more.
Given that type 2 diabetes mellitus is common in several ciliopathies, the NME7 gene (non-metastatic cells 7), encoding a recognized member of the ciliome, was studied in connection with glucose metabolism. The aim was to find out whether the variability in the gene is associated with the response to administered glucose during the 3 h oral glucose tolerance test. The study included 1262 individuals with different levels of glucose tolerance. Glycemic curves were categorized according to their shape as monophasic, biphasic, triphasic, and more complex multiphasic. The analysis showed a significant association of five linked NME7 polymorphisms with the biphasic course of the glycemic curve, a shape that has been shown to be metabolically protective. Specifically, minor alleles of rs4656659 and rs2157597 in combination with wild-type alleles of rs10732287, rs4264046, and rs10800438 were more frequent within the biphasic category. Moreover, haplotype analysis confirmed higher insulin sensitivity in carriers of this specific haplotype. In conclusion, a cluster of five linked NME7 polymorphisms showed an association with a biphasic glycemic curve. Considering the health benefits of the biphasic curve in terms of glycoregulation and taking into account the demonstrated link of the NME7 haplotype with insulin sensitivity, variability in the NME7 gene represents another piece of the complex mosaic influencing healthy energy processing. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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19 pages, 3701 KB  
Article
Lipid Biomarkers in Glioma: Unveiling Molecular Heterogeneity Through Tissue and Plasma Profiling
by Khairunnisa Abdul Rashid, Norlisah Ramli, Kamariah Ibrahim, Vairavan Narayanan and Jeannie Hsiu Ding Wong
Int. J. Mol. Sci. 2025, 26(19), 9820; https://doi.org/10.3390/ijms26199820 - 9 Oct 2025
Viewed by 448
Abstract
Gliomas are aggressive brain tumours with diverse histological and molecular features, complicating accurate diagnosis and treatment. Dysregulated lipid metabolism contributes to glioma progression, and analysing lipid profiles in plasma and tissue may enhance diagnostic and prognostic accuracy. This study investigated lipid dysregulation to [...] Read more.
Gliomas are aggressive brain tumours with diverse histological and molecular features, complicating accurate diagnosis and treatment. Dysregulated lipid metabolism contributes to glioma progression, and analysing lipid profiles in plasma and tissue may enhance diagnostic and prognostic accuracy. This study investigated lipid dysregulation to identify key lipid signatures that distinguish glioma from other brain diseases and examined the associations between lipid biomarkers in glioma tissue and plasma. Biospecimens from 11 controls and 72 glioma patients of varying grades underwent lipidomic profiling using liquid chromatography-mass spectrometry. Univariate and multivariate analyses identified differentially abundant lipids, and correlation analysis evaluated the associations between tissue and plasma biomarkers. Lipidomic analysis revealed distinct lipid profiles in the tissues and plasma of glioma patients compared to those of controls. Prominent lipid metabolites in glioma tissues included LPC 21:3 (AUC = 0.925), DG 43:11 (AUC = 0.906), and PC 33:1 (AUC = 0.892), which served as effective biomarkers. Conversely, in plasma, lipid metabolites such as phosphatidylethanolamine (PE 21:3, AUC = 0.862), ceramide-1-phosphate (CerP 26:1, AUC = 0.861), and sphingomyelin (SM 24:3, AUC = 0.858) were identified as the most promising lipid biomarkers. Significant positive and negative correlations were observed between the tissue and plasma lipid biomarkers of glioma patients. Lipidomic profiling revealed aberrant lipid classes and pathways in glioma tissues and plasma, enhancing understanding of glioma heterogeneity and potential clinical applications. Full article
(This article belongs to the Special Issue Circulating Biomarkers for the Diagnosis of Cancer)
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17 pages, 3090 KB  
Article
Cinnamaldehyde Inhibits Leptin-Induced MMP-1 by Modulating Leptin Receptor/STAT3 and Blocking RhoA/NF-κB Pathways in Human Intervertebral Disc Stem Cells
by Kuo-Feng Hua, Hsin-Chiao Yu and Hsien-Ta Hsu
Int. J. Mol. Sci. 2025, 26(19), 9819; https://doi.org/10.3390/ijms26199819 - 9 Oct 2025
Viewed by 427
Abstract
Obesity is a recognized risk factor for intervertebral disc (IVD) degeneration, a condition characterized by the progressive loss of extracellular matrix components in the nucleus pulposus. Elevated circulating leptin levels in obese individuals contribute to this degeneration by upregulating matrix metalloproteinase-1 (MMP-1) expression. [...] Read more.
