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Volume 27
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Int. J. Mol. Sci., Volume 27, Issue 4 (February-2 2026) – 468 articles

Cover Story (view full-size image): Muscular dystrophies are genetically heterogeneous disorders characterized by progressive muscle failure. While molecular research has traditionally focused on pathogenesis, this review bridges the gap between genetics and clinical practice. We reframe pathomechanisms—from sarcolemmal fragility to nuclear envelope dysfunction—through the lens of biomechanical consequences, such as rigid spine, contractures, and scoliosis. By integrating genotype-specific data with functional orthopaedic phenotyping, we propose a “precision orthopaedics” framework. This approach guides timely interventions, such as cardiac-stratified surgery in LMNA-related disorders or pulmonary-informed spinal fusion in DMD, aiming to translate genomic insights into durable functional outcomes for patients. View this paper
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43 pages, 3132 KB  
Review
Cytokines Associated with Activation of CD4+CD25+Foxp3+ T Regulatory Cells
by Ranje Al-atiyah, Nirupama D. Verma, Giang T. Tran, Suzanne J. Hodgkinson and Bruce M. Hall
Int. J. Mol. Sci. 2026, 27(4), 2085; https://doi.org/10.3390/ijms27042085 - 23 Feb 2026
Viewed by 929
Abstract
The survival and activation of both effector and regulatory CD4+T cells are promoted by cytokines in a complex series of interactions. Alloantigen-specific Regulatory T cells (Treg) constitutively express IL-2 receptor (CD25) and Foxp3. This discovery arose as the cells that transfer [...] Read more.
The survival and activation of both effector and regulatory CD4+T cells are promoted by cytokines in a complex series of interactions. Alloantigen-specific Regulatory T cells (Treg) constitutively express IL-2 receptor (CD25) and Foxp3. This discovery arose as the cells that transfer the alloantigen-specific transplant tolerance die in culture with specific alloantigens, unless the cultures are supplemented with cytokines from activated lymphocytes. One such cytokine was IL-2, but other cytokines are essential. We describe how the activation of Treg by antigens depends on cytokines produced by antigen-activated effector T cells. These cytokines also drive in parallel the activation of Treg. The Treg are induced to express similar transcription factors and chemokine receptors and have a similar cytokine responsiveness to the activated T effector cells. The activation of Treg by antigens is a two-step process: the first requires cytokines produced by effector T cells early in their activation, and the second step is driven by cytokines produced later by effector T cells during activation. Cytokines from Type 1 responses promote the induction of Th1-like Treg. Likewise, cytokines produced in Type 2, Type 3, and Tfh responses induce different pathways of Treg activation. Understanding the pathways for the activation and expansion of potent antigen-specific Treg will help produce Treg to control allograft rejection or autoimmunity. Currently, the complexity of the numerous potential pathways of activation of Treg remains incompletely understood. The dogma that IL-2 is the only driver of Treg activation may have hindered the development of highly potent antigen-specific Treg for therapy. Full article
(This article belongs to the Section Molecular Immunology)
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32 pages, 10754 KB  
Review
Current Research Advances and Future Prospects on Microbial Consortia for Sustainable PFAS Remediation
by Hafiz Abdul Kareem and Mohd Faheem Khan
Int. J. Mol. Sci. 2026, 27(4), 2084; https://doi.org/10.3390/ijms27042084 - 23 Feb 2026
Cited by 1 | Viewed by 814
Abstract
Soil contamination by per- and polyfluoroalkyl substances (PFAS) represents a pressing environmental and public health concern due to the exceptional persistence of carbon–fluorine bonds, which prevent natural attenuation and limit the effectiveness of conventional remediation. Agricultural and industrial soils serve as long-term sinks [...] Read more.
Soil contamination by per- and polyfluoroalkyl substances (PFAS) represents a pressing environmental and public health concern due to the exceptional persistence of carbon–fluorine bonds, which prevent natural attenuation and limit the effectiveness of conventional remediation. Agricultural and industrial soils serve as long-term sinks for PFAS, continuously releasing these pollutants into groundwater and facilitating their transfer through the food chain. Conventional chemical and physical remediation methods are often costly, energy-intensive, and yield incomplete removal, underscoring the need for sustainable and biologically driven alternatives. Microbial consortia have emerged as a promising solution due to their metabolic complementarities, cross-feeding interactions, and ecological resilience, which together enable PFAS transformation and partial defluorination under complex soil and subsurface conditions. Key enzymes such as oxygenases, reductive dehalogenases, and hydrolases are often operating within co-metabolic networks, which play central roles in these processes. Advances in metagenomics, CRISPR-based functional screening, and metabolic modelling are rapidly uncovering novel PFAS-degrading microbes and pathways. Integration of machine learning with multi-omics and environmental datasets further enables the prediction of degradation mechanisms, identification of keystone degraders, and rational design of synthetic consortia. Emerging sustainable strategies, including biochar- and nutrient-amended soil microcosms, plant–microbe partnerships for coupled soil–groundwater phytoremediation, and bioelectrochemical systems that offer new avenues for enhancing PFAS biodegradation in situ. This review synthesises recent research progress and provides critical perspectives on the mechanistic, ecological, and engineering dimensions of PFAS bioremediation, proposing an integrated conceptual framework linking microbial consortia dynamics, enzymatic pathways, and environmental engineering interventions to guide scalable field applications and sustainable management of PFAS-contaminated soil–groundwater ecosystems. Full article
(This article belongs to the Special Issue Emerging Trends of Biotechnology in Bioremediation and Biodegradation)
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20 pages, 997 KB  
Review
Decoding NOTCH1: From T-Cell Development Guardian to Driver of Pediatric T-Cell Lymphoblastic Lymphoma
by Fran Leijnen and Tim Lammens
Int. J. Mol. Sci. 2026, 27(4), 2083; https://doi.org/10.3390/ijms27042083 - 23 Feb 2026
Viewed by 763
Abstract
T-cell lymphoblastic lymphoma (T-LBL) is an aggressive malignancy of immature T-cells accounting for a substantial proportion of pediatric non-Hodgkin lymphoma cases. Current chemotherapeutic regimens achieve five-year event-free survival rates of 80–90%, yet relapse occurs in approximately 20% of patients and remains a major [...] Read more.
T-cell lymphoblastic lymphoma (T-LBL) is an aggressive malignancy of immature T-cells accounting for a substantial proportion of pediatric non-Hodgkin lymphoma cases. Current chemotherapeutic regimens achieve five-year event-free survival rates of 80–90%, yet relapse occurs in approximately 20% of patients and remains a major therapeutic challenge. This underscores the need for improved, molecularly informed treatment strategies. Recent genomic profiling has highlighted the central role of NOTCH1 signaling in T-LBL pathogenesis. NOTCH1, a transmembrane receptor critical for T-cell differentiation and maturation, requires tightly regulated activation during normal thymocyte development. Dysregulated signaling disrupts this balance, driving aberrant proliferation and impaired differentiation, characteristics of malignant transformation. While activating mutations have long been recognized as key oncogenic events, the recent identification of recurrent NOTCH1 translocations, associated with adverse outcomes, reveals an additional mechanism of pathway activation. These findings reinforce NOTCH1 as a pivotal oncogenic hub in T-cell malignancies and a compelling target for therapeutic intervention. This review synthesizes current insights into the molecular landscape of pediatric T-LBL, with a focus on the biological and clinical implications of NOTCH1 mutations and translocations. Furthermore, we examine emerging approaches to therapeutically exploit aberrant NOTCH1 signaling for the more precise and effective treatment of this disease and formulate outstanding research questions. Full article
(This article belongs to the Special Issue Hematologic Malignancies: From Molecular Pathology to Novel Therapeutics)
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19 pages, 1386 KB  
Article
Comparison of Severe COVID-19 Outcomes in Vaccinated and Unvaccinated Patients, with and Without Diabetes Mellitus in a Romanian Tertiary Healthcare Pneumology Hospital—A Retrospective Study
by Ioana-Mădălina Moşteanu, Adela Gabriela Ştefan, Beatrice Mahler, Adina Mitrea, Ionela Mihaela Vladu, Oana-Andreea Parliţeanu, Diana Clenciu, Eugen Moţa, Maria Magdalena Roşu, Delia-Viola Reurean Pintilei, Beatrice Elena Vladu, Alexandru Stoichiță, Diana Cristina Protasiewicz-Timofticiuc, Theodora Claudia Radu-Gheonea, Ion-Cristian Efrem, Anca Maria Amzolini and Maria Moţa
Int. J. Mol. Sci. 2026, 27(4), 2082; https://doi.org/10.3390/ijms27042082 - 23 Feb 2026
Viewed by 588
Abstract
The coronavirus disease 2019 (COVID-19) pandemic has had an unprecedented impact on public health. In the present study, we aimed to analyze the association of certain inflammatory biomarkers with severe COVID-19 and to explore the role of diabetes mellitus (DM) and vaccination status [...] Read more.
