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Volume 26
Issue 24
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Int. J. Mol. Sci., Volume 26, Issue 24 (December-2 2025) – 430 articles

Cover Story (view full-size image): Multistep cascades of enzymatic reactions can enhance the effectiveness of sustainable processes: a novel one-pot process for transformation of cellulose and castor oil into biodiesel by yeasts hybridized with cellulose-coated emulsion micro-particles incorporating cellulolytic enzymes and lipases. The system was designed to allow consolidated saccharification, fermentation, and transesterification (cSFT) with effective substrate channeling. This cascade includes the enzymatic hydrolysis of the cellulose coating, production of ethanol by yeast fermentation of the released glucose, and generation of biodiesel at the inner micro-particle interface of the oil core by lipase-catalyzed transesterification. This system can be a model for transformations of cellulose into valuable chemicals. View this paper
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15 pages, 991 KB  
Article
Human Serum Albumin: 3D Insight on Protein Hydration
by Marina V. Fedotova and Sergey E. Kruchinin
Int. J. Mol. Sci. 2025, 26(24), 12192; https://doi.org/10.3390/ijms262412192 - 18 Dec 2025
Viewed by 496
Abstract
Human serum albumin (HSA) is one of the main proteins in human blood plasma and serves as a molecular “taxi” transporting various compounds, including organic compounds, drugs, metal ions, etc., through the circulatory system throughout the human body. As with any other proteins, [...] Read more.
Human serum albumin (HSA) is one of the main proteins in human blood plasma and serves as a molecular “taxi” transporting various compounds, including organic compounds, drugs, metal ions, etc., through the circulatory system throughout the human body. As with any other proteins, HSA hydration plays an important role in maintaining its structure and functioning as well as influencing its ability to bind to ligands. This contribution presents, for the first time, a generalized picture of hydration of this biomacromolecule obtained within the framework of the 3D-RISM (three-dimensional Reference Interaction Site Model) theory of solvation. Based on 3D isodensity maps and structural parameters (hydration numbers, hydration layer thickness, fraction of hydrogen bonds, SASA, etc.), the most probable model of HSA hydration structure was reconstructed. With the description of HSA hydration, two important issues were also addressed in detail. The first is the correct determination of the hydration layer thickness, a common problem in protein science. The second is the possible state and behavior of hydration water in HSA–ligand binding. The presented results provide a deeper understanding of the relationship between solvent and HSA, which brings new knowledge to the understanding of protein hydration. Full article
(This article belongs to the Collection State-of-the-Art Macromolecules in Russia)
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32 pages, 6414 KB  
Review
The Role of Prostaglandins as Major Inflammatory Mediators in Colorectal Cancer
by Mario Macia Guardado, Valentina Lutz, Markus Hengstschläger and Helmut Dolznig
Int. J. Mol. Sci. 2025, 26(24), 12191; https://doi.org/10.3390/ijms262412191 - 18 Dec 2025
Viewed by 684
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related morbidity and mortality, with inflammation playing a pivotal role in its pathogenesis. Chronic inflammation in the intestine significantly increases the risk of CRC development. Main compounds participating in the inflammatory process are [...] Read more.
Colorectal cancer (CRC) is one of the leading causes of cancer-related morbidity and mortality, with inflammation playing a pivotal role in its pathogenesis. Chronic inflammation in the intestine significantly increases the risk of CRC development. Main compounds participating in the inflammatory process are prostaglandins; bioactive lipids derived from arachidonic acid metabolism via the cyclooxygenase (COX) pathway. While it is well known that prostaglandin E2 (PGE2) promotes CRC tumorigenesis, other prostaglandins, such as PGD2, PGF2α, and prostacyclin (PGI2), remain relatively underexplored. These prostaglandins may exert distinct or opposing effects on CRC development, but the current understanding of their functions is limited. Additionally, the impact of prostaglandins on immune regulation and the tumor microenvironment, is far from being fully understood. Addressing these knowledge gaps is crucial for identifying novel therapeutic targets and optimizing chemoprevention strategies. Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce the risk of CRC, largely by inhibiting prostaglandin producing enzymes. However, their use is limited due to their gastrointestinal and cardiovascular side effects. Therefore, understanding the intricate role of inflammation and prostaglandin signaling in CRC is critical to develop safer and more effective chemopreventive approaches. This review summarizes the current knowledge of prostaglandins, linking inflammation and CRC. It further addresses the potential of targeting prostaglandin pathways for chemoprevention. Furthermore, we discuss emerging pharmacological targets that modulate prostaglandin production, signaling or degradation, offering promise for preventing CRC development. Full article
(This article belongs to the Special Issue Signalling Pathways in Metabolic Diseases and Cancers)
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13 pages, 1736 KB  
Article
Antioxidant and Anti-Inflammatory Activity of Cell Suspension Culture Extracts of Plukenetia carabiasiae
by Janet María León-Morales, Soledad García-Morales, Maura Téllez-Téllez, Alexandre Cardoso-Taketa, Mónica Morales-Aguilar, Celso Gutiérrez-Báez and Anabel Ortiz-Caltempa
Int. J. Mol. Sci. 2025, 26(24), 12190; https://doi.org/10.3390/ijms262412190 - 18 Dec 2025
Viewed by 350
Abstract
The genus Plukenetia includes lianas or vines with oleaginous seeds rich in omega-3 and omega-6 fatty acids, proteins, and vitamin E, and the presence of flavonoids, steroids, and terpenoids has also been reported in leaves. Several species of Plukenetia have traditionally been cultivated [...] Read more.
The genus Plukenetia includes lianas or vines with oleaginous seeds rich in omega-3 and omega-6 fatty acids, proteins, and vitamin E, and the presence of flavonoids, steroids, and terpenoids has also been reported in leaves. Several species of Plukenetia have traditionally been cultivated in their native distribution areas, and their propagation is usually by seed. The aim of this work was to establish callus and cell suspension cultures of P. carabiaseae, an endemic species of Mexico, for the evaluation of the in vitro antioxidant and anti-inflammatory potential of its extracts. Three light conditions were evaluated for the establishment of P. carabiaseae callus lines from leaf explants. Friable calluses obtained under constant light were used to initiate a cell suspension cultures in Gamborg basal (B5) medium supplemented with 2,4-dichlorophenoxyacetic acid (2,4-D) and kinetin (CIN), as growth regulators. After 35 days of cultivation, different polarity extracts from biomass were obtained, showing that the acetone extract had the highest antioxidant activity and a high total phenolic content (30.57 mg of gallic acid equivalent (GAE)/g dry weight). The anti-inflammatory activity of the methanolic extract, evaluated in murine macrophages induced with bacterial lipopolysaccharides, was dose-dependent, without cytotoxic effects. This is the first report of the establishment of P. carabiasiae cell suspension culture and demonstrates its potential as a biotechnological source of antioxidant and anti-inflammatory metabolites. Full article
(This article belongs to the Special Issue Anti-Cancer, Anti-Inflammatory, and Antioxidation Active Substances: 3rd Edition)
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15 pages, 3762 KB  
Article
Srcap Chromatin Remodeler Is Required for Efficient Replication Dynamics in Mammalian Cells
by Stefka K. Dzhokova, Rossitsa H. Hristova, Peter S. Botev, Temenouga N. Guecheva and Anastas G. Gospodinov
Int. J. Mol. Sci. 2025, 26(24), 12189; https://doi.org/10.3390/ijms262412189 - 18 Dec 2025
Viewed by 310
Abstract
The SNF2-related chromatin remodeler Srcap is the principal ATPase responsible for the deposition of the histone variant H2A.Z at promoters and regulatory chromatin regions. Although this activity is known to modulate transcription, its contribution to DNA replication remains unexplored. Here we show that [...] Read more.