Obesity is a recognized risk factor for intervertebral disc (IVD) degeneration, a condition characterized by the progressive loss of extracellular matrix components in the nucleus pulposus. Elevated circulating leptin levels in obese individuals contribute to this degeneration by upregulating matrix metalloproteinase-1 (MMP-1) expression. Targeting MMP-1 expression with low-toxicity natural compounds may provide a promising strategy to prevent or mitigate IVD degeneration. In this study, we examined the effects of cinnamaldehyde (CA), a natural compound derived from Cinnamomum osmophloeum Kaneh, on leptin-induced MMP-1 expression in human IVD cartilage endplate-derived stem cells (SV40 cell line). Our results showed that leptin induced MMP-1 expression via activation of leptin receptor-mediated JAK2/STAT3, JAK2/RhoA/STAT3, and RhoA/ERK1/2/NF-κB signaling pathways. CA significantly reduced MMP-1 expression by inhibiting phosphorylation of the leptin receptor and STAT3 and blocking RhoA and NF-κB activation, without affecting JAK2 and ERK1/2 phosphorylation. These findings suggest that CA suppresses leptin-induced MMP-1 expression by modulating specific signaling pathways, highlighting its potential as a therapeutic agent for IVD degeneration associated with obesity. Full article
(This article belongs to the Special Issue Updates on Synthetic and Natural Antioxidants)
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23 pages, 2667 KB  
Article
Reactivation of the PI3K/mTOR Signaling Pathway Confers Resistance to the FGFR4 Inhibitor FGF401
by Hung Huynh and Wai Har Ng
Int. J. Mol. Sci. 2025, 26(19), 9818; https://doi.org/10.3390/ijms26199818 - 9 Oct 2025
Viewed by 549
Abstract
Hepatocellular carcinoma (HCC) is a deadly liver cancer characterized by dysregulated signaling and aberrant cell-cycle control. The FGFR4/FGF19 pathway is dysregulated in HCC and other cancers. Inhibitors targeting the FGF19/FGFR4 pathway, including the FGF19/FGFR4 inhibitor FGF401, have been investigated in HCC and other [...] Read more.
Hepatocellular carcinoma (HCC) is a deadly liver cancer characterized by dysregulated signaling and aberrant cell-cycle control. The FGFR4/FGF19 pathway is dysregulated in HCC and other cancers. Inhibitors targeting the FGF19/FGFR4 pathway, including the FGF19/FGFR4 inhibitor FGF401, have been investigated in HCC and other cancers; however, nearly all patients who initially respond eventually develop resistance shortly after starting therapy, highlighting the urgent need for new treatment strategies to overcome drug resistance. In the present study, we report that chronic treatment of the FGF19/FGFR4-expressing HCC25−0705A line with FGF401 led to acquired resistance. FGF401-resistant tumors exhibited upregulation of FGFRs and activation of the PI3K/AKT/mTOR/p70S6K pathway. Combination therapy with FGF401 and the mammalian target of rapamycin (mTOR) inhibitor everolimus (FGF401/everolimus) resulted in more complete tumor growth inhibition, delayed the onset of resistance, and prolonged overall survival (OS) in mice bearing orthotopic HCC tumors. The FGF401/everolimus combination effectively suppressed tumor cell proliferation; promoted apoptosis; reduced tumor hypoxia via blood vessel normalization; and downregulated key proteins involved in proliferation, survival, metastasis, and angiogenesis. These preclinical findings provide a strong rationale for clinical trials combining FGFR4 and mTOR inhibitors in HCC patients with FGF19/FGFR4/mTOR-dependent tumors. Full article
(This article belongs to the Special Issue Molecular Insights into Hepatocellular Carcinoma: From Carcinogenesis to Liver Transplantation)
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17 pages, 1640 KB  
Article
Exposure to Fluoride During Pregnancy and Lactation Induces Metabolic Imbalance in Pancreas: A Toxicological Insight Using the Rat Model
by Marta Skórka-Majewicz, Wojciech Żwierełło, Arleta Drozd, Irena Baranowska-Bosiacka, Donata Simińska, Agata Wszołek and Izabela Gutowska
Int. J. Mol. Sci. 2025, 26(19), 9817; https://doi.org/10.3390/ijms26199817 - 9 Oct 2025
Viewed by 412
Abstract
Fluoride is a widespread environmental toxin that disrupts metabolic and endocrine functions, but its impact on pancreatic inflammation and hormone secretion remains unclear. This study examined how chronic fluoride exposure affects pancreatic inflammation and secretory function in rats. Pregnant Wistar rats received sodium [...] Read more.