The coronavirus disease 2019 (COVID-19) pandemic has had an unprecedented impact on public health. In the present study, we aimed to analyze the association of certain inflammatory biomarkers with severe COVID-19 and to explore the role of diabetes mellitus (DM) and vaccination status in relation to COVID-19 severity, intensive care need and mortality. Associated comorbidities (DM, obesity, cardiovascular, neurological, endocrine, hepatic, renal, pulmonary, rheumatological, psychiatric, hematological diseases, cancer and HIV), as well as inflammatory biomarkers, like ferritin, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), fibrinogen, lactate dehydrogenase (LDH), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) were analyzed in 866 subjects, according to vaccination status. In unvaccinated subjects, the highest AUROC curve for severe COVID-19 was recorded for CRP (0.668), and in the vaccinated group, the highest was recorded for SII (0.694). In age- and comorbidity-adjusted analyses, diabetes mellitus was associated with higher odds of severe COVID-19, ICU admission, and mortality among unvaccinated patients. This analysis was not feasible in the vaccinated group because of the very low number of unfavorable outcomes. These findings emphasize the potential role of vaccination in attenuating the excess risk linked to comorbidities—particularly diabetes mellitus—and support the use of accessible inflammatory biomarkers for early risk stratification. The results should be interpreted within the specific epidemiological phases of the pandemic and in the context of the observational study design. Full article
(This article belongs to the Special Issue Molecular Diagnosis and Treatments of Diabetes Mellitus: 2nd Edition)
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15 pages, 1602 KB  
Article
Evaluation of In Vitro Efficiency of Ciclopirox Against Yersinia pestis and Francisella tularensis
by Idan Hefetz, Raphael Ber, David Gur and Yoav Gal
Int. J. Mol. Sci. 2026, 27(4), 2081; https://doi.org/10.3390/ijms27042081 - 23 Feb 2026
Viewed by 392
Abstract
Yersinia pestis and Francisella tularensis are Tier-1 pathogens with high interest for biodefense and public health. Evaluating the antibacterial activity of repurposed drugs against these high-priority pathogens is a key element in the ongoing effort to develop diversified antimicrobial strategies. Drug repurposing offers [...] Read more.
Yersinia pestis and Francisella tularensis are Tier-1 pathogens with high interest for biodefense and public health. Evaluating the antibacterial activity of repurposed drugs against these high-priority pathogens is a key element in the ongoing effort to develop diversified antimicrobial strategies. Drug repurposing offers a cost-effective and time-efficient approach to address antibiotic resistance by identifying new applications for existing therapeutics. In this study, we demonstrate in vitro antibacterial effect of the antifungal agent ciclopirox and offer this drug as a potential antibacterial treatment. Ciclopirox in vitro activity was previously reported against various Gram-negative bacteria, including resistant strains, primarily through iron chelation that disrupts key metabolic pathways and virulence mechanisms. Additionally, it exhibits antibiofilm activity and can potentiate the efficacy of certain antibiotics. Our findings reveal that ciclopirox effectively inhibits the in vitro growth of fully virulent strains of Y. pestis and F. tularensis, as well as avirulent isolates, including avirulent mutants that their wild-type susceptibility was reduced through selection to MIC levels defining them as “nonsusceptible” to ciprofloxacin (Y. pestis Kim53Δ70Δ10 and F. tularensis LVS) and doxycycline (LVS), or resistant to doxycycline (Kim53Δ70Δ10) according to CLSI interpretive criteria. Additionally, prolonged exposure of Y. pestis and F. tularensis to sub-MIC and MIC concentrations of ciclopirox did not lead to an increase in observed MIC during the study period. These results highlight ciclopirox as a potential candidate for treatment alternative, combined with other antibiotic substances or repurposed drugs against these bacterial threats. Full article
(This article belongs to the Special Issue Antibiotics Science: Molecular Insights, Detection Strategies, Resistance Challenges and Interdisciplinary Applications)
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16 pages, 976 KB  
Review
From Root Exudates to Eco-Corona: Mechanisms Shaping Nanoplastic Fate and Plant–Soil Interactions
by Agata Leszczuk and Adrian Zając
Int. J. Mol. Sci. 2026, 27(4), 2080; https://doi.org/10.3390/ijms27042080 - 23 Feb 2026
Viewed by 795
Abstract
Plastic contamination in agricultural soils constitutes an emerging threat to plant growth, nutrient acquisition, and food safety. Micro- and nanoplastics (NPs) elicit oxidative stress, perturb root morphology, and interfere with key physiological processes. Despite extensive studies in aquatic systems, the mechanistic understanding of [...] Read more.
Plastic contamination in agricultural soils constitutes an emerging threat to plant growth, nutrient acquisition, and food safety. Micro- and nanoplastics (NPs) elicit oxidative stress, perturb root morphology, and interfere with key physiological processes. Despite extensive studies in aquatic systems, the mechanistic understanding of NP behavior in soils, particularly the formation of soil-specific eco-coronas, remains limited. This review provides a mechanistic synthesis of current evidence on the role of root exudates, comprising proteins, amino acids, lipids, and low-molecular-weight metabolites, in modulating NP fate and plant responses within the rhizosphere. We delineate key processes, including exudate adsorption onto NP surfaces, eco-corona formation, aggregation, transport, root uptake, and species- and polymer-specific effects. Root exudation dynamically alters NP surface properties, mediates heteroaggregation, modulates mobility, and regulates interactions with plant roots. At the same time, NP exposure induces species-specific metabolic responses, including enhanced secretion of organic acids, stress-related metabolites, and secondary compounds (e.g., flavonoids). Despite extensive research in aquatic and hydroponic systems, mechanistic understanding of NPs behavior in soils, particularly regarding eco-corona formation and the modulatory role of root exudates, remains limited. This review synthesizes these insights to propose a conceptual framework linking eco-corona dynamics with root exudation processes, thereby providing a foundation for future soil-focused investigations. Full article
(This article belongs to the Special Issue Plant Cell/Organ Structure and Function Research)
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35 pages, 2527 KB  
Review
Extracellular Vesicle-Based Biomarkers in Spinal Cord Injury: A State-of-the-Art Review on Diagnostic and Prognostic Advances
by Trung Nhan Vo, Hae Eun Shin, Yeji Kim and Inbo Han
Int. J. Mol. Sci. 2026, 27(4), 2079; https://doi.org/10.3390/ijms27042079 - 23 Feb 2026
Viewed by 675
Abstract
Spinal cord injury (SCI) is a devastating neurological disorder that can result in permanent disability and reduced quality of life, characterized by heterogeneous injury mechanisms and limited tools for accurate early diagnosis and prognostic stratification. The clinical course of SCI is driven not [...] Read more.
Spinal cord injury (SCI) is a devastating neurological disorder that can result in permanent disability and reduced quality of life, characterized by heterogeneous injury mechanisms and limited tools for accurate early diagnosis and prognostic stratification. The clinical course of SCI is driven not only by the initial mechanical insult but also by complex secondary injury cascades involving neuroinflammation, axonal degeneration, demyelination, and maladaptive repair responses. Current diagnostic and prognostic approaches, which rely largely on neurological examination and imaging, provide limited insight into these dynamic molecular processes. In this context, extracellular vesicles (EVs) have emerged as a biologically compelling source of biomarkers for SCI. EVs are released by neurons, glial cells, endothelial cells, and immune cells and carry molecular cargo that reflects cellular stress, injury severity, and endogenous repair activity. Increasing evidence indicates that EV-associated proteins and regulatory microRNAs (miRNAs) encode injury-specific signatures related to neuronal and glial damage, inflammatory signaling, metabolic stress, and functional recovery potential. In this review, we summarize the current knowledge on EV biology in SCI and discuss emerging evidence supporting EV-derived proteins and miRNAs as promising tools for refining diagnosis and prognosis. Our aim is not only to consolidate established findings but also to highlight EV-based molecular signatures as a developing framework for precision biomarker discovery in SCI. Full article
(This article belongs to the Special Issue Molecular Advances in Biomarkers of Central Nervous System Diseases and Disorders)
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53 pages, 3624 KB  
Review
Photobiomodulation and Low-Level Laser Therapy as Complementary Strategies in Diabetes Treatment
by Natalia Kurhaluk, Vladimir Tomin, Renata Kołodziejska and Halina Tkaczenko
Int. J. Mol. Sci. 2026, 27(4), 2078; https://doi.org/10.3390/ijms27042078 - 23 Feb 2026
Viewed by 1080
Abstract
Diabetes mellitus is a multifactorial metabolic disorder associated with a number of chronic complications, including neuropathy, impaired wound healing, vascular dysfunction, and metabolic dysregulation. Despite advances in pharmacological treatments and lifestyle interventions, current therapies often fail to prevent or reverse these complications entirely. [...] Read more.
