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Volume 26
Issue 13
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Int. J. Mol. Sci., Volume 26, Issue 13 (July-1 2025) – 629 articles

Cover Story (view full-size image): Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, associated with limited therapeutic success and a five-year survival rate under 10%. A key barrier to effective treatment is the tumour’s dense desmoplastic stroma, which contributes to therapeutic resistance. This review outlines current ex vivo and preclinical models used to study human PDAC and evaluates their relevance in translational research. Special focus is placed on photodynamic therapy (PDT), a minimally invasive treatment capable of targeting tumour cells and modulating the tumour microenvironment to enhance the immune response. The development of complex, biomimetic models is essential for optimising PDT and other therapies in PDAC. View this paper
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15 pages, 575 KiB  
Review
Neuroactive Steroids as Novel Promising Drugs in Therapy of Postpartum Depression—Focus on Zuranolone
by Jolanta B. Zawilska and Ewa Zwierzyńska
Int. J. Mol. Sci. 2025, 26(13), 6545; https://doi.org/10.3390/ijms26136545 - 7 Jul 2025
Viewed by 504
Abstract
Postpartum depression (PPD) remains a significant health concern worldwide. Both non-pharmacological and pharmacological treatments are available for patients with PPD; however, the standard approach involving selective serotonin reuptake inhibitors (SSRIs) and other antidepressants fails to provide a rapid response. This narrative review presents [...] Read more.
Postpartum depression (PPD) remains a significant health concern worldwide. Both non-pharmacological and pharmacological treatments are available for patients with PPD; however, the standard approach involving selective serotonin reuptake inhibitors (SSRIs) and other antidepressants fails to provide a rapid response. This narrative review presents basic clinical and epidemiological data on PPD, summarizes currently used pharmacotherapies of PPD, highlights their limitations, and discusses new therapies based on a revised understanding of the disease’s pathogenesis. Numerous studies indicate that dysregulation of GABAergic neurotransmission, which may result from fluctuating levels of neuroactive steroids during pregnancy and the postpartum period, plays an important role in the complex pathology of PPD. Considering this, neuroactive steroids, which act as positive allosteric modulators of central GABAA receptors (GABAARs), may offer new promising avenues for treating PPD. The first rapid-acting neurosteroid approved by the FDA to treat PPD in women is brexanolone, although its use is constrained by pharmacokinetic properties. The first oral neuroactive steroid-based antidepressant approved by the FDA for PPD is zuranolone. This review discusses the molecular mechanism of zuranolone action and the results of preclinical and clinical studies regarding the effectiveness and safety of the drug in treating PPD. Full article
(This article belongs to the Special Issue Stress-Related Disorders and Depression: From Molecular Basis to Therapy (2nd Edition))
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13 pages, 624 KiB  
Review
Microgravity Therapy as Treatment for Decelerated Aging and Successful Longevity
by Nadine Mozalbat, Lital Sharvit and Gil Atzmon
Int. J. Mol. Sci. 2025, 26(13), 6544; https://doi.org/10.3390/ijms26136544 - 7 Jul 2025
Viewed by 297
Abstract
Aging is a complex biological process marked by a progressive decline in cellular function, leading to age-related diseases such as neurodegenerative disorders, cancer, and cardiovascular diseases. Despite significant advancements in aging research, finding effective interventions to decelerate aging remains a challenge. This review [...] Read more.