Fluoride is a widespread environmental toxin that disrupts metabolic and endocrine functions, but its impact on pancreatic inflammation and hormone secretion remains unclear. This study examined how chronic fluoride exposure affects pancreatic inflammation and secretory function in rats. Pregnant Wistar rats received sodium fluoride (NaF) at 50 mg/L in drinking water during gestation and lactation. Male offspring continued exposure until 3 months old. Controls received fluoride-free water. Pancreatic tissue and serum were collected. Fluoride levels were measured potentiometrically. Eicosanoids were quantified by SPE and HPLC. Serum insulin, glucagon, and somatostatin were measured by ELISA. Histological and biochemical markers of inflammation and oxidative stress were assessed. Fluoride exposure did not lead to significant accumulation in the pancreas or serum. However, fluoride-exposed rats exhibited a significant decrease in serum insulin and somatostatin concentrations, while glucagon levels remained unchanged. Additionally, the pancreas of fluoride-treated animals showed markedly elevated levels of pro-inflammatory eicosanoids, including prostaglandin E2, leukotrienes A4 and B4, and HETE/HODE derivatives, indicating activation of cyclooxygenase and lipoxygenase pathways. Sustained low-dose fluoride exposure induced pancreatic inflammation and disrupted endocrine homeostasis in rats. These findings suggest that chronic fluoride intake may impair insulin secretion and promote pre-diabetic alterations, warranting further research. Full article
(This article belongs to the Section Molecular Endocrinology and Metabolism)
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25 pages, 1374 KB  
Review
Gene-Exercise Interactions in Amyloid Metabolism and Clearance: Implications for Alzheimer’s Disease
by Maria Francesca Astorino, Giovanni Luca Cipriano, Ivan Anchesi, Maria Lui, Ivana Raffaele, Marco Calabrò and Concetta Crisafulli
Int. J. Mol. Sci. 2025, 26(19), 9816; https://doi.org/10.3390/ijms26199816 - 9 Oct 2025
Viewed by 636
Abstract
Alzheimer’s disease (AD), the most prevalent form of dementia, poses a critical global health challenge as its incidence rises with aging populations. Despite extensive research into its genetic and molecular underpinnings, effective therapeutic strategies remain limited. Growing evidence suggests that physical exercise may [...] Read more.
Alzheimer’s disease (AD), the most prevalent form of dementia, poses a critical global health challenge as its incidence rises with aging populations. Despite extensive research into its genetic and molecular underpinnings, effective therapeutic strategies remain limited. Growing evidence suggests that physical exercise may offer neuroprotective benefits, potentially mitigating AD progression through multifactorial mechanisms. This review synthesizes current findings on the interplay between aerobic exercise and AD pathophysiology, with a focus on amyloid-β (Aβ) metabolism, gene expression, and neuroinflammation. We explore how exercise influences Aβ clearance, modulates amyloid precursor protein (APP) processing, and impacts the activity of key enzymes such as secretases and neprilysin. Further, we highlight the gene–exercise crosstalk identified through transcriptomic data, particularly in the entorhinal cortex—an early site of Aβ deposition. Our analysis also discusses how exercise-induced modulation of molecular pathways—including mitochondrial function, oxidative stress responses, and neuroinflammatory cascades—may confer cognitive resilience. By integrating molecular, genetic, and systems biology data, this review underscores the potential of structured physical activity as a non-pharmacological intervention to delay or attenuate AD pathology. These insights support a precision medicine approach, which combines lifestyle interventions with molecular profiling, to improve prevention strategies and therapeutic outcomes in AD. Full article
(This article belongs to the Special Issue Molecular Insights into the Role of Exercise in Disease and Health, 2nd Edition)
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15 pages, 1079 KB  
Review
P2Y2 Receptor Signaling in Health and Disease
by Fatemeh Salarpour and Jean Sévigny
Int. J. Mol. Sci. 2025, 26(19), 9815; https://doi.org/10.3390/ijms26199815 - 9 Oct 2025
Viewed by 670
Abstract
P2Y2 receptors are a subclass of G protein-coupled receptors activated by the extracellular nucleotides ATP and UTP. These receptors are widely expressed in multiple tissues—including the brain, lungs, heart, and kidneys—and play pivotal roles in inflammation, wound healing, and cell migration. Through [...] Read more.
