International Journal of Molecular Sciences

14 pages, 568 KB

Open AccessArticle

Live Cell-Based Semi-Quantitative Stratification Highlights Titre-Dependent Phenotypic Heterogeneity in MOGAD: A Single-Centre Experience

by Donato Regina, Concetta Domenica Gargano, Tommaso Guerra, Antonio Frigeri, Damiano Paolicelli, Maddalena Ruggieri and Pietro Iaffaldano

Int. J. Mol. Sci. 2025, 26(19), 9615; https://doi.org/10.3390/ijms26199615 - 1 Oct 2025

Abstract

Myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD) is an inflammatory demyelinating disorder of the central nervous system characterised by heterogeneous clinical and radiological presentations. Accurate interpretation of serum anti–myelin oligodendrocyte glycoprotein (anti-MOG) antibody titres is critical to improve diagnostic precision and prognostic assessment. This [...] Read more.

Myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD) is an inflammatory demyelinating disorder of the central nervous system characterised by heterogeneous clinical and radiological presentations. Accurate interpretation of serum anti–myelin oligodendrocyte glycoprotein (anti-MOG) antibody titres is critical to improve diagnostic precision and prognostic assessment. This single-centre retrospective study evaluated 19 patients diagnosed with MOGAD in 2023, all of whom were seropositive for anti-MOG IgG, as confirmed by live cell-based assays (CBAs) using full-length human MOG and IgG1-specific secondary antibodies. Antibody quantification combined a ratiometric semi-quantitative fluorescence index with classical endpoint dilution titres, enabling classification into low, medium, and high titre groups. Stratification revealed titre-dependent phenotypic heterogeneity: high-titre patients were older at onset and predominantly presented with optic neuritis, often bilateral, and encephalic involvement, whereas low-titre patients more frequently exhibited spinal cord syndromes, cerebellar or brainstem symptoms, and a higher prevalence of cerebrospinal fluid-restricted oligoclonal bands. Semi-quantitative fluorescence ratios correlated consistently with endpoint titres, and exponential decay analysis demonstrated slower signal loss in high-titre sera, confirming assay reliability. No significant association emerged between titre level and monophasic versus relapsing disease course. Anti-MOG antibody titres could serve not only as a diagnostic biomarker but also to capture clinically relevant immunopathological diversity, supporting a titre-stratified approach to diagnosis and early prognostication. Incorporating semi-quantitative metrics alongside clinical and imaging features may refine the diagnostic algorithm and prevent misclassification of atypical presentations. Full article

(This article belongs to the Special Issue Multiple Sclerosis: The Latest Developments in Immunology and Therapy)

16 pages, 1426 KB

Open AccessArticle

Angiotensin II and EDH Pathways Underlie the Vascular Sympatho-Modulation by 5-HT in Female Rats

by Anaïs Clara Terol-Úbeda, Juan Francisco Fernández-González, Asunción Morán, Mónica García-Domingo and José Ángel García-Pedraza

Int. J. Mol. Sci. 2025, 26(19), 9614; https://doi.org/10.3390/ijms26199614 - 1 Oct 2025

Abstract

The vascular 5-HT sympatho-modulation may involve inhibitory or potentiating pathways: nitric oxide (NO), endothelium-dependent hyperpolarization (EDH)-K⁺ channels, prostanoids, angiotensin II (Ang-II), or endothelin. Compared to males, female rats show differences in the serotonergic sympatho-regulation; therefore, we aimed to study the involvement of [...] Read more.

The vascular 5-HT sympatho-modulation may involve inhibitory or potentiating pathways: nitric oxide (NO), endothelium-dependent hyperpolarization (EDH)-K⁺ channels, prostanoids, angiotensin II (Ang-II), or endothelin. Compared to males, female rats show differences in the serotonergic sympatho-regulation; therefore, we aimed to study the involvement of indirect pathways via 5-HT_1D-mediated inhibition and 5-HT_2A/3-mediated potentiation of vascular noradrenergic neurotransmission in females. An i.v. bolus of different inhibitors/blockers of modulators/mediators (NO, K⁺ channels, prostanoids, Ang-II, or endothelin) was administered prior to the infusion of the agonists, L-694,247 (5-HT_1D), TCB-2 (5-HT_2A), or 1-PBG (5-HT₃), in female pithed rats. In these conditions, the vascular sympathetic outflow was electrically stimulated to assess the vasopressor responses. The L-694,247 vascular sympatho-inhibition was abolished by a non-selective K⁺ channel blocker, tetraethylammonium. The 1-PBG sympatho-excitatory vascular effect was not modified by any of the inhibitors tested, whereas TCB-2 sympatho-potentiation was blocked solely by losartan (Ang-II type 1 receptor antagonist). Moreover, Ang-II levels were increased after TCB-2 infusion in females. The EDH pathway mediates the 5-HT_1D-induced sympatho-inhibition, while the 5-HT_2A-evoked sympatho-excitatory effect is associated with Ang-II. In contrast, the 5-HT₃ sympatho-potentiation does not involve any indirect pathway. These findings advance current understanding of the complex interactions between 5-HT and vascular homeostasis in female rats. Full article

(This article belongs to the Special Issue Molecular Mechanism in Cardiovascular Pathology)

21 pages, 3218 KB

Open AccessArticle

Genomic Signatures of Adaptive Evolution in Taenioides sp. During Northward Invasion

by Kun Huang, Tianwei Liu, An Xu, Jing Yu, Yijing Yang, Jing Liu, Fenghui Li, Denghui Zhu, Li Gong, Liqin Liu and Zhenming Lü

Int. J. Mol. Sci. 2025, 26(19), 9613; https://doi.org/10.3390/ijms26199613 - 1 Oct 2025

Abstract

The success and impact of biological invasions depend on adaptations to novel abiotic and biotic selective pressures. However, the genetic mechanisms underlying adaptations in invasive species are inadequately understood. Taenioides sp. is an invasive worm goby, originally endemic to brackish waters in the [...] Read more.

The success and impact of biological invasions depend on adaptations to novel abiotic and biotic selective pressures. However, the genetic mechanisms underlying adaptations in invasive species are inadequately understood. Taenioides sp. is an invasive worm goby, originally endemic to brackish waters in the estuaries of Southeastern China, and now colonizes multiple inland freshwaters of North China within decades as a byproduct of the East Route of South-to-North Water Transfer (ESNT) project. However, the molecular mechanisms underlying their adaptations to the climate of North China, especially the temperature regime, are unknown. Here, we performed genomic resequencing analysis to assess genetic diversity and population genetic structure, and further investigated the genomic signatures of local adaptation in the invasive population of Taenioides sp. during their northward invasion. We revealed that all invasive populations exhibited no genetic differentiation but low gene flow and an obvious signal of population bottleneck. Yangtze River estuary may serve as the source population, while Gaoyou Lake serves as a potential bridgehead of the invasion. Selective sweep analyses revealed 117 genomic regions, containing 673 candidate genes, under positive selection in populations at the invasive front. Redundancy analysis suggested that local temperature variables, particularly the monthly minimum temperature, represent critical evolutionary forces in driving adaptive divergence. Functional enrichment analyses revealed that multiple biological processes, including metabolism and energy production, substance transmembrane transport, and neural development and synaptic transmission, may play important roles in adaptation to regional temperature conditions. Our findings revealed a scenario of adaptive evolution in teleost species that underpins their regional climate adaptation and successful establishment of invasive populations in a human-facilitated invasion context. Proper management strategies should be established to manage Taenioides sp invasion as soon as possible. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

15 pages, 1122 KB

Open AccessArticle

Predictive Factors for Cervical Intraepithelial Neoplasia in Women with Abnormal Cytology According to Human Papillomavirus Genotype: An Observational Study

by Gonzalo Arturo Medina Bueno, Enrique Adolfo Jaramillo Saavedra, Natalia Torres Rendón and Damaris Diana Huareccallo Suni

Int. J. Mol. Sci. 2025, 26(19), 9612; https://doi.org/10.3390/ijms26199612 - 1 Oct 2025

Abstract

Introduction: Cervical cancer remains a leading cause of mortality among women, particularly in regions with limited resources. Persistent high-risk human papillomavirus (HR-HPV) infection is the main etiological factor for CIN and cervical cancer. This study aimed to evaluate the association between HPV genotypes, [...] Read more.