The SNF2-related chromatin remodeler Srcap is the principal ATPase responsible for the deposition of the histone variant H2A.Z at promoters and regulatory chromatin regions. Although this activity is known to modulate transcription, its contribution to DNA replication remains unexplored. Here we show that Srcap is required for efficient replication fork progression and origin firing in mammalian cells. Using RNA interference in human PC3 cells, we found that Srcap depletion leads to a ~25% reduction in fork elongation rate, decreased replication fork density, accumulation of the replication-stress marker γH2AX, and reduced chromatin-bound H2A.Z. High-resolution expansion microscopy further revealed diminished intensity and increased spacing of replication foci, consistent with reduced origin activation. Transcriptomic analysis of published data identified broad downregulation of replication-associated genes. These data uncover a dual mechanism by which Srcap sustains replication efficiency—through both H2A.Z-dependent chromatin organization and transcriptional maintenance of the replication machinery. Our findings establish Srcap as an important coordinator of replication dynamics, with implications for genome stability. Full article
(This article belongs to the Section Molecular Biology)
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15 pages, 3242 KB  
Article
Graphitic Carbon Nitride-Decorated Cobalt Diselenide Composites for Highly Efficient Hydrogen Evolution Reaction
by Abu Talha Aqueel Ahmed, Saravanan Sekar, Sutha Sadhasivam, Balaji Murugan, Sangeun Cho, Youngmin Lee, Sejoon Lee and Sankar Sekar
Int. J. Mol. Sci. 2025, 26(24), 12188; https://doi.org/10.3390/ijms262412188 - 18 Dec 2025
Viewed by 433
Abstract
Transition-metal dichalcogenides have emerged as promising non-noble-metal electrocatalysts for efficient hydrogen production through the hydrogen evolution reaction (HER). In this work, we fabricated the graphitic carbon nitride-decorated cobalt diselenide (gC3N4-CoSe2) nanocomposites via the facile hydrothermal method. The [...] Read more.
Transition-metal dichalcogenides have emerged as promising non-noble-metal electrocatalysts for efficient hydrogen production through the hydrogen evolution reaction (HER). In this work, we fabricated the graphitic carbon nitride-decorated cobalt diselenide (gC3N4-CoSe2) nanocomposites via the facile hydrothermal method. The prepared gC3N4-CoSe2 nanocomposites displayed an interconnected and aggregated morphology of gC3N4-decorated CoSe2 nanoparticles with offering large surface area of 82 m2/g. The gC3N4-CoSe2 nanocomposites exhibited excellent HER activity with a low overpotential (141 mV) and tiny Tafel slope (62 mV/dec) with excellent durability for 100 h at 10 mA/cm2 in an alkaline electrolyte. These outstanding HER performances of gC3N4-CoSe2 can be ascribed to the synergistic interaction between the electrochemically active porous CoSe2 nanoparticles and the highly conductive gC3N4 nanosheets. These results indicate that the gC3N4-CoSe2 nanocomposites hold promising and efficient HER electrocatalysts for sustainable green hydrogen production. Full article
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29 pages, 8498 KB  
Article
Nephroprotective Effects of Quercetin–Selenium Nanoparticles Against Glycerol-Induced AKI
by Ahmed M. Ashour, Ali Khames, Khaled M. Alam-ElDein, Ahmed Hassan Ibrahim Faraag, Nievin Ahmed Mahran, Badriyah Aljazzaf, Rabia Alghazeer, Fatma Akmal, Marwa Ahmed Mahmoud and Mohamed H. A. Gadelmawla
Int. J. Mol. Sci. 2025, 26(24), 12187; https://doi.org/10.3390/ijms262412187 - 18 Dec 2025
Viewed by 401
Abstract
Acute kidney injury (AKI) is defined as a quick and often reversible decline in renal performance, as shown by elevated creatinine or reduced urine volume. AKI is a common illness, particularly among hospitalized cases, and can be observed in up to 7% of [...] Read more.
Acute kidney injury (AKI) is defined as a quick and often reversible decline in renal performance, as shown by elevated creatinine or reduced urine volume. AKI is a common illness, particularly among hospitalized cases, and can be observed in up to 7% of hospital admissions and 30% of ICU admissions. This study was designed to explore the nephroprotective potential of eco-synthesized quercetin–selenium nanoparticles (QUR-SeNPs) against experimentally glycerol-induced rhabdomyolysis leading to AKI. Forty healthy adult male albino rats were employed in the experiment. Animals were randomly distributed equally into five groups: Control: orally administered with normal saline solution. GLY: orally administered with normal saline (0.9% NaCl) for 15 consecutive days, at day 14, animals of this group received a single dose of intramuscular (im.) injection of 50% glycerol (GLY) (10 mg/kg/day). GLY and quercetin (GLY&QUR): orally administered with quercetin daily for 15 days (50 mg/kg/day), at day 14, animals of this group received a single dose of im. injection of 50% glycerol (10 mg/kg/day). GLY&Na2SeO3: orally administered with sodium selenite daily for 15 days (0.5 mg/kg/day), at day 14, animals of this group received a single dose of im. injection of 50% glycerol (10 mg/kg/day). GLY&QUR-SeNPs: orally administered with selenium nanoparticles synthesized using quercetin daily for 15 days (0.5 mg/kg/day), at day 14, animals of this group received a single dose of im. injection of 50% glycerol (10 mg/kg/day). Oxidative stress, inflammatory, and apoptotic markers, in addition to histopathological, gene expression, and immunohistochemical analysis, were assessed for all groups. The results demonstrated that QUR-SeNPs effectively ameliorated renal functional, biochemical, and molecular disturbances through their synergistic antioxidant, anti-inflammatory, and anti-apoptotic potential, surpassing the effects of either quercetin or selenium alone. Biosynthesized selenium nanoparticles using QUR-SeNPs demonstrated remarkable nephroprotective activity by normalizing renal biomarkers, restoring antioxidant capacity, inhibiting inflammatory cytokines, and preventing apoptotic damage. The nanoparticle formulation exhibited superior efficacy to either QUR or Se alone, highlighting the synergistic interplay between selenium and quercetin through enhanced bioavailability, redox stability, and molecular targeting. Full article
(This article belongs to the Special Issue Advances in Natural Antioxidants in Human Health and Diseases)
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19 pages, 5105 KB  
Article
Low Levels of Mouse γδ T Cell Development Persist in the Presence of Null Mutants of the LAT Adaptor
by Mikel M. Arbulo-Echevarria, Luis M. Fernandez-Aguilar, Elke Kurz, Inmaculada Vico-Barranco, Raquel Muñoz-Fernández, Isaac Narbona-Sánchez, Manuel Carrasco, Bernard Malissen, Michael L. Dustin and Enrique Aguado
Int. J. Mol. Sci. 2025, 26(24), 12186; https://doi.org/10.3390/ijms262412186 - 18 Dec 2025
Viewed by 369
Abstract
Activation through the T cell receptor (TCR) initiates a signaling cascade in T cells that induces extensive molecular and cellular changes. The adaptor protein Linker for Activation of T cells (LAT) plays an essential role in transducing activation and regulatory signals downstream of [...] Read more.
Activation through the T cell receptor (TCR) initiates a signaling cascade in T cells that induces extensive molecular and cellular changes. The adaptor protein Linker for Activation of T cells (LAT) plays an essential role in transducing activation and regulatory signals downstream of the TCR. Phosphorylation of LAT tyrosine residues recruits multiple signaling proteins, leading to the assembly of the LAT signalosome, which is crucial for relaying signals that regulate T cell development and function. We previously showed that substitution of a negatively charged amino acid segment preceding the fifth tyrosine residue of LAT (Tyr127 in humans or Tyr132 in mouse LAT) enhances some early TCR signaling events, whereas downstream responses, such as Ca2+ influx and Erk phosphorylation, are partially inhibited. To investigate the physiological relevance of this segment in vivo, we generated a new LAT knock-in mouse strain (LatNIL) in which the negatively charged segment was replaced with a non-charged sequence. Unexpectedly, this mutation led to an alternative splicing event in the Lat gene that excluded exons 6 and 7, resulting in a frameshift, a premature stop codon at residue 145, and the loss of the six C-terminal tyrosine residues of LAT. Homozygous LatNIL/NIL mice showed a phenotype similar to that of LAT-knockout and Lat4YF mice (in which the four C-terminal tyrosines had been mutated to phenylalanine). Interestingly, homozygous LatNIL/NIL mice exhibited a distinct population of γδ T cells in lymphoid organs, which has not been observed in LAT-KO or Lat4YF mice. These γδ T cells expressed higher levels of CD27 compared to those in wild-type and LAT-KO mice, suggesting altered activation or differentiation states. Together, these data highlight how subtle alterations in LAT structure can profoundly impact T cell signaling and lineage composition. Full article
(This article belongs to the Section Molecular Immunology)
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29 pages, 16121 KB  
Article
Functionalized Carbon Dots from Bio-Based Precursors as Promising Fluorescent Probes for Cancer Cell Imaging
by Łukasz Janus, Julia Radwan-Pragłowska, Aleksandra Kołodziej-Nowak and Aleksandra Sierakowska-Byczek
Int. J. Mol. Sci. 2025, 26(24), 12185; https://doi.org/10.3390/ijms262412185 - 18 Dec 2025
Viewed by 361
Abstract
This study reports the microwave-assisted synthesis and surface modification of carbon quantum dots (CQDs) from natural precursors and their evaluation as fluorescent probes for cancer cell visualization. CQDs were obtained using amino-glucose as the carbon source and betaine, marine collagen, or dopamine as [...] Read more.