P2Y2 receptors are a subclass of G protein-coupled receptors activated by the extracellular nucleotides ATP and UTP. These receptors are widely expressed in multiple tissues—including the brain, lungs, heart, and kidneys—and play pivotal roles in inflammation, wound healing, and cell migration. Through coupling with various G proteins, P2Y2 receptors initiate diverse intracellular signaling pathways that mediate calcium mobilization, cytokine release, and cytoskeletal reorganization. Recent studies highlight their dual roles in health and disease. In physiological contexts, P2Y2 receptors contribute to immune modulation and tissue repair. In pathological conditions, they are implicated in Alzheimer’s disease by promoting non-amyloidogenic processing of amyloid precursor protein and in dry eye disease by enhancing mucin secretion while modulating ocular inflammation. They also influence chloride secretion and mucosal hydration in cystic fibrosis and contribute to inflammatory regulation and epithelial repair in inflammatory bowel disease. Additionally, P2Y2 receptors modulate breast cancer progression by regulating cell adhesion, migration, and matrix remodeling. Their involvement in blood pressure regulation via epithelial sodium channel modulation and their facilitative role in HIV-1 entry further underscore their clinical significance. These multifaceted functions position P2Y2 receptors as promising therapeutic targets for diverse diseases, warranting further investigation for translational applications. Full article
(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in “Molecular Immunology”)
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25 pages, 1140 KB  
Review
The Etiological Role of Impaired Neurogenesis in Schizophrenia: Interactions with Inflammatory, Microbiome and Hormonal Signaling
by Miu Tsz-Wai So, Ata Ullah, Abdul Waris and Fahad A. Alhumaydhi
Int. J. Mol. Sci. 2025, 26(19), 9814; https://doi.org/10.3390/ijms26199814 - 9 Oct 2025
Viewed by 513
Abstract
Schizophrenia is a prevailing yet severely debilitating psychiatric disorder characterized by a convoluted etiology. Although antipsychotics have been available for over half a century, they primarily mitigate symptoms rather than providing definitive care. This limitation suggests that the neurotransmitter systems targeted by these [...] Read more.
Schizophrenia is a prevailing yet severely debilitating psychiatric disorder characterized by a convoluted etiology. Although antipsychotics have been available for over half a century, they primarily mitigate symptoms rather than providing definitive care. This limitation suggests that the neurotransmitter systems targeted by these medications are not the root cause of the disorder. Ongoing research seeks to elucidate the cellular, molecular, and circuitry pathways that contribute to the development of schizophrenia. Unfortunately, its precise pathogenesis remains incompletely understood. Accumulating evidence implicates dysregulated neurogenesis and aberrant neurodevelopmental processes as key contributors to disease progression. Recent advances in proteomics and imaging technology have facilitated the emergence of novel models of schizophrenia, emphasizing the roles of neuroinflammation, sex steroids, and cortisol. This paper aims to organize and map the intercorrelations and potential causal effects between various mechanistic models to gain deeper insight on how these mechanisms contribute to the cause, risks, and symptoms of the disorder. Furthermore, we discuss the potential therapeutic strategies that target these pathological pathways. Elucidating these mechanisms may ultimately advance our understanding of schizophrenia’s etiological foundations and guide the development of curative interventions. Full article
(This article belongs to the Special Issue Schizophrenia: From Molecular Mechanism to Therapy)
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21 pages, 2261 KB  
Article
Characterization of α-L-Rhamnosidase and β-D-Glucosidase Subunits of Naringinase Immobilized on a Magnetic Polysaccharide Carrier
by Joanna Bodakowska-Boczniewicz and Zbigniew Garncarek
Int. J. Mol. Sci. 2025, 26(19), 9813; https://doi.org/10.3390/ijms26199813 - 9 Oct 2025
Viewed by 374
Abstract
Naringinase consists of two enzymes: α-L-rhamnosidase and β-D-glucosidase. The enzyme was immobilized on a carrier prepared from carob gum activated with polyethyleneimine. Cross-linking with dextran aldehyde was used to improve the stability of the immobilization. Knowledge of the characteristics of naringinase subunits is [...] Read more.
