International Journal of Molecular Sciences

18 pages, 5224 KB

Open AccessArticle

The Synergistic Effect of Polysaccharides and Silane Coupling Agents on the Properties of Calcium Phosphate-Based Bone Substitutes

by Piotr Pańtak, Joanna P. Czechowska, Vladyslav Vivcharenko, Annett Dorner-Reisel and Aneta Zima

Int. J. Mol. Sci. 2025, 26(18), 8910; https://doi.org/10.3390/ijms26188910 (registering DOI) - 12 Sep 2025

Abstract

In this study, novel hybrid cementitious materials composed of calcium phosphates and polysaccharides were obtained and developed. Moreover, the impact of two distinct silane coupling agents—tetraethyl orthosilicate (TEOS) and 3-glycidoxypropyltrimethoxysilane (GPTMS)—on the physicochemical and biological properties of the resulting materials was systematically analyzed. [...] Read more.

In this study, novel hybrid cementitious materials composed of calcium phosphates and polysaccharides were obtained and developed. Moreover, the impact of two distinct silane coupling agents—tetraethyl orthosilicate (TEOS) and 3-glycidoxypropyltrimethoxysilane (GPTMS)—on the physicochemical and biological properties of the resulting materials was systematically analyzed. Comprehensive assessments were conducted to evaluate the chemical and phase compositions (using XRF, XRD, FTIR), setting behavior, mechanical strength, microstructure (SEM), porosity, in vitro chemical stability, and biological performance of bone cements. Notably, the synergistic effect of polysaccharides and silane coupling agents significantly enhanced the compressive strength of the cements, increasing it to 19.34 MPa. Additionally, the integration of citrus pectin into the liquid phase, along with the inclusion of hybrid hydroxyapatite–chitosan granules, not only enabled the formation of materials with high surgical handiness but also improved the materials’ physicochemical characteristics. The findings from this study emphasize the beneficial role of silane coupling agents in improving the properties of calcium phosphate-based bone substitutes. The developed materials demonstrate substantial potential for use in bone tissue engineering according to ISO 10993. However, further in vitro and in vivo studies are required to confirm their safety and effectiveness. Full article

(This article belongs to the Special Issue Bioceramics: Challenges and Medical Applications of Calcium-Phosphate-Based Biocompatible Ceramics)

20 pages, 1333 KB

Open AccessReview

Beyond Resistance: Tolerance and Resilience of Bacteria to Photodynamic and Oxidative Stress

by Aleksandra Rapacka-Zdonczyk

Int. J. Mol. Sci. 2025, 26(18), 8908; https://doi.org/10.3390/ijms26188908 (registering DOI) - 12 Sep 2025

Abstract

The increasing reliance on light-based antimicrobial technologies, such as antimicrobial blue light (aBL) and antimicrobial photodynamic inactivation (aPDI), underscores the urgent need to comprehend bacterial survival strategies beyond conventional resistance. Two key phenotypes—tolerance and resilience—have emerged as critical but often conflated mechanisms by [...] Read more.

The increasing reliance on light-based antimicrobial technologies, such as antimicrobial blue light (aBL) and antimicrobial photodynamic inactivation (aPDI), underscores the urgent need to comprehend bacterial survival strategies beyond conventional resistance. Two key phenotypes—tolerance and resilience—have emerged as critical but often conflated mechanisms by which bacteria withstand oxidative and photodynamic stress. While tolerance refers to delayed bacterial killing without changes in MIC, resilience encompasses the active restoration of cellular function after transient stress exposure. Both phenomena may impair treatment outcomes and contribute to long-term persistence, even in the absence of genetic resistance. This review dissects the molecular mechanisms underlying tolerance and resilience, with a focus on their relevance to bacterial responses to reactive oxygen species generated by light-based or chemical stressors. The regulatory and effector overlap between these phenotypes is examined, including antioxidant defense systems, DNA repair pathways, and metabolic rewiring. Furthermore, the role of phenotypic heterogeneity and cross-stress protection in blurring the boundary between survival and recovery is discussed, highlighting challenges in experimental interpretation. Finally, the implications of these adaptive strategies are evaluated in the context of antimicrobial efficacy and safety, with an emphasis on kinetic assays and multidimensional profiling as tools to capture complex treatment outcomes. Clarifying the distinction between tolerance and resilience may help guide the development of robust and evolutionarily stable antimicrobial phototherapies. Full article

(This article belongs to the Special Issue Molecular Research on Bacteria)

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46 pages, 3610 KB

Open AccessReview

Neuroactive Phytochemicals as Multi-Target Modulators of Mental Health and Cognitive Function: An Integrative Review

by Halina Tkaczenko, Lyudmyla Buyun, Renata Kołodziejska, Piotr Kamiński and Natalia Kurhaluk

Int. J. Mol. Sci. 2025, 26(18), 8907; https://doi.org/10.3390/ijms26188907 (registering DOI) - 12 Sep 2025

Abstract

The growing prevalence of mental health issues and cognitive impairment poses a significant challenge to global public health. Conditions such as depression, anxiety, neurodegenerative diseases, and stress-related cognitive dysfunction are becoming more common, while conventional pharmacotherapies are often limited by suboptimal efficacy, adverse [...] Read more.

The growing prevalence of mental health issues and cognitive impairment poses a significant challenge to global public health. Conditions such as depression, anxiety, neurodegenerative diseases, and stress-related cognitive dysfunction are becoming more common, while conventional pharmacotherapies are often limited by suboptimal efficacy, adverse side effects, and concerns about long-term use. Against this backdrop, neurophytochemistry—the study of plant-derived bioactive compounds—has emerged as a promising area of research. This review explores the potential of selected phytochemicals to support mental well-being and cognitive function via various molecular mechanisms. Compounds such as apigenin, hesperidin, and epigallocatechin gallate have been shown to have a significant impact on key regulatory pathways. These include enhancing neurogenesis via brain-derived neurotrophic factor, modulating neurotransmitter systems (such as GABA and serotonin), and attenuating oxidative stress and neuroinflammation. The therapeutic relevance of these compounds is discussed in the context of depression, anxiety, Alzheimer’s disease, Parkinson’s disease, and stress-related cognitive dysfunction, often referred to as ‘brain fog’. This review synthesizes evidence published between 2010 and 2025 from several scientific databases, including PubMed, Scopus, Web of Science, and Embase. Preliminary evidence from in vitro studies and animal models indicates that neurophytochemicals could enhance synaptic plasticity, protect neurons from oxidative damage, and modulate inflammatory pathways, particularly those involving NF-κB and the Nrf2/ARE antioxidant response. In addition, early human clinical trials have shown that phytochemical supplementation can lead to improvements in mood regulation, stress response, and cognitive performance. Furthermore, emerging evidence suggests that the gut–brain axis plays a key role in mediating the effects of phytochemicals. Several compounds have been found to modulate the composition of gut microbiota in ways that could enhance the function of the central nervous system. While the initial results are encouraging, more high-quality clinical trials and mechanistic studies are required to validate these findings, optimize dosage regimens, and guarantee the safety and efficacy of long-term use. Thus, neurophytochemicals represent a promising integrative approach to alleviating the increasing burden of mental and cognitive disorders through naturally derived therapeutic strategies. Full article

(This article belongs to the Collection Feature Papers in Bioactives and Nutraceuticals)

19 pages, 25729 KB

Open AccessArticle

Effects on Oral Squamous Carcinoma Cell Lines and Their Mechanisms of Pyrazole N-Aryl Sulfonate: A Novel Class of Selective Cyclooxygenase-2 Inhibitors

by Shiqi Wang, Mingxuan Shi, Huihui Wang, Xianlin Zeng, Dingtai Zhang, Zhiyuan Zhang, Zhaoqing Xu and Yi Li

Int. J. Mol. Sci. 2025, 26(18), 8906; https://doi.org/10.3390/ijms26188906 - 12 Sep 2025

Abstract

Oral squamous cell carcinoma (OSCC) is a highly aggressive malignancy with limited effective treatment options. This study aimed to explore the therapeutic potential of novel pyrazole N-aryl sulfonate derivatives (compounds 4b, 4d, and 5f) as selective cyclooxygenase-2 (COX-2; prostaglandin-endoperoxide synthase [...] Read more.

