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Biomolecules
Volume 16
Issue 2
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Biomolecules, Volume 16, Issue 2 (February 2026) – 160 articles

Cover Story (view full-size image): Soft tissue sarcoma remains difficult to treat due to heterogeneity, stemness-driven survival, and therapeutic resistance. Extracellular vesicles (EVs) mediate tumor–stroma communication; yet the impact of stemness-targeted therapies on EVs-associated miRNA networks is unclear. EVs miRNA cargo from mesenchymal stem/stromal cells (MSC) and sarcoma cells (SC) were profiled under basal conditions and after treatment with a synthetic tyrosine–peptide analog (TPA). Identified miRNAs regulate oncogenic and regenerative pathways, revealing regulatory nodes in refractory cancers. Pathway analyses indicate the need for functional validation, including macrophage polarization, angiogenesis, and tumor proliferation assays. EVs miRNAs profiling thus provides a framework for developing next-generation therapies for aggressive malignancies. View this paper
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34 pages, 4644 KB  
Review
Modulation and Reprogramming of Adipose Tissue Macrophages in Obesity
by Yan Liu, Xiaoying Huang, Linfeng Sang, Yang Zhang, Jiajie Cao and Qin Kong
Biomolecules 2026, 16(2), 339; https://doi.org/10.3390/biom16020339 - 23 Feb 2026
Viewed by 1276
Abstract
Chronic inflammation associated with obesity drives metabolic dysfunctions and induces immune cell maintenance. Adipose tissue macrophages (ATMs), the predominant immune population within adipose depots, exhibit substantial heterogeneity and serve as central pathological mediators in obesity-induced adipose inflammation and metabolic dysregulation. In this review, [...] Read more.
Chronic inflammation associated with obesity drives metabolic dysfunctions and induces immune cell maintenance. Adipose tissue macrophages (ATMs), the predominant immune population within adipose depots, exhibit substantial heterogeneity and serve as central pathological mediators in obesity-induced adipose inflammation and metabolic dysregulation. In this review, we highlight the reprogramming of ATMs’ metabolic pathways, including glucose and lipid homeostasis associated with obesity, with a focus on chronic metabolic inflammation. Additionally, we discuss underlying mechanisms supporting ATMs remodeling in obesity, including transcriptional control and epigenetic regulation. Full article
(This article belongs to the Special Issue Metabolic Syndrome and Type 2 Diabetes: From Molecular Pathogenesis to Novel Therapies)
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18 pages, 6736 KB  
Article
Therapeutic Potential of Deferiprone–Resveratrol Hybrid (DFP-RVT) Against Hepatic Iron Overload in β-Thalassemia Mice: A Proteomic Analysis
by Supawadee Maneekesorn, Yodying Yingchutrakul, Nattapon Simanon, Jakkaphan Kumsab, Chutikarn Butkinaree, Sutpirat Moonmuang, Jin Li, Pimlak Charoenkwan, Pimpisid Koonyosying, Narisara Paradee, Somdet Srichairatanakool and Hataichanok Chuljerm
Biomolecules 2026, 16(2), 338; https://doi.org/10.3390/biom16020338 - 23 Feb 2026
Viewed by 599
Abstract
Iron overload is a major pathological feature of β-thalassemia and a key driver of hepatic injury through oxidative stress and mitochondrial dysfunction. This study investigated the molecular effects of iron overload on liver mitochondria and evaluated the therapeutic potential of a deferiprone–resveratrol hybrid [...] Read more.
Iron overload is a major pathological feature of β-thalassemia and a key driver of hepatic injury through oxidative stress and mitochondrial dysfunction. This study investigated the molecular effects of iron overload on liver mitochondria and evaluated the therapeutic potential of a deferiprone–resveratrol hybrid (DFP-RVT) in a β-thalassemia mouse model. Proteomic analysis was performed on liver tissues from baseline control, iron-overloaded, and DFP-RVT-treated mice to identify differentially expressed proteins and affected pathways. Iron overload resulted in marked downregulation of mitochondrial proteins, particularly components of oxidative phosphorylation and iron–sulfur cluster-associated pathways, including frataxin. In contrast, DFP-RVT treatment restored the expression of multiple mitochondrial proteins involved in respiratory chain function and energy metabolism. Comparative proteomic profiling revealed opposing regulation patterns between iron-overloaded and DFP-RVT-treated groups, indicating recovery of mitochondrial integrity following iron chelation therapy. These findings suggest that iron-induced hepatic injury in β-thalassemia is closely linked to mitochondrial protein dysregulation and that DFP-RVT may mitigate this process by restoring mitochondrial protein expression and iron homeostasis. This study provides mechanistic insight into iron-mediated mitochondrial dysfunction and supports the therapeutic potential of DFP-RVT for iron overload-associated liver injury. Full article
(This article belongs to the Special Issue Iron Metabolism in Cells)
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21 pages, 5497 KB  
Article
A Developmental Study of MeCP2 with Core and Linker Histones Indicates a Dynamic Change During Adolescent Brain Development in a Region- and Strain-Specific Manner in Mice
by Ashraf Kadar Shahib, Seyyed Mohyeddin Ziaee, Kazem Nejati-Koshki, James R. Davie and Mojgan Rastegar
Biomolecules 2026, 16(2), 337; https://doi.org/10.3390/biom16020337 - 23 Feb 2026
Viewed by 511
Abstract
Chromatin organization during postnatal development is very important for establishing neuronal function and may be disrupted in neurodevelopmental disorders that are associated with impaired brain function. Both the Methyl CpG-binding protein 2 (MeCP2) and the linker histone H1 are important chromatin regulators. Still, [...] Read more.
Chromatin organization during postnatal development is very important for establishing neuronal function and may be disrupted in neurodevelopmental disorders that are associated with impaired brain function. Both the Methyl CpG-binding protein 2 (MeCP2) and the linker histone H1 are important chromatin regulators. Still, their developmental expression patterns and functional interactions across diverse genetic backgrounds are not well understood. This study examined changes in histone H1, histone H3, and MeCP2 levels in CD1 and C57BL/6 mice in two different strains, in the liver, cerebellum, and cerebral hemispheres obtained at two adolescent developmental stages [P21 (postnatal day 21) and P56]. We show that both strains have significant cerebral-specific increases in MeCP2 and H1, while H3 levels remain consistent. The CD1 strain exhibited hepatic H1 elevation between early (P21) and late (P56) adolescence, which was absent in the C57BL/6 strain. This highlights possible strain-dependent postnatal dynamic chromatin organization. Analysis of Mecp2T158M (Mecp2tm4.1Bird) mutant mice showed compensatory H1 elevation in the Purkinje layer of the cerebellum, indicating possible functional relation between these two chromatin-bound proteins. Despite having minimal MeCP2 protein levels, mutant mice had higher amounts of Mecp2 transcripts, suggesting post-transcriptional/post-translational regulations. Our results demonstrate that H1 and MeCP2 are subject to coordinated developmental control with possible interplay with the chromatin structure. Full article
(This article belongs to the Special Issue Molecular Advances in Rett Syndrome and Other Chromatin Related Disorders)
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16 pages, 4130 KB  
Article
KRSR and RGD Adsorption on TiO2 and Influence of Ion Concentration: A Molecular Dynamics Study
by Tamás Tarjányi, Csaba Ákos Rosztóczy and Tibor Szabó
Biomolecules 2026, 16(2), 336; https://doi.org/10.3390/biom16020336 - 23 Feb 2026
Viewed by 388
Abstract
Bioactive peptide coatings modulate cell–implant interactions on TiO2 surfaces; however, most molecular-level studies of peptide adsorption are performed under low or fixed ionic conditions. Physiological environments exhibit non-negligible and variable electrolyte concentrations, so understanding ionic strength effects is crucial for designing effective [...] Read more.