Diabetes mellitus is a multifactorial metabolic disorder associated with a number of chronic complications, including neuropathy, impaired wound healing, vascular dysfunction, and metabolic dysregulation. Despite advances in pharmacological treatments and lifestyle interventions, current therapies often fail to prevent or reverse these complications entirely. This narrative review examines the therapeutic potential of laser-based modalities, particularly low-level laser therapy (LLLT) and photobiomodulation therapy (PBMT), as complementary strategies in diabetes management. Analysis of experimental and clinical studies shows that laser therapy can enhance wound healing, alleviate neuropathic pain, improve glycaemic control and insulin sensitivity, modulate inflammatory and oxidative stress pathways, and support vascular function. These effects are primarily mediated through mitochondrial activation, nitric oxide release, angiogenesis, modulation of redox-sensitive transcription factors, and preservation of pancreatic β-cell function. Furthermore, laser therapy exhibits a favourable safety profile with minimal side effects. The review highlights the current challenges, such as the lack of standardised treatment parameters (e.g., wavelength, dosage, and duration) and the limited number of large-scale clinical trials. It emphasises the need for personalised protocols and integration of laser therapy with pharmacological and physiotherapeutic interventions. Continued research and interdisciplinary collaboration are needed to realise the potential of laser therapy as an integral component of comprehensive, evidence-based diabetes care. Full article
(This article belongs to the Special Issue Molecular Mechanism of Diabetes and Its Complications)
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16 pages, 2639 KB  
Article
Distinct Osteogenic Profiles of Tetracyclines from Different Generations in an Ex Vivo Embryonic Chick Femur Model
by Victor Martin, Ana Francisca Bettencourt, Catarina Santos, Maria Helena Fernandes and Pedro Sousa Gomes
Int. J. Mol. Sci. 2026, 27(4), 2077; https://doi.org/10.3390/ijms27042077 - 23 Feb 2026
Viewed by 384
Abstract
Tetracyclines are broad-spectrum bacteriostatic agents with well-established antimicrobial efficacy and a shared core chemical structure, differentiated by distinct functional substitutions across generations. Beyond their antibacterial action, tetracyclines also exhibit pleiotropic biological effects, including modulation of bone metabolism. Nevertheless, the selection of agents and [...] Read more.
Tetracyclines are broad-spectrum bacteriostatic agents with well-established antimicrobial efficacy and a shared core chemical structure, differentiated by distinct functional substitutions across generations. Beyond their antibacterial action, tetracyclines also exhibit pleiotropic biological effects, including modulation of bone metabolism. Nevertheless, the selection of agents and dosing for local bone applications remains largely empirical. Therefore, this study compares the tissue-level osteogenic potential of four tetracyclines from distinct generations using a translational ex vivo embryonic chick femur model. Organotypic femur cultures were maintained for 11 days and exposed to tetracycline (TC), doxycycline (DC), minocycline (MC), or sarecycline (SC), at 1 and 10 µg/mL, concentrations corresponding to clinically relevant local and systemic exposures. Osteogenic outcomes included microcomputed tomography, histological analyses, and quantitative gene expression. At 1 µg/mL, tetracyclines promoted osteogenic effects, increasing collagen deposition by approximately 30%, enhancing matrix maturation by 100%, stimulating tissue mineralization by 20–50%, and upregulating osteogenic marker expression, with TC exhibiting weaker activity. At 10 µg/mL, osteogenic stimulation was notably reduced across all groups. This study provides the first tissue-level, head-to-head comparison of four tetracyclines and their effects on bone biology. The findings indicate that tetracycline-induced osteogenic activity is both agent-specific and concentration-dependent, underscoring the importance of using lower doses to maximize osteogenic responses and supporting the preferential use of DC, MC, and SC in bone regeneration and adjunctive therapeutic applications. Full article
(This article belongs to the Special Issue The Future of Biomaterials in Dentistry: Innovations in Drug Delivery and Regenerative Medicine)
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12 pages, 972 KB  
Review
Targeting Neutrophil Function as Therapy for Hidradenitis Suppurativa
by Eric Meldrum and John R. Ingram
Int. J. Mol. Sci. 2026, 27(4), 2076; https://doi.org/10.3390/ijms27042076 - 23 Feb 2026
Viewed by 936
Abstract
Hidradenitis suppurativa (HS) is a chronic, recurrent inflammatory skin disease characterized by painful nodules, abscesses, and epithelialized tunnels, predominantly affecting flexural regions. With a global prevalence of approximately 1%, HS has a significant negative impact on quality of life. Multi-omics and histopathology studies [...] Read more.
Hidradenitis suppurativa (HS) is a chronic, recurrent inflammatory skin disease characterized by painful nodules, abscesses, and epithelialized tunnels, predominantly affecting flexural regions. With a global prevalence of approximately 1%, HS has a significant negative impact on quality of life. Multi-omics and histopathology studies have revealed a complex interplay between innate and adaptive immunity in HS, with neutrophils emerging as important drivers of inflammation. While therapies targeting TNF-α and IL-17 isoforms offer a degree of benefit, significant unmet need remains. Neutrophil signatures in HS lesions and the circulation underscore the rationale for selective modulation of neutrophil function. Strategies advancing through clinical trials include inhibition of chemokine-mediated trafficking, neutrophil serine protease inactivation and suppression of neutrophil extracellular traps (NETs), which amplify inflammatory and autoimmune responses. These emerging therapies mark a significant shift toward targeted neutrophil modulation, offering new opportunities to improve outcomes for patients with HS. Full article
(This article belongs to the Special Issue Hidradenitis Suppurativa: Molecular Mechanisms and Therapeutic Strategies)
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36 pages, 7083 KB  
Article
A Study on the Treatment of Rheumatoid Arthritis Using a Novel GelMA-HAMA Dual-Network Hydrogel Microneedle Loaded with MTX-NCs in Combination with Adalimumab
by Jianing Tian, Yuhang Shi, Chunyu Liu, Mu Liu, Lin Li, Yusi Zhu, Huilin Wang, Jin Su and Yang Ping
Int. J. Mol. Sci. 2026, 27(4), 2075; https://doi.org/10.3390/ijms27042075 - 23 Feb 2026
Cited by 1 | Viewed by 670
Abstract
This study developed a transdermal drug delivery system for Rheumatoid Arthritis (RA) using a dual-network hydrogel microneedle patch loaded with methotrexate nanocrystals (DHMN@MTX-NCs), and explored its synergistic therapy with Adalimumab (ADA) for a painless, long-acting, and targeted RA treatment. This study synthesized Methacrylated [...] Read more.