Oral squamous cell carcinoma (OSCC) is a highly aggressive malignancy with limited effective treatment options. This study aimed to explore the therapeutic potential of novel pyrazole N-aryl sulfonate derivatives (compounds 4b, 4d, and 5f) as selective cyclooxygenase-2 (COX-2; prostaglandin-endoperoxide synthase 2, PTGS2) inhibitors in OSCC. Using CCK-8 and Transwell assays, we evaluated the anti-proliferative and anti-migratory effects of these compounds on CAL-27 and SAS cell lines, while apoptosis was assessed by Hoechst 33342 staining and flow cytometry. Molecular mechanisms were investigated through RT-qPCR, Western blot, and ELISA, focusing on COX-2, MMP2, MMP9, BCL2, BAX, and the JAK/STAT3 pathway. The results demonstrated that compounds 4b, 4d, and 5f significantly inhibited cell proliferation and migration, induced apoptosis, and downregulated the expression of COX-2 and its downstream targets. Notably, these compounds exhibited lower cytotoxicity in VERO cells, indicating favorable biological safety. In conclusion, our findings suggest that pyrazole N-aryl sulfonate derivatives effectively suppress OSCC cell growth and migration by targeting COX-2 and the JAK/STAT3 pathway, highlighting their promise as potential targeted therapeutics for OSCC. Full article

(This article belongs to the Special Issue Molecular Studies on Oral Disease and Treatment)

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36 pages, 1299 KB

Open AccessReview

The Interplay of Inflammation and Gut-Microbiota Dysbiosis in Alzheimer’s Disease: Mechanisms and Therapeutic Potential

by Hanis Nabilah Abdol Samat, Nurul Nadirah Razali, Hazlina Mahadzir, Tengku Sifzizul Tengku Muhammad, King-Hwa Ling, Nur Izzati Mansor and Shahidee Zainal Abidin

Int. J. Mol. Sci. 2025, 26(18), 8905; https://doi.org/10.3390/ijms26188905 - 12 Sep 2025

Abstract

Alzheimer’s disease (AD) represents a major global health challenge, characterised by progressive neurodegeneration that leads to cognitive decline. Inflammation is a key factor in the pathogenesis of AD, affecting both neuroinflammation and systemic inflammation. In AD, neuroinflammation is marked by the activation of [...] Read more.

Alzheimer’s disease (AD) represents a major global health challenge, characterised by progressive neurodegeneration that leads to cognitive decline. Inflammation is a key factor in the pathogenesis of AD, affecting both neuroinflammation and systemic inflammation. In AD, neuroinflammation is marked by the activation of microglia and the release of pro-inflammatory cytokines, which exacerbate neuronal damage and cognitive deficits. Systemic inflammation further compromises the blood–brain barrier (BBB), increasing its permeability and permitting the entry of inflammatory molecules and immune cells into the brain, thereby advancing the disease’s hallmark features. Recent studies have elucidated the influence of gut microbiota dysbiosis on AD and inflammation. This imbalance is thought to be associated with alterations in the concentrations of short-chain fatty acids (SCFAs) and bile acids, which can modulate neuroinflammation and contribute to AD pathology. Additionally, imbalances in neurotransmitters resulting from gut microbiota dysbiosis can further disrupt brain function and facilitate AD progression. This review provides an overview of the hypothesis that systemic and central nervous system (CNS) inflammation, together with gut-microbiota dysbiosis, may interact to influence the development and progression of AD. Full article

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

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15 pages, 1909 KB

Open AccessArticle

Gαq-Stimulated Gene Expression Is Insensitive to Bromo Extra Terminal Domain Inhibitors in HEK 293 Cells

by Ashika Jain, Viviane Pagé, Dominic Devost, Darlaine Pétrin, Terence E. Hébert and Jason C. Tanny

Int. J. Mol. Sci. 2025, 26(18), 8904; https://doi.org/10.3390/ijms26188904 - 12 Sep 2025

Abstract

Bromodomain and extraterminal domain (BET) family proteins are ubiquitous transcriptional co-activators that function broadly in cellular differentiation, proliferation, and stress responses. Pharmacological inhibition of BET proteins with small molecules that disrupt bromodomain engagement with acetyllysine residues (such as JQ1) or drive their degradation [...] Read more.

Bromodomain and extraterminal domain (BET) family proteins are ubiquitous transcriptional co-activators that function broadly in cellular differentiation, proliferation, and stress responses. Pharmacological inhibition of BET proteins with small molecules that disrupt bromodomain engagement with acetyllysine residues (such as JQ1) or drive their degradation through the ubiquitin–proteasome system (such as dBET6) ameliorates pathological gene expression in a range of systems and shows promise as a potential therapeutic strategy. Understanding the cell-type and signaling pathway requirements that dictate BET dependence in a particular cellular context remains incomplete. We previously demonstrated that, in neonatal rat cardiomyocytes, GPCR-induced hypertrophy responses depended strongly on the BET protein Brd4 when signaling was coupled to Gαs, but not Gαq. Here, we tested whether Brd4 was differentially responsive to G protein isoforms in HEK 293 cells by expressing Gαs- or Gαq-coupled Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). Gαq induced the expression of a group of early response genes and inflammatory genes in a manner largely insensitive to pharmacological BET inhibition, consistent with our previous data in cardiomyocytes. Gαs activated a small subset of the Gαq-induced genes, but this effect was largely reversed by dBET6. Our data further suggest that there may be general signaling requirements to activate Brd4 across cell types. Full article

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

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13 pages, 671 KB

Open AccessArticle

A Pharmacological Dose of Liraglutide Improves Mitochondrial Performance in Mouse Leydig Cells

by Bruno Oliveira-Lopes, Patrícia C. Braga, Pedro F. Oliveira, Marco G. Alves and Raquel L. Bernardino

Int. J. Mol. Sci. 2025, 26(18), 8903; https://doi.org/10.3390/ijms26188903 - 12 Sep 2025

Abstract

Male fertility has declined over the years, partly due to metabolic disorders such as obesity and Type 2 diabetes. Antidiabetic drugs, including GLP-1 receptor agonists like liraglutide, are widely used to manage these conditions and aid in weight loss. Within the male reproductive [...] Read more.

Male fertility has declined over the years, partly due to metabolic disorders such as obesity and Type 2 diabetes. Antidiabetic drugs, including GLP-1 receptor agonists like liraglutide, are widely used to manage these conditions and aid in weight loss. Within the male reproductive tract, Leydig cells (LCs) are essential since they produce testosterone. Notably, the influence of antidiabetics on LCs remains a subject of limited investigation. Herein, we aimed to evaluate the effect of liraglutide on the physiology of LCs. To this end, we cultured LCs (BLTK1 cell line) without (control) or in the presence of selected concentrations of liraglutide. We then assessed their metabolic viability, cell proliferation, LDH release, ROS production, mitochondrial membrane potential, and in vivo mitochondrial cell performance, as well as the number of mtDNA copies. We also measured androstenedione production. Our results showed that liraglutide at pharmacological and supra-pharmacological concentrations increased the metabolic viability of LCs and reduced ROS production at all concentrations. Furthermore, the pharmacological concentration of liraglutide increased the basal respiration, maximal respiration, proton leak, and oxygen consumption rate related to ATP-linked production. Androstenedione production remained unchanged, which may be related to the inherent limitations of the cell line in supporting steroidogenesis. Overall, our findings suggest that liraglutide exhibits a potential protective effect on LC function, particularly by enhancing metabolic viability, reducing oxidative stress, and improving mitochondrial performance, highlighting its potential beyond the established role in diabetes and weight management. Full article

(This article belongs to the Special Issue Hormonal and Metabolic Markers in Health and Disease)

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17 pages, 2326 KB

Open AccessArticle

The Protective Mechanism of Moderate Intensity Continuous Training on TMAO-Induced Myocardial Injury Based on NMR Metabolomics

by Hong Zou, Lijing Gong, Caihua Huang, Donghai Lin and Yimin Zhang

Int. J. Mol. Sci. 2025, 26(18), 8902; https://doi.org/10.3390/ijms26188902 - 12 Sep 2025

Abstract

The purpose of this study was to explore the protective effect of 8 weeks of Moderate Intensity Continuous Training (MICT) on TMAO-induced myocardial injury in mice and its metabolic regulatory mechanism based on nuclear magnetic resonance (NMR) metabolomics methods. Male C57BL/6J mice were [...] Read more.