This study reports the microwave-assisted synthesis and surface modification of carbon quantum dots (CQDs) from natural precursors and their evaluation as fluorescent probes for cancer cell visualization. CQDs were obtained using amino-glucose as the carbon source and betaine, marine collagen, or dopamine as surface modifiers. Further functionalization with 7-amino-4-(trifluoromethyl)coumarin enhanced their fluorescence properties. Spectroscopic analyses confirmed successful surface modification, with coumarin-modified CQDs displaying a strong emission peak at ~500 nm and approximately 1.5-fold higher fluorescence intensity compared to unmodified CQDs. Cytotoxicity testing on MG-63 osteosarcoma cells showed cell viabilities above 80% for selected samples, fulfilling ISO 10993-5 criteria for non-toxicity. In vitro bioimaging of astrocytoma 1321N1 cells demonstrated bright and uniform intracellular staining, confirming effective cellular uptake. Compared with the literature reports of green-synthesized CQDs, our results indicate comparable or superior fluorescence performance and similar levels of biocompatibility. These findings highlight the potential of surface-engineered CQDs as biocompatible nanoprobes for cancer diagnostics and represent an initial step toward their application in the detection of circulating tumor cells (CTCs). Full article
(This article belongs to the Special Issue Omics-Driven Unveiling of the Structure and Function of Nanoparticles)
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25 pages, 16838 KB  
Article
Adenosine Triggers an ADK-Dependent Intracellular Signaling Pathway Interacts PFKFB3-Mediated Glycolytic Metabolism to Promote Newly Formed Myofibers Development
by Xiao Wu, Dawei Zeng, Baojia Wang, Jie Liu, Yue Zhang, Cong Huang, Qian Nie, Liangqin Shi and Yong Wang
Int. J. Mol. Sci. 2025, 26(24), 12184; https://doi.org/10.3390/ijms262412184 - 18 Dec 2025
Cited by 1 | Viewed by 347
Abstract
Myopathy encompasses a group of diseases characterized by abnormalities in both muscle function and structure. However, the underlying regulatory mechanisms of newly formed myofiber development remain poorly defined. No promising therapeutic approach has been developed, but numerous medication options are available to alleviate [...] Read more.
Myopathy encompasses a group of diseases characterized by abnormalities in both muscle function and structure. However, the underlying regulatory mechanisms of newly formed myofiber development remain poorly defined. No promising therapeutic approach has been developed, but numerous medication options are available to alleviate symptoms. Our previous studies demonstrated that adenosine kinase (ADK) is critical in regulating adenosine metabolism, pathological angiogenesis, pathological vascular remodeling, and vascular inflammatory diseases. Adenosine dynamically distributes between extracellular and intracellular, and adenosine concentration regulates ADK expression. However, the mechanism by which adenosine triggers an ADK-dependent intracellular signaling pathway to regulate skeletal muscle regeneration is not well defined. This study aimed to evaluate whether the adenosine-induced intracellular signaling pathway is involved in regulating myopathy, and how it regulates the development of newly formed myofibers. In this study, an intramuscular injection of cardiotoxin was used to induce a skeletal muscle injury model; satellite cells and C2C12 cells were employed. Whether adenosine regulates satellite cell activity, new myofiber formation and differentiation, as well as fusion of myofibers, were determined by H&E staining, BrdU incorporation assay, and spheroid sprouting assay. Interaction between ADK and PFKFB3 was evaluated by IF staining, PPI network analysis, molecular docking simulation, and CO-immunoprecipitation assay. The results demonstrated that adenosine dynamically distributes between extracellular and intracellular through concentrative nucleoside transports or equilibrative nucleoside transporters, and it rapidly induces an ADK-dependent intracellular signaling pathway, which interacts with PFKFB3-mediated glycolytic metabolism to promote satellite cell activity, new myofiber formation, differentiation, and fusion, and eventually enhances skeletal muscle regeneration after injury stress. The remarkable endogenous regeneration capacity of skeletal muscle, which is regulated by adenosine-triggered intracellular signaling, presents a promising therapeutic strategy for treating muscle trauma and muscular dystrophies. Full article
(This article belongs to the Section Molecular Endocrinology and Metabolism)
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15 pages, 5183 KB  
Article
Ring-Finger Protein 126 (RNF126) Promotes Anoikis Resistance and Peritoneal Colonization in Ovarian Cancer
by Anh Duc Vu, Shiori Mori, Kanako Akamatsu, Jun Nakayama and Takeharu Sakamoto
Int. J. Mol. Sci. 2025, 26(24), 12183; https://doi.org/10.3390/ijms262412183 - 18 Dec 2025
Viewed by 413
Abstract
Ovarian cancer (OC) represents the most lethal gynecologic malignancy because the majority of patients with OC are diagnosed at advanced stages with peritoneal colonization of OC cells owing to subtle and nonspecific nature of symptoms. Thus, peritoneal colonization-directed therapeutic approaches are urgently needed [...] Read more.
Ovarian cancer (OC) represents the most lethal gynecologic malignancy because the majority of patients with OC are diagnosed at advanced stages with peritoneal colonization of OC cells owing to subtle and nonspecific nature of symptoms. Thus, peritoneal colonization-directed therapeutic approaches are urgently needed for patients with advanced OC. Here, we investigated whether Ring-finger protein 126 (RNF126), an E3 ubiquitin ligase that is aberrantly upregulated in epithelial OC tissues, contributes to the peritoneal colonization of OC. RNF126-depleted OC cells showed comparable proliferation under normal culture conditions but displayed decreased growth under floating (anchorage-independent) conditions in vitro. Further analyses showed that RNF126 promoted anoikis resistance in vitro and increased peritoneal colonization in immunodeficient mice in a RING domain-dependent manner. Mechanistically, RNF126 activated the transcriptional factor NF-κB in OC cells under floating conditions in a RING domain-dependent manner, and this NF-κB activation was essential for anchorage-independent growth and peritoneal colonization of OC cells. Thus, RNF126 is a possible target for the prevention and/or therapy of peritoneally colonized OC. Full article
(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment: 3rd Edition)
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14 pages, 1429 KB  
Article
Altered Network Function in Hippocampus After Sub-Chronic Activation of Cannabinoid Receptors in Early Adolescence
by Johanna Rehn, Lucas Admeus and Bernat Kocsis
Int. J. Mol. Sci. 2025, 26(24), 12182; https://doi.org/10.3390/ijms262412182 - 18 Dec 2025
Viewed by 397
Abstract
The cannabinoid 1-receptor (CB1R) is found in particularly high levels in the hippocampus (HPC). Increased CB1R density and binding are observed in patients with schizophrenia, and epidemiological studies suggest that regular cannabis use during adolescence is a risk factor for the disease. CB1R [...] Read more.