Bioactive peptide coatings modulate cell–implant interactions on TiO2 surfaces; however, most molecular-level studies of peptide adsorption are performed under low or fixed ionic conditions. Physiological environments exhibit non-negligible and variable electrolyte concentrations, so understanding ionic strength effects is crucial for designing effective peptide-functionalized titanium implants. An amorphous TiO2 surface was generated from a crystalline rutile precursor and simulated in explicit water using classical molecular dynamics at nine NaCl concentrations. For each condition, seven independent simulations with different initial peptide placements/orientations were performed. Peptide backbone RMSD, minimum peptide–surface distance, and adsorption time ratio were analysed as functions of NaCl concentration. For both peptides, backbone RMSD remained stable and showed no statistically significant correlation with NaCl concentration. KRSR exhibited a significant increase in minimum distance with increasing NaCl concentration and a significant decrease in adsorption time ratio, indicating reduced persistence of close surface contact at higher salt levels. In contrast, RGD showed no significant dependence of either minimum distance or adsorption time ratio within the tested range. Within the limits of the applied force-field MD framework and the investigated NaCl range, KRSR adsorption on TiO2 is more sensitive to ionic strength than RGD, consistent with the stronger electrostatic contribution for the net-positively charged KRSR motif. Full article
(This article belongs to the Section Molecular Biophysics: Structure, Dynamics, and Function)
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15 pages, 1168 KB  
Review
Fibrinogen and Fibrin as Growth Factor Regulators: Pathological Implications, and Translational Opportunities
by Abha Sahni and Sanjeev K. Sahni
Biomolecules 2026, 16(2), 335; https://doi.org/10.3390/biom16020335 - 23 Feb 2026
Cited by 1 | Viewed by 630
Abstract
Fibrinogen and fibrin are multifunctional plasma proteins that play central roles in hemostasis, tissue repair, and extracellular matrix organization. Their complex molecular architecture enables specific interactions with key growth factors, including fibroblast growth factor-2 (FGF-2), vascular endothelial growth factor (VEGF), platelet-derived growth factor [...] Read more.
Fibrinogen and fibrin are multifunctional plasma proteins that play central roles in hemostasis, tissue repair, and extracellular matrix organization. Their complex molecular architecture enables specific interactions with key growth factors, including fibroblast growth factor-2 (FGF-2), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), and others, promoting growth factor localization, protection from proteolysis, and enhanced signaling. These interactions regulate essential biological processes such as angiogenesis, cell proliferation, and wound healing. Dysregulation of fibrinogen–fibrin contributes to pathological conditions, including thrombosis, chronic inflammation, cancer progression, neurological complications, and impaired tissue regeneration. Recent advances in fibrin-based biomaterials leverage these molecular interactions for controlled therapeutic delivery and regenerative medicine applications. Emerging recombinant fibrinogen technologies and precision biomaterial engineering further expand the translational potential of targeting fibrinogen–fibrin growth factor interactions to improve clinical outcomes. This review offers an integrated overview of fibrinogen and fibrin biology, detailing their molecular interactions with growth factors, their pathological implications, clinical significance, and future research directions, emphasizing the translational potential of leveraging these interactions to advance human health. Full article
(This article belongs to the Special Issue Fibrinogen and Fibrin in Human Diseases)
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17 pages, 717 KB  
Review
The Evolution of Symbiosis in Staphylococcus epidermidis: From a Protective Mutualist to a Parasitic Pathogen
by Stefanie Au, William Dela Cruz, Mehzabin Lala, Srinivasan Karthikeyan and Vishwanath Venketaraman
Biomolecules 2026, 16(2), 334; https://doi.org/10.3390/biom16020334 - 23 Feb 2026
Viewed by 556
Abstract
Staphylococcus epidermidis is more often known as a human skin commensal, serving as a primary protective bacterium on the skin’s surface. However, more recent literature highlights the role of S. epidermidis as a nosocomial pathogen and a multidrug-resistant organism that poses a global [...] Read more.
Staphylococcus epidermidis is more often known as a human skin commensal, serving as a primary protective bacterium on the skin’s surface. However, more recent literature highlights the role of S. epidermidis as a nosocomial pathogen and a multidrug-resistant organism that poses a global threat. The evolution of S. epidermidis can be owed to its accumulation of resistance mechanisms, including adhesion, biofilm formation, genomic islands, phage elements, integrated plasmids, and quorum sensing. It is suspected that through gene transfer, S. epidermidis is partially responsible for the feared multidrug-resistant Staphylococcus aureus through the mecA gene and many other genomic island transfers. Overall, prolonged nosocomial exposure and misuse of antibiotics have driven dramatic genomic remodeling in S. epidermidis, characterized by many methods of genetic recombination, SCCmec and insertion sequence acquisition, and accumulation of multiple resistance genes. Our review reviews the role of S. epidermidis as both a commensal and a pathogenic bacterium, summarizes the genes responsible for its multidrug resistance, and describes methods of combatting its invasion. Full article
(This article belongs to the Special Issue Evolutionary Genomics of Bacterial Endosymbionts: From Mutualism to Parasitism)
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81 pages, 3981 KB  
Review
Graph Learning in Bioinformatics: A Survey of Graph Neural Network Architectures, Biological Graph Construction and Bioinformatics Applications
by Lijia Deng, Ziyang Dong, Zhengling Yang, Bo Gong and Le Zhang
Biomolecules 2026, 16(2), 333; https://doi.org/10.3390/biom16020333 - 23 Feb 2026
Viewed by 777
Abstract
Graph Neural Networks (GNNs) have become a central methodology for modelling biological systems where entities and their interactions form inherently non-Euclidean structures. From protein interaction networks and gene regulatory circuits to molecular graphs and multi-omics integration, the relational nature of biological data makes [...] Read more.
Graph Neural Networks (GNNs) have become a central methodology for modelling biological systems where entities and their interactions form inherently non-Euclidean structures. From protein interaction networks and gene regulatory circuits to molecular graphs and multi-omics integration, the relational nature of biological data makes GNNs particularly well-suited for capturing complex dependencies that traditional deep learning methods fail to represent. Despite their rapid adoption, the effectiveness of GNNs in bioinformatics depends not only on model design but also on how biological graphs are constructed, parameterised and trained. In this review, we provide a structured framework for understanding and applying GNNs in bioinformatics, organised around three key dimensions: (1) graph construction and representation, including strategies for deriving biological networks from heterogeneous sources and selecting biologically meaningful node and edge features; (2) GNN architectures, covering spectral and spatial formulations, representative models such as Graph Convolutional Networks (GCNs), Graph Attention Networks (GATs), Graph Sample and AggregatE (GraphSAGE) and Graph Isomorphism Network (GIN), and recent advances including transformer-based and self-supervised paradigms; and (3) applications in biomedical domains, spanning disease–gene association prediction, drug discovery, protein structure and function analysis, multi-omics integration and biomedical knowledge graphs. We further examine training considerations, including optimisation techniques, regularisation strategies and challenges posed by data sparsity and noise in biological settings. By synthesising methodological foundations with domain-specific applications, this review clarifies how graph quality, architectural choice and training dynamics jointly influence model performance. We also highlight emerging challenges such as modelling temporal biological processes, improving interpretability, and enabling robust multimodal fusion that will shape the next generation of GNNs in computational biology. Full article
(This article belongs to the Special Issue Application of Bioinformatics in Medicine)
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13 pages, 716 KB  
Review
ABCA1: A Therapeutic Target for Improving Cholesterol Homeostasis in Peripheral Neuropathies
by Yeon Hwa Woo, Natalie E. Schmidt, Jan O. Johansson and Lucia Notterpek
Biomolecules 2026, 16(2), 332; https://doi.org/10.3390/biom16020332 - 22 Feb 2026
Viewed by 550
Abstract
ATP-binding cassette A1 (ABCA1) is a critical molecule in facilitating cholesterol transport in a variety of organs. In the nervous system, cholesterol supply is essential and rate-limiting for myelin biogenesis, which underlies efficient conduction of nerve impulses. When myelin is damaged or improperly [...] Read more.