The purpose of this study was to explore the protective effect of 8 weeks of Moderate Intensity Continuous Training (MICT) on TMAO-induced myocardial injury in mice and its metabolic regulatory mechanism based on nuclear magnetic resonance (NMR) metabolomics methods. Male C57BL/6J mice were randomly allocated into the following groups: Control group (Con, n = 15), TMAO-induced myocardial injury group (TMAO, n = 15), and TMAO-induced with MICT intervention group (Exe, n = 15). TMAO and Exe groups underwent 8 weeks of high-dose TMAO gavage to establish a myocardial injury model, with the Exe group additionally receiving 8 weeks of MICT intervention (60 min/session, 5 sessions/week, 50% MRC). After the 8 weeks of interventions, the mouse heart function was tested using cardiac ultrasound equipment; myocardial histology was evaluated using HE staining; and myocardial tissue samples were collected for NMR metabolomics analysis. Compared with the Con group, the HR in the TMAO group was significantly increased, while EF and LVFS were significantly decreased. Compared with the TMAO group, the HR in the Exe group was significantly reduced, and EF and LVFS were significantly increased; NMR metabolomics analysis showed that, compared with the Con group, five metabolic pathways including phenylalanine metabolism, tyrosine metabolism, and TCA cycle were significantly altered in the TMAO group; compared with the TMAO group, ten metabolic pathways related to amino acid metabolism (such as alanine, glycine, etc.), energy metabolism (TCA cycle), and oxidative stress (purine metabolism) were significantly regulated in the Exe group. MICT could effectively alleviate TMAO-induced myocardial injury in mice by regulating multiple targets within the myocardial metabolic pathways. These findings provide a theoretical basis for the clinical application of exercise intervention in myocardial injury treatment. Full article

(This article belongs to the Special Issue Biological and Molecular Aspects of Exercise Adaptation)

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16 pages, 599 KB

Open AccessReview

Immunohistochemical Assessment of Acute Myocardial Infarction: A Systematic Review

by Gianpiero D’Antonio, Nicola Di Fazio, Lavinia Pellegrini, Alessandro Ghamlouch, Fabio Del Duca, Raffaele La Russa, Paola Frati, Aniello Maiese and Gianpietro Volonnino

Int. J. Mol. Sci. 2025, 26(18), 8901; https://doi.org/10.3390/ijms26188901 - 12 Sep 2025

Abstract

In forensic medicine, spotting signs of an acute myocardial infarction (AMI) right after it happens is still a tough call, especially in sudden-death cases. Standard histology often misses changes in those critical first hours because the tissue damage is too subtle to see. [...] Read more.

In forensic medicine, spotting signs of an acute myocardial infarction (AMI) right after it happens is still a tough call, especially in sudden-death cases. Standard histology often misses changes in those critical first hours because the tissue damage is too subtle to see. To tackle this, we reviewed research (1990–2023) from PubMed and Web of Science, following PRISMA guidelines. We focused on studies that used immunohistochemistry to identify markers of early AMI in both human autopsies and animal models, specifically in the first six hours post-event. Our selection process narrowed 418 records to 37 key papers. We screened 49 markers in total, but only a handful stood out for reliable diagnosis: C5b-9, cardiac troponins, dystrophin, and H-FABP—all showing high specificity. Markers like S100A1 and IL-15 also showed promise, whereas JunB and connexin-43 appeared less dependable. We believe immunohistochemistry can add real value in early AMI identification, especially when using combinations of markers chosen for complementary strengths. Still, to make this approach practical in forensic settings, we need more studies on human samples and agreement on standardized lab protocols. Full article

(This article belongs to the Special Issue Molecular Advances in Forensic Science: Integrating Innovation and Investigation)

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25 pages, 2864 KB

Open AccessArticle

ALS Patients Exhibit Altered Levels of Total and Active MMP-9 and Several Other Biomarkers in Serum and CSF Compared to Healthy Controls and Other Neurologic Diseases

by Robert Bowser, Jiyan An, Kimberly Schwartz, Robert L. Sucholeiki and Irving Sucholeiki

Int. J. Mol. Sci. 2025, 26(18), 8900; https://doi.org/10.3390/ijms26188900 - 12 Sep 2025

Abstract

Matrix metalloproteinases 2 and 9 (MMP-2, MMP-9) have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, their protein levels and correlation with other biomarkers are not well understood. We measured total and active MMP-2/-9 and additional biomarkers (creatinine, neurofilament light, [...] Read more.

Matrix metalloproteinases 2 and 9 (MMP-2, MMP-9) have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, their protein levels and correlation with other biomarkers are not well understood. We measured total and active MMP-2/-9 and additional biomarkers (creatinine, neurofilament light, cystatin C, and alkaline phosphatase) in the serum of people with ALS (ALS, n = 30) and compared their levels with age-matched healthy controls (HC, n = 20) and other neurological diseases (diabetic nephropathy, Alzheimer’s disease, Parkinson’s disease; n = 8 each). We also measured MMP-2/-9 in a set of CSF samples from ALS (n = 30) and age-matched other neurological diseases (OND, n = 14). Lastly, we measured the competitive binding behavior of a dual MMP-2/MMP-9 inhibitor, AQU-118, against active MMP-9 in situ within the serum of ALS. We found significantly elevated levels of both total MMP-9 protein (two studies, 7.5 and 9.5-fold; both p < 0.0001) and active MMP-9 (2.5-fold; p < 0.0001) in ALS serum compared to HC. Serum NfL was significantly elevated (6-fold, p < 0.0001) and serum creatinine was significantly decreased (40%, p < 0.0001) in ALS compared to HC. There were significantly decreased levels of MMP-2 (two studies, 26 and 33%; p < 0.001 and p = 0.0001, respectively) in the serum of ALS as compared to HC. ALS also had significantly higher active MMP-9 in serum than patients with Alzheimer’s disease and higher than Parkinson’s disease or diabetic nephropathy. We confirmed that active MMP-9 in ALS is fully available for proteolytic activity in both serum and CSF and can be inhibited using an MMP-2/-9 inhibitor. Active MMP-9 is systemically elevated in ALS and therefore a therapeutic target for ALS drug development. Full article

(This article belongs to the Special Issue Predictive and Diagnostic Biomarkers in Inflammatory and Neurodegenerative Diseases)

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32 pages, 1282 KB

Open AccessReview

The Gut Microbiome and Colistin Resistance: A Hidden Driver of Antimicrobial Failure

by Ionela-Larisa Miftode, Andrei Vâţă, Radu-Ştefan Miftode, Alexandru Florinel Oancea, Maria-Antoanela Pasăre, Tudoriţa Gabriela Parângă, Egidia Gabriela Miftode, Irina Luanda Mititiuc and Viorel Dragoş Radu

Int. J. Mol. Sci. 2025, 26(18), 8899; https://doi.org/10.3390/ijms26188899 - 12 Sep 2025

Abstract

Colistin, a polymyxin antibiotic reintroduced as a last-resort therapy against multidrug-resistant Gram-negative bacteria, is increasingly being compromised by the emergence of plasmid-mediated colistin resistance genes (mcr-1 to mcr-10). The human gut microbiota serves as a major reservoir and transmission hub [...] Read more.

Colistin, a polymyxin antibiotic reintroduced as a last-resort therapy against multidrug-resistant Gram-negative bacteria, is increasingly being compromised by the emergence of plasmid-mediated colistin resistance genes (mcr-1 to mcr-10). The human gut microbiota serves as a major reservoir and transmission hub for these resistance determinants, even among individuals without prior colistin exposure. This review explores the mechanisms, dissemination, and clinical implications of mcr-mediated colistin resistance within the gut microbiota, highlighting its role in horizontal gene transfer, colonization, and environmental persistence. A comprehensive synthesis of the recent literature was conducted, focusing on epidemiological studies, molecular mechanisms, neonatal implications and decolonization strategies. The intestinal tract supports the enrichment and exchange of mcr genes among commensal and pathogenic bacteria, especially under antibiotic pressure. Colistin use in agriculture has amplified gut colonization with resistant strains in both animals and humans. Surveillance gaps remain, particularly in neonatal populations, where colonization may occur early and persist silently. Promising interventions, such as fecal microbiota transplantation and phage therapies, are under investigation but lack large-scale clinical validation. The gut microbiome plays a central role in the global spread of colistin resistance. Mitigating this threat requires integrated One Health responses, improved diagnostics for gut colonization, and investment in microbiome-based therapies. A proactive, multisectoral approach is essential to safeguard colistin efficacy and address the expanding threat of mcr-mediated resistance. Full article

(This article belongs to the Special Issue Molecular Research of Gut Microbiota in Human Health and Diseases)

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16 pages, 2961 KB

Open AccessArticle

Ecotoxicological Impacts of Perfluorooctane Sulfonate on the Freshwater Snail Lanistes carinatus: Oxidative Stress, Neurotoxicity, and Histopathological Alterations

by Mohamed Hamed, Mohammed Abdel-Wahab, Rashad E. M. Said and Alaa El-Din H. Sayed

Int. J. Mol. Sci. 2025, 26(18), 8898; https://doi.org/10.3390/ijms26188898 - 12 Sep 2025

Abstract

Perfluorooctane sulfonate (PFOS), which is known for its environmental persistence and bioaccumulation, poses substantial impacts to aquatic ecosystems. This study assesses the toxic effects of PFOS in the freshwater snail Lanistes carinatus using biomarkers for antioxidant activity, neurotoxicity, and tissue damage. Snails exposed [...] Read more.