The cannabinoid 1-receptor (CB1R) is found in particularly high levels in the hippocampus (HPC). Increased CB1R density and binding are observed in patients with schizophrenia, and epidemiological studies suggest that regular cannabis use during adolescence is a risk factor for the disease. CB1R was shown to interfere with neuronal network oscillations and to impair sensory gating and memory function. Neuronal oscillations are essential in multiple cognitive functions, and their impairment was documented in neurological and psychiatric diseases. The aim of this study was to investigate how adolescent pre-treatment with the CB1R-selective agonist CP-55940 may lead to abnormalities in theta synchronization in adulthood. Rats were pre-treated with CP-55940 or vehicle during adolescence (daily injections in PND 32–36 or PND 42–46). They were then tested in adulthood (PND over 70) under urethane anesthesia. Hippocampal theta rhythm was elicited by brainstem stimulation at five intensity levels 1 hour before and up to 5 h after injection. We found a significant decrease in elicited theta power after CP-55940 in adult rats, which was aggravated further in rats pre-treated in adolescence with the CB1R agonist. The effect was significantly larger in rats pre-treated during early adolescence (PND 32–36) compared to the group pre-treated during late adolescence (PND 42–46). We conclude that (1) exposure to cannabis during adolescence leads to increased sensitivity to CB1R agonist in adulthood, and (2) early adolescence, a critical period for development of HPC networks generating theta rhythms, is particularly prone to this sensitivity. Full article
(This article belongs to the Special Issue Biological Research of Rhythms in the Nervous System)
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20 pages, 2114 KB  
Article
Does the Chimerization Process Affect the Immunochemical Properties of WNV-Neutralizing Antibody 900?
by Anastasiya A. Isaeva, Valentina S. Nesmeyanova, Daniil V. Shanshin, Nikita D. Ushkalenko, Ekaterina A. Volosnikova, Tatiana I. Esina, Elena V. Protopopova, Victor A. Svyatchenko, Valery B. Loktev, Sergey E. Olkin, Elena D. Danilenko, Elena I. Kazachinskaia and Dmitriy N. Shcherbakov
Int. J. Mol. Sci. 2025, 26(24), 12181; https://doi.org/10.3390/ijms262412181 - 18 Dec 2025
Viewed by 422
Abstract
West Nile fever is an infectious disease caused by the West Nile virus (WNV), which is transmitted by mosquitoes. Epidemiological surveillance confirms the potential risk of WNV infection in human populations. The lack of specific antiviral therapeutics and vaccines against WNV underscores the [...] Read more.
West Nile fever is an infectious disease caused by the West Nile virus (WNV), which is transmitted by mosquitoes. Epidemiological surveillance confirms the potential risk of WNV infection in human populations. The lack of specific antiviral therapeutics and vaccines against WNV underscores the urgent need to develop effective therapeutic approaches. In this study, a recombinant chimeric monoclonal antibody (mAb) 900 was generated based on the broadly neutralizing and protective murine mAb 9E2. The antigen-binding regions of the murine mAb were fused with the constant domains (CH2–CH3) of human IgG1. Two key amino acid clusters, M252/S254/T256 and H433/N434, were introduced into the CH2–CH3 domains to enhance the affinity of mAb 900 for the neonatal Fc receptor (FcRn). The engineered mAb 900 was produced in CHO cells and purified to high homogeneity. Biophysical characterization confirmed its stability and correct dimeric assembly. Comparative analysis demonstrated that mAb 900 retained the high antigen-binding affinity and potent virus-neutralizing activity of its murine predecessor. Most importantly, mAb 900 demonstrated significant protective efficacy in a lethal mouse model of WNV infection. These results establish the proof of concept for mAb 900 as a promising candidate for further preclinical development against WNV infection. Full article
(This article belongs to the Special Issue Recombinant Proteins and Antibody Engineering for Diagnostic and Treatment of Emerging Infectious Diseases)
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28 pages, 6020 KB  
Article
Development of a High-Throughput Screening Platform and a Pathogenesis Model for Leishmania Infection Based on Mouse Hepatic Organoids
by María-Cristina González-Montero, Julia Andrés-Rodríguez, Miguel Criado, Sonia Andrés, Giulio Galli, Celia Fernández-Rubio, Yolanda Pérez-Pertejo, Rosa M. Reguera, Rafael Balaña-Fouce and Carlos García-Estrada
Int. J. Mol. Sci. 2025, 26(24), 12180; https://doi.org/10.3390/ijms262412180 - 18 Dec 2025
Viewed by 397
Abstract
The development of new alternative models is essential to overcome the limitations of traditional two-dimensional (2D) cell cultures and animal models. Three-dimensional (3D) models, such as organoids, better mimic the structural and functional complexity of mammalian organs, thereby reducing the ethical and economic [...] Read more.
The development of new alternative models is essential to overcome the limitations of traditional two-dimensional (2D) cell cultures and animal models. Three-dimensional (3D) models, such as organoids, better mimic the structural and functional complexity of mammalian organs, thereby reducing the ethical and economic issues related to animal experimentation. These systems provide more physiologically relevant environments, improving the accuracy of disease modeling and drug response prediction. In this context, we have developed mouse hepatic organoids from livers of adult BALB/c mice and characterized them by microscopy and transcriptional analysis. This model was applied to a robust and reproducible high-throughput screening (HTS) platform for testing cytotoxicity at the preclinical stage of drug discovery. In addition, mouse hepatic organoids were co-cultured with amastigotes of Leishmania donovani parasites to establish a model of host–parasite interaction, which was characterized by RNA-seq linked to differential expression analysis and cytokine production by the hepatic organoids. The findings provided in this work establish mouse hepatic organoids as an alternative model for drug discovery and pathogenesis studies. Full article
(This article belongs to the Special Issue Organoid Models in Host–Pathogen Interactions and Disease Pathogenesis)
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34 pages, 17047 KB  
Article
Synthesis, Anti-Tumour, and Antibacterial Activities of Monocarbonyl Curcumin Analogues of Piperidones
by Renhua Dong, Ruirui Xu and Xiuli Wang
Int. J. Mol. Sci. 2025, 26(24), 12179; https://doi.org/10.3390/ijms262412179 - 18 Dec 2025
Viewed by 305
Abstract
Curcumin has anti-tumour and antibacterial effects. In this research, fourteen kinds of piperidone monocarbonyl curcumin analogues with 3,5-dimethylene-4-piperidone as the parent scaffold and halogen substitution on both sides of the benzene ring were synthesized by Claisen–Schmidt reaction, and their anti-tumour effect, mechanism, and [...] Read more.
Curcumin has anti-tumour and antibacterial effects. In this research, fourteen kinds of piperidone monocarbonyl curcumin analogues with 3,5-dimethylene-4-piperidone as the parent scaffold and halogen substitution on both sides of the benzene ring were synthesized by Claisen–Schmidt reaction, and their anti-tumour effect, mechanism, and antibacterial activity were investigated. It was found that a series of curcumin analogues has different degrees of anti-tumour and antibacterial dual activity. Among them, 2,5-2Cl, 2Br-5Cl, 2-Cl, 2-F, and benzaldehyde have strong broad-spectrum anti-tumour effects and have obvious selective inhibitory effects on A549 cells. The IC50 value is less than 5 μmol/L. The five promising compounds, respectively, inhibited the expression of AKT and ERK to induce apoptosis of A549 cells to varying degrees. The newly synthesized analogues 2,5-2Cl and 2Br-5Cl had stronger inhibitory effects on the growth of A549 cells than other analogues, and they tended to mainly inhibit the expression of AKT and ERK, respectively. However, 2-Cl and 2-F have significantly better inhibitory effects on methicillin-resistant Staphylococcus aureus (MRSA) than antibiotics. Taken together, piperidone monocarbonyl curcumin analogues may be developed as good candidates for potential prevention and treatment of cancer and bacterial infection complications. Full article
(This article belongs to the Collection Bioactive Natural Compounds for Therapeutics and Nutraceutical Applications)
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28 pages, 7299 KB  
Article
The Nuclear Effector RIRG190 Interacts with SAS10 to Regulate Arbuscular Mycorrhizal Symbiosis
by María Victoria Aparicio Chacón, Annick De Keyser, Naomi Stuer, Toon Leroy, Evi Ceulemans, Juan Antonio López-Ráez, Alain Goossens, Judith Van Dingenen and Sofie Goormachtig
Int. J. Mol. Sci. 2025, 26(24), 12178; https://doi.org/10.3390/ijms262412178 - 18 Dec 2025
Viewed by 322
Abstract
Most land plants engage in a mutualistic interaction with arbuscular mycorrhizal fungi (AMF), for which Rhizophagus irregularis is a model species. Like plant pathogenic fungi, AMF genomes encode hundreds of putative effector proteins. However, for only a few, the molecular mechanisms by which [...] Read more.