Naringinase consists of two enzymes: α-L-rhamnosidase and β-D-glucosidase. The enzyme was immobilized on a carrier prepared from carob gum activated with polyethyleneimine. Cross-linking with dextran aldehyde was used to improve the stability of the immobilization. Knowledge of the characteristics of naringinase subunits is important for developing efficient and selective enzymatic reactions involving flavonoids. This study aimed to characterize two subunits of naringinase—α-L-rhamnosidase and β-D-glucosidase—free, immobilized on a magnetic polysaccharide carrier and cross-linked with dextran aldehyde. The characterization of free, immobilized, and stabilized naringinase, as well as α-L-rhamnosidase and β-D-glucosidase, included the effect of pH and temperature on enzyme activity, as well as the determination of their stability depending on the pH and temperature of the environment, and the determination of kinetic constants. Immobilization and subsequent stabilization of naringinase did not affect the optimal pH for the activity of α-L-rhamnosidase and β-D-glucosidase. Immobilization caused a change in the optimal temperature for the activity of α-L-rhamnosidase and β-D-glucosidase from 60 to 65°. Cross-linking of immobilized naringinase with dextran aldehyde increased the temperature stability of its subunits. Cross-linking also altered the pH stability profile of β-D-glucosidase. Immobilization and stabilization of naringinase slightly reduced the maximum reaction rate for α-L-rhamnosidase and β-D-glucosidase compared to the free enzyme. As a result of immobilization, the enzymes’ affinity for substrates for both subunits decreased. Full article
(This article belongs to the Special Issue The Characterization and Application of Enzymes in Bioprocesses)
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17 pages, 3452 KB  
Article
CAP-LAMP2b–Modified Stem Cells’ Extracellular Vesicles Hybrid with CRISPR-Cas9 Targeting ADAMTS4 to Reverse IL-1β–Induced Aggrecan Loss in Chondrocytes
by Kun-Chi Wu, Yu-Hsun Chang, Raymond Yuh-Shyan Chiang and Dah-Ching Ding
Int. J. Mol. Sci. 2025, 26(19), 9812; https://doi.org/10.3390/ijms26199812 - 9 Oct 2025
Viewed by 636
Abstract
Extracellular vesicles (EVs) from mesenchymal stem cells hold therapeutic promise for inflammatory and degenerative diseases; however, limited delivery and targeting capabilities hinder their clinical use. In this study, we sought to enhance the anti-inflammatory and chondroprotective effects of EVs through CAP-LAMP2b (chondrocyte affinity [...] Read more.