Perfluorooctane sulfonate (PFOS), which is known for its environmental persistence and bioaccumulation, poses substantial impacts to aquatic ecosystems. This study assesses the toxic effects of PFOS in the freshwater snail Lanistes carinatus using biomarkers for antioxidant activity, neurotoxicity, and tissue damage. Snails exposed to PFOS (1, 3, 10 mg/L for 14 days) displayed lipid peroxidation (LPO) levels that increased by 16.3–67.5%, and malondialdehyde (MDA) levels that rose by 10.0–58.4%, indicating oxidative damage. Enzyme activities for glutathione S-transferase (GST), glutathione peroxidase (GPx), and catalase (CAT) increased, ranging from 10.0 to 58.3%, 10.0 to 58.4%, and 10.0 to 58.4%, respectively, whereas levels of reduced glutathione (GSH) dropped by 15.0–41.5% and Superoxide dismutase (SOD) decreased by 15.0–41.4%. The activity of acetylcholinesterase (AchE) was reduced by a range of 15.0–40.0%, suggesting neurotoxic effects. Histopathological changes in the digestive gland were also noted. Further research on the effects of PFOS on mollusks is required, and investigation into sex-specific toxicity is needed. This shed light on L. carinatus as a sentinel species, providing helpful information for the monitoring and regulation of PFOS in aquatic environments. Full article

(This article belongs to the Special Issue Toxicological Impacts of Emerging Contaminants on Aquatic Organisms)

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14 pages, 1057 KB

Open AccessReview

Pathogenesis of Cutaneous Mycobacterial Infections—M. marinum and M. leprae

by William Dela Cruz, Erika Fernau and Vishwanath Venketaraman

Int. J. Mol. Sci. 2025, 26(18), 8897; https://doi.org/10.3390/ijms26188897 - 12 Sep 2025

Abstract

Mycobacterium marinum and Mycobacterium leprae are zoonotic mycobacteria causing chronic cutaneous infections that challenge host immunity and tissue integrity. Reactive oxygen species (ROS) play a complex role in the host defense system. While essential for pathogen elimination and intracellular signaling, excessive ROS can [...] Read more.

Mycobacterium marinum and Mycobacterium leprae are zoonotic mycobacteria causing chronic cutaneous infections that challenge host immunity and tissue integrity. Reactive oxygen species (ROS) play a complex role in the host defense system. While essential for pathogen elimination and intracellular signaling, excessive ROS can lead to immune dysregulation and impaired tissue healing. This review explores M. marinum and M. leprae pathogenesis through the role of ROS in redox imbalances, immunity, and cutaneous wound healing. Physiological ROS levels are vital for T-cell activation and differentiation. However, excessive ROS production, particularly in innate immune cells, can lead to T-cell suppression. M. leprae infection is associated with a significant reduction in key antioxidants such as glutathione (GSH), GSH peroxidase (GSH-Px), and GSH reductase (GR), a reduction that correlates with disease severity. For M. marinum, disrupting the pathogen’s redox balance through thioredoxin reductase (TrxR) inhibition sensitizes bacteria to ROS damage, reducing bacterial load. Overall, redox imbalance is central to the pathogenesis and persistence of cutaneous mycobacterial infections, compromising host defense and impairing tissue repair. Restoring and maintaining proper redox homeostasis, potentially by exploring the role of GSH as an antioxidant, represents a promising adjunct treatment to improve host outcomes in these challenging dermatological conditions. Full article

(This article belongs to the Special Issue Molecular Insights into Zoonotic Diseases)

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14 pages, 2734 KB

Open AccessArticle

Dual Therapeutic Impact of AXL Inhibitor AB-329: Chemotherapy Sensitization and Immune Microenvironment Reprogramming in TNBC

by Dileep Reddy Rampa, Jon A. Fuson, Huey Liu, Max Pan, Yujia Qin, Youping Deng, Naoto T. Ueno and Jangsoon Lee

Int. J. Mol. Sci. 2025, 26(18), 8896; https://doi.org/10.3390/ijms26188896 (registering DOI) - 12 Sep 2025

Abstract

AXL, a receptor tyrosine kinase, has emerged as a promising therapeutic target in triple-negative breast cancer (TNBC) due to its critical roles in tumor progression, metastasis, and immune evasion. In this study, we investigated the antitumor efficacy and immunomodulatory potential of AB-329, a [...] Read more.

AXL, a receptor tyrosine kinase, has emerged as a promising therapeutic target in triple-negative breast cancer (TNBC) due to its critical roles in tumor progression, metastasis, and immune evasion. In this study, we investigated the antitumor efficacy and immunomodulatory potential of AB-329, a selective AXL kinase inhibitor, in preclinical models of TNBC. Transcriptome analysis and single-cell RNA sequencing datasets revealed elevated AXL expression in mesenchymal TNBC subtypes and a negative association with immune cell infiltration. While AB-329 demonstrated moderate antiproliferative effects as a monotherapy, its combination with paclitaxel led to substantially enhanced antiproliferative and anti-metastatic effects compared to gemcitabine, DXd, and SN-38. In murine TNBC allograft models, the combination of AB-329 and paclitaxel significantly reduced tumor growth, and AB-329 increased activated natural killer (NK) cell infiltration in humanized mouse models. Analysis of human breast cancer tissue further confirmed that low AXL expression is associated with a higher presence of NK cells in the tumor. These findings suggest that AB-329 not only augments chemotherapy efficacy but also reshapes the tumor immune microenvironment, supporting its further development as a dual-action therapeutic strategy for AXL-positive TNBC. Full article

(This article belongs to the Special Issue Progress in New Agents to Treat Breast Cancer)

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32 pages, 1208 KB

Open AccessReview

Role of Mast Cells in Human Health and Disease: Controversies and Novel Therapies

by Miguel Ángel Galván-Morales, Juan Carlos Vizuet-de-Rueda, Josaphat Miguel Montero-Vargas and Luis M. Teran

Int. J. Mol. Sci. 2025, 26(18), 8895; https://doi.org/10.3390/ijms26188895 - 12 Sep 2025

Abstract

Mast cells have been implicated in allergic diseases such as asthma, rhinitis, conjunctivitis, atopic dermatitis, urticaria, and anaphylaxis. However, it is now well established that they also fulfill critical roles in tissue homeostasis, repair, and defense. Despite considerable progress, their ontogeny, proliferation, and [...] Read more.

Mast cells have been implicated in allergic diseases such as asthma, rhinitis, conjunctivitis, atopic dermatitis, urticaria, and anaphylaxis. However, it is now well established that they also fulfill critical roles in tissue homeostasis, repair, and defense. Despite considerable progress, their ontogeny, proliferation, and differentiation remain subjects of debate, as does their involvement in a wide spectrum of diseases, including cancer and cardiovascular disorders. What remains indisputable is their essential contribution to both innate and adaptive immune responses. Importantly, the activity of their effector molecules can elicit either protective or deleterious outcomes. A complete absence of mast cells (MCs) in humans would undoubtedly provide valuable insight into their fundamental role in immunity, much as neutropenia and agranulocytosis have historically clarified the functions of neutrophils. In this review, we provide a comprehensive overview of mast cell (MC) biology, emphasizing their functional diversity and pathogenic potential. Furthermore, we highlight emerging therapeutic strategies, particularly the use of inhibitors and monoclonal antibodies, which are reshaping current approaches to conditions such as allergy, mastocytosis, and related disorders. Full article

(This article belongs to the Special Issue Mast Cells in Human Health and Diseases—3rd Edition)

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17 pages, 267 KB

Open AccessArticle

The Influence of Clinical Factors and Genetic Variants of COL1A1 and TNFRSF11B on Bone Mineral Density in Postmenopausal Women

by Katarzyna Kotrych, Maciej Wojtuń, Aleksandra Górska, Anna Bogacz, Michał Soczawa, Izabela Uzar, Jarosław Gorący, Maciej Brązert, Bogusław Czerny and Adam Kamiński

Int. J. Mol. Sci. 2025, 26(18), 8894; https://doi.org/10.3390/ijms26188894 - 12 Sep 2025

Abstract

Osteoporosis is a chronic metabolic disease characterised by reduced bone mineral density (BMD) and increased susceptibility to fractures. Its development is influenced by both environmental and genetic factors that regulate bone metabolism. Among the genes involved in bone metabolism, COL1A1 and TNFRSF11B (OPG) [...] Read more.