ATP-binding cassette A1 (ABCA1) is a critical molecule in facilitating cholesterol transport in a variety of organs. In the nervous system, cholesterol supply is essential and rate-limiting for myelin biogenesis, which underlies efficient conduction of nerve impulses. When myelin is damaged or improperly formed due to genetic defects, a host of neurological symptoms may arise. A rare form of peripheral neuropathy in Tangier disease (TD) patients is associated with autosomal recessive mutations in ABCA1. Accordingly, when ABCA1 loses its function due to misexpression, the neuropathic phenotype is over-represented. Independently, studies have revealed the altered expression of ABCA1 and dysregulation of cholesterol metabolism in a host of inherited peripheral neuropathies engaging the Peripheral Myelin Protein 22 (PMP22), suggesting shared pathophysiology. While the role of ABCA1 has not been investigated broadly in peripheral nerves, the transporter molecule is a therapeutic target for human disorders, including multiple sclerosis and Alzheimer’s disease. Investigations in rodent models of type 1 Charcot–Marie–Tooth (CMT) neuropathies support the candidacy of this cholesterol transporter as a therapeutic target in efforts of peripheral myelin repair. Ongoing preclinical studies in central and peripheral nervous system disease models will provide critical information on the importance of ABCA1 as a target for disease modifying intervention. Full article
(This article belongs to the Special Issue Lipid Signaling in Human Disease)
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27 pages, 11407 KB  
Review
A Single-Cell Perspective on Remapping Human Adult Neurogenesis and Its Clinical Implications
by Xin Tian and Renqing Zhao
Biomolecules 2026, 16(2), 331; https://doi.org/10.3390/biom16020331 - 22 Feb 2026
Viewed by 655
Abstract
Recent advances in single-cell RNA sequencing (scRNA-seq) have substantially deepened our understanding of adult hippocampal neurogenesis (AHN), enabling the detection of neural stem cells, progenitors, and immature neurons in postmortem human brain tissue and revealing how these populations are altered in neurological disease. [...] Read more.
Recent advances in single-cell RNA sequencing (scRNA-seq) have substantially deepened our understanding of adult hippocampal neurogenesis (AHN), enabling the detection of neural stem cells, progenitors, and immature neurons in postmortem human brain tissue and revealing how these populations are altered in neurological disease. Additionally, scRNA-seq enables the identification of disease-specific cell subtypes and distinct gene expression signatures associated with neurological disorders, many of which are linked to alterations in AHN and cognitive function. Such cellular- and molecular-level insights into neurological disease mechanisms provide a strong foundation for the development of targeted therapeutic strategies. Indeed, scRNA-seq has also emerged as a powerful tool in drug discovery and development across multiple disease areas, including cancer, cardiovascular disorders, and neurological conditions. In this review, we offer a comprehensive and integrative perspective on the cellular and molecular landscape of human hippocampal neurogenesis, the pathological mechanisms underlying neurological disorders, and their implications for therapeutic development. Full article
(This article belongs to the Section Molecular Medicine)
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19 pages, 2630 KB  
Article
Adaptive Evolution of Odorant-Binding and Chemosensory Protein Gene Families in Genus Drosophila Fallén, 1823 (Diptera, Drosophilidae)
by Xing-Yu Pang, Si-Yang Liu, Quan-You Yu and Shou-Min Fang
Biomolecules 2026, 16(2), 330; https://doi.org/10.3390/biom16020330 - 20 Feb 2026
Viewed by 543
Abstract
Odorant-binding proteins (OBPs) and chemosensory proteins (CSPs) serve as carriers for signal molecules within the insect olfactory system, playing a crucial role in detecting chemical cues related to feeding and reproduction. However, their roles in host shift and environmental adaptation remain poorly understood. [...] Read more.
Odorant-binding proteins (OBPs) and chemosensory proteins (CSPs) serve as carriers for signal molecules within the insect olfactory system, playing a crucial role in detecting chemical cues related to feeding and reproduction. However, their roles in host shift and environmental adaptation remain poorly understood. This study identified the OBP and CSP gene families across 32 Drosophila species, revealing their adaptive evolutionary trajectory. It was found that the gene number of the OBP family varied widely between species, ranging from 37 to 66 genes, while the gene number of the CSP family was conserved. The OBP family experienced two major gene expansion events on the ancestral branches of the diet-diverse melanogaster lineage, leading to an increased number. Positive selection occurred during evolution in the orthologous groups of Obp22a, Obp57e and Obp83ef. Homology modeling and molecular docking revealed that variation in the positively selected sites across different Drosophila species resulted in significant changes to free binding energy and affinity for plant odors and insecticides. Our findings highlight gene expansion and functional diversification within the Drosophila OBP family may contribute to shaping the dietary spectrum and promoting adaptation to toxic substances. Full article
(This article belongs to the Section Bioinformatics and Systems Biology)
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34 pages, 2139 KB  
Review
Targeting Fatty Acids in Liver Cancer: Molecular Insights and Drug Approaches
by Antonio Cigliano, Dora Pischedda, Claudio Pandino, Grazia Galleri and Diego F. Calvisi
Biomolecules 2026, 16(2), 329; https://doi.org/10.3390/biom16020329 - 20 Feb 2026
Viewed by 715
Abstract
Primary liver cancer (PLC), commonly classified as hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), is a highly aggressive malignancy with a dismal prognosis. Recent research has highlighted the crucial role of dysregulation of fatty acid metabolism in HCC progression and therapeutic resistance. Here, [...] Read more.
Primary liver cancer (PLC), commonly classified as hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), is a highly aggressive malignancy with a dismal prognosis. Recent research has highlighted the crucial role of dysregulation of fatty acid metabolism in HCC progression and therapeutic resistance. Here, with a focus primarily on HCC, we review how alterations in the processes involving fatty acids dynamically contribute to the survival, proliferation, and development of the drug resistance of PLC cells. In particular, increased expression of fatty acid transporters, reprogramming of de novo lipogenesis, and altered fatty acid oxidation trigger the upregulation of oncogenic signaling pathways and adaptation to nutrient-deprived conditions inducing the rapid proliferation of PLC cells. Furthermore, fatty acid metabolism influences immune cell function and angiogenesis, thereby shaping the tumor microenvironment and promoting the progression of PLC. This review explores the complex relationship between fatty acid metabolism and the progression of PLC. It discusses future directions regarding the most promising druggable targets and their current status in clinical trials. Furthermore, it examines the advancement of innovative therapeutic strategies and highlights the significant challenges in targeting fatty acid metabolism. Finally, it discusses how precision therapies focused on fatty acid metabolism can be effectively integrated with current treatments. Full article
(This article belongs to the Special Issue Molecular Signalling Pathways in Tumorigenesis and Tumor Suppression)
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20 pages, 4476 KB  
Article
Notch Signaling Exacerbates Pulmonary Fibrosis by Regulating the Differentiation of CD4+ Tissue-Resident Memory T Cells
by Jia Shi, Ruiting Su, Lili Zhuang, Zhangmei Lin, Xinyuan Ruan, Yichao Qian, Jieying Zhu, Shuyi Wang and Niansheng Yang
Biomolecules 2026, 16(2), 328; https://doi.org/10.3390/biom16020328 - 20 Feb 2026
Viewed by 598
Abstract
The involvement of the immune system in pulmonary fibrosis is established, the precise contributions of tissue-resident memory T (TRM) cells are still poorly defined. This study sought to define the contribution of CD4+ TRM cells to pulmonary fibrosis, their [...] Read more.