Most land plants engage in a mutualistic interaction with arbuscular mycorrhizal fungi (AMF), for which Rhizophagus irregularis is a model species. Like plant pathogenic fungi, AMF genomes encode hundreds of putative effector proteins. However, for only a few, the molecular mechanisms by which they alter the host’s physiology are known. Here, we combined several reverse genetic approaches to unravel the role of the RIRG190 effector protein in arbuscular mycorrhiza (AM) symbiosis. Using multiple heterologous tools, evidence is provided that the RIRG190 effector is secreted and localizes to the plant nucleus. Moreover, by means of yeast two-hybrid (Y2H) and ratiometric bimolecular fluorescence complementation (rBIFC) assays, the data demonstrate that RIRG190 interacts with the protein Something About Silencing (SAS10), known to be involved in rRNA biogenesis in the nucleolus of cortical cells. Our findings suggest that rRNA biogenesis is a key process modulated by AMF, potentially to enhance plant metabolic activity, facilitating cell cycle progression, and to support the establishment of the symbiosis. Full article
(This article belongs to the Special Issue The Molecular Basis of Plant–Microbe Interactions)
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12 pages, 2828 KB  
Article
MSK1 Downstream Signaling Contributes to Inflammatory Pain in the Superficial Spinal Dorsal Horn
by Jahanzaib Irfan, Rizki Muhammad Febrianto, Angelina Mira D’Ercole, Nicole Li, Vijaya Danke, Erica Chen, Deemah Aldossary, Michelle Y. Meng, Paolo La Montanara, Jose Vicente Torres-Perez, David Zimmermann, Rosalie Li, Krisztina Deak-Pocsai, Daniel Segelcke, Bruno Pradier, Esther Miriam Pogatzki-Zahn, Simone Di Giovanni, Michaela Kress and Istvan Nagy
Int. J. Mol. Sci. 2025, 26(24), 12177; https://doi.org/10.3390/ijms262412177 - 18 Dec 2025
Viewed by 442
Abstract
The nuclear kinases mitogen- and stress-activated kinase 1 and 2 (MSK1 and MSK2), through regulating transcriptional processes, are pivotal for various adaptive responses, including inflammation, learning and addiction. Transcriptional alterations in neurons and glia cells within the pain signal-processing (nociceptive) pathway, including the [...] Read more.
The nuclear kinases mitogen- and stress-activated kinase 1 and 2 (MSK1 and MSK2), through regulating transcriptional processes, are pivotal for various adaptive responses, including inflammation, learning and addiction. Transcriptional alterations in neurons and glia cells within the pain signal-processing (nociceptive) pathway, including the superficial spinal dorsal horn (SSDH), are critical for the development and persistence of inflammatory pain that results from tissue injuries and subsequent inflammatory reactions. While previous reports have indicated that MSK1 contributes to transcriptional changes in inflamed tissues, the impact of MSK1 on nociceptive processing in the SSDH are poorly understood at present. Here, we report MSK1 immunoreactivity (IR) in a group of excitatory and inhibitory neurons as well as in microglia and oligodendrocytes in the SSDH. Injecting Complete Freund’s Adjuvant into the mouse hind paw produced robust non-evoked pain-related behavior, which was significantly attenuated by global depletion of MSK1. In wild-type mice, the inflammatory pain was accompanied by transient MSK1-dependent phosphorylation of the MSK1 downstream effector histone 3 at serine 10 at one hour but not two days after the injection; still, the number of nuclei exhibiting activated MSK1 expression remained highly restricted even at 1 h post-injection. Our data indicate that MSK1 contributes to inflammatory pain via epigenetic and transcriptional alterations; however, once initiated, MSK1’s downstream effects do not require further drive from the persistent activity of the MSK1 signaling pathway in the SSDH. Full article
(This article belongs to the Special Issue Editorial Board Members’ Collection Series: Pain)
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24 pages, 7363 KB  
Article
Preclinical Evaluation of Atorvastatin-Loaded PEGylated Liposomes in a Mouse Model of Traumatic Brain Injury
by Eun-Sol Hwang, Ja-Hae Kim, Ji-Hye Kim, Raveena Nagareddy, Yong-Yeon Jeong and Kang-Ho Choi
Int. J. Mol. Sci. 2025, 26(24), 12176; https://doi.org/10.3390/ijms262412176 - 18 Dec 2025
Viewed by 404
Abstract
Evidence on the therapeutic use of nanoparticles for traumatic brain injury (TBI) remains limited. This study aimed to evaluate the neuroprotective potential of atorvastatin-loaded polyethylene glycol (PEG)-conjugated liposomes (LipoStatin) in a mouse model of repetitive TBI. TBI was induced using five controlled head [...] Read more.
Evidence on the therapeutic use of nanoparticles for traumatic brain injury (TBI) remains limited. This study aimed to evaluate the neuroprotective potential of atorvastatin-loaded polyethylene glycol (PEG)-conjugated liposomes (LipoStatin) in a mouse model of repetitive TBI. TBI was induced using five controlled head impacts with a 120 g weight at 12-h intervals. Mice were randomly assigned to Sham, Control (saline-treated), Statin (free atorvastatin), Liposome (empty PEGylated liposomes without atorvastatin), and LipoStatin (atorvastatin-loaded PEGylated liposome) groups. LipoStatin (10 mg/kg/day) was intravenously administered for 5 days post-injury. Neurological function was evaluated using the neurological severity score (NSS), while blood–brain barrier (BBB) integrity and neuroinflammation were assessed on day 5, and cellular apoptosis on day 12. LipoStatin-treated mice exhibited the lowest NSSs. IVIS® imaging indicated significantly attenuated BBB disruption (p < 0.001), and Western blot analysis revealed restored caveolin-1 protein levels (p < 0.01), which are associated with BBB integrity. TNF-α levels were reduced considerably in the LipoStatin group compared to both the Control (p < 0.001) and Statin (p < 0.05) groups. Immunofluorescence showed reduced co-localization of caspase-3 with PDGFR-β and GFAP, indicating decreased pericyte and astrocyte apoptosis. These findings suggest that LipoStatin may confer neuroprotection in TBI by stabilizing BBB integrity, reducing inflammation, and mitigating cell death, supporting its potential as an improved nanocarrier-based therapeutic approach. Full article
(This article belongs to the Special Issue Stroke: Novel Molecular Mechanisms and Therapeutic Approaches)
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28 pages, 4688 KB  
Article
The Importance of Humic Acids in Shaping the Resistance of Soil Microorganisms and the Tolerance of Zea mays to Excess Cadmium in Soil
by Agata Borowik, Jadwiga Wyszkowska, Magdalena Zaborowska and Jan Kucharski
Int. J. Mol. Sci. 2025, 26(24), 12175; https://doi.org/10.3390/ijms262412175 - 18 Dec 2025
Viewed by 316
Abstract
Contamination with cadmium (Cd2+) poses a severe threat to the soil environment due to its toxic effect on bacteria, being of key importance to soil fertility and plant health. The present study aimed to evaluate the effect of a humic preparation, [...] Read more.
Contamination with cadmium (Cd2+) poses a severe threat to the soil environment due to its toxic effect on bacteria, being of key importance to soil fertility and plant health. The present study aimed to evaluate the effect of a humic preparation, Humus Active (HA), on the structure, diversity, and functional potential of soil bacteria under conditions of cadmium stress during Zea mays cultivation. A model study was conducted to analyze the response of bacteria to soil contamination with 60 mg Cd kg−1 under conditions of soil fertilization with humic acid at doses of 2 g (HA2) and 4 g (HA4) kg−1 of soil. Microbiological analyses were carried out with both culture and non-culture (16S rRNA gene amplicon sequencing method) methods. Bacteria function prediction was also performed using FAPROTAX software. The study results demonstrated that Cd caused a 92% reduction in Zea mays biomass and a significant decrease (by 52%) in the abundance of organotrophic bacteria. The NGS analysis showed that it also reduced the population of the Neobacillus bacteria in the soil (by 50%), simultaneously causing an over twofold increase in the population of the Nocardioides genus bacteria. The application of HA (particularly in the HA4 dose) substantially mitigated Cd phytotoxicity. In the Cd-contaminated soil, HA4 stimulated the growth of culturable actinobacteria. The soil bacteria community was predominated by chemoheterotrophic bacteria and the nitrogen cycle bacteria, driven by tolerant, Cd2+-resistant bacteria from the following genera: Bacillus, Nocardioides, and Arthrobacter. The study results enable concluding that even though Humus Active does not restore the original microbiome structure, it promotes the development of a new stress-resistant bacterial community exhibiting high bioremediating potential, thereby directly translating into improved plant condition. Subsequently, humic acids provide an innovative approach that not only extends knowledge about the mechanisms behind bacterial resistance but also enables developing practical methods for diminishing cadmium mobility in the soil. Full article
(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Microbiology)
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20 pages, 913 KB  
Review
Post-Translational Modifications in Respiratory Virus Infection: Recent Insights into the Development of In Vitro Models
by Emna Ben Khlifa, Alessia Campese, Andrea Corsi, Cristina Bombieri, Maria Grazia Romanelli, Maria Teresa Valenti, Donato Zipeto, Matteo Castelli, Patricia Marie-Jeanne Lievens and Alessandra Ruggiero
Int. J. Mol. Sci. 2025, 26(24), 12174; https://doi.org/10.3390/ijms262412174 - 18 Dec 2025
Viewed by 482
Abstract
Post-translational modifications (PTMs) are crucial chemical alterations occurring on proteins post-synthesis, impacting various cellular processes. During viral infections, PTMs are shown to play a multitude of roles in viral replication, host interaction, and immune evasion. Thus, these modifications can influence infectivity, with direct [...] Read more.