Osteoporosis is a chronic metabolic disease characterised by reduced bone mineral density (BMD) and increased susceptibility to fractures. Its development is influenced by both environmental and genetic factors that regulate bone metabolism. Among the genes involved in bone metabolism, COL1A1 and TNFRSF11B (OPG) are particularly important. The COL1A1 gene encodes the alpha-1 chain of type I collagen, a major component of the bone matrix, and plays a key role in maintaining bone mechanical strength. The TNFRSF11B gene encodes osteoprotegerin (OPG), a protein that inhibits bone resorption by binding the RANKL ligand and blocking osteoclast activation. Therefore, the aim of this study was to determine the association between the rs1107946 and rs1800012 polymorphisms of the COL1A1 gene and the rs2073617 polymorphism of the TNFRSF11B (OPG) gene and bone mineral density in postmenopausal women. The study included 590 postmenopausal women: 350 healthy controls, 105 with osteopenia, and 135 with osteoporosis. Genotyping was performed using real-time PCR and LightSNiP probes. Associations between genetic variables and BMD were assessed, taking into account environmental factors (BMI, smoking). The presence of the T allele of the rs1800012 variant was initially associated with lower BMD and an increased risk of osteopenia, but this association lost significance after adjustment for BMI and smoking. For rs1107946 and rs2073617,no statistically significant associations were observed. These findings suggest that the studied SNPs have, at most, modest effects on BMD, with environmental influences playing a stronger role. Further research in larger and more diverse cohorts, including FRAX-based risk estimation, is warranted. Full article

(This article belongs to the Special Issue Molecular Studies of Bone Biology and Bone Tissue: 2nd Edition)

18 pages, 1832 KB

Open AccessReview

Regulatory Roles of Noncanonical Inflammasomes in Diabetes Mellitus and Diabetes-Associated Complications

by Young-Su Yi

Int. J. Mol. Sci. 2025, 26(18), 8893; https://doi.org/10.3390/ijms26188893 - 12 Sep 2025

Abstract

Inflammation is an innate immune system protecting the body from infection and injury. This process proceeds through two distinct stages: a priming phase, characterized by transcriptional activation, and a triggering phase, in which inflammasomes, cytosolic multiprotein complexes, are activated to initiate inflammatory signaling [...] Read more.

Inflammation is an innate immune system protecting the body from infection and injury. This process proceeds through two distinct stages: a priming phase, characterized by transcriptional activation, and a triggering phase, in which inflammasomes, cytosolic multiprotein complexes, are activated to initiate inflammatory signaling cascades. Canonical inflammasomes, the first to be identified, have been extensively implicated in the pathogenesis of diverse inflammatory disorders. In contrast, noncanonical inflammasomes have only recently been characterized, and their precise contributions to immune regulation and disease development remain incompletely defined. Diabetes mellitus (DM), simply diabetes, represents a heterogeneous group of metabolic disorders marked by chronic hyperglycemia and is associated with a broad spectrum of complications. The involvement of canonical inflammasomes in DM and its complications has been well demonstrated. More recently, however, accumulating evidence has uncovered crucial roles for noncanonical inflammasomes in the pathogenesis of DM and related complications This review comprehensively discusses current advances in understanding the regulatory functions of murine caspase-11 and human caspase-4/5 noncanonical inflammasomes in the pathogenesis of DM and diabetes-associated complications, highlighting their potential as novel therapeutic targets. Full article

(This article belongs to the Special Issue Canonical and Noncanonical Inflammasomes in Inflammation and Diseases)

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10 pages, 660 KB

Open AccessBrief Report

Detection and Clinical Associations of Autoantibodies to Heterogeneous Nuclear Ribonucleoprotein (hnRNP) A2/B1 in Patients with Systemic Sclerosis

by Antonio Tonutti, Natasa Isailovic, Lukas Frischknecht, Francesca Motta, Minoru Satoh, Carlo Selmi, Maria De Santis and Angela Ceribelli

Int. J. Mol. Sci. 2025, 26(18), 8892; https://doi.org/10.3390/ijms26188892 - 12 Sep 2025

Abstract

Autoantibodies targeting heterogeneous nuclear ribonucleoproteins (hnRNPs) have been seldom described in autoimmune diseases but remain poorly characterized in systemic sclerosis (SSc). This study aims to investigate the prevalence and clinical significance of anti-hnRNP autoantibodies in SSc. Serum samples from 25 well-characterized SSc patients [...] Read more.

Autoantibodies targeting heterogeneous nuclear ribonucleoproteins (hnRNPs) have been seldom described in autoimmune diseases but remain poorly characterized in systemic sclerosis (SSc). This study aims to investigate the prevalence and clinical significance of anti-hnRNP autoantibodies in SSc. Serum samples from 25 well-characterized SSc patients were analyzed using protein immunoprecipitation (IP) to detect autoantibodies against hnRNP components A1, A2/B1, C1/C2, H, L, and U. Clinical data including organ involvement and autoantibody profiles were also collected over a 10-year follow-up period. Anti-hnRNP A2/B1 autoantibodies were identified in 40% of SSc patients and significantly associated with gastrointestinal involvement (80% vs. 27%; p = 0.015; OR 17, 95% CI 2.2–381). Additional components such as anti-hnRNP L antibodies exhibited variable protein-IP band patterns, with a trend toward an association between a “double” band pattern and cancer history (p = 0.066). Anti-hnRNP U antibodies were detected in a single patient presenting with severe digital ulcers. No patient tested positive for antibodies against other components, including A1, C1/C2, and H. In this preliminary hypothesis-generating study, anti-hnRNP autoantibodies were frequent in SSc patients with distinct prevalence and clinical associations depending on the target component. Anti-hnRNP A2/B1 correlate with gastrointestinal involvement but, contrary to previous reports, show no association with arthritis. Further exploration on anti-hnRNP L and the rarer anti-hnRNP U autoantibodies is warranted. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Targeted Regulation of Autoimmune Diseases)

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22 pages, 615 KB

Open AccessArticle

Effects of Cherry Consumption on Metabolic Health: A Pilot Clinical Study on Healthy Adults

by Filomena Carvalho, Alexandra Varges, Radhia Aitfella Lahlou, Eduardo Bárbara, Isa Santos, Cecília Fonseca and Luís R. Silva

Int. J. Mol. Sci. 2025, 26(18), 8891; https://doi.org/10.3390/ijms26188891 - 12 Sep 2025

Abstract

Cherry consumption has been associated with several metabolic health benefits, due to their rich profile of bioactive compounds, including anthocyanins. This pilot clinical study, which is, to our knowledge, the first evaluating consumption of whole cherries, aimed to evaluate the effects of daily [...] Read more.

Cherry consumption has been associated with several metabolic health benefits, due to their rich profile of bioactive compounds, including anthocyanins. This pilot clinical study, which is, to our knowledge, the first evaluating consumption of whole cherries, aimed to evaluate the effects of daily cherry consumption on oxidative stress, inflammation, glycaemic regulation, and other metabolic health markers in healthy adults. A total of 27 volunteers consumed 280 g of sweet cherries daily for 42 days, followed by a two-week post-intervention period. Significant improvements were observed in glucose regulation, including reduced HbA1c and estimated average glucose levels. Markers of inflammation, such as IL-6 and AGP-1 were significantly reduced during the intervention period. In addition, reductions in GGT and LDH indicated potential hepatoprotective effects. These results suggest that regular cherry consumption may serve as a preventive strategy against early metabolic dysfunction, highlighting the need for further investigation with larger, long-term clinical trials. Full article

(This article belongs to the Special Issue The Role of Natural Products in Treating Human Diseases)

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13 pages, 12457 KB

Open AccessArticle

Goblet Cell-Mediated Pathway: A Major Contributor to Increased Intestinal Permeability in Streptozotocin-Induced Type 1 Diabetic Mice

by Ming-Hsun Wu, Lee-Wei Chen, Jiann-Hwa Chen and Chieh-Wen Lai

Int. J. Mol. Sci. 2025, 26(18), 8890; https://doi.org/10.3390/ijms26188890 - 12 Sep 2025

Abstract

Gut barrier dysfunction and increased intestinal permeability are closely linked to the pathogenesis of type 1 diabetes and its complications. Streptozotocin (STZ)-induced diabetic mice, which mimic β-cell destruction and insulin deficiency, provide a widely used model for studying type 1 diabetes-associated intestinal barrier [...] Read more.