Extracellular vesicles (EVs) from mesenchymal stem cells hold therapeutic promise for inflammatory and degenerative diseases; however, limited delivery and targeting capabilities hinder their clinical use. In this study, we sought to enhance the anti-inflammatory and chondroprotective effects of EVs through CAP-LAMP2b (chondrocyte affinity peptide fused to an EV membrane protein) engineering and ADAMTS4 gene editing hybrid vesicle formation. Human umbilical cord MSCs (hUCMSCs) were characterized via morphology, immunophenotyping, and trilineage differentiation. EVs from control and CAP-LAMP2b-transfected hUCMSCs were fused with liposomes carrying CRISPR-Cas9 ADAMTS4 gRNA. DiI-labeled EV uptake was assessed via fluorescence imaging. CAP-LAMP2b was expressed in hUCMSCs and their EVs. EVs exhibited the expected size (~120 nm), morphology, and exosomal markers (CD9, CD63, CD81, HSP70). CAP-modified hybrid EVs significantly enhanced chondrocyte uptake compared to control EVs and liposomes. IL-1β increased ADAMTS4 expression, whereas CAP-LAMP2b-ADAMTS4 EVs, particularly clone SG3, reversed these effects by reducing ADAMTS4 and restoring aggrecan. Western blotting confirmed suppressed ADAMTS4 and elevated aggrecan protein. CAP-LAMP2b-ADAMTS4 EVs, therefore, showed superior uptake and therapeutic efficacy in inflamed chondrocytes, attenuating inflammatory gene expression and preserving matrix integrity. These results support engineered EVs as a promising cell-free approach for cartilage repair and osteoarthritis treatment. Full article
(This article belongs to the Section Molecular Biology)
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14 pages, 6164 KB  
Communication
The SGLT2 Inhibitor Dapagliflozin Disrupts the Cell Cycle at High Concentrations Without Altering Glycosphingolipid (De Novo)Biosynthesis
by Richard Jennemann and Roger Sandhoff
Int. J. Mol. Sci. 2025, 26(19), 9811; https://doi.org/10.3390/ijms26199811 - 9 Oct 2025
Viewed by 605
Abstract
Modern computational screening methods are valuable tools for repurposing approved drugs for novel therapeutic applications. They provide initial insights into alternative uses and may significantly shorten the lengthy process of drug development and regulatory approval. Treatment options for glycosphingolipidoses, lysosomal storage diseases involving [...] Read more.
Modern computational screening methods are valuable tools for repurposing approved drugs for novel therapeutic applications. They provide initial insights into alternative uses and may significantly shorten the lengthy process of drug development and regulatory approval. Treatment options for glycosphingolipidoses, lysosomal storage diseases involving glycosphingolipids (GSLs), are currently limited to a few drugs that inhibit de novo GSL biosynthesis, such as eliglustat and miglustat (Zavesca®). In the search for alternative drugs, dapagliflozin emerged as a promising candidate for off-target therapy. In the present study, we investigated whether dapagliflozin can indeed inhibit GSL synthesis, as predicted by previous computational analyses, and compared its effects with those of the glycosphingolipid synthesis inhibitor, the eliglustat analog Genz-123346, in murine 3T3 and Hepa 1-6 cell lines. While Genz-123346 significantly inhibited glycosphingolipid biosynthesis at concentrations as low as 1 µM, dapagliflozin, even up to 50 µM, had no effect on biosynthesis or de novo biosynthesis in either cell line. These results indicate that dapagliflozin, although assessing effects on the cell cycle, including proliferation at high concentrations, is not a suitable candidate for treating glycosphingolipid storage diseases by substrate reduction. Full article
(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling: Role in Health and Diseases—2nd Edition)
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21 pages, 3022 KB  
Article
ARGOS Genes in Cauliflower: Genome-Wide Identification and Functional Validation of BobARL2 Under Abiotic Stresses
by Mengmeng Duan, Guixiang Wang, Mei Zong, Shuo Han, Ning Guo and Fan Liu
Int. J. Mol. Sci. 2025, 26(19), 9810; https://doi.org/10.3390/ijms26199810 - 9 Oct 2025
Cited by 1 | Viewed by 425
Abstract
The Auxin-Regulated Gene Involved in Organ Size (ARGOS) proteins have crucial regulatory effects on organ size and responses to environmental stresses. Despite their importance, Brassica oleracea ARGOS gene members and their functions in response to abiotic stresses have not been thoroughly investigated. In [...] Read more.