Introduction: Cervical cancer remains a leading cause of mortality among women, particularly in regions with limited resources. Persistent high-risk human papillomavirus (HR-HPV) infection is the main etiological factor for CIN and cervical cancer. This study aimed to evaluate the association between HPV genotypes, age, and cytological findings and the presence of CIN2–3 in women presenting with abnormal cervical cytology. Methods: This cross-sectional study included 189 women with abnormal cytology who attended a tertiary center in Peru. All participants underwent partial HPV genotyping using the Cobas 4800 assay, colposcopic evaluation, and colposcopically directed biopsies, which served as the diagnostic reference. Sociodemographic characteristics and reproductive histories were also collected. Multiple logistic regression was performed to assess the associations among specific HPV genotypes, age, cytological results, and CIN2–3 outcomes. Results: Most participants were between 30 and 59 years of age (76.7%), and multiparity was common (77.8%). The most frequent cytological abnormalities were ASC-US (36.0%) and LSIL (28.0%), followed by HSIL (20.1%). HPV16 was detected in 24.3% of cases, HPV18 in 2.1%, and other HR-HPV types in 73.6%. HSIL cytology showed high concordance with histological CIN2–3 (>95%). Logistic regression demonstrated that age ≥ 30 years (aOR 4.50, 95% CI 1.90–10.65) and HPV16 infection (aOR 4.19, 95% CI 1.95–9.00) were the strongest independent predictors of high-grade disease. HPV18 was rare and not significantly associated, whereas other HR-HPV types showed an inverse association with CIN2–3. Conclusion: HPV16 and age ≥ 30 years were the most significant predictors of CIN2–3 in women with abnormal cytology, underscoring the dominant oncogenic role of HPV16. Integrating HPV genotyping, cytological findings, and age into risk-stratified algorithms could optimize cervical cancer prevention, ensuring timely detection of high-grade lesions while minimizing overtreatment in low-risk populations. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms of Human Papillomavirus Family (HPV) Induced Oncogenesis)

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28 pages, 1629 KB

Open AccessArticle

Molecular Adaptations to Repeated Radiation Exposure in Triple-Negative Breast Cancer: Dysregulation of Cell Adhesion, Mitochondrial Function, and Epithelial–Mesenchymal Transition

by Noah Dickinson, Alyssa Murray, Megan Davis, Kaitlyn Marshall-Bergeron, Jessica Dougherty, Wuroud Al-Khayyat, Ramya Narendrula, Maggie Lavoie, Emma Mageau, Ronan Derbowka, A. Thomas Kovala, Douglas R. Boreham, Natalie Lefort, Christopher Thome, Tze Chun Tai and Sujeenthar Tharmalingam

Int. J. Mol. Sci. 2025, 26(19), 9611; https://doi.org/10.3390/ijms26199611 - 1 Oct 2025

Abstract

Radiation resistance presents a significant challenge in the treatment of triple-negative breast cancer (TNBC). To investigate the molecular adaptations associated with radiation therapy resistance, MDA-MB-231 cells were subjected to a repeated radiation (RR) regimen totaling 57 Gy over 11 weeks, followed by clonal [...] Read more.

Radiation resistance presents a significant challenge in the treatment of triple-negative breast cancer (TNBC). To investigate the molecular adaptations associated with radiation therapy resistance, MDA-MB-231 cells were subjected to a repeated radiation (RR) regimen totaling 57 Gy over 11 weeks, followed by clonal selection. The resulting radiation-adapted cells (MDA-MB-231^RR) were analyzed using whole-transcriptome RNA sequencing, revealing substantial dysregulation of pathways related to cell adhesion, mitochondrial function, and epithelial–mesenchymal transition (EMT). These transcriptional changes were corroborated by functional assays. MDA-MB-231^RR cells exhibited reduced expression of adhesion receptors (ITGB1, ITGA2, ITGA6) and extracellular matrix proteins (fibronectin, collagen, laminins), accompanied by significantly impaired cell adhesion to fibronectin, collagen, and laminin substrates. Mitochondrial dysfunction was supported by downregulation of oxidative phosphorylation genes (MTCO1, MTND1) and confirmed by JC-1 dye assays demonstrating a marked reduction in mitochondrial membrane potential. EMT-associated changes included increased mesenchymal markers and loss of epithelial markers (CTNNB1, SNAI2, CK19), consistent with enhanced migratory potential. Taken together, this study delineates key molecular features of radiation adaptation in TNBC, providing a foundation for the development of targeted therapies to overcome treatment resistance. Full article

(This article belongs to the Special Issue Cancer Progression and Therapeutic Resistance Mechanisms)

19 pages, 918 KB

Open AccessReview

Cardiovascular Effects of Cannabidiol: From Molecular Mechanisms to Clinical Implementation

by Hrvoje Urlić, Marko Kumrić, Nikola Pavlović, Goran Dujić, Željko Dujić and Joško Božić

Int. J. Mol. Sci. 2025, 26(19), 9610; https://doi.org/10.3390/ijms26199610 - 1 Oct 2025

Abstract

Cannabidiol (CBD) and other phytocannabinoids are gaining attention for their therapeutic potential in cardiovascular disease (CVD), the world’s leading cause of death. This review highlights advances in understanding the endocannabinoid system, including CB1 and CB2 receptors, and the mechanisms by which CBD exerts [...] Read more.

Cannabidiol (CBD) and other phytocannabinoids are gaining attention for their therapeutic potential in cardiovascular disease (CVD), the world’s leading cause of death. This review highlights advances in understanding the endocannabinoid system, including CB1 and CB2 receptors, and the mechanisms by which CBD exerts anti-inflammatory, antioxidative, vasoprotective, and immunomodulatory effects. Preclinical and translational studies indicate that selective activation of CB2 receptors may attenuate atherogenesis, limit infarct size in ischemia–reperfusion injury, decrease oxidative stress, and lessen chronic inflammation, while avoiding the psychotropic effects linked to CB1. CBD also acts on multiple molecular targets beyond the CB receptors, affecting redox-sensitive transcription factors, vascular tone, immune function, and endothelial integrity. Early clinical trials and observational studies suggest that CBD may lower blood pressure, improve endothelial function, and reduce sympatho-excitatory peptides such as catestatin, with a favorable safety profile. However, limited bioavailability, small sample sizes, short study durations, and uncertainty about long-term safety present challenges to its clinical use. Further research is needed to standardize dosing, refine receptor targeting, and clarify the role of the endocannabinoid system in cardiovascular health. Overall, current evidence supports CBD’s promise as an adjunct in CVD treatment, but broader clinical use requires more rigorous, large-scale studies. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

23 pages, 673 KB

Open AccessReview

Time-Lapse Imaging in IVF: Bridging the Gap Between Promises and Clinical Realities

by Grzegorz Mrugacz, Igor Bołkun, Tomasz Magoń, Izabela Korowaj, Beata Golka, Tomasz Pluta, Olena Fedak, Paulina Cieśla, Joanna Zowczak and Ewelina Skórka

Int. J. Mol. Sci. 2025, 26(19), 9609; https://doi.org/10.3390/ijms26199609 - 1 Oct 2025

Abstract

Time-lapse imaging (TLI) has emerged as a transformative technology in in vitro fertilization (IVF). This is because it offers continuous, non-invasive embryo assessment through morphokinetic profiling. It demonstrates key advantages such as reduced embryologist subjectivity, detection of dynamic anomalies, and improved implantation rates [...] Read more.