The involvement of the immune system in pulmonary fibrosis is established, the precise contributions of tissue-resident memory T (TRM) cells are still poorly defined. This study sought to define the contribution of CD4+ TRM cells to pulmonary fibrosis, their origin, and regulatory mechanisms. We combined bioinformatic analysis of human fibrotic lung single-cell RNA-sequencing data with experiments in a bleomycin-induced C57BL/6 mouse model. Flow cytometry, targeted in vivo depletion, lymphocyte trafficking blockade, cell co-culture, and pharmacological inhibition were employed. CD4+ TRM cells were observed at higher frequencies within fibrotic lung tissue. Their presence correlated with disease severity, and they were found to exhibit a pro-inflammatory and pro-fibrotic phenotype. Their specific depletion alleviated fibrosis. These cells primarily originated from recruited circulating lymphocytes, as blocking this recruitment reduced TRM accumulation and attenuated disease. Furthermore, the Notch signaling pathway was activated in fibrotic lung CD4+ TRM cells, and its inhibition suppressed their differentiation and impaired their pro-fibrotic function. We conclude that CD4+ TRM cells are pathogenic drivers in pulmonary fibrosis, originating from circulating precursors and being regulated by Notch signaling, underscoring their relevance for therapeutic intervention. Full article
(This article belongs to the Special Issue Inflammation and Immunity in Lung Disease)
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15 pages, 1019 KB  
Article
Lurasidone Sub-Chronic Treatment During Adolescence Modulates Inflammatory and Inositol-Related Metabolic Pathways in the Prefrontal Cortex of Adult Male Rats Exposed to Prenatal Stress
by Monica Mazzelli, Samantha Saleri, Valentina Zonca, Moira Marizzoni, Marco Andrea Riva, Veronica Begni and Annamaria Cattaneo
Biomolecules 2026, 16(2), 327; https://doi.org/10.3390/biom16020327 - 20 Feb 2026
Viewed by 449
Abstract
Prenatal stress (PNS) predisposes individuals to mental disorders later in life. Adolescence is a period of heightened brain plasticity and vulnerability, when many mental disorders emerge, yet pharmacological strategies remain largely underexplored. In adult PNS rats, lurasidone (LUR) has been shown to reduce [...] Read more.
Prenatal stress (PNS) predisposes individuals to mental disorders later in life. Adolescence is a period of heightened brain plasticity and vulnerability, when many mental disorders emerge, yet pharmacological strategies remain largely underexplored. In adult PNS rats, lurasidone (LUR) has been shown to reduce PNS-induced risk; however, its effects following adolescent administration remain unclear. To investigate the long-lasting effects of PNS and their modulation following sub-chronic LUR adolescent treatment, a whole-genome expression analysis of the prefrontal cortex (PFC) of adult male PNS rats was performed. Twelve PNS and eleven control rats were randomly assigned to receive vehicle or LUR from postnatal day (PND) 35 to 49 and sacrificed at PND 50. Partek Genomics Suite and Ingenuity Pathway Analysis were used for differential expression and pathway analyses. Within the PFC, PNS induced an upregulation of pathways involved in environmental information processing and in immune system-related pathways, which was reduced after LUR, as observed by IL-8 signaling (z-scores before: 1.34 and after LUR: −2.65). In parallel, LUR administration itself modulated Inositol-related metabolic pathways. Overall, these findings suggest that LUR adolescent treatment may counteract some PNS-induced alterations, supporting adolescence as a critical window for early preventive strategies with translational relevance for stress-related neuropsychiatric disorders. Full article
(This article belongs to the Section Bioinformatics and Systems Biology)
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20 pages, 2310 KB  
Article
Modulation of α-Synuclein Oligomer and Aggregate Populations by pH and Metal Ions
by Ananya Nair, Punarvash Mitta, Lathan Lucas, Josephine C. Ferreon and Allan Chris M. Ferreon
Biomolecules 2026, 16(2), 326; https://doi.org/10.3390/biom16020326 - 20 Feb 2026
Viewed by 622
Abstract
α-Synuclein (α-syn) aggregation underlies synucleinopathies, yet the physicochemical determinants that govern which assembly states form under defined solution conditions remain incompletely resolved. Here, we examine how pH and metal ions reshape α-syn self-assembly. Across acidic and physiological pH conditions, α-syn populates monomeric, nanoscale [...] Read more.
α-Synuclein (α-syn) aggregation underlies synucleinopathies, yet the physicochemical determinants that govern which assembly states form under defined solution conditions remain incompletely resolved. Here, we examine how pH and metal ions reshape α-syn self-assembly. Across acidic and physiological pH conditions, α-syn populates monomeric, nanoscale oligomeric, and mesoscale aggregate states whose relative abundances evolve over time. Fluorescence microscopy reveals robust mesoscale assembly at pH 5, minimal aggregation at pH 7, and transient assemblies at pH 3, highlighting the limitations of imaging-based detection alone. Therefore, we use dynamic light scattering (DLS) to resolve oligomeric populations and quantify pH-dependent redistribution of assembly mass. Toxicity-mitigating modulators altered α-syn assembly in a strongly pH-dependent manner. Anle138b increased the abundance of oligomeric species at low pH, whereas EGCG produced divergent effects at pH 5 and pH 3. We further examined the effects of metal ions, finding that Fe3+ stabilized higher-order assemblies under acidic conditions, Cu2+ delayed assembly at pH 5 while enhancing aggregation at pH 3, and Zn2+ increased oligomerization primarily at low pH. Overall, these results demonstrate that α-syn assembly is highly sensitive to coupled effects of pH, metal chemistry, and time. Full article
(This article belongs to the Special Issue Protein Self-Assembly in Diseases and Function)
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41 pages, 7886 KB  
Review
Targeted Protein Degradation in Cancer: PROTACs, New Targets, and Clinical Mechanisms
by Bushra Faryal, Zain Ul Abideen, Muhammad Irfan, Haseeb Ahmed, Fazliddin Jalilov, Lola Abduraximova and Ghulam Abbas Ashraf
Biomolecules 2026, 16(2), 325; https://doi.org/10.3390/biom16020325 - 19 Feb 2026
Cited by 2 | Viewed by 1222
Abstract
The onset of proteolysis targeting chimeras (PROTACs) has reshaped the entire context of targeted cancer therapy by offering a novel approach for the selective degradation of disease-causing proteins, overcoming the limitations of traditional occupancy-driven inhibition. This heterobifunctional technology recruits endogenous E3 ubiquitin ligases [...] Read more.
The onset of proteolysis targeting chimeras (PROTACs) has reshaped the entire context of targeted cancer therapy by offering a novel approach for the selective degradation of disease-causing proteins, overcoming the limitations of traditional occupancy-driven inhibition. This heterobifunctional technology recruits endogenous E3 ubiquitin ligases to mark proteins of interest (POI) for proteosomal degradation via the ubiquitin-proteasome system (UPS). Unlike conventional inhibitors, PROTACs function catalytically and can target previously “undruggable proteins”, such as transcription factors, scaffold proteins, and non-enzymatic regulators, offering potential to overcome acquired resistance and achieve potent efficacy at sub-stoichiometric doses. The review explores the latest innovations in PROTAC design, including E3 ligase selection, linker chemistry, and ligand optimization, while highlighting promising preclinical and clinical candidates against oncogenic drivers, anti-apoptotic factors (BCL-xL), and nuclear hormone receptors. Furthermore, we critically examine key translational challenges, such as pharmacokinetics, off-target effects, and resistance mechanisms, and discuss viable solutions, including dual E3 ligase engagement, novel modalities like AUTACs/ATTECs, LYTACs, and AI-driven design. As the field rapidly evolves from foundational to clinical application, PROTACs are redefining therapeutic possibilities, offering a robust, flexible, and scalable framework for the future of precision oncology. Full article
(This article belongs to the Section Molecular Medicine)
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38 pages, 1912 KB  
Review
Glutamate Metabotropic Receptors-Linked Postsynaptic Density Proteins: An Emergent Hub for Antipsychotics’ Regulation of Synaptic Plasticity and Metaplasticity
by Annarita Barone, Licia Vellucci, Anita Nasti, Benedetta Mazza, Federica Iannotta, Felice Iasevoli and Andrea de Bartolomeis
Biomolecules 2026, 16(2), 324; https://doi.org/10.3390/biom16020324 - 19 Feb 2026
Viewed by 683
Abstract
Glutamate metabotropic receptors (mGluRs) and their molecular partners at the postsynaptic density (PSD) represent a highly dynamic molecular hub that integrates multiple neurotransmitter signals and regulates synaptic plasticity and metaplasticity, which are putatively involved in the pathophysiology of psychiatric illnesses, including schizophrenia. Group [...] Read more.