The Auxin-Regulated Gene Involved in Organ Size (ARGOS) proteins have crucial regulatory effects on organ size and responses to environmental stresses. Despite their importance, Brassica oleracea ARGOS gene members and their functions in response to abiotic stresses have not been thoroughly investigated. In this study, we identified 40 ARGOS genes via a genome wide analysis of cauliflower and two other B. oleracea morphotypes as well as Brassica rapa, Brassica nigra, and Raphanus sativus. Expression pattern analyses indicated that these genes are responsive to multiple abiotic stresses, including salinity, heat, cold, and diverse hormones. Notably, the expression of an ARGOS-like gene (BobARL2) was upregulated in cauliflower treated with 1-aminocyclopropane-1-carboxylic acid (ACC). Moreover, the overexpression of BobARL2 decreased ethylene sensitivity, resulting in less inhibition of root elongation compared to the wild-type. Additionally, the overexpression lines exhibited enhanced salt tolerance. A yeast two-hybrid assay and luciferase complementation imaging (LCI) assay confirmed that BobARL2 can interact with Reversion-to-ethylene sensitivity Like4 (BobRTL4), which negatively regulates ethylene signal transduction. These findings advance our understanding of the evolution and functional roles of ARGOS genes in cauliflower and other Brassicaceae species, particularly in relation to abiotic stress responses, while also offering valuable insights relevant to the genetic improvement and breeding of novel varieties. Full article
(This article belongs to the Special Issue Advance in Plant Abiotic Stress: 3rd Edition)
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6 pages, 303 KB  
Editorial
Special Issue “Skeletal Muscle Adaptations to Oxidative Stress”
by Guglielmo Duranti
Int. J. Mol. Sci. 2025, 26(19), 9809; https://doi.org/10.3390/ijms26199809 - 9 Oct 2025
Viewed by 528
Abstract
Skeletal muscle constitutes approximately 40% of total adult body weight, and its health is essential for overall well-being [...] Full article
(This article belongs to the Special Issue Skeletal Muscle Adaptations to Oxidative Stress)
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14 pages, 2950 KB  
Article
Serum Metabolomics Uncovers Immune and Lipid Pathway Alterations in Lambs Supplemented with Novel LAB-Bifidobacterium Cocktail
by Roman Wójcik, Angelika Król-Grzymała, Dawid Tobolski, Assel Paritova, Estefanía García-Calvo, Jan Miciński and Grzegorz Zwierzchowski
Int. J. Mol. Sci. 2025, 26(19), 9808; https://doi.org/10.3390/ijms26199808 - 9 Oct 2025
Viewed by 558
Abstract
The ban on antibiotic growth promoters in livestock has intensified the search for effective probiotic alternatives. This study assessed the impact of a novel probiotic cocktail—comprising Lactobacillus plantarum AMT14 and AMT4, L. rhamnosus AMT15, and Bifidobacterium animalis AMT30—on the serum metabolome of lambs [...] Read more.
The ban on antibiotic growth promoters in livestock has intensified the search for effective probiotic alternatives. This study assessed the impact of a novel probiotic cocktail—comprising Lactobacillus plantarum AMT14 and AMT4, L. rhamnosus AMT15, and Bifidobacterium animalis AMT30—on the serum metabolome of lambs using an untargeted GC/MS approach. Sixteen Kamieniec lambs were divided into control and probiotic groups, with serum collected on days 0, 15, and 30. Metabolomic profiling revealed significant alterations in lipid and amino acid metabolism in the probiotic group. By day 15, 38 metabolites were upregulated, including 9,12-octadecadienoic acid, arachidonic acid, and cholesterol. On day 30, key increases included D-glucose, oleic acid, glycine, decanoic acid, and L-leucine. Multivariate analyses (PCA, PLS-DA) demonstrated clear separation between groups, and ROC analysis identified strong biomarkers with high predictive accuracy. These results suggest that probiotic supplementation can beneficially modulate host metabolism, potentially enhancing immune and physiological function in lambs. This highlights the value of multi-strain LAB-Bifidobacterium probiotics as a promising strategy for improving health and reducing antibiotic reliance in ruminant production systems. Full article
(This article belongs to the Special Issue The Role of Metabolism-Related Pathways in Animal Growth, Development, Disease and Behavior)
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16 pages, 3986 KB  
Article
Polyphenols and Fibre: Key Players with Antioxidant Activity in Two Extracts from Pomegranate (Punica granatum)
by Jessica Maiuolo, Federico Liuzzi, Francesca Oppedisano, Anna Spagnoletta, Rosamaria Caminiti, Valeria Mazza, Saverio Nucera, Salvatore Ragusa, Luigi Tucci, Giuseppe Trunfio, Lucia Carmela Passacatini, Sara Ilari, Giancarlo Statti, Vincenzo Mollace and Carolina Muscoli
Int. J. Mol. Sci. 2025, 26(19), 9807; https://doi.org/10.3390/ijms26199807 - 9 Oct 2025
Viewed by 536
Abstract
The pomegranate fruit offers numerous health benefits to humans due to its rich composition of various chemical components, including polyphenols, fibre, flavonoids, minerals, vitamins, organic acids, alkaloids, and amino acids, among others. The antioxidant properties of pomegranate are well known, and this study [...] Read more.