Time-lapse imaging (TLI) has emerged as a transformative technology in in vitro fertilization (IVF). This is because it offers continuous, non-invasive embryo assessment through morphokinetic profiling. It demonstrates key advantages such as reduced embryologist subjectivity, detection of dynamic anomalies, and improved implantation rates in niche populations. However, its clinical utility remains debated. Large trials and meta-analyses reveal no universal improvement in live birth rates compared to conventional methods. Key challenges underlying the outcome include algorithm generalizability, lab-specific protocol variability, and high costs. Nevertheless, TLI shows promise in specific contexts. For instance, Preimplantation Genetic Testing for Aneuploidies (PGT-A) cycles where it reduces unnecessary biopsies by predicting euploidy. However, even in this, its benefits are marginal in unselected populations. This review synthesizes evidence to highlight that TLI’s value is context-dependent, not universal. As such, adoption must be cautious to avoid resource misallocation without significant IVF outcome improvements. In future, personalized protocols, integration with non-invasive biomarkers, and multicenter collaboration are crucial to optimize TLI’s potential in assisted reproduction. Full article

(This article belongs to the Special Issue Molecular Research on Reproductive Physiology and Endocrinology)

17 pages, 2301 KB

Open AccessArticle

Alogliptin Mitigates Methotrexate-Induced Nephrotoxicity in a Rat Model: Antagonizing Oxidative Stress, Inflammation and Apoptosis

by Marwa M. Fahmy, Heba A. Habib, Esraa M. Zeidan, Yousef A. Bin Jardan and Gehan H. Heeba

Int. J. Mol. Sci. 2025, 26(19), 9608; https://doi.org/10.3390/ijms26199608 - 1 Oct 2025

Abstract

Although methotrexate (MTX) is a magnificent cure for cancerous neoplasms and inflammatory disorders, its usage is bound due to associated hazards, especially nephrotoxicity. The present study investigated the possible therapeutic impact of alogliptin (ALO), prescribed for managing type 2 diabetes, on renal injury [...] Read more.

Although methotrexate (MTX) is a magnificent cure for cancerous neoplasms and inflammatory disorders, its usage is bound due to associated hazards, especially nephrotoxicity. The present study investigated the possible therapeutic impact of alogliptin (ALO), prescribed for managing type 2 diabetes, on renal injury caused by MTX and explored the mechanisms that could illustrate this suggested protective effect. Four rat groups were involved: control, ALO (20 mg/kg/d, intragastrically (I.G.)) for ten days, MTX, and MTX + ALO groups. The latter two groups were given MTX (20 mg/kg, I.P.) on the 7th day, while the MTX + ALO group was administered ten days of 20 mg/kg of ALO. A significant impairment in renal function, catalase activity, reduced glutathione content, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) expressions, coupled with an increase in kidney injury molecule-1 (KIM-1), malondialdehyde, tumor necrosis factor-alpha (TNF-α), and cleaved caspase-3 (c-caspase-3) expressions, was observed in MTX-intoxicated rats, evidenced by remarkable deterioration in renal construction. Conversely, ALO improved renal function and architecture. Moreover, ALO retrieved the oxidative balance, the attenuated Nrf2/HO-1 expression, and the elevated KIM-1, TNF-α, and c-caspase-3 expression. In conclusion, ALO might abrogate MTX-elicited kidney damage by rectifying the deviation in oxidative status, apoptotic and inflammatory pathways, paving the way for managing MTX-induced nephrotoxicity. Full article

(This article belongs to the Section Molecular Pharmacology)

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33 pages, 1189 KB

Open AccessReview

Pertussis—A Re-Emerging Threat Despite Immunization: An Analysis of Vaccine Effectiveness and Antibiotic Resistance

by Anna Duda-Madej, Jakub Łabaz, Ewa Topola, Hanna Bazan and Szymon Viscardi

Int. J. Mol. Sci. 2025, 26(19), 9607; https://doi.org/10.3390/ijms26199607 - 1 Oct 2025

Abstract

Pertussis is an infectious disease that contributes to hundreds of thousands of deaths worldwide each year. Despite the prevalence of preventive vaccination programs, there has been an increasing number of new cases of the disease over the past few decades. This poses a [...] Read more.

Pertussis is an infectious disease that contributes to hundreds of thousands of deaths worldwide each year. Despite the prevalence of preventive vaccination programs, there has been an increasing number of new cases of the disease over the past few decades. This poses a particular problem for the pediatric population among whom the highest mortality from the disease is recorded. Several reasons for this phenomenon can be mentioned, but what is particularly important from the microbiological point of view is the correlation of the increased number of pertussis cases with the introduction of a new form of vaccine—the acellular vaccine in place of the whole-cell vaccine. In this review, we summarized the current state of knowledge on potential factors that may contribute to the decline in immunization efficacy against the pathogen. The post-vaccination response profile, symptomatic of vaccination with vaccination-acellular, is characterized by recruitment of Th₂ and Th₁₇ lymphocytes; it has been reported that in the long term, this results in insufficient activation of B cells and low titers of antibodies to key bacterial antigens (hemagglutinin, pertactin). Moreover, the immune response proceeds by bypassing the recruitment of tissue-resident memory T cells, resulting in a lack of protection against colonization of the nasal cavity by the bacterium despite vaccination. The decline in vaccination efficacy should also be attributed to the phenotypic variability of Bordetella. The popularization of the PtxP3 strain, characterized by its ability to incompletely activate immune mechanisms, poses a real threat to public health. The growing resistance of B. pertussis to standardly used antibiotics including macrolides also remains a problem. This makes it difficult to eradicate pathogens from the nasal cavity area and increases the pool of bacterial carriers in the population area. The increasing prevalence of the disease prompts reflection on more effective methods of prevention. Particularly promising in this field seem to be new vaccines, especially mucosally implemented, e.g., intranasal, or developed on the basis of B. pertussis antigens other than those used so far. Full article

(This article belongs to the Section Molecular Immunology)

22 pages, 5322 KB

Open AccessArticle

Vincristine Beyond Mitosis: Uncovering a First Link to G-Quadruplex DNA in Cancer Cells

by Anna Di Porzio, Carolina Persico, Francesca Romano, Alessandra Barra, Immacolata Aiello, Ludovica D’Auria, Sara Abate, Federica D’Aria, Concetta Giancola, Elpidio Cinquegrana, Francesco Saverio Di Leva, Jussara Amato, Simona Marzano, Nunzia Iaccarino and Antonio Randazzo

Int. J. Mol. Sci. 2025, 26(19), 9606; https://doi.org/10.3390/ijms26199606 - 1 Oct 2025

Abstract

Vincristine is a classical chemotherapeutic agent widely used for its ability to disrupt microtubule polymerization, yet additional molecular effects may contribute to its anticancer activity. G-quadruplexes (G4s), non-canonical nucleic acid structures enriched in regulatory regions of the genome and in mitochondrial DNA, have [...] Read more.

