International Journal of Molecular Sciences

10 pages, 681 KB

Open AccessCase Report

Personalized Follow Up and Genetic Diagnosis Update of FMR1-Related Conditions: A Change in Diagnosis, Prognosis and Expectations

by Ana Roche-Martínez, Ariadna Ramírez-Mallafré, Lorena Joga-Elvira, Camen Manso-Bazus, Marta Rubio-Roy and Neus Baena-Diez

Int. J. Mol. Sci. 2025, 26(20), 10101; https://doi.org/10.3390/ijms262010101 - 16 Oct 2025

Abstract

Fragile X syndrome (FXS, OMIM#300624) is the most common inherited cause of X-linked intellectual disability and behavior difficulties. In 99% of cases, it is caused by the pathological expansion (>200 repeats, full mutation -FM) of the CGG trinucleotide located at the 5′ UTR [...] Read more.

Fragile X syndrome (FXS, OMIM#300624) is the most common inherited cause of X-linked intellectual disability and behavior difficulties. In 99% of cases, it is caused by the pathological expansion (>200 repeats, full mutation -FM) of the CGG trinucleotide located at the 5′ UTR of the FMR1 (Fragile X Messenger Ribonucleoprotein 1) gene, leading to the lack of production of the FMRP. Clinical manifestations are well known in boys but are sometimes overlooked in girls, who may remain underdiagnosed. Premutation (PM) populations (55–200 repeats) may present other medical issues, such as FXPOI or FXTAS. Mosaic conditions, such as a combination of PM and FM lines in the same patient, may lead to milder phenotypes. With the improvement of genetic testing, information regarding the exact number of CGG triplet repeats and methylation status could help explain milder phenotypes in patients who may produce some FMRP. Chromosome X preferential inactivation (XCI) in FXS women can also play a role in clinical severity. We present four non-related families who were followed up in our FXS clinic. Some of their members showed FM on Southern blot, but had milder symptoms than expected. To rule out size mosaicism, a RT-PCR was performed, giving a different and more consistent molecular diagnosis. When mosaicism was not present, methylation status was performed, excluding full methylation. For females, XCI showed preferential inactivation in one case. Revisiting old molecular diagnoses should be considered in clinical practice, especially for patients with a milder phenotype than expected from their molecular reports. This personalized follow up may change their former diagnosis, prognosis, and expectations. Full article

(This article belongs to the Special Issue Current Molecular Science of Fragile X Syndrome and Associated Disorders)

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25 pages, 7428 KB

Open AccessArticle

In Silico Analysis of MiRNA Regulatory Networks to Identify Potential Biomarkers for the Clinical Course of Viral Infections

by Elena V. Mikheeva, Kseniya S. Aulova, Georgy A. Nevinsky and Anna M. Timofeeva

Int. J. Mol. Sci. 2025, 26(20), 10100; https://doi.org/10.3390/ijms262010100 - 16 Oct 2025

Abstract

MiRNA expression profiles exhibit notable alterations in numerous diseases, particularly viral infections. Consequently, miRNAs may be regarded as both therapeutic targets and markers for the development of complications. MiRNAs can significantly influence the modulation of immune responses, offering an extra layer of regulation [...] Read more.

MiRNA expression profiles exhibit notable alterations in numerous diseases, particularly viral infections. Consequently, miRNAs may be regarded as both therapeutic targets and markers for the development of complications. MiRNAs can significantly influence the modulation of immune responses, offering an extra layer of regulation during viral infections. In this study, miRNAs associated with viral infections were analyzed using an in silico approach. Computer modeling predicted a number of miRNAs capable of influencing the functionality of specific components of the immune system. As a result, 242 miRNAs common to the three types of infections were identified. A network of miRNA-gene regulatory interactions, encompassing 502 nodes (224 miRNAs and 278 genes) and 2236 interactions, was developed. Within this network, subnetworks were identified that are involved in the operation of specific connections in the immune response to viruses. For each step of the immune response, the miRNAs involved in governing these processes were examined. These predicted miRNAs are of particular interest for further analysis aimed at establishing the relationship between their differential expression and disease symptom severity. The obtained data lay the foundation for identifying the most promising molecules as predictive biomarkers and the subsequent development of a diagnostic system. Full article

(This article belongs to the Special Issue Harnessing Bioinformatics for miRNA Research: Methods, Insights and Applications)

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22 pages, 885 KB

Open AccessArticle

Navigating the Deep Eutectic Solvent Landscape: Experimental and Machine Learning Solubility Explorations of Syringic, p-Coumaric, and Caffeic Acids

by Piotr Cysewski, Tomasz Jeliński, Maciej Przybyłek, Natalia Gliniewicz, Marcel Majkowski and Michał Wąs

Int. J. Mol. Sci. 2025, 26(20), 10099; https://doi.org/10.3390/ijms262010099 - 16 Oct 2025

Abstract

Efficiently identifying suitable solvents for active pharmaceutical ingredients (APIs) is critical in drug formulation, yet the vast number of possible solvent-solute combinations presents a significant experimental challenge. This study addresses this by developing a robust machine learning (ML) model for accurately predicting the [...] Read more.