Gut barrier dysfunction and increased intestinal permeability are closely linked to the pathogenesis of type 1 diabetes and its complications. Streptozotocin (STZ)-induced diabetic mice, which mimic β-cell destruction and insulin deficiency, provide a widely used model for studying type 1 diabetes-associated intestinal barrier impairment. However, the cellular pathways mediating this dysfunction, particularly the role of goblet cells, remain incompletely elucidated. This study aimed to investigate the association between the gut barrier function and diabetes. Using real-time intravital multiphoton microscopy, we investigated intestinal barrier integrity in STZ-induced type 1 diabetic mice. Three groups were analysed: the control, STZ-diabetic, and STZ-diabetic mice treated with fructooligosaccharide (FOS) for 1 week. Intestinal permeability was assessed by measuring fluorescein isothiocyanate (FITC)-dextran concentrations in the portal vein and visualising translocation into villi. Epithelial morphology was examined, focusing on goblet cell density and leakage pathways. STZ-diabetic mice demonstrated a significant increase in intestinal permeability, evidenced by elevated FITC-dextran levels in the portal vein and villi. Multiphoton imaging revealed a notable rise in the goblet cell-to-enterocyte ratio in diabetic mice, while the gap density remained unchanged. The predominant route of macromolecular leakage in STZ-diabetic mice was via goblet cells rather than by paracellular gaps. One-week FOS supplementation significantly reduced goblet cell density and partially restored barrier function without altering the distribution of leakage pathways. These findings highlight goblet cell-mediated transcellular leakage as a major mechanism of gut barrier dysfunction in type 1 diabetic mice. Short-term FOS treatment partially reverses these alterations. Targeting goblet cell function may offer a promising therapeutic strategy to restore gut barrier integrity in diabetes. Full article

(This article belongs to the Special Issue Targeted Therapy for Immune Diseases)

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22 pages, 4343 KB

Open AccessArticle

A Murine Model of Glioblastoma Initiating Cells and Human Brain Organoid Xenograft for Photodynamic Therapy Testing

by Alejandra Mosteiro, Diouldé Diao, Carmen Bedia, Leire Pedrosa, Gabriela Ailén Caballero, Iban Aldecoa, Mar Mallo, Francesc Solé, Ana Sevilla, Abel Ferrés, Gloria Cabrera, Marta Muñoz-Tudurí, Marc Centellas, Estela Pineda, Àngels Sierra Jiménez and José Juan González Sánchez

Int. J. Mol. Sci. 2025, 26(18), 8889; https://doi.org/10.3390/ijms26188889 - 12 Sep 2025

Abstract

Glioblastoma (GB) is one of the most aggressive brain tumors, characterized by high infiltrative capacity that enables tumor cells to invade healthy brain tissue and evade complete surgical resection. This invasiveness contributes to resistance against conventional therapies and a high recurrence rate. Strategies [...] Read more.

Glioblastoma (GB) is one of the most aggressive brain tumors, characterized by high infiltrative capacity that enables tumor cells to invade healthy brain tissue and evade complete surgical resection. This invasiveness contributes to resistance against conventional therapies and a high recurrence rate. Strategies capable of eliminating residual tumor cells are urgently needed. Photodynamic therapy (PDT) using 5-aminolevulinic acid (5-ALA), an FDA- and EMA-approved compound, induces selective accumulation of the photosensitizer protoporphyrin IX (PpIX) in metabolically active tumor cells, enabling targeted cytotoxicity through light activation. A major limitation to its clinical application is the unclear variation in the cytotoxic effect of PDT according to individual tumoral differences. In this study, we propose and validate an in vivo model of patient-derived GB initiating cells (GICs) and brain organoids to test the effects of PDT. First, patient-derived GICs were molecularly characterized by flow cytometry and copy number variation profiling using OncoScan CNV Assays, then co-cultured with human brain organoids to generate a hybrid model recapitulating key aspects of the tumor microenvironment. 5-ALA photodynamic therapy (PDT) efficacy was assessed in vitro by GFP-based viability measurements, LDH release assays, and TUNEL staining. Then, a murine model was generated to study PDT in vivo, based on a heterotopic (renal subcapsular engraftment) xenograft of the GICs-human brain organoid co-culture. PDT was tested in the model; in each subject, one kidney tumoral engraftment was treated and the contralateral served as a control. Immunofluorescence analysis was used to study the cell composition of the brain organoid-tumoral engraftment after PDT, and the effects on non-GIC cells. The antitumoral effect was determined by the degree of cell death analysis with the TUNEL technique. The GICs-brain organoid co-culture resulted in tumoral growth and infiltration both in vitro and in vivo. The pattern of growth and infiltration varied according to the tumoral genetic profile. 5-ALA PDT resulted in a reduction in the number of GICs and an increase in apoptotic cells in all four lines tested in vitro. A correlation was found between the induced phototoxicity in vivo with the molecular typification of GICs cell lines in vitro. There were no changes in the number or distribution of neuronal cells after the application of PDT, while a reduction in active astrocytes was observed. 5-ALA PDT could be effective in eradicating GICs with a heterogeneous molecular profile. The hybrid human-murine model presented here could be useful in investigating adjuvant therapies in GB, under the concept of personalized medicine. Full article

(This article belongs to the Section Molecular Oncology)

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27 pages, 1306 KB

Open AccessReview

Druggability of Sodium Calcium Exchanger (NCX): Challenges and Recent Development

by Antonia Scognamiglio, Angela Corvino, Giuseppe Caliendo, Ferdinando Fiorino, Elisa Perissutti, Vincenzo Santagada and Beatrice Severino

Int. J. Mol. Sci. 2025, 26(18), 8888; https://doi.org/10.3390/ijms26188888 - 12 Sep 2025

Abstract

Na⁺/Ca²⁺ exchangers (NCXs) are membrane transporters crucial for calcium homeostasis in excitable tissues, particularly in the central nervous system. Growing evidence indicates that NCX dysfunction contributes to calcium overload and neuronal damage in several neurological conditions. Thus, pharmacological modulation of [...] Read more.

Na⁺/Ca²⁺ exchangers (NCXs) are membrane transporters crucial for calcium homeostasis in excitable tissues, particularly in the central nervous system. Growing evidence indicates that NCX dysfunction contributes to calcium overload and neuronal damage in several neurological conditions. Thus, pharmacological modulation of NCX isoforms (NCX1, NCX2, and NCX3) has emerged as a potential therapeutic strategy for disorders such as stroke, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), and Parkinson’s disease (PD). However, the identification of selective modulators directed at specific NCX isoforms, or even different splice variants, remains challenging and limits their clinical validation. This Review aims to provide an updated overview of small-molecule NCX modulators, described over the last two decades. Chemical structures, mechanisms of action, and isoform specificity are discussed, along with the most commonly used biological assays for their functional evaluation. Full article

(This article belongs to the Section Molecular Pharmacology)

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8 pages, 444 KB

Open AccessReview

Targeted Biologic Therapies for Hidradenitis Suppurativa

by Isabella J. Tan, Helen N. Nguyen, Sydney M. Wolfe, Priya Agarwal and Bernard A. Cohen

Int. J. Mol. Sci. 2025, 26(18), 8887; https://doi.org/10.3390/ijms26188887 - 12 Sep 2025

Abstract

Chronic inflammatory disorders of the apocrine gland (CIDAP), such as hidradenitis suppurativa (HS), are characterized by painful, recurrent lesions in apocrine gland-rich areas. First-line treatments—including retinoids and antibiotics—often fail to prevent recurrence and biofilm formation, necessitating the use of targeted biologic therapies. This [...] Read more.