This study developed a transdermal drug delivery system for Rheumatoid Arthritis (RA) using a dual-network hydrogel microneedle patch loaded with methotrexate nanocrystals (DHMN@MTX-NCs), and explored its synergistic therapy with Adalimumab (ADA) for a painless, long-acting, and targeted RA treatment. This study synthesized Methacrylated Hyaluronic Acid and Methacrylated Gelatin. MTX-NCs were prepared by solvent-antisolvent precipitation and incorporated into a dual-network hydrogel microneedle patch via centrifugal molding. Evaluations included pharmaceutical properties, mechanical strength, drug release, in vitro anti-inflammatory effects on RAW 264.7 cells, and therapeutic efficacy in a rat RA model. The experimental results show that the prepared MTX-NCs present a spherical shape, an average size of 325.72 nm, a PDI of 0.154, and a drug-loading capacity of 61.3%. The microneedle patch exhibited high puncture efficiency and suitable swelling. In vitro, DHMN@MTX-NCs combined with ADA most strongly inhibited macrophage migration, upregulated IL-10, and downregulated TNF-α, IL-1β, NO, iNOS, and COX-2. In vivo, both monotherapy and combination therapy reduced joint swelling, bone erosion, and histopathological damage. Ultimately, the study demonstrated the synergistic anti-inflammatory efficacy of DHMN@MTX-NCs combined with ADA, providing a novel, non-invasive, and targeted therapeutic strategy for RA. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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29 pages, 1393 KB  
Review
The Electromechanical Connectome: Integrating Voltage, Mechanical Nano-Forces, and Subcellular Fluid Phase Dynamics in Human Neural Computation
by Florin Mihail Filipoiu, Catalina-Ioana Tataru, Nicolaie Dobrin, Matei Șerban, Răzvan-Adrian Covache-Busuioc, Corneliu Toader, Mugurel Petrinel Radoi, Octavian Munteanu and Mihaly Enyedi
Int. J. Mol. Sci. 2026, 27(4), 2074; https://doi.org/10.3390/ijms27042074 - 23 Feb 2026
Viewed by 673
Abstract
Electrophysiology, mechanobiology, and the study of soft matter within cells demonstrate increasing amounts of evidence that neuronal signaling arises from interactions between membrane potential, force, and phase. Herein, we have attempted to collect and organize the evidence for each of these areas of [...] Read more.
Electrophysiology, mechanobiology, and the study of soft matter within cells demonstrate increasing amounts of evidence that neuronal signaling arises from interactions between membrane potential, force, and phase. Herein, we have attempted to collect and organize the evidence for each of these areas of study into an approximate structure called the electromechanical connectome: a three-way state–space (membrane potentials, nanoscale mechanical forces, and cytoplasmic rheology, including phase-separated liquid–liquid droplets) where membrane potentials, nanoscale mechanical forces, and cytoplasmic rheology, and phase-separated liquid–liquid droplets are likely to influence one another, influencing synaptic processing, plasticity and network stability. We will also attempt to illustrate the following: how changes in electrostatic fields can be used to alter the arrangement of lipids, hydration, and dielectric microdomains, and the contact geometry between organelles and activity dependent transcription; how mechanical dynamics associated with spines, axons, and the active zone of synapses may be used to modify the energy landscape of channels, the docking and priming of vesicles, and the transport of cytoskeletons; and how viscosity corridors, along with phase-separated micro-reactors, can be used to regulate the kinetics of signaling, molecular trafficking and metabolic processes in local environments. With these connections in mind, we will propose a multiphysical attractor model in which cognition is the result of navigating through metastable manifolds, while neurodegenerative disease may be a result of the progressive loss of electromechanical coherence, phase boundary control and energetic flexibility. Finally, we will present testable hypotheses and use AI-enabled digital twin methods to potentially quantify the early deformation of manifolds and provide precision biomarkers and therapeutic options. Full article
(This article belongs to the Special Issue New Advances in Neuroscience: Molecular Biological Insights)
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14 pages, 1259 KB  
Article
Breast-Cancer-Derived Secretomes from MCF-7 Cells Modulate Bacterial Pathogenic Traits
by Suha M. Mahmood, Huda K. Al-Nasrallah, Alanoud Aldossry, Mysoon M. Al-Ansari and Monther Al-Alwan
Int. J. Mol. Sci. 2026, 27(4), 2073; https://doi.org/10.3390/ijms27042073 - 23 Feb 2026
Viewed by 455
Abstract
Breast cancer is the most frequently diagnosed malignancy among women worldwide, with the luminal A subtype being the most prevalent. Several studies have reported a complex interplay between breast cancer cells and the local microbiome; however, the mechanisms by which tumor cell-secreted factors [...] Read more.
Breast cancer is the most frequently diagnosed malignancy among women worldwide, with the luminal A subtype being the most prevalent. Several studies have reported a complex interplay between breast cancer cells and the local microbiome; however, the mechanisms by which tumor cell-secreted factors influence bacterial biological properties remain insufficiently explored. In this study, we established an in vitro model that partially recapitulates the luminal A breast cancer microenvironment by exposing three breast-associated bacterial species, Pseudomonas aeruginosa, Enterococcus faecalis, and Escherichia coli, to conditioned media (CM) derived from MCF-7 (tumor) or MCF-10A (non-tumor control) cell lines. A combination of complementary approaches, including ultrastructural morphological assessment, biofilm formation assays, antimicrobial susceptibility testing, and virulence gene abundance profiling by genomic qPCR, was employed to reveal distinct tumor-microbiota interactions. Exposure to MCF-7 CM induced dose-dependent structural alterations in P. aeruginosa and E. faecalis, with pronounced membrane blebbing and structural disruption in E. faecalis. Biofilm formation was differentially modulated in a species- and concentration-dependent manner, with a persistent increase observed in E. coli. Antibiotic susceptibility profiles were selectively altered in E. faecalis, which displayed increased sensitivity to vancomycin, penicillin, and imipenem, along with decreased sensitivity to chloramphenicol. P. aeruginosa exhibited increased sensitivity to imipenem along with reduced sensitivity to meropenem and gentamicin, whereas no significant changes were observed in E. coli. qPCR analyses demonstrated that MCF-7 CM was associated with enrichment of multiple virulence-associated genes (e.g., lasB, exoS, pilB, plcH, fsrC, esp, fimH, and papG), reflecting enhanced pathogenic and adhesive potential. Collectively, these findings suggest that luminal A breast cancer-derived factors can reprogram microbial phenotypes in a species-specific manner, providing mechanistic insight into breast tumor-microbiome crosstalk and a platform to explore microbiome-targeted interventions. Full article
(This article belongs to the Special Issue Interplay Between the Human Microbiome and Diseases)
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15 pages, 2147 KB  
Article
Suppressive Potential of Ethanolic Extracts of Parkia speciosa Hassk. Empty Pods Against Colon Cancer Cell Migration and Invasion
by Athit Chaiwichien, Supawadee Osotprasit, Tepparit Samrit, Pornanan Kueakhai and Narin Changklungmoa
Int. J. Mol. Sci. 2026, 27(4), 2072; https://doi.org/10.3390/ijms27042072 - 23 Feb 2026
Viewed by 376
Abstract
Parkia speciosa (P. speciosa), a plant utilized in traditional medicine, has shown promise in various therapeutic applications and contains multiple bioactive components (saponins, alkaloids, flavonoids, polyphenols, and terpenoids). These bioactive compounds have attracted increasing scientific interest due to their ability to modulate [...] Read more.
Parkia speciosa (P. speciosa), a plant utilized in traditional medicine, has shown promise in various therapeutic applications and contains multiple bioactive components (saponins, alkaloids, flavonoids, polyphenols, and terpenoids). These bioactive compounds have attracted increasing scientific interest due to their ability to modulate key cancer-associated pathways, including the inhibition of cell proliferation and migration and the suppression of oxidative stress and inflammation mechanisms. However, despite P. speciosa’s historically long and wide-ranging usage, a comprehensive investigation of these properties has not been conducted for its pod. This study investigated the effects of P. speciosa empty pod extract (PSET) on human colorectal cancer cells. The extract demonstrated significant dose-dependent inhibition of colorectal cell migration, invasion, and colony formation while exhibiting no cytotoxicity toward normal colon epithelial cells. Western blot analysis confirmed reduced expression of Matrix metalloproteinases 2 (MMP2), Matrix metalloproteinases 9 (MMP9), and N-cadherin, indicating suppression of the epithelial–mesenchymal transition (EMT). These findings demonstrate that the PSET effectively inhibits metastasis in colorectal cancer cells through the EMT pathway, suggesting its potential as a dietary supplement or therapeutic agent for colorectal cancer treatment. Our research provides support for the development of natural, less toxic alternative cancer treatments. Therefore, PSET shows potential for development as a dietary supplement or therapeutic agent for the treatment of colon cancer. Full article
(This article belongs to the Special Issue Antitumor Activity of Natural Products)
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18 pages, 836 KB  
Article
Tear-Based Oxidative Stress Biomarkers in Primary and Sarcoidosis-Associated Dry Eye Disease
by Calina-Anda Sandu, Vlad Constantin Donica, Ioana-Miruna Balmus, Ioana Madalina Bilha, Cosmin Victor Ganea, Ioana Alexandra Sandu, Anisia Iuliana Alexa, Alexandra Lori Donica, Valentina Esanu, Alin Ciobica and Camelia Margareta Bogdanici
Int. J. Mol. Sci. 2026, 27(4), 2071; https://doi.org/10.3390/ijms27042071 - 23 Feb 2026
Viewed by 378
Abstract
Dry eye disease (DED) has increasingly been linked to oxidative stress; however, the specific redox mechanisms underlying different clinical phenotypes remain incompletely understood. This study aimed to evaluate tear film oxidative stress profiles in patients with primary DED and sarcoidosis-associated DED (S-DED) by [...] Read more.