Efficiently identifying suitable solvents for active pharmaceutical ingredients (APIs) is critical in drug formulation, yet the vast number of possible solvent-solute combinations presents a significant experimental challenge. This study addresses this by developing a robust machine learning (ML) model for accurately predicting the solubility of three phenolic acids (syringic, p-coumaric, and caffeic) in various deep eutectic solvents (DESs), integrating both experimental and computational investigations. Measured solubility data showed that the choline chloride combined with triethylene glycol in a 1:2 molar ratio was the most efficient system for the dissolution of the studied APIs. Different ML models, utilizing nu-Support Vector Regression (nuSVR) as the core regressor and based on descriptor sets derived from COSMO-RS (Conductor-like Screening Model for Real Solvents) computations, were systematically evaluated. A novel methodology termed DOO-IT (Dual-Objective Optimization with ITerative feature pruning) was employed to address the common challenges of model development with limited, high-value datasets. The final optimal 10-descriptor nuSVR model, selected from an exhaustive, multi-run search, demonstrated outstanding predictive power, offering a highly reliable computational tool for guiding experimental screening, significantly accelerating the exploration of DES-based formulations. This research also provides a strong foundation for future machine learning-guided discovery of chemicals, offering an effective and transferable framework for developing QSPR models for various chemical systems. Full article

(This article belongs to the Special Issue Structure-Based Design of Drugs and Biologically Active Molecules Based on Computer-Aided Drug Discovery)

16 pages, 2267 KB

Open AccessArticle

Comparison of the Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Cardiac Fibroblast Properties

by Claire Baufays, Julien Cumps, Cécile Dufeys, Audrey Ginion, Luc Bertrand, Sandrine Horman, Christophe Beauloye and Alice Marino

Int. J. Mol. Sci. 2025, 26(20), 10098; https://doi.org/10.3390/ijms262010098 - 16 Oct 2025

Abstract

Recent clinical trials have shown significant cardioprotective effects of antidiabetic sodium-glucose cotransporter 2 inhibitors (SGLT2i), including canagliflozin, empagliflozin, and dapagliflozin. These drugs significantly reduce hospitalizations for heart failure with reduced and preserved ejection fraction in both diabetic and non-diabetic patients. Yet, the mechanisms [...] Read more.

Recent clinical trials have shown significant cardioprotective effects of antidiabetic sodium-glucose cotransporter 2 inhibitors (SGLT2i), including canagliflozin, empagliflozin, and dapagliflozin. These drugs significantly reduce hospitalizations for heart failure with reduced and preserved ejection fraction in both diabetic and non-diabetic patients. Yet, the mechanisms underlying their protective effects, beyond their glucose-lowering properties, remain poorly understood. This study aimed to elucidate the direct effects of SGLT2i on cardiac fibroblasts, key mediators of myocardial fibrosis, ventricular remodeling, and heart failure. Using primary human cardiac fibroblast cultures, we compared the impact of canagliflozin, empagliflozin, and dapagliflozin on fibroblast properties. All three inhibitors significantly prevented myofibroblast differentiation. Notably, only canagliflozin significantly reduced fibroblast proliferation and migration. While all SGLT2i increased AMP-activated protein kinase (AMPK) phosphorylation, their effects on myodifferentiation were AMPK-independent. In contrast, the effect of canagliflozin on migration was partially dependent on AMPK, as demonstrated using the AMPK inhibitor BAY-3827. These findings reveal distinct cellular effects of individual SGLT2i on cardiac fibroblasts, suggesting heterogeneous potential to modulate extracellular matrix remodeling. Among them, canagliflozin may be more potent in preventing myocardial fibrosis in the context of heart failure. Full article

(This article belongs to the Special Issue Heart Failure: From Molecular Basis to Therapeutic Strategies)

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11 pages, 2653 KB

Open AccessArticle

Therapeutic Potential of Selected Probiotic Strains in a Murine Model of Ovalbumin-Induced Atopic Dermatitis and Asthma

by Fang-Yu Zhang, Chi-Yu Yang, Jong-Shian Liou, Chien-Hsun Huang, Pei-Yu Lin and I-Jen Wang

Int. J. Mol. Sci. 2025, 26(20), 10097; https://doi.org/10.3390/ijms262010097 - 16 Oct 2025

Abstract

Atopic dermatitis (AD) and asthma are key manifestations of the atopic march, characterized by a progressive development of allergic diseases from early skin inflammation to later respiratory involvement. Emerging evidence highlights the role of gut microbiota in modulating immune responses. However, the therapeutic [...] Read more.