Chronic inflammatory disorders of the apocrine gland (CIDAP), such as hidradenitis suppurativa (HS), are characterized by painful, recurrent lesions in apocrine gland-rich areas. First-line treatments—including retinoids and antibiotics—often fail to prevent recurrence and biofilm formation, necessitating the use of targeted biologic therapies. This review evaluated U.S.-based randomized controlled trials and cohort studies published between 2014 and 2024 on the efficacy of such therapies in adult HS patients. A total of 13 studies met inclusion criteria. Agents targeting interleukins (IL-17A, IL-17F, IL-23, IL-1α, IL-36) and TNF-α were assessed, with outcomes including HiSCR, Sartorius scores, DLQI, and patient-reported measures. IL-17 inhibitors (secukinumab, bimekizumab) and IL-1 inhibitors (bermekimab, anakinra) demonstrated promising reductions in inflammatory burden and improved quality of life. TNF-α inhibitors, particularly adalimumab and infliximab, consistently achieved HiSCR and HSS improvements. Guselkumab (IL-23) showed limited efficacy in HiSCR but modest pain relief. Safety profiles were generally acceptable across agents, with few serious adverse events. Limitations across studies included small sample sizes, lack of control arms, and short follow-up durations. These findings underscore the therapeutic potential of biologic agents in managing HS. A greater emphasis on biomarker-guided treatment selection and interdisciplinary collaboration is warranted to optimize long-term outcomes for patients. Full article

(This article belongs to the Section Molecular Immunology)

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16 pages, 3399 KB

Open AccessArticle

Uncovering Rare Structural Chromosomal Rearrangements: Insights from Molecular Cytogenetics

by Márta Czakó, András Szabó, Ágnes Till, Anna Zsigmond and Kinga Hadzsiev

Int. J. Mol. Sci. 2025, 26(18), 8886; https://doi.org/10.3390/ijms26188886 - 12 Sep 2025

Abstract

Complex chromosomal rearrangements (CCRs) are rare structural abnormalities involving at least three chromosomal breakpoints and often two or more chromosomes. Owing to their inherent genomic complexity, CCRs are frequently associated with abnormal phenotypes, including developmental delay, congenital anomalies, and infertility. In this study, [...] Read more.

Complex chromosomal rearrangements (CCRs) are rare structural abnormalities involving at least three chromosomal breakpoints and often two or more chromosomes. Owing to their inherent genomic complexity, CCRs are frequently associated with abnormal phenotypes, including developmental delay, congenital anomalies, and infertility. In this study, we report four male patients, three of them with de novo rare structural chromosomal rearrangement detected through a combination of Giemsa-Trypsin (GTG) banding, fluorescence in situ hybridization (FISH), and high-resolution microarray techniques (SNP array and array CGH). Each of the four cases turned out to be of a different type: in addition to two exceptional CCRs, an inv dup del 18q and a cluster rearrangement involving the long arm of chromosome 4 were identified. Despite the limitations of the testing methods, we performed a detailed analysis of the relationship between the most detailed genotype data and the associated phenotype. Our study provides further valuable evidence that the use of molecular cytogenetic methods is of paramount importance even in cases with abnormal karyotypes detected by light microscopy, as high-resolution data may reveal unsuspected genomic complexity, which is essential for genetic counseling in these patients. Full article

(This article belongs to the Special Issue Exploring Rare Diseases: Genetic, Genomic and Metabolomic Advances)

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24 pages, 2857 KB

Open AccessArticle

Effects of 17β-Estradiol Treatment on Metabolic Function and Aortic Relaxation in Castrated Male Rats

by Rifat Ara Islam, Md Rahatullah Razan, Ankita Poojari, Mohammad Moshiur Rahman, Hao Wei, Hana S. Alhamadsheh, Melanie Felmlee, Atefeh Rabiee, Mitra Esfandiarei and Roshanak Rahimian

Int. J. Mol. Sci. 2025, 26(18), 8885; https://doi.org/10.3390/ijms26188885 (registering DOI) - 12 Sep 2025

Abstract

Exogenous estrogen use in male-to-female individuals has been linked to increased cardiovascular disease risk, though the mechanisms remain unclear. This study examines the effects of 17β-estradiol (E₂) on metabolic and aortic function in castrated (CAS) male Sprague Dawley rats. CAS rats [...] Read more.

Exogenous estrogen use in male-to-female individuals has been linked to increased cardiovascular disease risk, though the mechanisms remain unclear. This study examines the effects of 17β-estradiol (E₂) on metabolic and aortic function in castrated (CAS) male Sprague Dawley rats. CAS rats received subcutaneous E₂ (CAS + E₂) or placebo (CAS + PL) pellets for ~35 days, with intact males serving as controls. Endothelium-dependent vasorelaxation (EDV) in response to acetylcholine and contractile responses to phenylephrine were measured in aorta before and after pharmacological inhibitors. Metabolic parameters and expression of proteins associated with vascular and insulin signaling were also determined in aorta and white adipose tissue (WAT). E₂ treatment reduced body weight, improved HbA1c and enhanced glucose tolerance in CAS rats compared to the CAS + PL group. Improved glucose homeostasis was associated with upregulation of estrogen receptor alpha, phosphorylated Akt/Akt, and glucose transporter-4 expression in WAT. However, E₂ increased plasma triglyceride and impaired EDV, indicating compromised vascular function. Our results suggest that impaired aortic relaxation in the CAS + E₂ group may be partly attributable to increased contractility. Additionally, we observed reduced G protein-coupled estrogen receptor and elevated inducible nitric oxide synthase expression, warranting further investigation into whether these factors contribute to the effects of E₂ on aortic relaxation. Full article

(This article belongs to the Special Issue Molecular Mechanisms, Pathogenesis, and Novel Therapeutic Strategies in Cardiovascular Disease)

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18 pages, 2064 KB

Open AccessArticle

Targeted Atherosclerosis Treatment Using Vascular Cell Adhesion Molecule-1 Targeting Peptide-Engineered Plant-Derived Extracellular Vesicles

by Chanwoo Choi and Won Jong Rhee

Int. J. Mol. Sci. 2025, 26(18), 8884; https://doi.org/10.3390/ijms26188884 (registering DOI) - 12 Sep 2025

Abstract

Atherosclerosis is a chronic vascular disease characterized by lipid accumulation, endothelial dysfunction, and persistent inflammation, which can ultimately lead to life-threatening complications, such as myocardial infarction and stroke. Current therapies primarily focus on lowering cholesterol levels or preventing blood clot formation. However, the [...] Read more.

Atherosclerosis is a chronic vascular disease characterized by lipid accumulation, endothelial dysfunction, and persistent inflammation, which can ultimately lead to life-threatening complications, such as myocardial infarction and stroke. Current therapies primarily focus on lowering cholesterol levels or preventing blood clot formation. However, the multifactorial and dynamic nature of atherosclerotic progression is not addressed. We designed a therapeutic platform based on onion-derived extracellular vesicles (Onex), nanovesicles originating from onions with excellent biocompatibility and strong anti-inflammatory effects. Onex was engineered with the VHPK peptide, to construct V-Onex, specifically targeting vascular cell adhesion molecule-1 (VCAM-1), which is strongly upregulated in inflamed endothelial cells during atherosclerosis. Engineered V-Onex exhibited excellent biocompatibility and stability without inducing cytotoxicity in human umbilical vein endothelial cells (HUVECs) and THP-1 cells. V-Onex selectively accumulated in inflamed endothelial cells and significantly reduced the expression of inflammatory markers in HUVECs and THP-1 cells. It also suppresses the migration of endothelial cells and reduces their interaction with monocytes, both of which contribute to plaque formation. In THP-1 cells, V-Onex inhibited the uptake of oxidized low-density lipoprotein and reduced foam cell formation. Collectively, V-Onex is a promising modular targeted nanovesicle platform capable of modulating multiple pathological processes associated with atherosclerosis. Full article

(This article belongs to the Special Issue Roles and Function of Extracellular Vesicles in Diseases: 3rd Edition)

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11 pages, 1417 KB

Open AccessArticle

Biodegradable Nanoparticles Encapsulating Murine Double Minute 2 siRNA to Treat Peritoneal Dissemination of Colon Cancer

by Tomoaki Kurosaki, Akari Okada, Yuuki Takashima, Hitoshi Sasaki and Yukinobu Kodama

Int. J. Mol. Sci. 2025, 26(18), 8883; https://doi.org/10.3390/ijms26188883 (registering DOI) - 12 Sep 2025

Abstract

The study aim was to apply murine double minute 2 (MDM2)-siRNA to a biodegradable siRNA delivery vector, ternary complex, for treating colorectal cancer peritoneal dissemination. The ternary complex containing MDM2-siRNA (MDM2-siRNA complex) was constructed by mixing MDM2-siRNA, dendrigraft poly-L-lysine, and γ-polyglutamic acid. Cellular [...] Read more.