Aging is a complex biological process marked by a progressive decline in cellular function, leading to age-related diseases such as neurodegenerative disorders, cancer, and cardiovascular diseases. Despite significant advancements in aging research, finding effective interventions to decelerate aging remains a challenge. This review explores microgravity as a novel therapeutic approach to combat aging and promote healthy longevity. The hallmarks of aging, including genomic instability, telomere shortening, and cellular senescence, form the basis for understanding the molecular mechanisms behind aging. Interestingly, microgravity has been shown to accelerate aging-like processes in model organisms and human tissues, making it an ideal environment for studying aging mechanisms in an accelerated manner. Spaceflight studies, such as NASA’s Twins Study and experiments aboard the International Space Station (ISS), reveal striking parallels between the physiological changes induced by microgravity and those observed in aging populations, including muscle atrophy, bone density loss, cardiovascular deconditioning, and immune system decline in a microgravity environment. However, upon microgravity recovery, cellular behavior, gene expression, and tissue regeneration were seen, providing vital insights into aging mechanisms and prospective therapeutic approaches. This review examines the potential of microgravity-based technologies to pioneer novel strategies for decelerating aging and enhancing healthspan under natural gravity, paving the way for breakthroughs in longevity therapies. Full article
(This article belongs to the Section Molecular Endocrinology and Metabolism)
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13 pages, 1204 KiB  
Article
Acute Immune Cell Dynamics During Myocardial Infarction and Their Association with Mortality
by Harris Avgousti, Reina Nagasaka, Adovich S. Rivera, Anna Pawlowski, Edward B. Thorp and Matthew J. Feinstein
Int. J. Mol. Sci. 2025, 26(13), 6543; https://doi.org/10.3390/ijms26136543 - 7 Jul 2025
Viewed by 295
Abstract
Acute neutrophil responses following myocardial infarction (MI) play a central role in remodeling, contributing to both repair and potential maladaptive responses. Although prior studies have investigated circulating immune cell indices at a single time point during hospitalization for MI, limited data exist on [...] Read more.
Acute neutrophil responses following myocardial infarction (MI) play a central role in remodeling, contributing to both repair and potential maladaptive responses. Although prior studies have investigated circulating immune cell indices at a single time point during hospitalization for MI, limited data exist on acute intra-individual changes in circulating immune profiles during evolving MI. We analyzed clinical measurements, such as the count and proportion of immune cell components in a serial complete blood count, with differential tests conducted for patients hospitalized with ST-elevation MI (STEMI) in various hospitals in the Northwestern Medicine system from 1 January 2002 to 1 August 2024. Patients with STEMI diagnosis, troponin peaks ≥ 5 ng/mL, and cell count and proportion data prior to the troponin peak and within 24 h after the troponin peak were included. Primary analyses investigated the associations between the troponin peak and peri-STEMI changes in immune cell subsets. Multivariable-adjusted Cox models were used to investigate associations between these peri-STEMI immune cell changes and mortality at 1 year and 3 years. Among the 694 STEMI patients meeting the inclusion criteria, a higher troponin peak was associated with a modest peri-MI increase in neutrophil proportion. Higher adjusted peri-STEMI increases in neutrophil count and proportion were strongly associated with mortality at one and three years [hazard ratio (HR) = 1.31 (95% confidence interval (CI) 1.15–1.49) and HR = 1.27 (95% CI 1.14–1.45) per 1000 cells/μL absolute neutrophil increase, respectively]. Individuals with higher STEMI-related neutrophil increases had higher mortality at one year and three years, independent of the extent of troponin elevation. Full article
(This article belongs to the Special Issue Cardioimmunology: Inflammation and Immunity in Cardiovascular Disease)
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11 pages, 1069 KiB  
Article
Evaluation of Torquetenovirus (TTV) Particle Integrity Utilizing PMAxx™
by Giuseppe Sberna, Claudia Minosse, Cosmina Mija, Eliana Specchiarello, Pietro Giorgio Spezia, Sara Belladonna, Giulia Berno, Lavinia Fabeni, Giulia Matusali, Silvia Meschi, Daniele Focosi and Fabrizio Maggi
Int. J. Mol. Sci. 2025, 26(13), 6542; https://doi.org/10.3390/ijms26136542 - 7 Jul 2025
Viewed by 191
Abstract
Torquetenovirus (TTV) is a ubiquitous, non-pathogenic DNA virus that has been suggested as a biomarker of immune competence, with the viral load correlating with the level of immunosuppression. However, by detecting non-intact viral particles, standard PCR-based quantification may overestimate the TTV viremia. To [...] Read more.