Dry eye disease (DED) has increasingly been linked to oxidative stress; however, the specific redox mechanisms underlying different clinical phenotypes remain incompletely understood. This study aimed to evaluate tear film oxidative stress profiles in patients with primary DED and sarcoidosis-associated DED (S-DED) by assessing lipid peroxidation, antioxidant enzyme activity, and total tear protein content, and to explore their relationship with clinical tear film dysfunction. Tear samples were analyzed for superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities, as well as for malondialdehyde (MDA) and total protein levels, alongside standard clinical tests of tear film stability and secretion. Both DED groups exhibited significant oxidative alterations compared to controls, but with distinct redox signatures. Primary DED was characterized by markedly increased tear MDA levels, indicating predominant lipid peroxidation, whereas S-DED showed a more pronounced impairment of antioxidant defense, reflected by preserved or increased SOD activity in the context of significantly reduced GPx activity. Total tear protein levels were reduced in both groups, with evidence suggesting qualitative protein alterations in S-DED. The tear collection method significantly influenced the measured levels of several oxidative stress markers, underscoring the importance of sampling technique when interpreting tear-based redox profiles. Oxidative stress markers correlated with clinical measures of tear film dysfunction, supporting their physiological relevance. These findings demonstrate that DED encompasses heterogeneous oxidative stress mechanisms and that sarcoidosis acts as a modifier of ocular surface redox homeostasis. Distinct tear-based redox profiles differentiate primary from sarcoidosis-associated dry eye, highlighting the potential value of oxidative biomarkers for phenotyping DED beyond tear deficiency alone. Full article
(This article belongs to the Special Issue Molecular Research and Advances in Ocular Disease)
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16 pages, 3078 KB  
Article
Catharanthus roseus Extract-Loaded Zn-Substituted Hydroxyapatite Nanocomposites as a Multifunctional Antioxidant and Anticancer Therapeutic Applications
by Sankar Sekar, Sutha Sadhasivam, Saravanan Sekar, Youngmin Lee, Sekar Vaithilingam, Nandhakumar Srinivasan, Elangovan Krishnan, Sejoon Lee and Balaji Murugan
Int. J. Mol. Sci. 2026, 27(4), 2070; https://doi.org/10.3390/ijms27042070 - 23 Feb 2026
Cited by 1 | Viewed by 484
Abstract
During recent decades, bone cancer-related diseases have remained hard to treat because of poor diagnosis, systemic toxicity, and restricted conventional treatments. Hence, the fabrication of functionalised nanoparticles offers a promising alternative by limiting side effects and improving therapeutic outcomes. In this study, zinc-substituted [...] Read more.
During recent decades, bone cancer-related diseases have remained hard to treat because of poor diagnosis, systemic toxicity, and restricted conventional treatments. Hence, the fabrication of functionalised nanoparticles offers a promising alternative by limiting side effects and improving therapeutic outcomes. In this study, zinc-substituted hydroxyapatite (Zn-HA) nanoparticles were fabricated from biogenic tuna fish bone waste via a thermal decomposition method and subsequently functionalised with Catharanthus roseus (CR) flower extract to synthesise a Zn-HA/CR nanocomposite. Structural and compositional characterisations verified Zn ions incorporation into the HA lattice and efficient CR-derived phytochemical functionalisation without altering the hexagonal HA phase. Compared to pure hydroxyapatite, the Zn-HA/CR nanocomposite exhibited improved surface morphology, enhanced swelling behaviour and degradation, and increased microhardness. The nanocomposite demonstrated significantly enhanced antibacterial activity against Staphylococcus aureus and Escherichia coli. The Zn-HA/CR nanocomposite also showed strong, dose-dependent antioxidant activity in DPPH assays. Furthermore, in vitro cytotoxicity studies using MG-63 (HOS) osteosarcoma cancer cells revealed that the proposed nanocomposite leads to pronounced morphological alterations and reduced cell viability. The prepared Zn-HA/CR nanocomposite would be a potential nanocomposite for enhanced antioxidant and anticancer activity, which highlights this composite as a multifunctional biomaterial platform for therapeutic applications. Full article
(This article belongs to the Special Issue Molecular and Nanostructured Materials for Energy, Environmental, and Biomedical Applications)
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20 pages, 13526 KB  
Article
PTEN Inhibition Suppresses Differentiation in Periodontal Ligament Stem Cells
by Suphalak Phothichailert, Nunthawan Nowwarote, Chatvadee Kornsuthisopon, Supreda Suphanantachat Srithanyarat, Vorapat Trachoo, Worachat Namangkalakul, Hiroshi Egusa and Thanaphum Osathanon
Int. J. Mol. Sci. 2026, 27(4), 2069; https://doi.org/10.3390/ijms27042069 - 23 Feb 2026
Viewed by 494
Abstract
Phosphatase and Tensin Homolog (PTEN) functions in numerous biological processes, encompassing cell proliferation, growth, self-renewal, and differentiation. This study examined the modulatory function of the PTEN inhibitor in periodontal ligament stem cells (PDLSCs). PDLSCs were treated with VO-OHpic at a concentration range from [...] Read more.
Phosphatase and Tensin Homolog (PTEN) functions in numerous biological processes, encompassing cell proliferation, growth, self-renewal, and differentiation. This study examined the modulatory function of the PTEN inhibitor in periodontal ligament stem cells (PDLSCs). PDLSCs were treated with VO-OHpic at a concentration range from 0.625 to 5 μM. MTT assay and Coomassie Blue staining were conducted to determine cell viability and colony-forming unit ability, respectively. The scratch assay was employed to examine cell migration. Mineral deposition and intracellular lipid accumulation were assessed. The qRT-PCR and immunofluorescence were used to evaluate mRNA and protein expression, respectively. RNA sequencing was employed for transcriptomic analysis. VO-OHpic exposure showed no cytotoxic effects in PDLSCs; however, at 5 μM, it markedly decreased colony-forming efficiency and impaired cell migration. Under osteogenic induction conditions, 5 μM VO-OHpic markedly attenuated mineralisation and downregulated the osteogenic marker gene expression partly through ERK signalling. Indeed, VO-OHpic impaired intracellular lipid accumulation during adipogenic differentiation, as evidenced by reduced expression of adipogenic marker genes. RNA sequencing analysis revealed that VO-OHpic treatment upregulated genes in the TGF-β and calcium signalling pathways, suggesting a regulatory role in PDLSC differentiation. In conclusion, PTEN regulates PDLSC colony formation, migration, and differentiation, suggesting a pivotal role for PTEN in maintaining periodontal tissue homeostasis. Full article
(This article belongs to the Special Issue Molecular Perspectives in Tissue Engineering and Regenerative Medicine)
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29 pages, 5241 KB  
Review
Microbiome–Genome Crosstalk in Colorectal Cancer: Colibactin Signatures and Fusobacterium nucleatum in Epidemiology, Driver Selection, and Translation
by Sungwon Jung
Int. J. Mol. Sci. 2026, 27(4), 2068; https://doi.org/10.3390/ijms27042068 - 23 Feb 2026
Viewed by 703
Abstract
Colibactin, a genotoxin produced by pks+ E. coli, imprints highly specific mutational signatures SBS88 and ID18 in colorectal cancer (CRC) and even in normal colonic crypts. Population-scale analyses show these signatures are enriched in early-onset CRC, vary geographically, and are [...] Read more.