Glutamate metabotropic receptors (mGluRs) and their molecular partners at the postsynaptic density (PSD) represent a highly dynamic molecular hub that integrates multiple neurotransmitter signals and regulates synaptic plasticity and metaplasticity, which are putatively involved in the pathophysiology of psychiatric illnesses, including schizophrenia. Group I mGluRs (mGluR1 and mGluR5) interact with PSD adaptor and scaffolding proteins, such as Homer, Shank, Norbin, and PICK1, as well as intracellular downstream effectors, creating a molecular network that resembles a Lego-like structure, where modular protein interactions fine-tune glutamatergic transmission. Evidence from preclinical research indicates that dysregulation of mGluR expression and function, along with disrupted PSD protein expression, may contribute to the pathophysiology of schizophrenia by altering glutamatergic neurotransmission and synaptic stability. Antipsychotic mechanisms of action may involve, at least in part, the modulation of mGluR activity mediated through PSD proteins. Notably, novel agents that enhance spinogenesis by acting at the level of PSD proteins, such as SPG302, may open promising avenues for therapeutics aimed at restoring synaptic integrity. While Group I mGluRs dominate postsynaptic regulation, Group II (mGluR2/3) and III (mGluR4/6/7/8) receptors -primarily presynaptic- inhibit neurotransmitter release and plasticity, offering complementary therapeutic avenues. Emerging strategies, such as allosteric modulators of mGluRs, aim to rebalance synaptic signaling in treatment-resistant schizophrenia. This review synthesizes how PSD proteins and mGluRs interact in schizophrenia, exploring their potential as druggable targets for novel therapies. Full article
(This article belongs to the Section Molecular Biology)
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19 pages, 6731 KB  
Article
Phosphoproteomic Profiling of Multiple Myeloma Based on Ex Vivo Drug Sensitivity Resistance Testing Identifies Phosphorylation Signatures Associated with Drug Response
by Katie Dunphy, Ellen Purcell, Caroline A. Heckman, Paul Dowling, Despina Bazou and Peter O’Gorman
Biomolecules 2026, 16(2), 323; https://doi.org/10.3390/biom16020323 - 19 Feb 2026
Viewed by 542
Abstract
Multiple myeloma (MM) is characterised by the clonal expansion of plasma cells in the bone marrow followed by end-organ damage. Despite a significant increase in the five-year survival rate in recent years, MM is still considered an incurable disease as patients will repeatedly [...] Read more.
Multiple myeloma (MM) is characterised by the clonal expansion of plasma cells in the bone marrow followed by end-organ damage. Despite a significant increase in the five-year survival rate in recent years, MM is still considered an incurable disease as patients will repeatedly relapse and develop resistance to standard-of-care therapies. A central theme for the personalization of MM therapy is understanding the biological mechanisms of drug resistance and identifying clinically relevant biomarkers of therapeutic response. Highly effective protocols for the enrichment of phosphorylated peptides followed by high-resolution mass spectrometry makes possible the quantitation of thousands of site-specific phosphorylation events, principally on serine, threonine or tyrosine residues. In this study, phosphoproteomic analysis of 20 MM patient cell lysates was performed, stratified based on their ex vivo drug response profiles to Bortezomib and Lenalidomide, two of the most foundational therapeutic agents in the management of MM. In this study, patients who are highly sensitive to these drugs show increased phosphorylation of proteins concerned with translation and RNA processing including the spliceosome, RNA transport and RNA binding pathways, while highly resistant patients demonstrated an increased phosphorylation of proteins involved with tight junctions, the Rap1 signalling pathway and the phosphatidylinositol signalling system. This study has established a phosphoproteomic dataset displaying unique phosphorylation signatures associated with drug sensitivity in MM patient plasma cells. The identification of phosphorylation signatures associated with drug resistance provides the foundation for further exploration of these mechanisms and associated signalling pathways to further characterise drug resistance mechanisms in MM and identify promising biomarkers of therapeutic response and targets for drug re-sensitization in MM. Full article
(This article belongs to the Special Issue Multiple Myeloma: From Pathophysiology to Novel Therapeutic Approaches)
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29 pages, 4394 KB  
Article
Feedback Regulation of Pancreatic Juice Secretion in Pigs
by Jose Luis Valverde Piedra and Sylwia Edyta Szymanczyk
Biomolecules 2026, 16(2), 322; https://doi.org/10.3390/biom16020322 - 19 Feb 2026
Viewed by 457
Abstract
Pancreatic exocrine secretion is regulated by the physicochemical properties and nutrient composition of gastric and intestinal chyme. The present study examined integrative feedback mechanisms involved in the physiological control of pancreatic secretion, with particular emphasis on interactions between pancreatic juice, bile, and gut-derived [...] Read more.
Pancreatic exocrine secretion is regulated by the physicochemical properties and nutrient composition of gastric and intestinal chyme. The present study examined integrative feedback mechanisms involved in the physiological control of pancreatic secretion, with particular emphasis on interactions between pancreatic juice, bile, and gut-derived regulatory and metabolic signals. A chronic porcine model enabling selective withdrawal and controlled reintroduction of pancreatic juice and bile into defined intestinal segments was employed. Duodenal and ileal exposure to pancreatic juice suppressed pancreatic enzyme secretion, while intraduodenal administration of pancreatin elicited a biphasic inhibitory response. Interruption of bile flow to the duodenum resulted in increased pancreatic protein output and was associated with reduced circulating cholecystokinin concentrations. In contrast, intraduodenal infusion of bile acids attenuated pancreatic exocrine secretion. Prolonged bile deprivation led to sustained pancreatic hypersecretion accompanied by a marked reduction in biliary leptin output. Collectively, these findings indicate that pancreatic exocrine secretion in pigs is regulated by multiple interacting feedback pathways operating along the gastrointestinal tract. The observed responses support functional contributions of protease-dependent luminal feedback, distal intestinal sensing, hormone-dependent regulation, and bile-associated metabolic modulation. Full article
(This article belongs to the Special Issue Digestive Enzymes in Health and Disease)
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15 pages, 1563 KB  
Article
DERA-Catalyzed Chemoenzymatic Access to Nucleobase-Substituted Candidate Statin Precursors
by Romina Fernández Varela, Eman Abdelraheem, Lautaro Giaimo, Luciano Cortés, Leticia Lafuente, Ana Laura Valino, Peter-Leon Hagedoorn, Ulf Hanefeld, Adolfo Iribarren and Elizabeth Lewkowicz
Biomolecules 2026, 16(2), 321; https://doi.org/10.3390/biom16020321 - 19 Feb 2026
Viewed by 513
Abstract
Aldolases are powerful biocatalysts for the stereoselective formation of carbon–carbon bonds and are widely used in the synthesis of chiral intermediates for pharmaceutical applications. Among them, 2-deoxyribose-5-phosphate aldolase (DERA) has been extensively exploited for the preparation of the conserved side chain of statins. [...] Read more.
Aldolases are powerful biocatalysts for the stereoselective formation of carbon–carbon bonds and are widely used in the synthesis of chiral intermediates for pharmaceutical applications. Among them, 2-deoxyribose-5-phosphate aldolase (DERA) has been extensively exploited for the preparation of the conserved side chain of statins. In this work, we report a novel chemoenzymatic approach for the synthesis of nucleobase-substituted lactol products as potential precursors of new statin analogues. A C49M variant of DERA from Pectobacterium atrosepticum (PaDERA C49M) was employed to catalyze sequential aldol additions using aldehyde-functionalized nucleobases as non-natural electrophilic substrates. The formation of nucleobase-containing lactols was confirmed, demonstrating for the first time the acceptance of nucleobase-derived aldehydes in DERA-catalyzed aldol reactions. This strategy provides access to structurally novel statin side-chain precursors and expands the synthetic potential of DERA toward the generation of new classes of bioactive compounds. Full article
(This article belongs to the Special Issue Recent Advances in the Enzymatic Synthesis of Bioactive Compounds)
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23 pages, 3707 KB  
Article
Local ADSC Delivery Methods Accelerate Healing of Large Unburned Full-Thickness Skin Defects by Promoting an Optimal Wound Microenvironment
by Semra Gürünlüoğlu, Basri Satılmış, Mehmet Gül, Muhammed Dündar, Kubilay Gürünlüoğlu, Ezgi Karaaslan, Ahmet Koç, Mehmet Aslan, Sezai Yılmaz, Mehmet Demircan and Tevfik Tolga Şahin
Biomolecules 2026, 16(2), 320; https://doi.org/10.3390/biom16020320 - 18 Feb 2026
Viewed by 1445
Abstract
Background: This study introduces an experimental model of a large, full-thickness skin defect and evaluates how adipose-derived stem cells characterized by high self-renewal and differentiation capacity affect both wound healing and the wound microenvironment when delivered using two different local application methods. Materials [...] Read more.