Post-translational modifications (PTMs) are crucial chemical alterations occurring on proteins post-synthesis, impacting various cellular processes. During viral infections, PTMs are shown to play a multitude of roles in viral replication, host interaction, and immune evasion. Thus, these modifications can influence infectivity, with direct impact on the anti-viral host immune responses and potentially viral adaptation across species. This field is still scarcely explored, whilst understanding PTMs is not only important to advance the knowledge of virus pathology but also potentially to provide insights for vaccine development. In this review, we attempt to summarize the latest findings mainly published over the last 10 years, focusing on the roles of PTMs involved in virus infection and anti-viral immune responses, in the context of relevant human respiratory infections: influenza A virus (IAV), respiratory syncytial virus (RSV), and SARS-CoV-2. We decided to concentrate on these three viruses because they currently represent a global health problem due to recurrent outbreaks and pandemic potential. A deeper characterization of the PTMs may help in understanding virus–host interaction with possible implications on curative strategies. Further, we will report on cutting-edge technologies to study in vitro virus infection in different cellular-based systems. In particular, we describe and discuss the application of 2D and 3D lung organoid cell-culture systems as in vitro models to mimic respiratory environments and to study the PTMs in a controlled setting. Finally, we will discuss the importance of PTMs in the context of next-generation vaccine design, especially for their potential role to offer effective protection against respiratory viruses. Full article
(This article belongs to the Special Issue Viral Infections and Immune Responses)
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18 pages, 5040 KB  
Article
B-Cell Receptor-Associated Protein 31 Deficiency Aggravates Ethanol-Induced Liver Steatosis and Liver Injury via Attenuating Fatty Acid Oxidation and Glycogen Synthesis
by Shubin Yu, Yaodong Xia, Chunyan Zhang, Xiangyue Han, Xiaoyue Feng, Liya Li, Hang Ma and Jialin Xu
Int. J. Mol. Sci. 2025, 26(24), 12173; https://doi.org/10.3390/ijms262412173 - 18 Dec 2025
Viewed by 435
Abstract
Alcoholic liver disease (ALD) is a spectrum of alcohol-induced disorders and represents a major global health challenge. B-cell receptor-associated protein 31 (BAP31) is an endoplasmic reticulum-resident chaperone involved in protein transport, apoptosis, cancer biology, and lipid metabolism. To explore its role in ALD, [...] Read more.
Alcoholic liver disease (ALD) is a spectrum of alcohol-induced disorders and represents a major global health challenge. B-cell receptor-associated protein 31 (BAP31) is an endoplasmic reticulum-resident chaperone involved in protein transport, apoptosis, cancer biology, and lipid metabolism. To explore its role in ALD, we used hepatocyte-specific BAP31 knockout mice (BAP31-LKO) and wild-type (WT) littermates exposed to ethanol to assess BAP31′s biochemical and metabolic impact. Following ethanol exposure, BAP31-LKO mice exhibited elevated serum alanine transaminase (23.2%, p < 0.05) and aspartate transaminase (31.4%, p < 0.05) levels compared to WT mice. Increased malondialdehyde (8.5%, p < 0.05) and reduced superoxide dismutase (22.8%, p < 0.05) in BAP31-LKO mice indicate exacerbated liver injury. Furthermore, BAP31 deficiency increased triglyceride (35.7%, p < 0.05) and free fatty acid (16.2%, p < 0.05) accumulation following ethanol treatment, while the expression of fatty acid oxidation-related genes, including Pparα, Cd36, Fatp2, Cpt2, and Acox1, was reduced in BAP31-LKO mice. The mRNA levels of Xbp1, Xbp1s, and Chop, as well as protein levels of p-eIF2α, IRE1α, GRP78, and CHOP, were increased in BAP31-LKO mice compared to WT controls, indicating aggravated ethanol-induced ER stress. Hepatic glycogen content was also reduced in BAP31-LKO mice, along with reduced Ppp1r3c expression, demonstrating impaired glycogen synthesis. Consistently, BAP31 knockdown amplified ethanol-induced lipid accumulation, inflammation, impaired glycogen storage, ER stress, and suppression of Pparα signaling in HepG2 cells. Together, these findings demonstrate that BAP31 deficiency exacerbates ethanol-induced liver steatosis, inflammation, and liver injury by impairing fatty acid oxidation and glycogen synthesis, and by amplifying ER stress responses. Full article
(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Toxicology)
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17 pages, 3543 KB  
Article
Coordinated Auxin–Cytokinin–Nitrogen Signaling Orchestrates Root Suckering in Populus
by Hongying Pang, Wanwan Lyu, Yajuan Chen, Liping Ding, Lin Zheng and Hongzhi Wang
Int. J. Mol. Sci. 2025, 26(24), 12172; https://doi.org/10.3390/ijms262412172 - 18 Dec 2025
Viewed by 398
Abstract
Root suckering is a key mode of clonal propagation in white poplar group, such as aspens (Populus section Leuce), enabling rapid vegetative spread, yet the molecular triggers remain elusive. Here, we developed a rapid protocol that produces abundant root suckers with [...] Read more.
Root suckering is a key mode of clonal propagation in white poplar group, such as aspens (Populus section Leuce), enabling rapid vegetative spread, yet the molecular triggers remain elusive. Here, we developed a rapid protocol that produces abundant root suckers with the root cutting of white poplar (Populus davidiana × P. bolleana) roots in greenhouse. Anatomical analyses and daily resolution transcriptomes resolved three sequential developmental stages: primordium initiation (Days 0–1), SAM (shoot apical meristem) establishment (Days 1–4), and organ differentiation/growth (Days 4–6). Weighted gene co-expression network analysis revealed that auxin- and cytokinin-mediated signaling, integrated with nitrogen metabolism, orchestrates SAM formation and maintenance. Exogenous application of 0.5–1.0 mg L−1 NAA suppressed sucker emergence by 48–60%, whereas inhibition of cytokinin biosynthesis with lovastatin reduced initiation by 60%. These data establish that auxin negatively regulates and cytokinin is indispensable for de novo shoot apical meristem establishment during poplar root-suckering, underscoring that a precise auxin–cytokinin balance governs the timing and extent of this developmental process. Cambial regulators WUSCHEL-Related Homeobox 4-1/2 (WOX4-1/2), together with core meristem regulators WUSCHEL (WUS) and SHOOT MERISTEMLESS (STM), were specifically induced during SAM establishment that underpin vascular integration between the nascent shoot and the parental root. These results uncover the molecular pathway controlling root suckering and provide potential targets for molecular breeding to either enhance or suppress root suckering in Populus. Full article
(This article belongs to the Section Molecular Plant Sciences)
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18 pages, 1073 KB  
Review
Immune Checkpoint Inhibitor Therapy in Hormone Receptor-Positive Breast Cancer
by David Lin, Jin Sun Lee Bitar, Isabella Ma and Yuan Yuan
Int. J. Mol. Sci. 2025, 26(24), 12171; https://doi.org/10.3390/ijms262412171 - 18 Dec 2025
Cited by 1 | Viewed by 595
Abstract
Recent progress in immunotherapy has led to the routine use of immune checkpoint inhibitors (ICIs) in TNBC therapy and significant improvement in clinical outcomes. Incorporation of ICI into HR+/HER2− or HER2+ breast cancer has been hindered by its poor immunogenicity, and many novel [...] Read more.