Atopic dermatitis (AD) and asthma are key manifestations of the atopic march, characterized by a progressive development of allergic diseases from early skin inflammation to later respiratory involvement. Emerging evidence highlights the role of gut microbiota in modulating immune responses. However, the therapeutic potential of specific probiotic strains in preventing or mitigating the atopic march remains underexplored. This study aimed to evaluate the immunomodulatory and therapeutic effects of selected probiotic strains in a murine model of ovalbumin (OVA)-induced AD and asthma. Mice received oral administration of B. plebeiu, B. ovatus, F. duncaniae, F. taiwanense, and F. prausnitzii for four weeks before being exposed to OVA to induce AD and, later, asthma. Skin reactions were assessed after OVA application, and asthma was induced via aerosolized OVA. Afterward, blood and lung fluid samples were collected to evaluate immune markers such as total IgE, OVA-specific IgE, and IL-4. The results showed that B. plebeius improved skin histology in AD, while B. ovatus initially induced AD symptoms but later reduced them significantly between days 40 and 54. B. plebeius and B. ovatus reduced serum total IgE in asthma. B. plebeiu, B. ovatus, F. duncaniae, F. taiwanense, and F. prausnitzii significantly lowered OVA-IgE levels in serum and IL-4 levels in lung fluid (p < 0.05). These selected probiotic strains helped reduce allergic skin responses and, later, asthma by decreasing inflammation, particularly IL-4. These findings support the potential of these probiotics to prevent or mitigate the progression from AD to asthma and offer promising insight into targeted probiotic interventions for allergic diseases. Full article

(This article belongs to the Special Issue Advances in Molecular Approaches to Asthma Management)

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34 pages, 1239 KB

Open AccessReview

Endothelial Dysfunction as the Common Pathway Linking Obesity, Hypertension and Atherosclerosis

by Ewelina Młynarska, Kinga Bojdo, Hanna Frankenstein, Katarzyna Krawiranda, Natalia Kustosik, Wiktoria Lisińska, Jacek Rysz and Beata Franczyk

Int. J. Mol. Sci. 2025, 26(20), 10096; https://doi.org/10.3390/ijms262010096 - 16 Oct 2025

Abstract

Endothelial dysfunction plays a central role in the pathogenesis of cardiovascular diseases, driven by a complex interplay of oxidative stress, metabolic imbalances, and adipokine dysregulation. Excessive reactive oxygen species reduce nitric oxide bioavailability by impairing endothelial nitric oxide synthase function, leading to vascular [...] Read more.

Endothelial dysfunction plays a central role in the pathogenesis of cardiovascular diseases, driven by a complex interplay of oxidative stress, metabolic imbalances, and adipokine dysregulation. Excessive reactive oxygen species reduce nitric oxide bioavailability by impairing endothelial nitric oxide synthase function, leading to vascular inflammation and impaired vasodilation. Adipose tissue-derived hormones such as leptin, adiponectin, and resistin exert opposing effects on vascular homeostasis, influencing inflammation and oxidative stress in obesity and metabolic syndrome. Dyslipidemia, particularly through oxidized LDL, initiates endothelial injury and foam cell formation, accelerating atherosclerosis. Furthermore, hypertension and obesity exacerbate vascular dysfunction by disrupting the balance between vasodilators and vasoconstrictors, enhancing oxidative stress, and altering perivascular adipose tissue function. These interrelated mechanisms contribute to the progression of atherosclerotic cardiovascular disease and diabetic vascular complications. A deeper understanding of these processes is essential for developing targeted interventions to restore endothelial health and reduce cardiometabolic risk. Full article

(This article belongs to the Special Issue Endothelial Dysfunction and Its Related Cardiometabolic Disorders: From Mechanisms to Targeted Therapies)

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20 pages, 2411 KB

Open AccessArticle

Selective Paracrine Modulation of Stromal Cells: Wharton’s Jelly MSC Secretome Enhances Adipose-Derived MSC Functionality While Maintaining Dermal Fibroblast Quiescence

by Tanya Stoyanova, Lora Topalova, Stanimir Kyurkchiev, Regina Komsa-Penkova, Svetla Todinova and George Altankov

Int. J. Mol. Sci. 2025, 26(20), 10095; https://doi.org/10.3390/ijms262010095 - 16 Oct 2025

Abstract

Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) secrete a rich array of paracrine factors including growth factors, cytokines, and extracellular vesicles that hold promises for regenerative medicine. This study evaluated the effects of WJ-MSC-derived secretome on adipose-derived mesenchymal stem cells (AD-MSCs) and human dermal [...] Read more.

Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) secrete a rich array of paracrine factors including growth factors, cytokines, and extracellular vesicles that hold promises for regenerative medicine. This study evaluated the effects of WJ-MSC-derived secretome on adipose-derived mesenchymal stem cells (AD-MSCs) and human dermal fibroblasts (HDFs), focusing on their adhesion, spreading, proliferation, endogenous collagen secretion, and migration. Morphometric analysis revealed that the secretome enhanced cell adhesion and spreading on rat tail collagen (RTC) substrates after 24 h. AD-MSCs showed a ~30% increase in the cell spreading area (from 4007 μm² to 5081 μm²p < 0.05), though without notable shape changes. In contrast, fetal bovine serum (FBS) promoted cell elongation with a reduced aspect ratio. Proliferation assays demonstrated a selective stimulatory effect of the secretome on AD-MSCs with a significant increase at day 3, while HDFs’ proliferation remained unchanged. Cell cycle profiling showed transient S-phase accumulation in AD-MSCs (24–48 h), followed by G0/G1 arrest (72 h), while HDFs remained in G0/G1. Immunofluorescence analysis confirmed the enhanced extracellular deposition of endogenously synthesized collagen in AD-MSCs, while no comparable response was observed in HDFs. Scratch assays showed increased migration in both cell types upon secretome exposure compared to collagen-only controls, suggesting a paracrine-mediated pro-migratory effect. These results demonstrate that WJ-MSC secretome boosts the regenerative capacity in AD-MSCs while keeping fibroblasts quiescent, highlighting its strong potential for cell-free therapies in tissue engineering, wound repair, and regenerative medicine. Full article