Vincristine is a classical chemotherapeutic agent widely used for its ability to disrupt microtubule polymerization, yet additional molecular effects may contribute to its anticancer activity. G-quadruplexes (G4s), non-canonical nucleic acid structures enriched in regulatory regions of the genome and in mitochondrial DNA, have emerged as relevant modulators of cellular homeostasis. In this study, we investigated whether vincristine can influence G4 biology. Cancer cells treated with vincristine were analyzed by immunofluorescence, revealing a consistent increase in nuclear and mitochondrial G4 foci. In particular, mitochondrial G4s were significantly elevated by approximately 1.5–2.5 fold compared to untreated cells, an effect accompanied by a detectable reduction in membrane potential, indicative of impaired organelle function. In addition, biophysical analyses on representative G4-forming sequences were carried out. Proton nuclear magnetic resonance titrations showed localized chemical shift perturbations upon vincristine addition, circular dichroism confirmed preservation of G4 topology, and isothermal titration calorimetry indicated weak but enthalpically favorable interactions. Taken together, these results suggest that vincristine perturbs both the cellular G4 landscape and mitochondrial homeostasis, while also engaging G4 DNA in vitro. Although additional studies are required to establish the mechanistic details, this work provides proof-of-concept for a previously unrecognized dimension of vincristine’s anticancer action. Full article

(This article belongs to the Section Molecular Biology)

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23 pages, 1018 KB

Open AccessReview

Gender and Allergy: Mechanisms, Clinical Phenotypes, and Therapeutic Response—A Position Paper from the Società Italiana di Allergologia, Asma ed Immunologia Clinica (SIAAIC)

by Maria Teresa Ventura, Antonio Francesco Maria Giuliano, Elisa Boni, Luisa Brussino, Rosalba Buquicchio, Mariaelisabetta Conte, Maria Teresa Costantino, Maria Angiola Crivellaro, Irene Maria Rita Giuliani, Francesca Losa, Stefania Nicola, Paola Parronchi, Silvia Peveri, Erminia Ridolo, Paola Triggianese and Vincenzo Patella

Int. J. Mol. Sci. 2025, 26(19), 9605; https://doi.org/10.3390/ijms26199605 - 1 Oct 2025

Abstract

Sex and gender play a critical role in allergic diseases, influencing immune response, clinical phenotypes, treatment strategies, outcomes, and health-related quality of life. Despite mounting evidence across multiple studies examining sex/gender differences in a multitude of allergic diseases, most address isolated conditions, not [...] Read more.

Sex and gender play a critical role in allergic diseases, influencing immune response, clinical phenotypes, treatment strategies, outcomes, and health-related quality of life. Despite mounting evidence across multiple studies examining sex/gender differences in a multitude of allergic diseases, most address isolated conditions, not taking into consideration the vast interplay of hormonal, genetic, immunological, and sociocultural factors and their unique consequences for clinicians and researchers. With this position paper, we aim to assess currently available evidence on the sex- and gender-specific characteristics of the most common allergic diseases, providing an overview of present knowledge and future areas of improvement for clinicians and researchers. This position paper was developed by the Società Italiana di Allergologia, Asma ed Immunologia Clinica (SIAAIC): a panel of experts who conducted a literature review focusing on sex and gender differences across major allergic diseases. A consensus-based approach was employed to assess the immunological, clinical, and therapeutic implications of available evidence, offering a recommendation for researchers and clinicians alike. Data highlights marked differences driven by sex and gender in disease prevalence, immune pathways, clinical phenotype and severity, as well as therapeutic outcomes. Female patients appear to show a higher prevalence of Th2-driven ailments, autoimmune overlap, and allergic drug reactions, whereas males are more likely to experience fatal anaphylaxis and severe mastocytosis. Sex hormones can modulate multiple immune pathways leading to mast cell activation, antibody production, and cytokine expression, thus contributing to divergent disease trajectories. In conclusion, sex and gender are a key determinant in allergic diseases, and their integration in future research is essential to develop a tailored approach to treatment. Efforts should prioritise the identification of sex- and gender-specific biomarkers, therapeutic strategies, and equitable access to healthcare services. A sex- and gender-aware approach could potentially improve outcomes, optimise treatment strategies, and address current gaps in allergy practice. Full article

(This article belongs to the Section Molecular Immunology)

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17 pages, 876 KB

Open AccessReview

Synaptic Pathology in Traumatic Brain Injury and Therapeutic Insights

by Poojith Nuthalapati, Sophie E. Holmes, Hamada H. Altalib and Arman Fesharaki-Zadeh

Int. J. Mol. Sci. 2025, 26(19), 9604; https://doi.org/10.3390/ijms26199604 - 1 Oct 2025

Abstract

Traumatic brain injury (TBI) results in a cascade of neuropathological events, which can significantly disrupt synaptic integrity. This review explores the acute, subacute and chronic phases of synaptic dysfunction and loss in trauma which commence post-TBI, and their contribution to the subsequent neurological [...] Read more.

Traumatic brain injury (TBI) results in a cascade of neuropathological events, which can significantly disrupt synaptic integrity. This review explores the acute, subacute and chronic phases of synaptic dysfunction and loss in trauma which commence post-TBI, and their contribution to the subsequent neurological sequelae. Central to these disruptions is the loss of dendritic spines and impaired synaptic plasticity, which compromise neuronal connectivity and signal transmission. During the acute phase of TBI, mechanical injury triggers presynaptic glutamate secretion and Ca²⁺ ion-mediated excitotoxic injury, accompanied by cerebral edema, mitochondrial dysfunction and the loss of the mushroom-shaped architecture of the dendritic spines. The subacute phase is marked by continued glutamate excitotoxicity and GABAergic disruption, along with neuroinflammatory pathology and autophagy. In the chronic phase, long-term structural remodeling and reduced synaptic densities are evident. These chronic alterations underlie persistent cognitive and memory deficits, mood disturbances and the development of post-traumatic epilepsy. Understanding the phase-specific progression of TBI-related synaptic dysfunction is essential for targeted interventions. Novel therapeutic strategies primarily focus on how to effectively counter acute excitotoxicity and neuroinflammatory cascades. Future approaches may benefit from boosting synaptic repair and modulating neurotransmitter systems in a phase-specific manner, thereby mitigating the long-term impact of TBI on neuronal function. Full article

(This article belongs to the Section Molecular Neurobiology)

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18 pages, 5837 KB

Open AccessArticle

Clove Essential Oil and Eugenol as Natural Antifungal Agents to Reduce Postharvest Losses in Melon (Cucumis melo)

by Silvia Giménez-Santamarina, Natalia Torres-Pagan, Silvina Larran, Josefa Roselló and M. Pilar Santamarina

Int. J. Mol. Sci. 2025, 26(19), 9603; https://doi.org/10.3390/ijms26199603 - 1 Oct 2025

Abstract

Melon is a global crop with a value of USD 31 billion. However, up to 30% of yield is lost due to phytopathogens. Essential oils are a sustainable approach to crop protection and storage, enhancing food security and reducing agricultural losses. We evaluated [...] Read more.

Melon is a global crop with a value of USD 31 billion. However, up to 30% of yield is lost due to phytopathogens. Essential oils are a sustainable approach to crop protection and storage, enhancing food security and reducing agricultural losses. We evaluated the antifungal potential of clove essential oil and pure eugenol against Alternaria alternata, Curvularia hawaiiensis, Fusarium oxysporum f. sp. lycopersici (FOL), Fusarium solani f. sp. cucurbitae (FSC), Rhizoctonia solani, and Verticillium dahliae in vitro. We also evaluated the resistance of melons, including eugenol-poor Cucumis melo cv. vedrantais (CMV) and eugenol-rich C. melo cv. makuwa (CMM), to infection caused by FOL and FSC. Chemical analysis of clove oil reveals that eugenol was the main compound, at 89.28%. Clove oil and eugenol at 300 μg/mL reduced the growth of all fungal species. Pure eugenol exhibited the strongest antifungal activity, with 95–100% growth inhibition. Eugenol-rich melons did not show necrosis or internal rot when inoculated with FSC, and had minimal lesions, while eugenol-poor melons revealed more advanced rot symptoms. Clove oil and eugenol are antifungal alternatives that may improve food safety. These findings demonstrate the high potential of eugenol to reduce postharvest losses in melon and contribute to future breeding programmes aimed at developing contamination-resistant cultivars. Full article

(This article belongs to the Special Issue Antioxidant and Antibacterial Properties of Phytochemicals)

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2 pages, 161 KB

Open AccessEditorial

Special Issue: “Advances in Osteogenesis”

by Andrea Del Fattore

Int. J. Mol. Sci. 2025, 26(19), 9602; https://doi.org/10.3390/ijms26199602 - 1 Oct 2025

Abstract

Alterations in bone formation activity lead to the onset of several bone diseases characterized by increased or reduced bone mass; the consequence of the unbalanced bone formation can be severe, and in some cases lethal [...] Full article