Recent progress in immunotherapy has led to the routine use of immune checkpoint inhibitors (ICIs) in TNBC therapy and significant improvement in clinical outcomes. Incorporation of ICI into HR+/HER2− or HER2+ breast cancer has been hindered by its poor immunogenicity, and many novel combination strategies aim to convert immune cold tumors into immune hot tumors and increase the immunogenicity of HR+/HER2− breast cancer. A few recent clinical trials have shown its potential promise in high-risk HR+/HER2− early-stage breast cancer, but there is insufficient evidence to support routine use of immunotherapy in HR+ breast cancer, and longer-term follow-up is required to understand its impact on survival. This review presents an overview of immunotherapies currently under clinical development and updated key results from clinical trials, with a focus on HR+/HER2− breast cacner. Full article
(This article belongs to the Special Issue Breast Cancer: From Pathophysiology to Novel Therapies)
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15 pages, 2350 KB  
Article
Dasatinib and Quercetin Alleviate Retinal Ganglion Cell Dendritic Shrinkage and Promote Axonal Regeneration in Mice with Optic Nerve Injury
by Xin Bin, Shuyi Zhou, Yanxuan Xu, Si Chen, Shaowan Chen, Wen Yao, Yingjie Cao, Kunliang Qiu and Tsz Kin Ng
Int. J. Mol. Sci. 2025, 26(24), 12170; https://doi.org/10.3390/ijms262412170 - 18 Dec 2025
Viewed by 343
Abstract
Optic nerve (ON) injury by trauma induces progressive retinal ganglion cell (RGC) death and axonal loss, which leads to irreversible visual impairment and even blindness. Recently, we discovered that cellular senescence is involved in RGC survival regulation post-ON injury, and senolytic (dasatinib and [...] Read more.
Optic nerve (ON) injury by trauma induces progressive retinal ganglion cell (RGC) death and axonal loss, which leads to irreversible visual impairment and even blindness. Recently, we discovered that cellular senescence is involved in RGC survival regulation post-ON injury, and senolytic (dasatinib and quercetin) treatments can promote RGC survival and electroretinography activity. Here, we aimed to further evaluate the effects of dasatinib and quercetin on RGC dendrites and axons in mice with an ON crush injury. Longitudinal in vivo imaging analysis demonstrated that the RGC dendritic shrinkage was significantly reduced in mice with both individual and combined treatment of dasatinib and quercetin as compared to the vehicle treatment group. Similarly, dasatinib and quercetin treatments significantly promoted axonal regeneration post-ON injury as compared to the vehicle-treated mice. RNA sequencing analysis showed that the differentially expressed genes were enriched in the response to glucocorticoid, calcium ion binding, and cerebral cortex development. Sybr green PCR and immunofluorescence analyses validated that the axonal extension-related gene, meteorin (Metrn), was significantly upregulated in the dasatinib-only and combined dasatinib and quercetin treatments. In summary, this study revealed that dasatinib and quercetin alleviated RGC dendritic shrinkage and promoted axonal regeneration in mice after ON injury, probably mediated through meteorin, suggesting the dendrite repair and axonal regeneration potentials of dasatinib and quercetin for traumatic optic neuropathy treatment. Full article
(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)
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12 pages, 3416 KB  
Case Report
Previously Unreported TMEM38B Variant in Osteogenesis Imperfecta Type XIV: A Case Report and Systematic Review of the Literature
by Thomas Zoller, Martina Righetti, Riccardo Cont, Ruggero Lanzafame, Irene Ambrosetti, Alessandra Guzzo, Angelo Pietrobelli and Franco Antoniazzi
Int. J. Mol. Sci. 2025, 26(24), 12169; https://doi.org/10.3390/ijms262412169 - 18 Dec 2025
Viewed by 349
Abstract
Osteogenesis imperfecta (OI) type XIV is a rare recessive disorder caused by TMEM38B pathogenic variants that disrupt an endoplasmic reticulum protein essential for calcium homeostasis and bone mineralization. This leads to severe bone fragility, early-onset fractures, skeletal deformities, low bone mass, scoliosis, and [...] Read more.
Osteogenesis imperfecta (OI) type XIV is a rare recessive disorder caused by TMEM38B pathogenic variants that disrupt an endoplasmic reticulum protein essential for calcium homeostasis and bone mineralization. This leads to severe bone fragility, early-onset fractures, skeletal deformities, low bone mass, scoliosis, and variable features like blue sclerae or dental abnormalities. We present a case report of a 21-year-old Italian male with a novel homozygous TMEM38B splice variant (c.112 + 1G > T), detailing the clinical presentation, genetic findings, and therapeutic outcomes. The patient exhibited multiple skeletal deformities and showed a moderate response to bisphosphonate therapy (neridronate). In addition, a systematic review of PubMed and Scopus identified 12 relevant studies from an initial set of 82 publications, encompassing data from 56 patients diagnosed with OI type XIV. Unlike classical collagen-related OI, TMEM38B-related OI necessitates genetic screening beyond classical collagen genes (COL1A1 and COL1A2). While bisphosphonates provide some clinical benefit, persistent fractures underscore the need for long-term management and innovative therapies. This case report and systematic review enhance understanding of OI type XIV and underscore the clinical importance of TMEM38B variants in bone fragility disorders. Full article
(This article belongs to the Special Issue Molecular Studies of Bone Biology and Bone Tissue: 2nd Edition)
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18 pages, 1158 KB  
Article
Circulating Aggrecan, Biglycan, and Decorin as Biomarkers of Osteoarticular Alterations in Juvenile Idiopathic Arthritis—A Preliminary Study
by Kornelia Kuźnik-Trocha, Katarzyna Winsz-Szczotka, Krystyna Olczyk, Anna Gruenpeter and Katarzyna Komosińska-Vassev
Int. J. Mol. Sci. 2025, 26(24), 12168; https://doi.org/10.3390/ijms262412168 - 18 Dec 2025
Viewed by 327
Abstract
Proteoglycans and their fragments have potential as diagnostic or theragnostic biomarkers to identify diseases characterized by dysregulated extracellular matrix remodeling, such as juvenile idiopathic arthritis (JIA). Therefore, our study aimed to evaluate the diagnostic utility of plasma proteoglycan profiles, namely, aggrecan, decorin, and [...] Read more.
Proteoglycans and their fragments have potential as diagnostic or theragnostic biomarkers to identify diseases characterized by dysregulated extracellular matrix remodeling, such as juvenile idiopathic arthritis (JIA). Therefore, our study aimed to evaluate the diagnostic utility of plasma proteoglycan profiles, namely, aggrecan, decorin, and biglycan, released from osteoarticular structures into the blood of children with juvenile idiopathic arthritis. These profiles are potential biomarkers of tissue destruction and/or indicators of the efficacy of therapy with the biologic agent etanercept (ETA). This study was conducted on 263 blood samples collected from 25 healthy children and 34 children at various stages of juvenile idiopathic arthritis disease: immediately after diagnosis, following treatment with disease-modifying antirheumatic drugs (DMARD) (methotrexate, sulfasalazine, and prednisone), and during 3, 6, 12, 18, and 24 months of therapy with etanercept. Quantitative levels of aggrecan, biglycan, and decorin were measured using ELISA kits. In children with JIA, plasma aggrecan levels were elevated at diagnosis, decreased after ineffective DMARD therapy, and increased again at 24 months of etanercept treatment despite clinical improvement. By contrast, biglycan levels were similar to those in healthy controls but decreased during etanercept therapy. Decorin levels were initially high in untreated and DMARD-treated patients but returned to normal after 24 months of biologic treatment. After considering these findings and the ROC analysis, we conclude that decorin appears to be a promising biomarker for diagnosing and monitoring etanercept therapy in JIA, and biglycan is a useful biochemical marker for assessing the effectiveness of ETA treatment. Full article
(This article belongs to the Special Issue Glycoconjugates: From Structure to Therapeutic Application)
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45 pages, 1852 KB  
Review
Gut–Brain Axis and Bile Acid Signaling: Linking Microbial Metabolism to Brain Function and Metabolic Regulation
by Bojan Stanimirov, Maja Đanić, Nebojša Pavlović, Dragana Zaklan, Slavica Lazarević, Momir Mikov and Karmen Stankov
Int. J. Mol. Sci. 2025, 26(24), 12167; https://doi.org/10.3390/ijms262412167 - 18 Dec 2025
Viewed by 1517
Abstract
The gut–brain axis is a bidirectional communication network in which gut microbiota and their metabolites influence central nervous system (CNS) function. Among these metabolites, bile acids have emerged as key signaling molecules that modulate metabolic and neuroendocrine pathways. Microbiota-mediated modifications of bile acid [...] Read more.