Colibactin, a genotoxin produced by pks+ E. coli, imprints highly specific mutational signatures SBS88 and ID18 in colorectal cancer (CRC) and even in normal colonic crypts. Population-scale analyses show these signatures are enriched in early-onset CRC, vary geographically, and are imprinted early during tumor evolution, where probabilistic attribution indicates that colibactin contributes to a measurable fraction of APC driver mutations in colibactin-positive cancers. Beyond colibactin, Fusobacterium nucleatum exerts clade-specific effects on tumor ecology and therapy response, with data supporting both chemoresistance and sensitization to anti-PD-1 in microsatellite stable (MSS) CRC. This article covers mechanistic, genomic, and molecular epidemiology evidence, outlines analytic standards for signature detection (whole-genome sequencing (WGS)/whole-exome sequencing (WES), single-sample fitting, and limits at low mutation counts), and charts translational paths spanning noninvasive screening (stool metagenomics + mutational signatures in tissue/circulating tumor DNA (ctDNA)), risk stratification, and microbial-targeted interventions (antibiotics, phages, ClbP inhibitors). Framing microbiome–genome crosstalk as a tractable axis enables testable clinical hypotheses for precision oncology. Full article
(This article belongs to the Special Issue Cancer Genomics, 2nd Edition)
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14 pages, 1850 KB  
Article
Investigating the In Vitro Mitochondria-Mediated Anticancer Activity of the Plant Metabolite Ursolic Acid
by Josephine S. Modica-Napolitano, Amanda Clarke, Lauren Nixdorf, Bridget Shanahan, Nicholas Iacovella, Carlos Reyes, Annick Guerin and Azam Noori
Int. J. Mol. Sci. 2026, 27(4), 2067; https://doi.org/10.3390/ijms27042067 - 23 Feb 2026
Viewed by 616
Abstract
This study investigated the cellular and mitochondrial toxicities of the pentacyclic triterpenoid and plant-specialized metabolite ursolic acid (UA) in human breast adenocarcinoma cell lines. Cell viability and clonogenic assays showed that UA induced potent cytotoxic and antiproliferative effects in MDA-MB-231 and MCF7 cells. [...] Read more.
This study investigated the cellular and mitochondrial toxicities of the pentacyclic triterpenoid and plant-specialized metabolite ursolic acid (UA) in human breast adenocarcinoma cell lines. Cell viability and clonogenic assays showed that UA induced potent cytotoxic and antiproliferative effects in MDA-MB-231 and MCF7 cells. Confocal images of living cells showed that UA caused a depolarization of the mitochondrial membrane potential and spectrophotometric measurement of electron transport chain enzyme activity in isolated organelles showed that UA induced a dose-dependent decrease in mitochondrial succinate-cytochrome reductase activity. These results demonstrate a direct, site-specific inhibitory effect of UA on mitochondrial bioenergetic function. Furthermore, the efficacy of a drug combination aimed concurrently at both major pathways of ATP production in breast cancer cells was investigated. The data show that when MDA-MB-231 and MCF7 cells were treated with UA in combination with either 2-deoxy-D-glucose or 3-bromopyruvate, two inhibitors of glycolysis, the resulting cytotoxicity was greater than that induced by any of the compounds used independently. The results of this study are important in that they demonstrate direct mitochondrial targets of UA and suggest the possibility of using this natural, plant-derived metabolite in combination with glycolytic inhibitors as a novel and effective dual treatment strategy for breast cancer cell killing. Full article
(This article belongs to the Special Issue New Insights into Mitochondria in Health and Diseases)
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50 pages, 2435 KB  
Review
Functional Foods as Modulators of Epigenetic Mechanisms Affecting Metabolic Health in Adolescence
by Natalia Kurhaluk, Renata Kołodziejska, Zbigniew Mazur, Oleksandr Lukash, Oleksandr Yakovenko and Halina Tkaczenko
Int. J. Mol. Sci. 2026, 27(4), 2066; https://doi.org/10.3390/ijms27042066 - 23 Feb 2026
Cited by 1 | Viewed by 861
Abstract
Adolescence represents a critical window of metabolic plasticity, during which profound hormonal, neurobiological, and physiological remodelling increases susceptibility to nutritional exposures. In parallel with the rising prevalence of obesity, insulin resistance, metabolic syndrome, and non-alcoholic fatty liver disease among young people, there is [...] Read more.
Adolescence represents a critical window of metabolic plasticity, during which profound hormonal, neurobiological, and physiological remodelling increases susceptibility to nutritional exposures. In parallel with the rising prevalence of obesity, insulin resistance, metabolic syndrome, and non-alcoholic fatty liver disease among young people, there is growing interest in the potential for functional food components to modulate epigenetic pathways that govern metabolic programming. This narrative review synthesises current evidence (2015–2025) from PubMed, Scopus, Web of Science, and Embase to elucidate how diet-derived bioactive compounds influence epigenetic regulation relevant to adipogenesis, appetite control, insulin signalling, and lipid homeostasis during adolescence. Particular emphasis is placed on molecular mechanisms, including DNA methylation changes in genes regulating adipocyte differentiation, hypothalamic neuropeptide expression, and pancreatic β-cell function; histone modifications, such as acetylation and methylation events that remodel chromatin accessibility in metabolic tissues; and modulation of microRNA networks implicated in lipid metabolism, inflammatory signalling, and insulin secretion. Furthermore, the review examines the interplay between diet, the gut microbiota, and the epigenome, highlighting the role of microbially derived short-chain fatty acids (SCFAs) as endogenous histone deacetylase inhibitors and mediators of epigenetic remodelling in adipose tissue. By linking these mechanisms to specific functional food components, including polyphenols, long-chain omega-3 fatty acids, fermentable dietary fibre, and other bioactive molecules, we demonstrate how nutritional signals can counteract maladaptive metabolic trajectories and potentially reduce the intergenerational transmission of metabolic risk. A deeper understanding of these epigenetic effects provides the foundation for developing personalised nutrition strategies aimed at preventing metabolic disorders from emerging during adolescence and beyond. Full article
(This article belongs to the Special Issue The Environment, Human Stress, and Gut Microbiome: A Triad in Disease Development)
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18 pages, 567 KB  
Article
Exploration of Early-Treatment-Associated Changes in Metabolic and Inflammatory Biomarkers in First-Episode Psychosis in Italian Patients
by Elisabetta Maffioletti, Clarissa Ferrari, Roberta Zanardini, Roberta Rossi, Sarah Tosato, Chiara Bonetto, Mario Ballarin, Antonio Lasalvia, Mirella Ruggeri, Massimo Gennarelli, Andrea Geviti, on behalf of the GET-UP Group and Luisella Bocchio-Chiavetto
Int. J. Mol. Sci. 2026, 27(4), 2065; https://doi.org/10.3390/ijms27042065 - 23 Feb 2026
Viewed by 358
Abstract
Studies conducted in first-episode psychosis (FEP) patients have shown alterations in inflammation and metabolism. Our objective was to investigate potential treatment-related effects on these systems in Italian FEP patients undergoing either an experimental treatment consisting of a multi-element psychosocial intervention (EXP), including cognitive–behavioural [...] Read more.
Studies conducted in first-episode psychosis (FEP) patients have shown alterations in inflammation and metabolism. Our objective was to investigate potential treatment-related effects on these systems in Italian FEP patients undergoing either an experimental treatment consisting of a multi-element psychosocial intervention (EXP), including cognitive–behavioural therapy, or treatment as usual (TAU). A total of 191 FEP patients with first contact between April 2010 and March 2011 were clinically assessed at baseline and after 9 months of treatment, and the serum levels of 19 analytes were determined through single or multiplex enzyme-linked immunosorbent assays (ELISAs). A significant increase was observed in leptin levels and a significant decrease in Glucagon-Like Peptide-1 (GLP-1) levels during the treatment (time effect, p < 0.001 for both), with no significant interaction between time and treatment type. Although ghrelin levels changed significantly over time in the whole cohort (p = 0.008), a significant decrease was observed only in the EXP group (post hoc test: p = 0.001). None of the biomarkers measured at baseline showed a predictive effect on treatment efficacy, and no significant associations were identified between changes in clinical scores and changes in biomarker levels. These results suggest that early-phase psychosis treatments are associated with possible effects on metabolic regulation. Full article
(This article belongs to the Collection Feature Paper Collection in Molecular Endocrinology and Metabolism)
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23 pages, 1541 KB  
Review
Characterization of Conformational Instability of Monoclonal Antibodies During Chromatographic Purification
by Krystian Baran and Rafał Podgórski
Int. J. Mol. Sci. 2026, 27(4), 2064; https://doi.org/10.3390/ijms27042064 - 23 Feb 2026
Viewed by 619
Abstract
Monoclonal antibodies represent one of the fastest-growing sectors of the biopharmaceutical industry. Their high therapeutic efficacy and reduced incidence of adverse effects compared to conventional therapies have led to an increasing demand for these products. The costliest stages of monoclonal antibody production are [...] Read more.