(This article belongs to the Special Issue Advances in Osteogenesis)

18 pages, 1779 KB

Open AccessArticle

Genomic Characterization of a Rare K30-ST198 Hypervirulent Klebsiella pneumoniae Clone with Distinctive Virulence Features

by Domingo Fernández Vecilla, Jorge Rodríguez Grande, Nuria Fraile Valcárcel, Mary Paz Roche Matheus, Gotzon Iglesias Hidalgo, Cristina Aspichueta Vivanco, José Luis Díaz de Tuesta del Arco, Sergio García-Fernández, María Siller Ruiz, Zaira Moure, Daniela Vallejo Iriarte, Athanasia Varsaki, Jorge Calvo Montes, María Pía Roiz Mesones, María Carmen Fariñas and Alain A. Ocampo-Sosa

Int. J. Mol. Sci. 2025, 26(19), 9601; https://doi.org/10.3390/ijms26199601 - 1 Oct 2025

Abstract

Hypervirulent Klebsiella pneumoniae (hvKp) has emerged as a significant public health concern, yet rare sublineages remain poorly characterized. Here, we described a K30-ST198 hvKp sublineage identified in four isolates from two patients, including three sequential strains (K30B1, K30B2, K30B3) recovered over eight months [...] Read more.

Hypervirulent Klebsiella pneumoniae (hvKp) has emerged as a significant public health concern, yet rare sublineages remain poorly characterized. Here, we described a K30-ST198 hvKp sublineage identified in four isolates from two patients, including three sequential strains (K30B1, K30B2, K30B3) recovered over eight months from recurrent liver abscesses and one strain (K30-HUMV1) from a urinary tract infection. All isolates exhibited a yYpermucoviscous phenotype and resistance restricted to ampicillin and amoxicillin. Screening with the eazyplex hvKp assay detected ybt and rmpA in all strains, yielding a virulence score of 1. Biofilm production was strong in K30B1, K30B2, moderate in K30-HUMV1, but weak in K30B3. In the Galleria mellonella infection model, K30B1 showed higher virulence than the other isolates. Whole-genome sequencing identified the ICEKp1 carrying hypervirulence-associated genes (ybt, pagO, rmpAC, iroBCDN) together with additional virulence factors (fim, mrkD, uge, ureA, wabG, wcaJ, mliC), while antibiotic resistance genes were limited to fosA and bla_SHV-77. Protein structures and their functional domains were predicted using AlphaFold v3.0.1 and ColabFold v1.5.5, based on pLDDT scores, providing further insights into gene functionality. This work represents one of the first detailed characterizations of K30-ST198 hvKp, underscoring the need for integrated genomic, phenotypic, and structural approaches in hvKp surveillance. Full article

(This article belongs to the Collection Microbial Virulence Factors)

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13 pages, 2422 KB

Open AccessArticle

Co-Targeting PD-1 and IL-33/ST2 Pathways for Enhanced Acquired Anti-Tumor Immunity in Breast Cancer

by Marina Z. Jovanović, Milena Jurišević, Milan Jovanović, Nevena Gajović, Miodrag Jocić, Marina M. Jovanović, Boško Milev, Krstina Doklestić Vasiljev and Ivan Jovanović

Int. J. Mol. Sci. 2025, 26(19), 9600; https://doi.org/10.3390/ijms26199600 - 1 Oct 2025

Abstract

Despite advances in immunotherapy, the treatment of breast cancer still remains a major global problem. In a previous study, we showed that co-blockade of Interleukin-33/ST2 and Programmed death-1/Programmed death-ligand (PD-1/PD-L) signaling pathways strongly slows progression by enhancing the antitumor capacity of natural killer [...] Read more.

Despite advances in immunotherapy, the treatment of breast cancer still remains a major global problem. In a previous study, we showed that co-blockade of Interleukin-33/ST2 and Programmed death-1/Programmed death-ligand (PD-1/PD-L) signaling pathways strongly slows progression by enhancing the antitumor capacity of natural killer (NK) cells. The main aim of this study is to elucidate the exact effect of co-blockade on the T lymphocyte and macrophage effector cells. 4T1 cells were used to induct breast cancer in female BALB/C and BALB/C ST2^−/− mice. The mice, both BALB/C and BALB/C ST2^−/−, were treated with anti-PD-1 antibody on certain days. After the mice were sacrificed, T cells and macrophages were analyzed using flow cytometry; dual co-blockade increased significantly the percentage of M1 macrophages in the tumor microenvironment, followed by an increase in expression of CD86⁺ and TNFα⁺. T cell accumulation was significantly higher in the spleen and within the tumor microenvironment, with elevation in activation markers such as Interleukin-17, CD69, NKG2D, and FasL and a decrease in Interleukin-10 and FoxP3 expression. Co-blockade of the PD-1/PD-L axes and IL-33/ST2 axes shows promising results in reestablishing an effective immune response and offers a new perspective on improving immune response to breast carcinoma. Full article

(This article belongs to the Section Molecular Oncology)

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21 pages, 2137 KB

Open AccessArticle

One Pot Synthesis of the C-3 Complex (Curcumin, Demethoxycurcumin, and Bis-Demethoxycurcumin): Their Joint and Independent Biological Actions

by Marco A. Obregón-Mendoza, Rubén Sánchez-Obregón, Rosario Tavera-Hernández, Leidys L. Pérez-González, Antonio Nieto-Camacho, Rogelio Rodríguez-Sotres, Carolina Escobedo-Martínez, Irma Romero and Raúl G. Enríquez

Int. J. Mol. Sci. 2025, 26(19), 9599; https://doi.org/10.3390/ijms26199599 - 1 Oct 2025

Abstract

Curcumin (CUR) is the primary metabolite isolated from the Curcuma longa L. rhizome. Most synthetic and biological studies have focused mainly on the curcumin molecule due to its essential biological activity as an antioxidant, anti-cancer, and anti-Alzheimer’s disease agent. However, the natural extract [...] Read more.

Curcumin (CUR) is the primary metabolite isolated from the Curcuma longa L. rhizome. Most synthetic and biological studies have focused mainly on the curcumin molecule due to its essential biological activity as an antioxidant, anti-cancer, and anti-Alzheimer’s disease agent. However, the natural extract of turmeric also contains two essential curcuminoids (demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC)), which altogether comprise the so-called C-3 complex. They are present in commercial compositions for treating biliary or digestive ailments. The vegetal rhizome’s extraction typically leads to a mixture of the three main curcuminoids, CUR, DMC, and BDMC, in variable proportions, and each of these metabolites has reported specific synthetic routes. Herein, we have performed the synthesis and isolation of the three major curcuminoids using the method called scrambling of aldehydes followed by aldol di-condensation reactions. A density functional theory (DFT) approach supported the experimental results by inspecting the predicted energies for the aldol condensation. Thus, the di-condensation reaction is substantially favoured (ΔG° = −2685.9 kJ/mol) over the mono-condensation reaction (ΔG° = −1393.753 kJ/mol). Our approach allows us to mimic closely the proportions of these curcuminoids found in extracts from natural sources that follow the order CUR > DMC > BDMC, respectively. The proportion of aldehydes can be modified in the scrambling reaction with an adequate mixture of aldehydes to render the order DMC > CUR > BDMC. This is an advantageous way to increase the amount of the unsymmetric DMC metabolite. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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19 pages, 4129 KB

Open AccessArticle

Comprehensive Virome Analysis of Commercial Lilies in South Korea by RT-PCR, High-Throughput Sequencing, and Phylogenetic Analyses

by Dongjoo Min, Yeonhwa Jo, Jisoo Park, Gyeong Geun Min, Jin-Sung Hong and Won Kyong Cho

Int. J. Mol. Sci. 2025, 26(19), 9598; https://doi.org/10.3390/ijms26199598 - 1 Oct 2025

Abstract

Viral diseases pose a significant threat to lily (Lilium spp.) cultivation; however, large-scale assessments of virus prevalence and diversity in South Korea are limited. This study combined RT-PCR surveys, high-throughput sequencing (HTS), and analyses of 48 lily hybrid transcriptomes to characterize the [...] Read more.