(This article belongs to the Section Biochemistry)

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24 pages, 6410 KB

Open AccessReview

Pro-Inflammatory and Anti-Inflammatory Interleukins in Periodontitis: Molecular Roles, Immune Crosstalk, and Therapeutic Perspectives

by Mireya Martínez-García and Enrique Hernández-Lemus

Int. J. Mol. Sci. 2025, 26(20), 10094; https://doi.org/10.3390/ijms262010094 - 16 Oct 2025

Abstract

Periodontitis is a chronic, multifactorial inflammatory disease initiated by dysbiotic biofilms and driven by a dysregulated host immune response. Central to its pathogenesis is a complex network of cytokines, particularly interleukins, with both pro-inflammatory and anti-inflammatory roles. This narrative review comprehensively analyzes current [...] Read more.

Periodontitis is a chronic, multifactorial inflammatory disease initiated by dysbiotic biofilms and driven by a dysregulated host immune response. Central to its pathogenesis is a complex network of cytokines, particularly interleukins, with both pro-inflammatory and anti-inflammatory roles. This narrative review comprehensively analyzes current knowledge on the molecular biology, cellular sources, immune pathways, and systemic effects of key interleukins in periodontitis. We highlight the dual roles of interleukins such as IL-17 and IL-10, discuss recent advances in understanding their regulatory networks, and explore translational perspectives, including diagnostic biomarkers and cytokine-targeted therapies. Emphasis is placed on dissecting the fine balance between destructive inflammation and protective resolution mechanisms, aiming to inform novel, immune-modulatory treatment strategies for periodontal disease. Full article

(This article belongs to the Special Issue Pro-inflammatory and Anti-inflammatory Interleukins in Various Diseases 2.0)

23 pages, 1270 KB

Open AccessReview

Pleiotropic Mucosal Innate Immune Memory in the Gastrointestinal Tract

by Rachel H. Cohen, Sean P. Colgan and Ian M. Cartwright

Int. J. Mol. Sci. 2025, 26(20), 10093; https://doi.org/10.3390/ijms262010093 - 16 Oct 2025

Abstract

Research in the past fifteen years has established that innate immune cells can develop immune memory, termed trained immunity. Trained innate immune cells exhibit distinct lasting epigenetic and metabolic changes that prime these cells upon repeated exposure. The gastrointestinal tract provides an important [...] Read more.

Research in the past fifteen years has established that innate immune cells can develop immune memory, termed trained immunity. Trained innate immune cells exhibit distinct lasting epigenetic and metabolic changes that prime these cells upon repeated exposure. The gastrointestinal tract provides an important immunological barrier and is home to many innate immune cells, where trained immunity serves an essential role. This review summarizes what is currently known about the basic mechanisms behind innate immune memory, the roles of innate immune cells within the intestine, intestinal-specific trained immunity, and therapeutic potential for targeting trained immunity in the context of gastrointestinal disorders. Full article

(This article belongs to the Special Issue Editorial Board Member's Collection Series: The Memory of the Immune Cells)

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20 pages, 1463 KB

Open AccessReview

The Role of Interleukin-8 (IL-8) in Treatment-Resistant Depression: A Review of Mechanisms, Biomarker Potential, and Therapeutic Implications

by Katarzyna Aleksandra Lisowska

Int. J. Mol. Sci. 2025, 26(20), 10092; https://doi.org/10.3390/ijms262010092 (registering DOI) - 16 Oct 2025

Abstract

Treatment-resistant depression (TRD) remains a major clinical challenge, with a substantial proportion of patients with major depressive disorder (MDD) failing to respond to conventional antidepressant therapies. Increasing evidence suggests that dysregulation of immune signaling contributes to the pathophysiology of TRD. While proinflammatory cytokines [...] Read more.

Treatment-resistant depression (TRD) remains a major clinical challenge, with a substantial proportion of patients with major depressive disorder (MDD) failing to respond to conventional antidepressant therapies. Increasing evidence suggests that dysregulation of immune signaling contributes to the pathophysiology of TRD. While proinflammatory cytokines such as IL-6 and TNF-α have been extensively studied, less is known about the role of chemokines such as interleukin-8 (IL-8). This review aims to synthesize current knowledge on the biological functions of IL-8, its involvement in neuroimmune mechanisms, and its potential as a biomarker and therapeutic target in treatment-resistant depression. Clinical and preclinical studies evaluating IL-8 levels in MDD and TRD patients were discussed with a focus on treatment response, neuroinflammatory pathways, and predictive modeling. Methodological factors affecting IL-8 measurement and interpretation were critically assessed. Even though clinical studies indicate that IL-8 levels may predict treatment response to antidepressants, including ketamine, findings are inconsistent, partly due to methodological variability, small sample sizes, and confounding factors such as comorbid medical conditions. Therefore, future longitudinal and multimodal studies are warranted to validate its utility in psychiatric precision medicine. Full article