The pomegranate fruit offers numerous health benefits to humans due to its rich composition of various chemical components, including polyphenols, fibre, flavonoids, minerals, vitamins, organic acids, alkaloids, and amino acids, among others. The antioxidant properties of pomegranate are well known, and this study aims to compare these activities in two extracts obtained from the fruit (“Whole Fruit Extract”, WFE and “Internal Membranes Extract”, IME). Various experiments were conducted using both extracts: (1) quantification of polyphenols and flavonoids using the Folin–Ciocalteu colorimetric assay and the aluminium chloride assay, respectively; (2) the measurement of the antioxidant activity was carried out by Reducing Power, Chelating Activity of Ferrous Ions (Fe2+), Radical Absorbance Capacity of Oxygen, Free Radical Scavenging Activity DPPH, and antioxidant effect in vitro; (3) quantitative and quantitative evaluation of the fibre was performed. IME has demonstrated a significantly greater antioxidant effect than WFE, despite possessing a smaller amount of both polyphenols and flavonoids (polyphenols: 68 mg GAE/g for WFE; 47 mg GAE/g for IME; flavonoids: 51mg QE/g for WFE; 35 mg QE/g for IME). For this reason, we evaluated the fibre composition in both extracts. The higher amount of glucans, xylans, and pectin in IME suggested that these fibrous components may be responsible for the greater antioxidant effect detected compared to WFE. Full article
(This article belongs to the Special Issue Updates on Synthetic and Natural Antioxidants)
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13 pages, 10889 KB  
Article
Transthyretin Amyloidosis—One of the Causes of Heart Failure in Patients with Severe Clinical Course of COVID-19
by Zarina Gioeva, Liudmila Mikhaleva, Nikita Gutyrchik, Nikolay Shakhpazyan, Valentina Pechnikova, Konstantin Midiber, Andrej Kontorshchikov, Elizaveta Zentsova and Lev Kakturskij
Int. J. Mol. Sci. 2025, 26(19), 9806; https://doi.org/10.3390/ijms26199806 - 9 Oct 2025
Viewed by 541
Abstract
Wild-type transthyretin amyloidosis is an underdiagnosed condition that significantly contributes to mortality in the elderly population. This histopathological study describes autopsy findings in patients with severe clinical course of COVID-19 and ATTR not identified during life. Autopsy findings in the myocardium were analyzed [...] Read more.
Wild-type transthyretin amyloidosis is an underdiagnosed condition that significantly contributes to mortality in the elderly population. This histopathological study describes autopsy findings in patients with severe clinical course of COVID-19 and ATTR not identified during life. Autopsy findings in the myocardium were analyzed in 19 patients with pre-existing ATTR who died from severe COVID-19. RT PCR was used for pre- and post-mortem detection of SARS-CoV-2 RNA. Immunohistochemical typing was performed with a broad panel of antibodies against different amyloid types. Autopsy specimens from the myocardium and lungs were positive for SARS-CoV-2 RNA in 10 (53%) cases. Microscopic examination of the myocardium revealed focal cardiosclerosis and cardiomyocyte dissociation in 15 (68%) cases, hypertrophy and atrophy of cardiomyocytes in 17 (77%) and 7 (32%), respectively, and myocarditis in 4 (18%) cases. Immunohistochemical analysis determined ATTR amyloidosis in all cases. In patients with rapidly progressive heart failure, the postmortem examination revealed multiple sites of interstitial amyloid deposits and focal cardiosclerosis in the myocardium. Pre-existing cardiac amyloidosis contributes to the aggressive clinical course of COVID-19. Coupled with the toxic effect of the SARS-CoV-2 virus on the myocardium, the disease may lead to progressive heart failure and poor outcomes. Full article
(This article belongs to the Special Issue Molecular Pathology and Treatment of Heart Failure)
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