Viral diseases pose a significant threat to lily (Lilium spp.) cultivation; however, large-scale assessments of virus prevalence and diversity in South Korea are limited. This study combined RT-PCR surveys, high-throughput sequencing (HTS), and analyses of 48 lily hybrid transcriptomes to characterize the lily virome. RT-PCR screening of 100 samples from 13 regions showed that 87% were infected, primarily with lily mottle virus (LMoV, 65%), Plantago asiatica mosaic virus (PlAMV, 34%), cucumber mosaic virus (CMV, 34%), and lily symptomless virus (LSV, 25%). Mixed infections were approximately twice as frequent as single infections and were associated with greater symptom severity, particularly in triple-virus combinations. High-throughput sequencing expanded detection to six viruses, including milk vetch dwarf virus (MDV) and lily virus B (LVB), the latter confirmed as a variant of strawberry latent ringspot virus (SLRSV). Near-complete genomes of several viruses were assembled and validated through RT-PCR. Transcriptome mining identified eight virus species across 26 cultivars; PlAMV was the most common, and viral loads varied significantly among hybrids. Phylogenetic analyses revealed close relationships between Korean and Chinese isolates and host-related clustering in PlAMV. These findings highlight the complexity of lily viromes in South Korea and provide essential resources for diagnostics, disease management, and biosecurity. Full article

(This article belongs to the Special Issue Molecular Approach to Fern Development)

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43 pages, 2230 KB

Open AccessReview

NGS Approaches in Clinical Diagnostics: From Workflow to Disease-Specific Applications

by Desiree Brancato, Simone Treccarichi, Francesca Bruno, Elvira Coniglio, Mirella Vinci, Salvatore Saccone, Francesco Calì and Concetta Federico

Int. J. Mol. Sci. 2025, 26(19), 9597; https://doi.org/10.3390/ijms26199597 - 1 Oct 2025

Abstract

Next-Generation Sequencing (NGS) techniques have become a cornerstone of molecular diagnostics, enabling high-throughput, parallel analysis of multiple disease-associated genes. Their targeted design allows streamlined interpretation and optimised diagnostic yield, especially in disorders with known genetic heterogeneity. In this review, we provide a comprehensive [...] Read more.

Next-Generation Sequencing (NGS) techniques have become a cornerstone of molecular diagnostics, enabling high-throughput, parallel analysis of multiple disease-associated genes. Their targeted design allows streamlined interpretation and optimised diagnostic yield, especially in disorders with known genetic heterogeneity. In this review, we provide a comprehensive overview of the clinical application of NGS techniques—targeted gene panels, whole exome sequencing (WES) and whole genome sequencing (WGS)—detailing the methodological workflow and the critical steps involved in their implementation. Particular emphasis is placed on the genes identified through NGS that are implicated in neurodevelopmental, neurodegenerative, psychiatric, neuromuscular, cardiovascular, and metabolic disorders. We also compare the advantages and limitations of panel-based diagnostics versus WES and WGS, and discuss future directions, including the integration of long-read sequencing technologies into multidisciplinary clinical practice. Finally, we consider how these advances may ultimately bridge biomedical research and clinical practise to improve the diagnosis and management of multifactorial diseases. Full article

(This article belongs to the Special Issue Molecular Progression of Genome-Related Diseases: 2nd Edition)

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22 pages, 935 KB

Open AccessReview

Role of Growth Factors in the Pathogenesis of Systemic-Sclerosis-Associated Fibrosis

by Fabian A. Mendoza, Sonsoles Piera-Velazquez and Sergio A. Jimenez

Int. J. Mol. Sci. 2025, 26(19), 9596; https://doi.org/10.3390/ijms26199596 - 1 Oct 2025

Abstract

Systemic Sclerosis (SSc) is a systemic autoimmune disease of unknown etiology characterized by a severe fibroproliferative vasculopathy and frequently progressive cutaneous and internal organ fibrosis. The small-vessel vasculopathy and the tissue fibrotic alterations are responsible for the most serious clinical and pathological manifestations [...] Read more.

Systemic Sclerosis (SSc) is a systemic autoimmune disease of unknown etiology characterized by a severe fibroproliferative vasculopathy and frequently progressive cutaneous and internal organ fibrosis. The small-vessel vasculopathy and the tissue fibrotic alterations are responsible for the most serious clinical and pathological manifestations of the disease and for its high mortality. Despite the high severity and frequent mortality, there are currently no optimal therapeutic approaches for SSc, and its complex pathogenesis has not been fully elucidated. Numerous studies have suggested that growth factors and related regulatory macromolecules released from inflammatory and other cells present in the affected tissues play a crucial role in the frequently progressive cutaneous and visceral fibrosis. Here, we will review some of the recent studies describing the role of various growth factors and related macromolecules in the development and progression of the fibrotic process in SSc. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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14 pages, 1849 KB

Open AccessArticle

Gene Expression Profile of Placenta and Adipose Tissue in Women with Gestational Diabetes Mellitus

by Renata Saucedo, Erika Magallón-Gayón, Rocio Alejandra Chavez-Santoscoy, Mary Flor Díaz-Velázquez, Aldo Ferreira-Hermosillo, Diana Ojeda-López, Wendy Porras-Marcial, Debbie López-Sánchez and Jorge Valencia-Ortega

Int. J. Mol. Sci. 2025, 26(19), 9595; https://doi.org/10.3390/ijms26199595 - 1 Oct 2025

Abstract

Placenta and visceral adipose tissue (VAT) are implicated in the development of gestational diabetes mellitus (GDM). In the present study, we examined the whole-transcriptomic profile of both tissues in GDM women to elucidate the molecular basis of GDM pathogenesis. The whole-transcriptome profile was [...] Read more.

Placenta and visceral adipose tissue (VAT) are implicated in the development of gestational diabetes mellitus (GDM). In the present study, we examined the whole-transcriptomic profile of both tissues in GDM women to elucidate the molecular basis of GDM pathogenesis. The whole-transcriptome profile was analyzed in placenta and VAT from at-term patients with GDM and controls using RNA-seq. qPCR was used to validate several differentially expressed genes (DEGs). A total of 179 DEGs were observed in the placenta and 4 in VAT, including both up- and downregulated genes. The expression of the selected mRNAs for validation was consistent with the sequencing results. An analysis of the placental upregulated DEGs in the GDM women showed enrichment in functions including the G-protein-coupled receptor signaling pathway, organophosphate biosynthetic process, and phospholipid metabolic process, while the downregulated DEGs were enriched in cell motility and the cell migration process. The target pathways of DEGs in VAT are related to cancer and to the activation of the complement cascade. Molecular pathways involved in G-protein-coupled receptor signaling, the organophosphate biosynthetic process, the phospholipid metabolic process, and cell motility and cell migration are altered in the placentas of GDM women. Moreover, a disordered complement cascade might take place in the VAT of GDM women. Full article

(This article belongs to the Special Issue Advanced Molecular Research on Pregnancy Complication Mechanisms)

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33 pages, 1831 KB

Open AccessReview

Sex Hormones and Metabolic Dysfunction-Associated Steatotic Liver Disease

by Ralf Weiskirchen and Amedeo Lonardo

Int. J. Mol. Sci. 2025, 26(19), 9594; https://doi.org/10.3390/ijms26199594 - 1 Oct 2025

Abstract

Positioned at the intersection of sex medicine and endocrinology, metabolic dysfunction-associated steatotic liver disease (MASLD) is often managed by specialists who may not be fully familiar with the complex roles of sex hormones in its pathogenesis and clinical course. To address this gap, [...] Read more.