(This article belongs to the Special Issue Pathophysiology and Pharmacology in Psychiatry)

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13 pages, 1343 KB

Open AccessArticle

Diagnostic Performance of Universal Transport Medium for Viral Polymerase Chain Reaction in Aqueous Humor Samples of Suspected Viral Uveitis: A Pilot Methods Study

by Chungwoon Kim, Yoo-Ri Chung, Ji Hun Song, Young Joon Choi and Hae Rang Kim

Int. J. Mol. Sci. 2025, 26(20), 10091; https://doi.org/10.3390/ijms262010091 - 16 Oct 2025

Abstract

We investigated the diagnostic efficacy of the universal transport medium™ (UTM^®) as a transport medium for aqueous humor polymerase chain reaction (PCR) testing in patients with clinically suspected viral uveitis. This retrospective study included 31 patients (31 eyes) with presumed viral [...] Read more.

We investigated the diagnostic efficacy of the universal transport medium™ (UTM^®) as a transport medium for aqueous humor polymerase chain reaction (PCR) testing in patients with clinically suspected viral uveitis. This retrospective study included 31 patients (31 eyes) with presumed viral uveitis who underwent anterior chamber sampling and compared the viral detection rates between using UTM^® and conventional test tubes only. The positivity rate for any virus, including cytomegalovirus, herpes simplex virus, and varicella zoster virus, was significantly higher in the UTM^T® group than in the test tube group (64.3% vs. 23.5%, p = 0.033). Logistic regression analysis also revealed that the use of UTM^® significantly increased the PCR positivity rate (odds ratio, 5.850; 95% confidence interval, 1.222–27.994; p = 0.027). Thus, the use of UTM^® was associated with improved detection of causative pathogens in patients with presumed viral uveitis. Full article

(This article belongs to the Special Issue Advances in the Pathophysiology and Treatment of Eye Diseases)

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13 pages, 475 KB

Open AccessReview

The Evolving Role of FDG–PET in Behavioral Variant Frontotemporal Dementia: Current Applications and Future Opportunities

by Serafeim Ioannidis, Natalia Konstantinidou, Alexandros Giannakis, Chrissa Sioka and Panagiotis Ioannidis

Int. J. Mol. Sci. 2025, 26(20), 10090; https://doi.org/10.3390/ijms262010090 (registering DOI) - 16 Oct 2025

Abstract

The diagnosis of behavioral variant of frontotemporal dementia (bvFTD)—a common cause of early-onset dementia—remains challenging due to a lack of determined biomarkers. 18F-fluorodeoxyglucose-positron emission tomography (FDG–PET) scan detects early glucose metabolism alterations in specific brain regions. The detection of distinct hypometabolic patterns in [...] Read more.

The diagnosis of behavioral variant of frontotemporal dementia (bvFTD)—a common cause of early-onset dementia—remains challenging due to a lack of determined biomarkers. 18F-fluorodeoxyglucose-positron emission tomography (FDG–PET) scan detects early glucose metabolism alterations in specific brain regions. The detection of distinct hypometabolic patterns in early stages of bvFTD has established FDG–PET as an indispensable adjunctive diagnostic tool in inconclusive cases, as well as in distinguishing between different types of dementia. Moreover, its role in the differential diagnosis of the often overlapping bvFTD and primary psychiatric disorders (PPD) is being studied by exploring disease-specific hypometabolic areas. Finally, the identification of early metabolic alterations and even earlier alterations in distinct metabolic brain networks may assist the diagnosis of presymptomatic carriers of disease-related gene mutations and lead to the development of novel biomarkers. The aim of our review is to underscore the role of FDG–PET as an approved yet promising tool that may lead to a new era in the diagnosis of bvFTD by establishing novel biomarkers and integrating AI as an assistant modality to inform diagnosis and decision-making. Full article

(This article belongs to the Special Issue Molecular Advances in Neuroimaging)

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16 pages, 3767 KB

Open AccessArticle

Genome-Wide Characterization of Kiwifruit Invertase Gene Family Reveals Roles of AcCWINV4 in Sugar Accumulation and Cold Tolerance

by Aoning Zhang, Xiaomeng Yang, Deshuai Liu, Zhexing Luo, Zhihao Zhang, Junwei Huo, Deguo Han, Yan Zhang and Lihua Zhang

Int. J. Mol. Sci. 2025, 26(20), 10089; https://doi.org/10.3390/ijms262010089 - 16 Oct 2025

Abstract

Invertase, a core catalyst in sugar metabolism, irreversibly hydrolyzes sucrose into hexoses, establishing the fundamental biochemical pathway for carbon allocation in plants and playing pivotal roles in plant growth development, fruit quality regulation, and stress response. In the present study, we identified a [...] Read more.