Background: This study introduces an experimental model of a large, full-thickness skin defect and evaluates how adipose-derived stem cells characterized by high self-renewal and differentiation capacity affect both wound healing and the wound microenvironment when delivered using two different local application methods. Materials and Methods: In this preclinical study, we established an excisional full-thickness skin defect model involving approximately 30% of the total body surface area (TBSA). Five experimental groups were formed, each containing equal numbers of male and female rats: (1) subdermal ADSC injection (ADSC-I) (n = 8), (2) application of an acellular dermal matrix (ADM) seeded with ADSCs (n = 8) (ADSC-ADM), (3) ADM alone (n = 8), (4) subdermal saline injection (n = 8) (SS-I), and (5) an untreated skin-defect sham group (n = 8). Wound healing and wound microenvironment parameters were assessed at regular intervals using macroscopic and microscopic evaluations, as well as various quantitative measurements. The study was terminated when complete wound closure was achieved in all animals of at least one experimental group. Results: The most favorable healing outcomes were observed in the two ADSC-treated groups. More favorable microenvironmental conditions in the stem cell groups were detected from day 14 onward. Complete closure of the dermal defects occurred by day 32 in the ADSC-I group, whereas none of the other groups achieved full wound closure within the study period. Conclusions: Local application of adipose-derived stem cells may accelerate wound healing by favorably modulating the wound microenvironment. Full article
(This article belongs to the Special Issue Molecular Advances in Wound Healing and Skin Regeneration)
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16 pages, 1136 KB  
Article
Immunomodulatory Effects of Nintedanib on Human Blood Monocytes/Macrophages from Patients with Idiopathic Pulmonary Fibrosis
by Maria Talmon, Arianna Mares, Hari Baskar Balasubramanian, Chiara Mocchetti, Lara Camillo, Piero Balbo, Luigia Grazia Fresu and Filippo Patrucco
Biomolecules 2026, 16(2), 319; https://doi.org/10.3390/biom16020319 - 18 Feb 2026
Viewed by 543
Abstract
Background: Nintedanib (NTD) is an inhibitor of several tyrosine kinases whose role in the pathogenesis of idiopathic pulmonary fibrosis (IPF) is well recognized. Therefore, NTD was approved for the management of IPF about ten years ago. NTD has been demonstrated to have immunomodulatory [...] Read more.
Background: Nintedanib (NTD) is an inhibitor of several tyrosine kinases whose role in the pathogenesis of idiopathic pulmonary fibrosis (IPF) is well recognized. Therefore, NTD was approved for the management of IPF about ten years ago. NTD has been demonstrated to have immunomodulatory effects in vitro. We now evaluated the effects of NTD on monocyte/macrophage phenotype isolated from IPF patients treated with NTD. Methods: Monocytes were isolated from IPF patients naïve for treatments and used as such or differentiated into M1- and M2-like macrophages. The cellular phenotype (characterized by the expression pro- and anti-fibrotic surface markers) and responsiveness (characterized by oxidative stress and cytokine expression/release) were evaluated, at T0 (before treatment starts) and after 6 months of treatment with a 150 mg capsule of NTD twice a day (T1). Results: Following differentiation, both M1 and M2 macrophage populations, derived from monocytes isolated from patients treated with NTD, present a higher percentage of cells positive for anti-fibrotic CD80/CD86 and expressing less profibrotic CD206/CD163. Importantly, gene expression and release of the pro-fibrotic factor TGF-β were significantly decreased at T1. Conclusions: These results show that although it does not have a direct effect on monocyte phenotype/responsiveness, NTD in vivo appears to prime monocytes to differentiate preferentially towards an anti-fibrotic macrophage phenotype, suggesting that it has an immunomodulatory effect on macrophage polarization. This data leads us to hypothesize that NTD could also induce this change in vivo, thus contributing to the improvement of the patient’s fibrotic state. Full article
(This article belongs to the Special Issue Molecular Pathology, Diagnostics, and Therapeutics of Lung Disease)
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24 pages, 19064 KB  
Article
Structural and Computational Analysis of Pseudomonas aeruginosa DNA Gyrase Reveals Molecular Characteristics That May Contribute to Ciprofloxacin Resistance
by Lalith Perera, Libertad García-Villada, Andrea M. Kaminski, Natalya Degtyareva, Lars C. Pedersen and Paul W. Doetsch
Biomolecules 2026, 16(2), 318; https://doi.org/10.3390/biom16020318 - 18 Feb 2026
Viewed by 369
Abstract
Pseudomonas aeruginosa is considered a priority pathogen by the World Health Organization due to its resistance to antibiotics. Isolates resistant to ciprofloxacin (CPFX), a bactericide commonly used against P. aeruginosa, usually carry the mutations T83I or D87N in the GyrA subunit of [...] Read more.
Pseudomonas aeruginosa is considered a priority pathogen by the World Health Organization due to its resistance to antibiotics. Isolates resistant to ciprofloxacin (CPFX), a bactericide commonly used against P. aeruginosa, usually carry the mutations T83I or D87N in the GyrA subunit of the DNA gyrase. Yet, the molecular mechanisms by which these mutations confer CPFX-resistance to P. aeruginosa are unknown. Here we solved the crystal structure of the P. aeruginosa gyrase catalytic cleavage core and used it to carry out molecular dynamic (MD) simulations of CPFX-gyrase binding in the wild-type as well as the T83I and the D87N mutant systems. Our results show that DNA plays the most prominent stabilizing role once CPFX is bound, with relatively minor contributions from Thr83 or Asp87. Interestingly, we found a solvent cavity adjacent to these residues that may provide CPFX access to the active site. Interaction energy analysis using Umbrella Sampling indicates that Thr83 and Asp87 may influence CPFX trajectory during binding. In the mutant systems, the repulsive potential increases at the cavity site, which may hinder CPFX accessing the binding site. These results shed light on P. aeruginosa resistance to CPFX and may help provide a methodology to identify new therapeutic agents to target fluoroquinolone resistant bacteria. Full article
(This article belongs to the Special Issue Recent Molecular Research on Protein Structure and Function)
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14 pages, 1835 KB  
Article
Metabolic Comparison of Mature and Immature Bovine Cumulus–Oocyte Complexes with Standardization of Bioenergetic Assessment
by Cristina Algieri, Emilia Attolini, Eleonora Iacono, Salvatore Nesci and Barbara Merlo
Biomolecules 2026, 16(2), 317; https://doi.org/10.3390/biom16020317 - 18 Feb 2026
Viewed by 437
Abstract
This study compared the bioenergetic profiles of immature and in vitro–matured bovine cumulus–oocyte complexes (COCs) using Seahorse extracellular flux technology, with the aim of establishing standardized conditions for real-time metabolic assessment during in vitro maturation (IVM). Groups of five COCs were analysed prior [...] Read more.