Positioned at the intersection of sex medicine and endocrinology, metabolic dysfunction-associated steatotic liver disease (MASLD) is often managed by specialists who may not be fully familiar with the complex roles of sex hormones in its pathogenesis and clinical course. To address this gap, we review the molecular actions of testosterone, estradiol, and progesterone on liver functions, as well as the role of sex-hormone binding globulin (SHBG) in MASLD histogenesis, highlighting disparities by sex as well as reproductive status. We also discuss how sex hormones influence fatty acid metabolism, gut dysbiosis, mitochondrial activity, gluco-lipidic homeostasis, lipotoxicity, inflammation, and MASLD-related liver tumorigenesis. Furthermore, we examine observational studies on associations between endogenous and exogenous sex hormones and SHBG with MASLD, with attention to hypogonadism in either sex or polycystic ovary syndrome. We summarize the role of sex hormones in modulating MASLD risk across life stages such as menopause, breastfeeding, and lactation. Lastly, we review the hepatic effects of hormone replacement therapy (HRT) on MASLD in both sexes, prospects, and safety of HRT and contraceptives among individuals with chronic liver disease. In conclusion, sex hormones play significant roles in MASLD pathobiology, underscoring the importance of sex-specific approaches in clinical practice and research. Full article

(This article belongs to the Special Issue Hormonal Regulatory Networks in Aging, Cancers, Alzheimer’s Disease, and Therapeutics)

27 pages, 930 KB

Open AccessReview

Gut Permeability and Microbiota in Parkinson’s Disease: Mechanistic Insights and Experimental Therapeutic Strategies

by Yicheng Liang, Yuhang Zhao, Alessio Fasano and Chien-Wen Su

Int. J. Mol. Sci. 2025, 26(19), 9593; https://doi.org/10.3390/ijms26199593 - 1 Oct 2025

Abstract

Globally, Parkinson’s disease (PD) is the neurodegenerative condition with the most rapidly increasing prevalence, and a growing body of evidence associates its pathology with impairments in the gut–brain axis. Traditionally viewed as a disease marked by the loss of dopaminergic neurons, emerging evidence [...] Read more.

Globally, Parkinson’s disease (PD) is the neurodegenerative condition with the most rapidly increasing prevalence, and a growing body of evidence associates its pathology with impairments in the gut–brain axis. Traditionally viewed as a disease marked by the loss of dopaminergic neurons, emerging evidence emphasizes that chronic neuroinflammation is a driver of neurodegeneration, with gut-originating inflammation playing a crucial role. Increased intestinal permeability, often called “leaky gut,” allows harmful substances, toxins, and misfolded α-synuclein into the systemic circulation, potentially exacerbating neuroinflammation and spreading α-synuclein pathology to the brain through the vagus nerve or compromised blood–brain barrier (BBB). This review synthesizes current insights into the relationship between gut health and PD, emphasizing the importance of gut permeability in disrupting intestinal barrier function. This paper highlights innovative therapeutic approaches, particularly personalized therapies involving gut microbiome engineering, as promising strategies for restoring gut integrity and improving neurological outcomes. Modulating specific gut bacteria to enhance the synthesis of certain metabolites, notably short-chain fatty acids (SCFAs), represents a promising strategy for reducing inflammatory responses and decelerating neurodegeneration in Parkinson’s disease. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

12 pages, 1742 KB

Open AccessArticle

Climate Change and Severe Drought Impact on Aflatoxins and Fungi in Brazil Nuts: A Molecular Approach

by Ariane Mendonça Kluczkovski, Janaína Santos Barroncas, Hanna Lemos, Heloisa Lira Barros, Leiliane Sodré, Liliana de Oliveira Rocha, Taynara Souza Soto, Maria Luana Vinhote and Augusto Kluczkovski, Jr.

Int. J. Mol. Sci. 2025, 26(19), 9592; https://doi.org/10.3390/ijms26199592 - 1 Oct 2025

Abstract

The Brazil nut production chain, which is reliant on Amazonian environmental conditions, is significantly affected by climate change, particularly extreme droughts, which decrease production and compromise sanitary quality. This study evaluated the influence of severe drought on aflatoxin concentrations and sequence toxigenic fungi [...] Read more.

The Brazil nut production chain, which is reliant on Amazonian environmental conditions, is significantly affected by climate change, particularly extreme droughts, which decrease production and compromise sanitary quality. This study evaluated the influence of severe drought on aflatoxin concentrations and sequence toxigenic fungi in Brazil nuts harvested during the 2023 off-season. Aflatoxins were quantified using high-performance liquid chromatography, while fungal sequencing involved DNA extraction, PCR, and sequencing analysis. Findings indicated that all Brazil nut samples collected during extreme drought contained detectable aflatoxins, with 10% exceeding the legal threshold of 10 µg/kg. Phylogenetic analysis identified four isolates as Penicillium citrinum. Additional morphological and sequencing analyses identified Aspergillus species from the Circumdati and Flavi sections, although one isolate could not be taxonomically classified. These results demonstrate the aflatoxin production by fungi in Brazil nuts in an unprecedented way under drought conditions. Furthermore, the diversity of fungal species during drought underscores the risk of contamination, emphasizing the necessity for monitoring future harvests to improve management and ensure product safety. Full article

(This article belongs to the Section Molecular Toxicology)

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14 pages, 2863 KB

Open AccessArticle

HSPA1A Can Alleviate CFA-Induced Inflammatory Pain by Modulating Macrophages

by Wenjie Zhang, Xiaojun Xie, Xiaomin Xiong and Feiyu Chen

Int. J. Mol. Sci. 2025, 26(19), 9591; https://doi.org/10.3390/ijms26199591 - 1 Oct 2025

Abstract

Current clinical approaches for managing inflammatory pain are frequently accompanied by adverse effects, significantly compromising patients’ quality of life. This study investigates the analgesic potential of Heat Shock Protein Family A Member 1A (HSPA1A) in alleviating Complete Freund’s Adjuvant (CFA)-induced inflammatory pain. The [...] Read more.

Current clinical approaches for managing inflammatory pain are frequently accompanied by adverse effects, significantly compromising patients’ quality of life. This study investigates the analgesic potential of Heat Shock Protein Family A Member 1A (HSPA1A) in alleviating Complete Freund’s Adjuvant (CFA)-induced inflammatory pain. The immunomodulatory mechanisms were elucidated through behavioral studies, flow cytometry, transcriptomics, proteomics, and cellular metabolic analyses. Findings indicate that HSPA1A mitigates CFA-induced mechanical allodynia, an effect independent of T or B lymphocytes and neutrophils but positively correlated with macrophage abundance. Transcriptomic RNA sequencing suggests involvement of inflammation-associated pathways. In vitro experiments demonstrate that HSPA1A suppresses the polarization of bone marrow-derived macrophages toward the pro-inflammatory M1 phenotype in an inflammatory model, with decreased mRNA expression of pro-inflammatory cytokines Interleukin-1β (Il1b) and Tumor Necrosis Factor (TNF). Macrophage metabolism undergoes reprogramming, characterized by reduced glycolysis and enhanced oxidative phosphorylation. Proteomic pathway analysis reveals suppression of pro-inflammatory and glycolytic proteins, coupled with upregulation of anti-inflammatory and tricarboxylic acid cycle-related proteins. In summary, HSPA1A likely exerts its analgesic effects by inhibiting glycolysis in macrophages, providing novel insights into inflammatory pain management and highlighting potential therapeutic targets for future clinical drug development with substantial translational potential. Full article

(This article belongs to the Section Molecular Immunology)

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22 pages, 3208 KB

Open AccessArticle

A High-Throughput Sequencing Strategy for Clinical Repertoire Profiling of T Cell Receptor Beta Chain: Development and Reference Values Across Healthy Adults, Paediatrics, and Cord Blood Units

by Emma Enrich, Mireia Antón-Iborra, Carlos Hobeich, Rut Mora-Buch, Ana Gabriela Lara-de-León, Alba Parra-Martínez, Belén Sánchez, Francisco Vidal, Pere Soler-Palacin and Francesc Rudilla

Int. J. Mol. Sci. 2025, 26(19), 9590; https://doi.org/10.3390/ijms26199590 - 1 Oct 2025

Abstract

T cell receptor (TCR) profiling using next-generation sequencing (NGS) enables high-throughput, in-depth analysis of repertoire diversity, offering numerous clinical applications. We developed a DNA-based strategy to analyse the TCRβ-chain using NGS and established reference values for T cell repertoire characteristics in 74 healthy [...] Read more.