Invertase, a core catalyst in sugar metabolism, irreversibly hydrolyzes sucrose into hexoses, establishing the fundamental biochemical pathway for carbon allocation in plants and playing pivotal roles in plant growth development, fruit quality regulation, and stress response. In the present study, we identified a total of 25 invertase genes from the kiwifruit (Actinidia chinensis cv Hongyang) genome and systematically analyzed the physicochemical properties, chromosomal localization, genomic features, and gene evolution patterns of the AcINV family. The evaluation of selection pressure indices robustly demonstrated that the INV family underwent purification selection during domestication. Furthermore, based on the correlation between gene expression levels during the post-harvest ripening stage of kiwifruit and soluble sugar content, we identified the potential gene AcCWINV4 as being associated with sugar accumulation. Furthermore, virus-induced gene silencing (VIGS) of AcCWINV4 confirmed its functional role in fruit sugar accumulation and plant response to cold stress. This study provides critical theoretical support for breeding cold-tolerant and high-quality kiwifruit varieties using molecular biological methods. Full article

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

17 pages, 916 KB

Open AccessArticle

Clinical Variability and Genotype–Phenotype Correlation in Spanish Patients with Type 1 Gaucher Disease: A Focus on Non-c.[1226A>G]; [1448T>C] Genotypes

by Irene Serrano-Gonzalo, Francisco Bauza, Laura Lopez de Frutos, Isidro Arevalo-Vargas, Mercedes Roca-Espiau, Marcio Andrade-Campos, Esther Valero-Tena, Sonia Roca-Esteve, David Iniguez and Pilar Giraldo

Int. J. Mol. Sci. 2025, 26(20), 10088; https://doi.org/10.3390/ijms262010088 - 16 Oct 2025

Abstract

The clinical heterogeneity of type 1 Gaucher disease (GD1) underscores the limited correlation between the GBA1 genotype and phenotype. This study examined GD1 patients from the Spanish Gaucher Disease Registry carrying heterozygous GBA1 genotypes distinct from NM_000157: c.[1226A>G](N370S); [1448T>C](L444P). Among 374 patients with [...] Read more.

The clinical heterogeneity of type 1 Gaucher disease (GD1) underscores the limited correlation between the GBA1 genotype and phenotype. This study examined GD1 patients from the Spanish Gaucher Disease Registry carrying heterozygous GBA1 genotypes distinct from NM_000157: c.[1226A>G](N370S); [1448T>C](L444P). Among 374 patients with GD1, 195 (52.1%) had alternative heterozygous combinations, including variants corresponding to severe (37.9%) or moderate (42.1%) mutation, whereas only 20% patients harbored mild variants—all of them in combination with N370S. Descriptive statistics and predictive models based on logistic regression and decision trees were applied. Patients carrying N370S with a different L444P variant showed significantly higher rates of advanced bone disease (59.9%) compared to those with homozygous N370S (38.3%) or N370S; L444P (41.0%) (p = 0.002). Decision tree analysis identified the bone marrow burden score (S-MRI) as the strongest predictor of osteopenia/osteoporosis at diagnosis. Genotype also emerged as a key discriminator for Parkinson’s disease: patients with non-N370S; L444P genotypes showed a markedly higher likelihood of developing Parkinsonism. Overall, GD1 patients with genotypes other than N370S; L444P present more severe phenotypes, particularly with greater skeletal involvement and neurological complications. These findings highlight the importance of genotype stratification and predictive modeling in improving risk assessment and clinical management in GD1. Full article

(This article belongs to the Special Issue Machine Learning Applications in Bioinformatics and Biomedicine: 3rd Edition)

20 pages, 725 KB

Open AccessReview

The Impact of the Apelinergic System on the Cardiovascular System

by Rafał Wyderka, Łukasz Osuch, Bogusława Ołpińska, Maria Łoboz-Rudnicka, Dorota Diakowska, Anna Leśków and Joanna Jaroch

Int. J. Mol. Sci. 2025, 26(20), 10087; https://doi.org/10.3390/ijms262010087 - 16 Oct 2025

Abstract

The apelin–ELABELA–APJ axis, collectively known as the apelinergic system, has emerged as a key regulator of cardiovascular homeostasis. Acting through G-protein-coupled mechanisms, it modulates vascular tone, cardiac contractility, angiogenesis, fluid balance, and metabolism. Growing evidence indicates that dysregulation of apelinergic signaling contributes to [...] Read more.

The apelin–ELABELA–APJ axis, collectively known as the apelinergic system, has emerged as a key regulator of cardiovascular homeostasis. Acting through G-protein-coupled mechanisms, it modulates vascular tone, cardiac contractility, angiogenesis, fluid balance, and metabolism. Growing evidence indicates that dysregulation of apelinergic signaling contributes to the development and progression of atherosclerosis, hypertension, and heart failure. Experimental studies demonstrate cardioprotective actions of apelin and ELABELA, including anti-fibrotic, anti-inflammatory, vasodilatory, and pro-angiogenic effects, whereas some findings suggest context-dependent pro-atherogenic or vasoconstrictive roles. Clinical data show that circulating apelinergic peptides vary across cardiovascular conditions, being upregulated in acute coronary syndromes and diminished in chronic ischemic or hypertensive disease. In heart failure, early compensatory activation is followed by progressive depletion, and low ELABELA levels correlate with disease severity. Moreover, the apelinergic system may exert anti-arrhythmic effects through modulation of myocardial electrophysiology and structural remodeling. Novel synthetic APJ agonists and stabilized peptide analogs show promising preclinical efficacy in reducing cardiac remodeling, improving contractility, and lowering blood pressure. Altogether, the apelinergic pathway represents a multifaceted modulator and a promising therapeutic target in cardiovascular medicine, warranting further translational studies to elucidate its diagnostic and treatment potential. Full article