The gut–brain axis is a bidirectional communication network in which gut microbiota and their metabolites influence central nervous system (CNS) function. Among these metabolites, bile acids have emerged as key signaling molecules that modulate metabolic and neuroendocrine pathways. Microbiota-mediated modifications of bile acid composition affect receptors such as farnesoid X receptor (FXR)and Takeda G protein-coupled receptor 5 (TGR5), thereby influencing neuronal activity, appetite control, glucose metabolism, and energy balance. Emerging evidence indicates that bile acids act both directly on the CNS and indirectly via endocrine and immune mediators, linking microbial metabolism to brain function. By integrating microbiological, metabolic, and neuroendocrine perspectives, bile acids can be viewed as critical messengers in the communication between the gut microbiota and the CNS. The purpose of this review is thus to synthesize current mechanisms underlying these interactions and highlight their therapeutic potential in metabolic and neurodegenerative disorders. Full article
(This article belongs to the Special Issue Bile Acids and Bile Acid Modifications in Health and Disease)
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23 pages, 8286 KB  
Article
Characterisation of the Novel Cutibacterium acnes Phage KIT09 and First Report of CRISPR-Cas-Independent Bacteriophage Resistance in Phylotype IA1
by Phuoc-Dung Nguyen, Koki Nakanishi, Huan Pham-Khanh Nguyen, Hoang Viet Nguyen, Masao Kitao, Masanao Yoshimoto and Kaeko Kamei
Int. J. Mol. Sci. 2025, 26(24), 12166; https://doi.org/10.3390/ijms262412166 - 18 Dec 2025
Viewed by 486
Abstract
Despite being a commensal bacterium, Cutibacterium acnes has been widely considered a major opportunistic pathogen due to its capacity for biofilm production and inflammatory induction, causing device-related, post-implant infections, and skin inflammatory diseases. In this study, we isolated and characterised the novel bacteriophage [...] Read more.
Despite being a commensal bacterium, Cutibacterium acnes has been widely considered a major opportunistic pathogen due to its capacity for biofilm production and inflammatory induction, causing device-related, post-implant infections, and skin inflammatory diseases. In this study, we isolated and characterised the novel bacteriophage Cutibacterium acnes phage KIT09 as a potential antimicrobial candidate for the treatment of Cutibacterium acnes-related infections such as acne vulgaris and postsurgical infections. Subsequently, phage-resistant bacterial mutants were generated through phage KIT09 exposure and characterised. Wastewater samples were collected for the isolation of C. acnes phages, followed by their characterisation using C. acnes National Institute of Technology and Evaluation (NITE) Biological Resources Center (NBRC) 107605 (phylotype IA1). Resistant mutants were isolated after prolonged exposure of the newly isolated phage to host bacteria and then characterised. A novel C. acnes phage, designated KIT09, was isolated, demonstrating prolonged bacteriolysis lasting up to 96 h at a multiplicity of infection of 10, and exhibiting high thermal and pH stability. Following sustained selective pressure by phage KIT09, three phage-resistant bacterial isolates were obtained, forming smaller colonies than the wild-type strain, but maintaining a high phage adsorption capacity (>90% after 20 min). Whole-genome sequencing revealed 12 nucleotide mutations across five genes, including six non-synonymous substitutions. Three genes encoding a two-component histidine kinase, DNA processing protein A (DprA), and a ThuA-containing domain protein were mutated in all resistant isolates. Characterisation of the novel phage KIT09 demonstrated its robust lytic activity and environmental stability against C. acnes phylotype IA1. Isolated resistant mutants retained high phage adsorption, accompanied by recurrent mutations in genes encoding a two-component histidine kinase, DprA, and a ThuA-domain protein, suggesting the presence of alternative, CRISPR-Cas–independent resistance mechanisms in C. acnes. Full article
(This article belongs to the Special Issue Bacteriophage—Molecular Studies (6th Edition))
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7 pages, 592 KB  
Editorial
Special Issue: Emerging Topics in Metal Complexes: Pharmacological Activity, 2nd Edition
by Agnieszka Ścibior, Manuel Aureliano and Juan Llopis
Int. J. Mol. Sci. 2025, 26(24), 12165; https://doi.org/10.3390/ijms262412165 - 18 Dec 2025
Viewed by 218
Abstract
This Special Issue (SI), titled “Emerging Topics in Metal Complexes: Pharmacological Activity, 2nd Edition”, includes reports updating our knowledge about magnesium (Mg) and neurodegeneration, various metal-containing complexes in terms of their potential therapeutic applications (i [...] Full article
(This article belongs to the Special Issue Emerging Topics in Metal Complexes: Pharmacological Activity, 2nd Edition)
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41 pages, 783 KB  
Review
The Role of miRNAs in Parkinson’s Disease: A Systematic Review
by Michalis Chrysanthou, Christiana C. Christodoulou and Eleni Zamba Papanicolaou
Int. J. Mol. Sci. 2025, 26(24), 12164; https://doi.org/10.3390/ijms262412164 - 18 Dec 2025
Viewed by 555
Abstract
Over the years, there has been extensive research conducted on Parkinson’s Disease (PD), a neurodegenerative disorder known for causing motor impairment and behavioral changes. In more recent years, the roles of dysregulated microRNAs (miRNAs) in PD pathology have been studied in the hopes [...] Read more.
Over the years, there has been extensive research conducted on Parkinson’s Disease (PD), a neurodegenerative disorder known for causing motor impairment and behavioral changes. In more recent years, the roles of dysregulated microRNAs (miRNAs) in PD pathology have been studied in the hopes of developing new diagnostic methods or even treatments. This systematic review pinpoints and examines studies between 2010 and 2024 that have identified significant dysregulation of miRNAs in patients with PD. Upon filtering out the search results by a series of exclusion criteria, this review was conducted using 56 relevant studies. These studies revealed a vast array of significantly dysregulated miRNAs identified in the samples of patients with PD, when compared to healthy controls. A number of these miRNAs, such as miR-29c-3p, are likely biomarkers for more accurate PD diagnosis, and many, such as miR-485-3p, were found to be involved in PD pathogenesis. With further research, miRNAs could become a helpful diagnostic and prognostic tool for PD, with some of them even being candidate therapeutic targets for future treatments. Full article
(This article belongs to the Special Issue Circulating Non-Coding RNAs as Diagnostic and Prognostic Markers of Human Diseases: 3rd Edition)
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24 pages, 697 KB  
Review
GLP-1 Signalling as a Therapeutic Avenue in Parkinson’s Disease: A Comprehensive Review
by María Paz Orozco, Valentina Vintimilla Rivadeneira and Jose E. Leon-Rojas
Int. J. Mol. Sci. 2025, 26(24), 12163; https://doi.org/10.3390/ijms262412163 - 18 Dec 2025
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Abstract
Parkinson’s disease (PD) is a complex neurodegenerative disorder characterised by progressive motor and non-motor impairment, in which current therapies remain symptomatic and fail to halt dopaminergic neuron loss. Growing evidence linking metabolic dysfunction, type 2 diabetes, and neurodegeneration has renewed interest in glucagon-like [...] Read more.
Parkinson’s disease (PD) is a complex neurodegenerative disorder characterised by progressive motor and non-motor impairment, in which current therapies remain symptomatic and fail to halt dopaminergic neuron loss. Growing evidence linking metabolic dysfunction, type 2 diabetes, and neurodegeneration has renewed interest in glucagon-like peptide 1 (GLP-1) receptor agonists as potential disease-modifying agents. While several recent reviews have explored the role of incretin-based therapies, the present work provides an integrative perspective by combining a mechanistic analysis of GLP-1 signalling pathways with a model-specific synthesis of preclinical findings and an appraisal of clinical translational relevance. We consolidate evidence across PI3K/Akt, MAPK/ERK, cAMP/PKA–CREB, and AMPK pathways, emphasising their convergence on mitochondrial homeostasis, proteostasis, neuroinflammation, and synaptic resilience. To enhance translational clarity, we summarise preclinical studies across major PD models, evaluate dose comparability and blood–brain barrier penetration, and identify pharmacokinetic and mechanistic factors that may explain divergent clinical outcomes. We also compare the therapeutic potential of key GLP-1 agonists, including exendin-4, liraglutide, semaglutide, lixisenatide, and emerging dual agonists. By integrating biochemical, preclinical, and clinical domains, this review provides a comprehensive framework for interpreting the current evidence and guiding the future development of incretin-based neuroprotective strategies in PD. Full article
(This article belongs to the Special Issue New Challenges of Parkinson’s Disease, 2nd Edition)
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