Monoclonal antibodies represent one of the fastest-growing sectors of the biopharmaceutical industry. Their high therapeutic efficacy and reduced incidence of adverse effects compared to conventional therapies have led to an increasing demand for these products. The costliest stages of monoclonal antibody production are the separation and purification processes, which underscores the need for continuous development and optimization of applied methodologies. Active pharmaceutical ingredients must exhibit high purity and preserved biological activity in order to meet stringent regulatory requirements. Macromolecules such as monoclonal antibodies possess complex conformational structures that significantly influence their stability. The application of multi-step chromatographic processes during purification from cell culture harvests may induce structural alterations, including protein unfolding and aggregation, ultimately resulting in decreased product quality and therapeutic effectiveness. Such structural changes may also increase immunogenicity risk and reduce product shelf life, posing additional challenges for downstream processing. In addition, chromatographic media create microenvironments that differ markedly from bulk solution (e.g., high local protein concentration, confined pore spaces and heterogeneous surface chemistry). These effects can promote either self-association driven by colloidal interactions or partial unfolding followed by irreversible aggregation, depending on the unit operation and operating window. Practical mitigation is therefore rarely achieved by a single lever; instead, it requires an integrated view of resin selection, buffer composition (pH, salt type and ionic strength, and stabilizing additives), residence time and temperature, as well as an analytics strategy that combines orthogonal aggregation assays with structural probes. This work discusses the phenomena of unfolding and aggregation of therapeutic proteins, with particular emphasis on monoclonal antibodies occurring during chromatographic purification. Furthermore, key analytical methods, characterization techniques, and mitigation strategies aimed at improving product quality and reducing manufacturing costs are reviewed. Full article
(This article belongs to the Special Issue Antibody Engineering and Therapeutic Applications)
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21 pages, 2923 KB  
Article
Restoration of Defective CFTR in Human Nasal Respiratory Epithelial Cells by CFTR Modulators and mRNA Transfection
by Roshani Narayan Singh, Marilia Marta Horn, Marin Juko, Ami Kampshoff, Jochen Schmid, Heymut Omran, Dandan Zhang, Joseph Rosenecker, Wolf-Michael Weber and Jörg Große-Onnebrink
Int. J. Mol. Sci. 2026, 27(4), 2063; https://doi.org/10.3390/ijms27042063 - 23 Feb 2026
Viewed by 602
Abstract
The cystic fibrosis transmembrane conductance regulator (CFTR) is a member of the atypical ATP-binding cassette (ABC) family that functions as a phosphorylation-regulated epithelial anion channel. Cystic fibrosis (CF) is characterised by variants in the CFTR gene that lead to impaired epithelial chloride–ion transport [...] Read more.
The cystic fibrosis transmembrane conductance regulator (CFTR) is a member of the atypical ATP-binding cassette (ABC) family that functions as a phosphorylation-regulated epithelial anion channel. Cystic fibrosis (CF) is characterised by variants in the CFTR gene that lead to impaired epithelial chloride–ion transport and increased mucus viscosity. Although CFTR modulators such as Trikafta® have transformed the care of many CF patients, individuals harbouring rare CFTR variants still have no effective treatment options. In this study, we used primary air–liquid interface (ALI) airway cultures obtained from 21 CF patients (pwCF) and 21 healthy controls (HC) to evaluate the therapeutic efficacy of CFTR restoration based on chitosan-mediated CFTR mRNA and modulators. While modulators restored CFTR channel function in most cultures derived from CF patients, those with class I or other rare variants showed no improvement. Chitosan-mediated CFTR mRNA delivery successfully restored CFTR function in ALI cultures of patients carrying rare CFTR variants with limited or no observed clinical response to modulator therapy, assessed by electrophysiology using our newly developed Multi Transepithelial Current Clamp (MTECC) Ussing chamber. This was then confirmed by morphological visualisation of CFTR protein expression in modulator-responsive patient samples using immunofluorescence (IF) staining. IF revealed an increase in CFTR signal and the restoration of epithelial barrier integrity following chitosan-mRNA and modulator treatment as a secondary outcome alongside CFTR functional measurements. Notably, MUC5AC expression, a major gel-forming mucin expressed by airway goblet cells and mucus viscosity were elevated in CF cultures, but were markedly reduced following successful intervention, approaching the levels seen in HCs. These findings establish the potential of chitosan-mRNA delivery as a therapeutic approach for CF patients, particularly those who do not respond to modulators. They also provide a practical, comparative evaluation of advanced mRNA-based treatments in patient-derived airway models. Full article
(This article belongs to the Special Issue Transporters in Health and Disease)
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16 pages, 12822 KB  
Article
Selenium-Thioredoxin Axis Contributes to Ferroptosis Resistance in Pancreatic Cancer Cells
by Arslan Amer, Micah Idowu, Aqsa Ahsan, Alyssa Abbas, Tahiyat Alothaim and Xiaohu Tang
Int. J. Mol. Sci. 2026, 27(4), 2062; https://doi.org/10.3390/ijms27042062 - 23 Feb 2026
Viewed by 1266
Abstract
Pancreatic ductal adenocarcinoma (PDAC) shows substantial heterogeneity in cysteine dependence and ferroptosis sensitivity. We identify two PDAC subtypes distinguished by EMT status: mesenchymal-like cells are highly cysteine-dependent and rapidly undergo ferroptosis upon cystine deprivation or system xc− inhibition, whereas epithelial-type cells are [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) shows substantial heterogeneity in cysteine dependence and ferroptosis sensitivity. We identify two PDAC subtypes distinguished by EMT status: mesenchymal-like cells are highly cysteine-dependent and rapidly undergo ferroptosis upon cystine deprivation or system xc− inhibition, whereas epithelial-type cells are ferroptosis-resistant. Selenium supplementation protects cells from erastin-induced ferroptosis, and this protection persists even when intracellular glutathione (GSH) is depleted, supporting an additional GPX4-independent protective mechanism. Sepp1 knockdown does not alter sensitivity, indicating that selenium’s protective effect is independent of Sepp1. Instead, epithelial-type cells rely on both cytosolic and mitochondrial thioredoxin reductases (TrxR1 and TrxR2) to maintain ferroptosis resistance. Chemical inhibition of thioredoxin reductases abolishes selenium-mediated protection and sensitizes epithelial cells to ferroptosis inducers, while dual genetic suppression of TrxR1 and TrxR2 similarly restores ferroptosis sensitivity. These findings uncover a selenium–thioredoxin redox axis that functions independently of GPX4 and contributes ferroptosis resistance in epithelial-type PDAC cells. Co-targeting cysteine metabolism and thioredoxin reductases may therefore represent a rational strategy to overcome ferroptosis resistance in some PDAC subtypes. Full article
(This article belongs to the Special Issue The Role of Omics in Cancer Diagnosis and Treatment)
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15 pages, 10759 KB  
Article
Perillaldehyde-Encapsulated Lipid Nanoparticle Hydrogel for Enhanced Wound Healing, Improved Stability and Biocompatibility
by Jiansang Wulu, Wenfang Jin, Sirong Peng, Qing Yang, Jing Li and Zhifeng Zhang
Int. J. Mol. Sci. 2026, 27(4), 2061; https://doi.org/10.3390/ijms27042061 - 23 Feb 2026
Viewed by 410
Abstract
Volatile phytochemicals such as perillaldehyde (PAH) exhibit antimicrobial and anti-inflammatory activities relevant to wound repair; however, topical use is limited by volatility, chemical instability, and potential irritation associated with burst exposure. Here, we developed a nano-in-hydrogel dressing by encapsulating PAH into lipid nanoparticles [...] Read more.
Volatile phytochemicals such as perillaldehyde (PAH) exhibit antimicrobial and anti-inflammatory activities relevant to wound repair; however, topical use is limited by volatility, chemical instability, and potential irritation associated with burst exposure. Here, we developed a nano-in-hydrogel dressing by encapsulating PAH into lipid nanoparticles (PAH-L) and incorporating them into a carbomer hydrogel (PAH-L-G). PAH-L showed a uniform nanoscale size distribution, high encapsulation efficiency, and good colloidal stability. After gel incorporation, PAH-L-G formed an interconnected porous network with rapid swelling and a more sustained release profile than free PAH or PAH-L. Hemocompatibility and cytocompatibility assays indicated low hemolysis and high fibroblast viability. In a full-thickness rat wound model, PAH-L-G accelerated wound closure and improved histological regeneration without obvious local irritation. Overall, the lipid-nanoparticle-in-hydrogel strategy stabilizes PAH and enables controlled topical delivery, supporting PAH-L-G as a promising wound dressing platform. Full article
(This article belongs to the Section Molecular Nanoscience)
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28 pages, 12625 KB  
Article
GWAS-Based Mining of Candidate Genes for Low-Nitrogen Tolerance in Maize
by Baobao Wang, Luo Xu, Ying Huang, Shaoxin Wang, Zhongjian Li, Rui Guo, Liang Ma, Liping Xu, Zhaohan Yue, Jianying Feng and Dengfeng Zhang
Int. J. Mol. Sci. 2026, 27(4), 2060; https://doi.org/10.3390/ijms27042060 - 23 Feb 2026
Viewed by 503
Abstract
Nitrogen (N) is an essential yield-limiting factor in maize, and identifying genes that improve nitrogen use efficiency (NUE) is critical for sustainable agriculture and environmental protection. However, the genetic basis of NUE in maize remains poorly understood. In this study, we performed a [...] Read more.