(This article belongs to the Special Issue Progress in Adipokines Research in Cardiovascular Health and Diseases)

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25 pages, 5748 KB

Open AccessArticle

Caffeic Acid Inhibits Degranulation, Cytokine Secretions, and IP3 Receptor 2 Gene Expression in Compound 48/80-Stimulated Mouse P815 Mast Cells

by Kai-Chi Chang and Jin-Yuarn Lin

Int. J. Mol. Sci. 2025, 26(20), 10086; https://doi.org/10.3390/ijms262010086 - 16 Oct 2025

Abstract

Caffeic acid (CA), 3-O-caffeoylquinic acid (3-CQA), and 5-O-caffeoylquinic acid (5-CQA) were subjected to treating stimulated mouse P815 mast cells to unravel their antiallergic potential. β-Hexosaminidase release, appearance, morphology change, cytokine secretions, and degranulation-related pathway gene expressions, including Mas-related G [...] Read more.

Caffeic acid (CA), 3-O-caffeoylquinic acid (3-CQA), and 5-O-caffeoylquinic acid (5-CQA) were subjected to treating stimulated mouse P815 mast cells to unravel their antiallergic potential. β-Hexosaminidase release, appearance, morphology change, cytokine secretions, and degranulation-related pathway gene expressions, including Mas-related G protein-coupled receptor, member B2 (MRGP receptor B2), and inositol 1,4,5-triphosphate receptor 2 (IP3 receptor 2), in the stimulated mast cells were measured. An ELISA was used to determine the secreted cytokines. The relative gene expression folds were analyzed with reverse transcription real-time quantitative polymerase chain reaction. Correlations between gene expressions and different parameters were analyzed using the Pearson product–moment correlation coefficient (r). The results showed that CA had a superior effect than 3-CQA and 5-CQA on reducing β-hexosaminidase release, IL-4, and IL-6 cytokine secretions by the compound 48/80 (C48/80)- and 5-hydroxymethyl-2-furaldehyde (5-HMF)-stimulated mast cells. CA increased intact mast cell numbers but reduced granule releases, evidencing that CA may soothe activated mast cells. CA reduced IP3 receptor 2 gene expression. There were positive correlations between IP3 receptor 2 gene expression and IL-4 and IL-6 cytokine secretions. Our results conclude that CA might inhibit degranulation, IL-4 and IL-6 cytokine secretions, and IP3 receptor 2 gene expression in C48/80-stimulated mouse P815 mast cells. Full article

(This article belongs to the Special Issue Trends in Allergy and Autoimmunity: Pathogenesis, Biomarkers, and Treatment)

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27 pages, 1963 KB

Open AccessReview

Vascular Disruption Therapy as a New Strategy for Cancer Treatment

by Jesús Gómez-Escudero, Patricia Berlana-Galán, Elena Guerra-Paes, Irene Torre-Cea, Laura Marcos-Zazo, Iván Carrera-Aguado, Daniel Cáceres-Calle, Fernando Sánchez-Juanes and José M. Muñoz-Félix

Int. J. Mol. Sci. 2025, 26(20), 10085; https://doi.org/10.3390/ijms262010085 - 16 Oct 2025

Abstract

A functional blood vessel network is required to deliver oxygen and nutrients to the cancer cells for their growth. Angiogenesis, the formation of new blood vessels from pre-existing ones, is one of the major mechanisms to create this vascular network. Anti-angiogenic therapy was [...] Read more.

A functional blood vessel network is required to deliver oxygen and nutrients to the cancer cells for their growth. Angiogenesis, the formation of new blood vessels from pre-existing ones, is one of the major mechanisms to create this vascular network. Anti-angiogenic therapy was conceived as the inhibition of the cellular and molecular players involved in tumor angiogenesis such as vascular endothelial growth factor and its main receptors. Due to limitations of this therapy, different approaches of vessel modulation such as vascular normalization or vascular promotion have been studied showing benefits in different tumor models and clinical trials. In contrast to anti-angiogenic therapy, which inhibits the blood vessels that are being formed, vascular disruption therapy aims to destroy already formed tumor vessels. These malignant vascular structures differ from other blood vessels in terms of endothelial cell states, pericyte coverage and basement membrane development. The molecules used for vascular disruption are microtubule-binding molecules, flavonoids that induce endothelial cell apoptosis or molecules vectorized to endothelial receptors. Many vascular disruption agents have been tested in clinical trials showing some promising results, but with some limitations that include resistant rim cells or the development of hypoxia that induces cancer regrowth and poor delivery of the anti-tumor agents. The main objective of this review is to focus on vascular disruption agents therapy, novel molecules, new ways to overcome therapy resistance to them, current clinical status and, especially, the upcoming challenges and applications of these molecules. Full article