This study compared the bioenergetic profiles of immature and in vitro–matured bovine cumulus–oocyte complexes (COCs) using Seahorse extracellular flux technology, with the aim of establishing standardized conditions for real-time metabolic assessment during in vitro maturation (IVM). Groups of five COCs were analysed prior to maturation and after 22 h of IVM using the Seahorse XFp Analyzer to measure oxygen consumption rate (OCR, pmoL/min) and extracellular acidification rate (ECAR, mpH/min), providing dynamic readouts of oxidative phosphorylation and glycolysis that extend beyond conventional endpoint assays. To optimize assay performance, three media were first evaluated: TCM199, DMEM/F12, and HEPES-buffered synthetic oviductal fluid (HSOF). HSOF yielded the most reliable readings for immature COCs, whereas TCM199 provided superior conditions for mature COCs. Adhesion strategies were then tested by comparing uncoated wells with wells coated with fibronectin, concanavalin A, or Matrigel®. Sequential injections of oligomycin and rotenone plus antimycin A enabled partitioning of mitochondrial and glycolytic contributions to ATP production. COC maturation was associated with a clear metabolic shift from glycolysis toward oxidative metabolism. Immature COCs displayed a predominantly glycolytic phenotype, while mature COCs showed increased active mitochondrial ATP production. Adhesion conditions markedly affected the detected metabolic profile: concanavalin A and fibronectin supported effective attachment and were associated with robust energy metabolism, whereas Matrigel® and poor adhesion were linked to quiescent profiles with low OCR and ECAR signals. Together, these data define practical assay parameters for extracellular flux analysis of COCs and highlight the increasing reliance on mitochondrial function as a hallmark of oocyte maturation, supporting improved metabolic phenotyping for IVM optimization. Full article
(This article belongs to the Section Molecular Reproduction)
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16 pages, 5226 KB  
Article
Effects of Nintedanib on Orofacial Fibroblasts and Myoblasts
by Zhihao Wang, Frank A. D. T. G. Wagener, Edwin M. Ongkosuwito and Johannes W. Von den Hoff
Biomolecules 2026, 16(2), 316; https://doi.org/10.3390/biom16020316 - 18 Feb 2026
Viewed by 362
Abstract
Following surgical interventions or acquired trauma, fibrosis often inhibits muscle and skin regeneration. Nintedanib, an antifibrotic drug for lung fibrosis, may help prevent orofacial fibrosis. This study evaluates Nintedanib’s potential for inhibiting myofibroblast differentiation and affecting the fusion of orofacial myoblasts into myotubes. [...] Read more.
Following surgical interventions or acquired trauma, fibrosis often inhibits muscle and skin regeneration. Nintedanib, an antifibrotic drug for lung fibrosis, may help prevent orofacial fibrosis. This study evaluates Nintedanib’s potential for inhibiting myofibroblast differentiation and affecting the fusion of orofacial myoblasts into myotubes. Rat gingival fibroblasts and satellite cells (SCs) were isolated and cultured with TGF-β1 to induce myofibroblast differentiation and prevent myotube formation. Adding 1 and 10 ng/mL TGF-β1 significantly increased the percentage of myofibroblasts. Although Nintedanib did not affect the percentage of myofibroblasts, it strongly decreased the total number of fibroblasts and myofibroblasts. Additionally, Nintedanib at a concentration of 2 μM markedly reduced the expression of Ki-67 in fibroblasts and myofibroblasts. In the SC cultures, 0.2 ng/mL TGF-β1 reduced the fusion index of SCs. Treatment with 2 μM Nintedanib significantly increased the fusion index of SCs. Furthermore, MyoD and MyoG gene expression in SCs was also significantly enhanced by Nintedanib at a concentration of 2 μM. Nintedanib promotes myotube formation while inhibiting (myo)fibroblast proliferation. This dual action stresses its potential as an anti-fibrotic therapy after orofacial surgery or traumatic injury affecting muscle tissue. Full article
(This article belongs to the Section Chemical Biology)
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31 pages, 986 KB  
Review
Exploring the Potential of Receptor Silencing in the Tumor Microenvironment by RNA Interference
by Karina Mayumi Tani Bezerra de Melo, Beatriz Mendonça Alves Bandeira, Pedro Vinícius Silva Novis, Micaela Evellin dos Santos Silva, Ingrid Andrêssa de Moura, Antonio Carlos de Freitas and Anna Jéssica Duarte Silva
Biomolecules 2026, 16(2), 315; https://doi.org/10.3390/biom16020315 - 17 Feb 2026
Viewed by 610
Abstract
Cancer is a heterogeneous disease caused by genetic and epigenetic factors, leading to alterations in signaling pathways and regulatory processes. Overall, the more commonly employed conventional treatments present side effects and resistance. Due to the diverse cellular composition of the tumor microenvironment, inhibition [...] Read more.
Cancer is a heterogeneous disease caused by genetic and epigenetic factors, leading to alterations in signaling pathways and regulatory processes. Overall, the more commonly employed conventional treatments present side effects and resistance. Due to the diverse cellular composition of the tumor microenvironment, inhibition of cell communication by RNA interference (RNAi) has emerged as a strategy to regulate the expression of receptors linked to carcinogenesis. This review examines RNAi-mediated receptor silencing as a strategy to modify the tumor microenvironment, primarily in tumor cells, enhancing its vulnerability to immune cell destruction and reducing resistance to conventional therapies. In the tumor microenvironment, the silencing of immune checkpoints like PD-1 and CTLA-4 has demonstrated the ability to restore T cell function and enhance the efficacy of adoptive cell therapies. Additionally, the targeting of G protein-coupled receptors, including CXCR4, CCR5, and A2aR, as well as growth factor receptors such as VEGFR and EGFR, and interleukin receptors, interferes with pathways that are critical for tumor promotion, resulting in diminished angiogenesis, metastasis, and immunosuppression. These strategies utilize advanced delivery systems, including nanoparticles and exosomes, and show that silencing multiple targets can produce more effective antitumor outcomes than single-target methods, underscoring the significant potential of RNA interference in cancer treatment. Full article
(This article belongs to the Special Issue Feature Papers in Molecular Biology Section 2025)
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14 pages, 600 KB  
Communication
SnakeBITE: A SNAKEmake-Based Interface for Third-Generation Sequencing Data Analysis
by Andrea Bimbocci, Marta Baragli and Alberto Magi
Biomolecules 2026, 16(2), 314; https://doi.org/10.3390/biom16020314 - 16 Feb 2026
Viewed by 389
Abstract
In recent years, the use of computational pipelines for the analysis of omic data has become routine in bioinformatics, particularly with the advent of Next-Generation Sequencing (NGS) technologies. These technologies generate vast amounts of data that necessitate sophisticated analysis methods, often requiring programming [...] Read more.
In recent years, the use of computational pipelines for the analysis of omic data has become routine in bioinformatics, particularly with the advent of Next-Generation Sequencing (NGS) technologies. These technologies generate vast amounts of data that necessitate sophisticated analysis methods, often requiring programming skills and command-line interface proficiency. This complexity poses challenges for users from various backgrounds, including clinicians and biologists. Current solutions often involve workflow management tools and graphical user interfaces to simplify pipeline creation and execution. However, these tools predominantly cater to NGS data and are not fully adaptable to Third-Generation Sequencing (TGS) data, such as that produced by Oxford Nanopore Technologies (ONT). Here we present SnakeBITE, a modular genomic data analysis pipeline builder based on the Snakemake workflow manager, integrated with an interactive Shiny-based interface. SnakeBITE enables users to configure and execute TGS data analysis workflows locally without requiring programming expertise. The application supports the full ONT genomics data analysis pipeline, including base calling, alignment, variant calling, and annotation. Our results demonstrate SnakeBITE’s capacity to handle various stages of ONT data analysis efficiently, offering a user-friendly and highly customizable tool that bridges the gap between sophisticated data analysis and user accessibility. Full article
(This article belongs to the Section Bioinformatics and Systems Biology)
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20 pages, 3824 KB  
Article
Evaluation of GlcNAc-Configured Glycomimetics as Pharmacological Chaperones of NAGLU for the Treatment of Mucopolysaccharidosis IIIB
by Nissrine Ballout, Jérôme Désiré, Angela Johana Espejo-Mojica, Katherin Niño-Traslaviña, Daniel Sandoval, Carlos Javier Alméciga-Díaz, Yves Blériot and Jérôme Ausseil
Biomolecules 2026, 16(2), 313; https://doi.org/10.3390/biom16020313 - 16 Feb 2026
Viewed by 481
Abstract
The interaction of a set of four N-acetyl-glucosamine (GlcNAc) glycomimetics with human N-acetyl-glucosaminidase (NAGLU), the genetically defective enzyme in patients suffering from mucopolysaccharidosis (MPS) IIIB, also known as Sanfilippo B syndrome, was investigated to identify potential pharmacological chaperones. Glycomimetic–NAGLU binding was [...] Read more.