Torquetenovirus (TTV) is a ubiquitous, non-pathogenic DNA virus that has been suggested as a biomarker of immune competence, with the viral load correlating with the level of immunosuppression. However, by detecting non-intact viral particles, standard PCR-based quantification may overestimate the TTV viremia. To improve the clinical relevance of TTV quantification, in this study, we investigated the use of PMAxx™, a virion viability dye that selectively blocks the amplification of compromised virions. Serum samples from 10 Hepatitis C Virus-positive (HCV+) individuals, 81 liver transplant recipients (LTRs), and 40 people with HIV (PWH) were treated with PMAxx™ and analyzed for TTV DNA loads by digital droplet PCR (ddPCR). Furthermore, anti-SARS-CoV-2 IgG levels and neutralizing antibody (nAbs) titers were measured post-COVID-19 vaccination. Using ddPCR, the PMAxx™ treatment significantly reduced the TTV DNA levels in all the groups (mean reduction: 0.66 Log copies/mL), indicating the abundant presence of non-intact, circulating viral genomes. However, correlations between TTV DNA and SARS-CoV-2 IgG or nAbs were weak or absent in both PMAxx™-treated and untreated samples. These findings suggest that while PMAxx™ enhanced the specificity of TTV quantification, it did not improve the predictive value of TTV viremia at assessing vaccine-induced humoral responses. Full article
(This article belongs to the Section Molecular Microbiology)
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19 pages, 47429 KiB  
Article
Overexpression of (P)RR in SHR and Renin-Induced HepG2 Cells Leads to Spontaneous Hypertension Combined with Metabolic Dysfunction-Associated Fatty Liver Disease
by Chen Gao, Xinyi Guo, Lingzhi Zhang, Xueman Lin and Hua Sun
Int. J. Mol. Sci. 2025, 26(13), 6541; https://doi.org/10.3390/ijms26136541 - 7 Jul 2025
Viewed by 273
Abstract
Hypertension and metabolic dysfunction-associated fatty liver disease (MAFLD) are both common chronic diseases globally. Nearly half of patients with hypertension are complicated by MAFLD. The mechanisms of the bidirectional promotion between the two remain unclear. The (pro) renin receptor ((P)RR) is one of [...] Read more.
Hypertension and metabolic dysfunction-associated fatty liver disease (MAFLD) are both common chronic diseases globally. Nearly half of patients with hypertension are complicated by MAFLD. The mechanisms of the bidirectional promotion between the two remain unclear. The (pro) renin receptor ((P)RR) is one of the classic members of the renin–angiotensin system (RAS) and serves as the receptor for prorenin. Although the role of (P)RR in the induction and progression of hypertension has been extensively studied, its role and underlying mechanisms in MAFLD remain underreported. In this study, we aim to investigate the role of (P)RR in the pathogenesis of hypertension combined with MAFLD. In this study, SHRs were used for the model for hypertension combined with MAFLD. Liver lipid content analysis, liver H&E staining, the detection of (P)RR, ERK and downstream proteins related to fatty acid synthesis and transport, and RNA sequencing and data analysis were performed. In the in vitro experiments, we activated (P)RR using renin and established the lipid deposition model of HepG2 cells induced by renin for the first time. (P)RR was specifically blocked using handle region peptide (HRP), and Nile red fluorescence staining, (P)RR/ERK/PPARγ protein expression analysis, and immunofluorescence were performed to further verify the role of (P)RR in the pathogenesis of hypertension combined with MAFLD. Our results demonstrate that (P)RR plays a role in the development and progression of hypertension combined with MAFLD. The hepatic TG and FFA levels in the SHRs were increased, and the protein expression of the (P)RR/ERK/PPARγ pathway and downstream proteins related to fatty acid synthesis and transport were upregulated. HRP reversed the activation of these proteins and reduced intracellular lipid accumulation. In conclusion, our study first reveals that (P)RR is a potential therapeutic target for hypertension combined with MAFLD. And we found the (P)RR/ERK/PPARγ axis for the first time, which plays an important role in the progression of spontaneous hypertension combined with MAFLD. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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19 pages, 969 KiB  
Article
The Role of Single Nucleotide Polymorphisms at the Arg399Gln Locus of the XRCC1 Gene in Patients with Non-Small Cell Lung Cancer (NSCLC)
by Beata Smolarz, Bartosz Cieślik-Wolski, Józef Kozak, Honorata Łukasiewicz, Dariusz Samulak, Dariusz Trzmielak, Hanna Romanowicz and Marianna Makowska
Int. J. Mol. Sci. 2025, 26(13), 6540; https://doi.org/10.3390/ijms26136540 - 7 Jul 2025
Viewed by 250
Abstract
In recent years, an increasingly important role in the etiopathogenesis of lung cancer has been attributed to genetic predisposition. Current genetic research suggests that the increased risk of this cancer may be due to gene polymorphism within repair genes. In the case of [...] Read more.