(This article belongs to the Special Issue Novel Molecular Pathways in Oncology, 3rd Edition)

16 pages, 1776 KB

Open AccessReview

Therapeutic Potential and Cancer Cell Death-Inducing Effects of Apigenin and Its Derivatives

by Pritam Bhagwan Bhosale, Se Hyo Jeong, Hun Hwan Kim, Jeong Doo Heo, Kwang Hyun Hwang, Yeon Gyu Moon, Meejung Ahn, Je Kyung Seong, Chungkil Won and Gon Sup Kim

Int. J. Mol. Sci. 2025, 26(20), 10084; https://doi.org/10.3390/ijms262010084 - 16 Oct 2025

Abstract

Cancer remains one of the leading global health challenges, driving extensive research into natural dietary compounds with potential preventive and therapeutic benefits. This review data from preclinical research on the significance of a diet abundant in flavonoids in reducing cancer risk. An increasing [...] Read more.

Cancer remains one of the leading global health challenges, driving extensive research into natural dietary compounds with potential preventive and therapeutic benefits. This review data from preclinical research on the significance of a diet abundant in flavonoids in reducing cancer risk. An increasing number of experimental studies suggest that flavonoids play a protective role by modulating diverse mechanisms associated with cancer, including carcinogen activation, cellular signaling, cell cycle control, inflammation, angiogenesis, and oxidative damage. The aim of this review is to discuss apigenin and its related forms, focusing on their therapeutic potential. It explores the biological effects of apigenin and its sugar-based derivatives, along with evidence from studies suggesting their possible role in cancer prevention. Apigetrin, a glycoside form of apigenin found in many foods and medicinal herbs, shows several health benefits, including antioxidant, anti-inflammatory, anticancer, pain-relieving, and brain-protective effects. The article highlights recent advancements in research on the anti-tumor properties of apigenin, vitexin, and apigetrin, along with their potential mechanisms. It provides a comprehensive summary of their anticancer actions, offering insights and references for cancer treatment strategies. Results obtained from both cell-based and animal studies indicate that apigenin, vitexin, and apigetrin possess protective effects against cancer development, demonstrating anticancer activity by promoting apoptosis and/or autophagy. Full article

(This article belongs to the Special Issue The Role of Natural Compounds in Cancer and Inflammation, 2nd Edition)

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17 pages, 5584 KB

Open AccessArticle

Knocking Down FRMD4A, a Factor Associated with the Brain Development Disorder and a Risk Factor for Alzheimer’s Disease, Using RNA-Targeting CRISPR/Cas13 Reveals Its Role in Cell Morphogenesis

by Asahi Honjo, Hideji Yako, Yuki Miyamoto, Moeri Yagi, Masahiro Yamamoto, Akinori Nishi, Hiroyuki Sakagami and Junji Yamauchi

Int. J. Mol. Sci. 2025, 26(20), 10083; https://doi.org/10.3390/ijms262010083 - 16 Oct 2025

Abstract

Genetic truncation or mutation of the gene encoding band 4.1, ezrin, radixin, and moesin (FERM) domain protein containing 4A (FRMD4A) is associated with brain developmental diseases, including microcephaly with global developmental delay. It has also been identified as a risk factor for Alzheimer’s [...] Read more.

Genetic truncation or mutation of the gene encoding band 4.1, ezrin, radixin, and moesin (FERM) domain protein containing 4A (FRMD4A) is associated with brain developmental diseases, including microcephaly with global developmental delay. It has also been identified as a risk factor for Alzheimer’s disease. By analogy with other FERM domain-containing proteins, FRMD4A is believed to regulate cell morphogenesis and/or cell polarization in central nervous system (CNS) cells; however, it remains unclear whether and how dysfunction of FRMD4A and/or its closely homologous protein FRMD4B causes abnormal morphogenesis in neuronal cells. Here, we describe for the first time the roles of FRMD4A and FRMD4B in process elongation in neuronal cells. Knockdown of Frmd4a or Frmd4b using specific RNA-targeting clustered regularly interspaced short palindromic repeat (CRISPR) and Cas13-fitted gRNAs led to decreased process elongation in primary cortical neurons. Similar decreases in neuronal marker expression were observed in the N1E-115 cell line, a model of neuronal differentiation. Furthermore, hesperetin, an aglycone of the citrus flavonoid hesperidin known to promote neuroprotective signaling, recovered the decreased process elongation induced by the knockdown of Frmd4a or Frm4b. Hesperetin also stimulated phosphorylation of mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPKs/ERKs), which could help promote neuronal processes. These results suggest that FRMD4A and FRMD4B regulate process elongation through a possible signaling pathway linked to the sustained phosphorylation of MAPKs/ERKs. Crucially, this study reveals that, at the molecular and cellular levels, hesperetin can restore normal phenotypes when FRMD4A protein or FRMD4B protein is impaired. Full article

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

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