The interaction of a set of four N-acetyl-glucosamine (GlcNAc) glycomimetics with human N-acetyl-glucosaminidase (NAGLU), the genetically defective enzyme in patients suffering from mucopolysaccharidosis (MPS) IIIB, also known as Sanfilippo B syndrome, was investigated to identify potential pharmacological chaperones. Glycomimetic–NAGLU binding was initially studied by molecular docking simulations and a thermal shift assay. The effects of the glycomimetics on NAGLU activity enhancement were studied in fibroblast cells from seven MPS IIIB patients. A significant increase in NAGLU activity in four cell lines in the presence of glycomimetic MK 8719, a molecule tested in a Phase 1 study in healthy volunteers to treat Alzheimer’s disease, was demonstrated. Furthermore, MK 8719 prevented the increase in glycosaminoglycan (GAG) levels in four MPS IIIB fibroblast cells, suggesting that this molecule may be worth investigating further as a pharmacological chaperone for MPS IIIB. These results represent an important contribution towards the development of a specific therapy for MPS IIIB. Full article
(This article belongs to the Section Chemical Biology)
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21 pages, 2078 KB  
Article
Comparative Proteomic Analysis of Gonadal Tissue in Solea senegalensis Reveals Reproductive Deregulation Associated with F1 Individuals
by Marco Anaya-Romero, Alberto Arias-Pérez, María Esther Rodríguez, Manuel Alejandro Merlo, Silvia Portela-Bens, Ismael Cross and Laureana Rebordinos
Biomolecules 2026, 16(2), 312; https://doi.org/10.3390/biom16020312 - 16 Feb 2026
Cited by 1 | Viewed by 593
Abstract
Reproductive dysfunction in captive-bred Senegalese sole (Solea senegalensis) limits aquaculture production consolidation, particularly due to reduced fertility and poor sperm quality in F1 males. To elucidate the molecular mechanisms underlying this problem, a quantitative proteomic analysis was conducted using LC–MS/MS on [...] Read more.
Reproductive dysfunction in captive-bred Senegalese sole (Solea senegalensis) limits aquaculture production consolidation, particularly due to reduced fertility and poor sperm quality in F1 males. To elucidate the molecular mechanisms underlying this problem, a quantitative proteomic analysis was conducted using LC–MS/MS on gonadal tissues from wild and F1 males and females. A total of 2221 proteins were identified, of which 1797 were retained after quality filtering. Comparative analyses revealed clear segregation by origin (F1 [cultivated] and wild) and sex (male and female), and 86 proteins were differentially expressed between F1 and wild males. Functional enrichment showed significant downregulation of key reproductive processes in F1 males, including sperm–egg recognition, binding of sperm to zona pellucida, and acrosome reaction, suggesting impaired gamete interaction and fertilization ability. Conversely, F1 males displayed metabolic and proteolytic pathway enrichment, which is indicative of compensatory energy demands. Protein–protein interaction network analysis identified a reproductive subnetwork dominated by zona pellucida sperm-binding proteins, which exhibited reduced connectivity in F1 males. These results demonstrate a coordinated suppression of molecular components essential for sperm–egg communication and acrosomal exocytosis, providing proteomic evidence for the systemic deregulation of the reproductive machinery in F1 fish. This study identifies potential protein biomarkers linked to reproductive performance, offering molecular targets to improve broodstock management and fertilization success in S. senegalensis aquaculture. Full article
(This article belongs to the Special Issue Molecular Insights into Sex and Evolution)
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19 pages, 5095 KB  
Article
gga-let-7c-3p Inhibits Chicken Abdominal Adipogenesis by Regulating PPARD Gene
by Xi Cheng, Shuohan Li, Ke Zhang, Yulong Guo, Hong Li, Zhuanjian Li, Yadong Tian, Xiangtao Kang, Xiaojun Liu and Weihua Tian
Biomolecules 2026, 16(2), 311; https://doi.org/10.3390/biom16020311 - 16 Feb 2026
Viewed by 476
Abstract
MicroRNAs (miRNAs) have been increasingly involved in mammalian lipid metabolism. However, their regulatory roles and molecular mechanisms in abdominal fat deposition in chicken remain largely unexplored. In this study, based on the previous miRNA transcriptome data during chicken abdominal preadipocytes’ adipogenic differentiation, we [...] Read more.
MicroRNAs (miRNAs) have been increasingly involved in mammalian lipid metabolism. However, their regulatory roles and molecular mechanisms in abdominal fat deposition in chicken remain largely unexplored. In this study, based on the previous miRNA transcriptome data during chicken abdominal preadipocytes’ adipogenic differentiation, we explored the biological functions and regulatory mechanisms of a differentially expressed miRNA, gga-let-7c-3p, in adipogenesis. Gain- and loss-of-function assays elucidated that gga-let-7c-3p significantly decreased viability, proliferation, cell cycle progression, intracellular lipid droplet accumulation and triglyceride content, as well as the mRNA expression of proliferation- and lipid metabolism-related genes in chicken abdominal preadipocytes. Dual-luciferase reporter assay confirmed that gga-let-7c-3p could directly interact with the 3′UTR of the transcription factor—peroxisome proliferator activated the receptor delta (PPARD) gene and thus inhibited its post-transcriptional expression. The PPARD gene significantly decreased viability, proliferation, and cell cycle progression, while it increased intracellular lipid droplet accumulation and triglyceride content of chicken abdominal preadipocytes, paralleling with the mRNA expression of proliferation- and lipid metabolism-related genes. Collectively, gga-let-7c-3p could inhibit the proliferation and adipogenic differentiation of chicken abdominal preadipocytes, at least by targeting the PPARD gene. These findings reveal the regulatory mechanisms of the gga-let-7c-3p/PPARD axis in chicken abdominal adipogenesis, and could provide potential molecular markers for lean line broiler breeding. Full article
(This article belongs to the Section Molecular Genetics)
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14 pages, 1997 KB  
Article
In Vivo Evaluation of Oxidative Stress Induced by Intraperitoneal Administration of Mannosylerythritol Lipid Biosurfactant in Swiss Mice
by Paulo Emilio Feuser, Ana Letícia Silva Coelho, Mariana de Melo Cardoso, Rahisa Scussel, Mírian Ívens Fagundes, Lariani Tamires Witt Titbohl, Isabela Karina Della-Flora, Ricardo Andrez Machado-de-Ávila, Paulo Cesar Lock Silveira, Debora de Oliveira and Cristiano José de Andrade
Biomolecules 2026, 16(2), 310; https://doi.org/10.3390/biom16020310 - 16 Feb 2026
Viewed by 398
Abstract
Mannosylerythritol lipid-B (MEL-B) is a glycolipid whose biological properties have been widely investigated, especially in the skincare, food, and therapeutic fields. Despite this, few studies have addressed the toxicity of this glycolipid in vivo. Therefore, this work aimed to evaluate the in vivo [...] Read more.
Mannosylerythritol lipid-B (MEL-B) is a glycolipid whose biological properties have been widely investigated, especially in the skincare, food, and therapeutic fields. Despite this, few studies have addressed the toxicity of this glycolipid in vivo. Therefore, this work aimed to evaluate the in vivo oxidative stress induced by MEL-B in Swiss mice. MEL-B (50 and 150 mg/kg) was administered intraperitoneally at two exposure times, 24 and 72 h. Biochemical damage was quantified in the gastrocnemius, lungs, kidneys, heart, liver, and spleen. This study assessed the levels of reactive oxygen species, oxidative damage markers, antioxidant defenses, protein concentration, triglycerides, creatine kinase (CK-MB), and lactate dehydrogenase (LDH). DCF (2′,7′-dichlorofluorescein), sulfhydryl, and SOD (superoxide dismutase) levels were used to assess oxidative damage and antioxidant defenses in cells. The results indicate that MEL-B did not trigger acute toxicity in the tested animals in a systemic context. Oxidative stress was observed in the liver samples, likely due to the metabolization of MEL-B. The levels of triglycerides and of CK-MB and LDH enzymes did not present any significant alteration (p < 0.05), indicating that glycolipids do not trigger tissue damage. These findings open new perspectives for the safe use of MEL-B in cosmetic and medicinal products. Full article
(This article belongs to the Section Chemical Biology)
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