The study aim was to apply murine double minute 2 (MDM2)-siRNA to a biodegradable siRNA delivery vector, ternary complex, for treating colorectal cancer peritoneal dissemination. The ternary complex containing MDM2-siRNA (MDM2-siRNA complex) was constructed by mixing MDM2-siRNA, dendrigraft poly-L-lysine, and γ-polyglutamic acid. Cellular uptake of the ternary complex and suppressive effect on MDM2-mRNA were determined in a mouse colorectal cancer cell line. Tumor-growth inhibition by the MDM2-siRNA complex was evaluated in peritoneal dissemination model mice. The MDM2-siRNA complex, with an approximately 177 nm particle size and −35 mV ζ-potential, prevented degradation of the inner siRNA by RNase. In the in vitro study, the ternary complex was highly taken up by the cells, and 2 μg/mL of the MDM2-siRNA complex significantly decreased MDM2-mRNA to about 30% of control cells. Intraperitoneal administration in colorectal cancer peritoneal dissemination model mice showed little effect of the ternary complex containing scramble-siRNA on cancer growth in the peritoneal cavity. Conversely, the MDM2-siRNA complex significantly reduced peritoneal dissemination to less than 1/1000th of control mice and successfully prolonged survival time. In this study, we found that the biodegradable MDM2-siRNA complex had a suppressive effect on MDM2-mRNA in cancer cells and tumor growth of peritoneal dissemination. Full article

(This article belongs to the Special Issue Advancements in Novel Drug Delivery Systems for Gene and Drug Delivery)

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17 pages, 1120 KB

Open AccessArticle

Circulating Levels of SMPDL3B Define Metabolic Endophenotypes and Subclinical Kidney Alterations in Myalgic Encephalomyelitis

by Bita Rostami-Afshari, Wesam Elremaly, Neil R. McGregor, Katherine Jin Kai Huang, Christopher W. Armstrong, Anita Franco, Christian Godbout, Mohamed Elbakry, Rim Abdelli and Alain Moreau

Int. J. Mol. Sci. 2025, 26(18), 8882; https://doi.org/10.3390/ijms26188882 (registering DOI) - 12 Sep 2025

Abstract

Myalgic Encephalomyelitis (ME) is a complex, multisystem disorder with poorly understood pathophysiological mechanisms. SMPDL3B, a membrane-associated protein expressed in renal podocytes, is essential for lipid raft integrity and glomerular barrier function. We hypothesize that reduced membrane-bound SMPDL3B may contribute to podocyte dysfunction and [...] Read more.

Myalgic Encephalomyelitis (ME) is a complex, multisystem disorder with poorly understood pathophysiological mechanisms. SMPDL3B, a membrane-associated protein expressed in renal podocytes, is essential for lipid raft integrity and glomerular barrier function. We hypothesize that reduced membrane-bound SMPDL3B may contribute to podocyte dysfunction and impaired renal physiology in ME. To investigate this, we quantified soluble SMPDL3B in plasma and urine as a surrogate marker of membrane-bound SMPDL3B status and assessed renal clearance and plasma metabolomic profiles. In a cross-sectional study of 56 ME patients and 16 matched healthy controls, ME patients exhibited significantly lower urine-to-plasma ratios of soluble SMPDL3B and reduced renal clearance, suggesting podocyte-related abnormalities. Plasma metabolomics revealed dysregulation of metabolites associated with renal impairment, including succinic acid, benzoic acid, phenyllactic acid, 1,5-anhydroglucitol, histidine, and citrate. In ME patients, plasma SMPDL3B levels inversely correlated with 1,5-anhydroglucitol concentrations and renal clearance. Multivariable modeling identified the urine-to-plasma SMPDL3B ratio as an independent predictor of clearance. Female ME patients showed more pronounced SMPDL3B alterations, reduced clearance, and greater symptom severity. Non-linear associations between soluble SMPDL3B and lipid species further suggest systemic metabolic remodeling. These findings support soluble SMPDL3B as a potential non-invasive biomarker of renal-podocyte involvement in ME, highlighting sex-specific differences that may inform future therapeutic strategies. Full article

(This article belongs to the Special Issue Molecular Pathologies and Treatment for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome)

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18 pages, 1890 KB

Open AccessCase Report

Switch from Ibalizumab to Lenacapavir in a Rescue Regimen for a Heavily Treatment-Experienced (HTE) Patient with Multidrug-Resistant (MDR) HIV-1 Infection

by Salvatore Martini, Lorenzo Salmoni, Roberta Palladino, Antonio Russo, Nunzia Cuomo, Adriana Raddi, Mario Starace, Carmine Minichini, Mariantonietta Pisaturo and Nicola Coppola

Int. J. Mol. Sci. 2025, 26(18), 8881; https://doi.org/10.3390/ijms26188881 - 12 Sep 2025

Abstract

Despite the progress of antiretroviral therapy, there are still some patients with (MDR) HIV infection. In this case, international guidelines suggest using new-generation drugs, such as Ibalizumab (IBA) or Lenacapavir (LEN), in combination with an optimized background regimen. Our clinical case concerns a [...] Read more.

Despite the progress of antiretroviral therapy, there are still some patients with (MDR) HIV infection. In this case, international guidelines suggest using new-generation drugs, such as Ibalizumab (IBA) or Lenacapavir (LEN), in combination with an optimized background regimen. Our clinical case concerns a Heavily Treatment-Experienced (HTE) patient with MDR HIV-1 infection. Rescue therapy began in April 2022, combining residual drugs with low-level resistance and IBA. At this time, HIV-RNA results included 37.800 copies/mL, and CD4+ included 147 cells/µL. IBA was administered intravenously every 15 days. After 12 months, to optimize adherence, IBA was re-placed by LEN, which has long-acting posology, with subcutaneous injections every 6 months. IBA achieved viral suppression in only one month with an improvement in the CD4+ count and showed a progressive disappearance of viral mutations in the reservoir. It was well tolerated except for the onset of hypertension after infusions. After 12 months, IBA was switched to LEN, which showed good tolerability, preserving efficacy and stable pressure on HIV-DNA. Our case report about an HTE patient shows that IBA was efficacious in the rescue regimen, while also acting on the reservoir. LEN, adopted in a switch strategy which differed from that described in the literature, preserved efficacy and stable pressure on HIV-DNA. Full article

(This article belongs to the Special Issue Viral and Host Targets to Fight RNA Viruses)

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12 pages, 453 KB

Open AccessArticle

Determination of a New Biomarker at the Level of Gene Alteration in Cisplatin Ototoxicity

by Deniz Kızmazoğlu, Aylin Erol, Tekincan Çağrı Aktaş, Yüksel Olgun, Ayşe Banu Demir, Zekiye Altun, Safiye Aktaş and Nur Olgun

Int. J. Mol. Sci. 2025, 26(18), 8880; https://doi.org/10.3390/ijms26188880 - 12 Sep 2025

Abstract

Cisplatin is an alkylating chemotherapeutic drug used in the treatment of many pediatric solid tumors, and cisplatin ototoxicity is characterized by sensorineural, bilateral, irreversible, and progressive hearing loss. The aim of this study is to identify biomarkers that may serve as predictors of [...] Read more.

Cisplatin is an alkylating chemotherapeutic drug used in the treatment of many pediatric solid tumors, and cisplatin ototoxicity is characterized by sensorineural, bilateral, irreversible, and progressive hearing loss. The aim of this study is to identify biomarkers that may serve as predictors of cisplatin-induced ototoxicity in pediatric cancers. In our preliminary study, patients with severe hearing loss were analyzed using the comparative genomic hybridization (CGH) method. Mutations were identified in the following genes: ADAM6, SIX3, GNAS, NDUFV1, H19, DEFA4, and ZIM2. Based on these data, we aimed to investigate the mutation status of these candidate genes in a larger population of pediatric cancer patients treated with cisplatin. DNA samples were extracted from the mononuclear cells of peripheral blood samples obtained from 82 patients. These genes were analyzed using the RT-PCR technique, and ototoxicity was assessed using the Brock and Muenster classifications. Hearing loss was detected in 28% of patients; 76.8% and 23.2% had mild and severe hearing loss, respectively. A significant correlation was found between ZIM2 gene amplification and the presence of ototoxicity (rho = 0.461, p = 0.003), especially in advanced-stage cancer patients with severe hearing loss (rho = 0.38, p = 0.017). Our findings suggest that ZIM2 is a promising biomarker for predicting cisplatin ototoxicity. Full article

(This article belongs to the Special Issue Hearing Loss: Molecular Biological Insights)

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Int. J. Mol. Sci., Volume 26, Issue 18 (September-2 2025) – 154 articles

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