T cell receptor (TCR) profiling using next-generation sequencing (NGS) enables high-throughput, in-depth analysis of repertoire diversity, offering numerous clinical applications. We developed a DNA-based strategy to analyse the TCRβ-chain using NGS and established reference values for T cell repertoire characteristics in 74 healthy donors, including 44 adults, 20 paediatrics, and 10 cord blood units (CBUs). Additionally, four paediatric patients with combined immunodeficiency (CID) or severe CID (SCID) due to deleterious mutations in recombination activating genes (RAG) were analysed. The developed strategy demonstrated high specificity, reproducibility, and sensitivity, and all functional variable and joining genes were detected with minimal PCR bias. All donors had a Gaussian-like distribution of complementary-determining region 3 length, with lower presence of non-templated nucleotides and higher proportion of non-functional clonotypes in CBUs. Both CBUs and paediatrics showed greater convergence and TCRβ diversity was significantly lower in adults and donors with cytomegalovirus-positive serostatus. Finally, an analysis of paediatric patients with RAG-SCID/CID showed significantly shorter CDR3 region length and lower repertoire diversity compared to healthy paediatrics. In summary, we developed a reliable and feasible TCRβ sequencing strategy for application in the clinical setting, and established reference values that could assist in the diagnosis and monitoring of pathological conditions affecting the T cell repertoire. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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4 pages, 172 KB

Open AccessEditorial

Special Issue “Diet and Lifestyle: Impact on the Molecular and Cellular Mechanism of NCDs”

by Elena Azzini, Valeria Gasperi and Angela Polito

Int. J. Mol. Sci. 2025, 26(19), 9589; https://doi.org/10.3390/ijms26199589 - 1 Oct 2025

Abstract

The global health risks associated with the ongoing crisis caused by the SARS-CoV-2 virus have profoundly shifted our thinking [...] Full article

(This article belongs to the Special Issue Diet and Lifestyle: Impact on the Molecular and Cellular Mechanism of NCDs)

12 pages, 4493 KB

Open AccessArticle

Transcriptomic Insights into Anthocyanin Biosynthesisin Aronia melanocarpa Callus Under Different Light Conditions

by Mingjun Hou, Bingrui Wang, Chang An, Yulai Wu, Mohammad Gul Arabzai, Xiaopeng Fan, Changbing Liu and Zongshen Zhang

Int. J. Mol. Sci. 2025, 26(19), 9588; https://doi.org/10.3390/ijms26199588 - 1 Oct 2025

Abstract

Aronia melanocarpa is rich in anthocyanins, compounds with significant medicinal and industrial value, making it an attractive species for enhanced production. Compared with fruits or intact plants, callus tissue offers a uniform, controllable in vitro system that is particularly suitable for dissecting regulatory [...] Read more.

Aronia melanocarpa is rich in anthocyanins, compounds with significant medicinal and industrial value, making it an attractive species for enhanced production. Compared with fruits or intact plants, callus tissue offers a uniform, controllable in vitro system that is particularly suitable for dissecting regulatory mechanisms under defined environmental conditions. Although light quality is known to influence anthocyanin biosynthesis, its specific regulatory mechanisms in A. melanocarpa remain unclear. In this study, callus tissues were cultured under six light regimes: full-spectrum LED, blue:red (5:1), red:blue (5:1), red:blue:white (1:1:1), red:white (5:1), and pure blue light. Anthocyanin content was quantified using the pH differential method, and the results showed that the blue:red (5:1) treatment produced the highest accumulation, reaching 14.06 mg/100 g. Transcriptome sequencing was then performed to compare the gene expression profiles between calli cultured under blue:red (5:1) light and those maintained in darkness. A total of 10,547 differentially expressed genes (DEGs) were identified, including 6134 upregulated and 4413 downregulated genes. Functional enrichment analysis indicated that these DEGs were mainly involved in anthocyanin biosynthesis and transport. Importantly, key structural genes such as PAL, C4H, 4CL, CHS, ANS, UFGT, and GST were significantly upregulated under blue:red (5:1) light, as further validated by qRT-PCR. Overall, our findings demonstrate that a blue:red (5:1) light ratio enhances anthocyanin accumulation by promoting the expression of biosynthetic and transport-related genes. This study not only provides new transcriptomic insights into the light-mediated regulation of secondary metabolism in A. melanocarpa callus, but also establishes a foundation for optimizing in vitro culture systems for sustainable anthocyanin production. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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9 pages, 240 KB

Open AccessEditorial

Special Issue “The Promising Future of CAR-Based Therapies: A Matter of Molecular Details”

by Fabio Nicolini, Orsola Montini, Matteo Zurlo, Sarah Tettamanti and Massimiliano Mazza

Int. J. Mol. Sci. 2025, 26(19), 9587; https://doi.org/10.3390/ijms26199587 - 1 Oct 2025

Abstract

In the rapidly advancing field of cancer immunotherapy, Chimeric Antigen Receptor (CAR)-T cell therapy is redefining treatment paradigms and offering renewed hope to patients with hematologic malignancies [...] Full article

(This article belongs to the Special Issue The Promising Future of CAR-Based Therapies: A Matter of Molecular Details)

18 pages, 15081 KB

Open AccessArticle

Leveraging GWAS-Identified Markers in Combination with Bayesian and Machine Learning Models to Improve Genomic Selection in Soybean

by Yongguo Xue, Xiaofei Tang, Xiaoyue Zhu, Ruixin Zhang, Yubo Yao, Dan Cao, Wenjin He, Qi Liu, Xiaoyan Luan, Yongjun Shu and Xinlei Liu

Int. J. Mol. Sci. 2025, 26(19), 9586; https://doi.org/10.3390/ijms26199586 - 1 Oct 2025

Abstract

Soybean (Glycine max (L.) Merr.) is one of the most important global economic crops, extensively utilized in the production of food, animal feed, and industrial raw materials. As the demand for soybeans continues to rise, improving both the yield and quality of [...] Read more.

Soybean (Glycine max (L.) Merr.) is one of the most important global economic crops, extensively utilized in the production of food, animal feed, and industrial raw materials. As the demand for soybeans continues to rise, improving both the yield and quality of soybeans has become a central focus of agricultural research. To accelerate the genetic improvement of soybean, genome selection (GS) and genome-wide association studies (GWAS) have emerged as effective tools and have been widely applied in various crops. In this study, we conducted GWAS and GS model evaluations across five soybean phenotypes (Glycitin content, Oil, Pod, Total isoflavone content, and Total tocopherol content) to explore the effectiveness of different GWAS methods and GS models in soybean genetic improvement. We applied several GWAS methods, including fastGWA, BOLT-LMM, FarmCPU, GLM, and MLM, and compared the predictive performance of various GS models, such as BayesA, BayesB, BayesC, BL, BRR, SVR_poly, SVR_linear, Ridge, PLS_Regression, and Linear_Regression. Our results indicate that markers selected through GWAS, when used in GS, achieved a prediction accuracy of 0.94 at a 5 K density. Furthermore, Bayesian models proved to be more stable than machine learning models. Overall, this study offers new insights into soybean genome selection and provides a scientific foundation for future soybean breeding strategies. Full article

(This article belongs to the Special Issue Advances in Plant Genomics and Genetics: 3rd Edition)

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