Nitrogen (N) is an essential yield-limiting factor in maize, and identifying genes that improve nitrogen use efficiency (NUE) is critical for sustainable agriculture and environmental protection. However, the genetic basis of NUE in maize remains poorly understood. In this study, we performed a genome-wide association study (GWAS) using a mixed linear model (MLM) controlling for population structure and kinship, based on an association panel of 282 maize inbred lines genotyped via the Maize 50K GBTS array (53,162 SNPs). Ten NUE-related traits (grain yield, hundred-kernel weight, ear length, ear diameter, kernel row number, kernel number per row, SPAD value, ASI, plant height, ear height) were evaluated under two N levels during the 2024–2025 growing seasons. The GWAS analysis detected 122 significant SNPs in gene regions linked to low N tolerance under the studied conditions. Linkage disequilibrium analysis and functional annotation narrowed down 26 candidate genes, whose GO and KEGG enrichment analyses (Fisher’s exact test) identified three core genes (Zm00001d027880, Zm00001d034047, Zm00001d010574). Furthermore, several inbred lines (H1710, 23N272, and 23N41) demonstrating superior low-nitrogen tolerance were identified. The primary subsequent focus in future research for these genetic materials will be their utilization to breed new cultivars with enhanced nitrogen use efficiency. Full article
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23 pages, 2600 KB  
Review
Immunological Analysis of Oral Cytobrush Specimens for Early Detection of Oral Cancer Biomarkers: A Comprehensive Review
by Reem Hanna, Alberto Luigi Rebaudi, Saman Warnakulasuriya, Senada Koljenovic, Maria Menini, Francesco Laganà, Bernardo Bianchi, Paolo Iacoviello, Mauro Labanca, Marco Greppi, Federico Rebaudi, Silvia Pesce, Alberto Rebaudi and Emanuela Marcenaro
Int. J. Mol. Sci. 2026, 27(4), 2059; https://doi.org/10.3390/ijms27042059 - 23 Feb 2026
Viewed by 612
Abstract
Early identification of the risk of malignant transformation in oral potentially malignant disorders (OPMDs) is critical for improving outcomes in oral squamous cell carcinoma (OSCC). This comprehensive review examines immunological biomarkers obtained from minimally invasive oral cytobrush (OCB) specimens for the early detection [...] Read more.
Early identification of the risk of malignant transformation in oral potentially malignant disorders (OPMDs) is critical for improving outcomes in oral squamous cell carcinoma (OSCC). This comprehensive review examines immunological biomarkers obtained from minimally invasive oral cytobrush (OCB) specimens for the early detection of OSCC within a precision medicine framework. The objectives were to (1) identify and characterise key immunological biomarkers associated with early oral carcinogenesis; (2) evaluate the diagnostic utility of OCB sampling for detecting these biomarkers; and (3) explore the potential of OCB-based profiling to support personalised screening and patient management. The review highlights the potential advantages of OCB compared with conventional diagnostic methods, as reported in the literature, particularly its ability to capture early malignant changes through immunological analysis. Evidence is discussed for biomarker pathways related to cell-cycle and differentiation dysregulation (p53, Ki-67, CKs), inflammation-driven epithelial transformation (IL-1β, IL-6, IL-8, TNF-α), and immune suppression and checkpoint activation (PD-L1, B7-H6). OCB provides reliable and patient-friendly cyto-salivary samples that are suitable for immunological and molecular analyses. Aberrant biomarker expression detected in OCB specimens correlates with epithelial dysplasia and reflects early non-invasive neoplastic transformation, supporting the diagnostic value of integrated biomarker panels. Overall, OCB-based immunoanalysis represents a practical, non-invasive approach for the early detection of OSCC. Emerging technologies, including AI and multi-omics approaches, may further support the precision and predictive values of immunological analysis for OSCC. When combined with relevant biomarker pathways reflecting tumour biology and host immune responses, this strategy could offer a strong foundation for precision-medicine screening. It may also support personalised monitoring in patients with OPMDs. Full article
(This article belongs to the Special Issue Oral Squamous Cell Carcinoma: Insights into Molecular Pathways and Emerging Therapeutic Approaches)
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14 pages, 2570 KB  
Article
Identification of Neferine as a DOR Agonist Activating Gi and Gz Signaling: In Silico and In Vitro Studies
by Zenghao Bi, Yuting Liang, Xinyu Tang, Yun Shu, Zhuangyuan Xie, Guoqing Xu, Jing Mo, Pang Jit Seng, Yifan Qing, Zhaotong Cong, Liang Leng and Shilin Chen
Int. J. Mol. Sci. 2026, 27(4), 2058; https://doi.org/10.3390/ijms27042058 - 23 Feb 2026
Viewed by 503
Abstract
Benzylisoquinoline alkaloids (BIAs) exhibit diverse biological activities, such as neuroprotective effects. The delta-opioid receptor (DOR) has emerged as a promising therapeutic target due to its potential role in enhancing neuroprotection and regeneration. However, reports on the binding of BIAs to the DOR remain [...] Read more.
Benzylisoquinoline alkaloids (BIAs) exhibit diverse biological activities, such as neuroprotective effects. The delta-opioid receptor (DOR) has emerged as a promising therapeutic target due to its potential role in enhancing neuroprotection and regeneration. However, reports on the binding of BIAs to the DOR remain scarce. Here, neferine, a BIA from Nelumbo nucifera, as a potential DOR agonist. Molecular docking ranked neferine among the top of 15 BIAs. Initial binding was detected by cellular membrane chromatography and quantitatively confirmed by bio-layer interferometry, with a KD value of 37.4 μM. ONE vector G protein Optical biosensor revealed that Gi2, Gi3 and GZ signaling could be activated by neferine through DOR modulation. Consistent with the Gi/z activation, neferine dose-dependently inhibited cAMP accumulation with an EC50 of 0.25 µM. Transcriptomic analysis in DOR-overexpressing HEK293T cells indicated that neferine stimulation predominantly regulates gene networks governing cell cycle and stress adaptation. However, direct transcriptional signature for neuroprotection was not predominant in our system, suggesting that DOR signaling may exhibit context-dependent effects. In conclusion, we identified the neferine as a natural DOR agonist through in silico and in vitro approach, providing a reference for further investigation into its pharmacological potential. Full article
(This article belongs to the Section Molecular Informatics)
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3 pages, 149 KB  
Editorial
Special Issue “Inflammatory Airway Diseases: Diagnosis, Pathology, Molecular Mechanisms and Treatment Options”
by Emma Matthews and Stefanie Krick
Int. J. Mol. Sci. 2026, 27(4), 2057; https://doi.org/10.3390/ijms27042057 - 22 Feb 2026
Viewed by 340
Abstract
The lung is a unique organ because of its continuous exposure to the external environment, which requires a complex and tightly regulated immune network [...] Full article
(This article belongs to the Special Issue Inflammatory Airway Diseases: Diagnosis, Pathology, Molecular Mechanisms and Treatment Options)
3 pages, 143 KB  
Editorial
Special Issue “Cytokines in Inflammatory Signaling: 2nd Edition”
by Wai Po Chong
Int. J. Mol. Sci. 2026, 27(4), 2056; https://doi.org/10.3390/ijms27042056 - 22 Feb 2026
Viewed by 291
Abstract
Cytokines serve as critical mediators of the immune response, orchestrating host defense against pathogens, cellular proliferation, and tissue homeostasis; however, dysregulation of cytokine signaling can precipitate chronic inflammation, autoimmune disorders, and metabolic diseases, underscoring the delicate balance required for physiological integrity [...] Full article
(This article belongs to the Special Issue Cytokines in Inflammatory Signaling: 2nd Edition)
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