In recent years, an increasingly important role in the etiopathogenesis of lung cancer has been attributed to genetic predisposition. Current genetic research suggests that the increased risk of this cancer may be due to gene polymorphism within repair genes. In the case of lung cancer, observations about genes involved in the DNA repair system by cutting bases of nitrogen—base excision repair (BER)—seem to be interesting. Most attention has been devoted to the XRCC1 gene, which coordinates the various stages of BER. The aim of this study was to assess the role of the single nucleotide polymorphism Arg399Gln in the XRCC1 gene as a factor influencing the risk of lung cancer. The study involved 118 patients with non-small cell lung cancer (NSCLC). The control group consisted of 60 people who did not have cancer. The study proved that the polymorphism of the XRCC1 gene is characterized by a statistically significant relationship with the onset of cancer. There were no statistically significant differences between the Arg399Gln polymorphism of the XRCC1 gene and risk factors for non-small cell lung cancer, such as age, sex, smoking and its duration, or place of residence, as well as between the histological type of the tumor or its severity. Detailed analysis of three genotypes—Arg/Arg, Arg/Gln, and Gln/Gln—showed that the incidence of particular genotypes in the group of patients was, respectively, 16.10%, 27.12%, and 58.78%. In the case of the Gln/Gln genotype, the most common associated histopathological type was squamous cell carcinoma, and in the case of adenocarcinoma, the most common genotype was Arg/Arg. It was estimated that each Arg allele reduced the chance of tumor occurrence to 0.48 times the reference value, i.e., the Gln/Gln genotype class for the Arg/Gln genotype and the Arg/Gln genotype for the Arg/Arg genotype. The relationship between the male sex and the occurrence of cancer remained insignificant, in contrast to the presence of nicotinism. Studies suggest that the Arg399Gln polymorphism of the XRCC1 gene has limited prognostic significance in non-small cell lung cancer. Full article
(This article belongs to the Section Molecular Oncology)
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17 pages, 5071 KiB  
Article
Defactinib in Combination with Mitotane Can Be an Effective Treatment in Human Adrenocortical Carcinoma
by Henriett Butz, Lőrinc Pongor, Lilla Krokker, Borbála Szabó, Katalin Dezső, Titanilla Dankó, Anna Sebestyén, Dániel Sztankovics, József Tóvári, Sára Eszter Surguta, István Likó, Katalin Mészáros, Andrea Deák, Fanni Fekete, Ramóna Vida, László Báthory-Fülöp, Erika Tóth, Péter Igaz and Attila Patócs
Int. J. Mol. Sci. 2025, 26(13), 6539; https://doi.org/10.3390/ijms26136539 - 7 Jul 2025
Viewed by 312
Abstract
Adrenocortical carcinoma (ACC) is an aggressive cancer with a poor prognosis. Mitotane, the only FDA-approved treatment for ACC, targets adrenocortical cells and reduces cortisol levels. Although it remains the cornerstone of systemic therapy, its overall impact on long-term outcomes is still a matter [...] Read more.
Adrenocortical carcinoma (ACC) is an aggressive cancer with a poor prognosis. Mitotane, the only FDA-approved treatment for ACC, targets adrenocortical cells and reduces cortisol levels. Although it remains the cornerstone of systemic therapy, its overall impact on long-term outcomes is still a matter of ongoing clinical debate. Drug repurposing is a cost-effective way to identify new therapies, and defactinib, currently in clinical trials as part of combination therapies for various solid tumours, may enhance ACC treatment. We aimed to assess its efficacy in combination with mitotane. We tested the combination of mitotane and defactinib in H295R, SW13, and mitotane-sensitive and -resistant HAC15 cells, using functional assays, transcriptomic profiling, 2D and 3D cultures, bioprinted tissues, and xenografts. We assessed drug interactions with NMR and toxicity in vivo, as mitotane and defactinib have never been previously administered together. Genomic data from 228 human ACC and 158 normal adrenal samples were also analysed. Transcriptomic analysis revealed dysregulation of focal adhesion along with mitotane-related pathways. Focal adhesion kinase (FAK) signalling was enhanced in ACC compared to normal adrenal glands, with PTK2 (encoding FAK) upregulated in 44% of tumour samples due to copy number alterations. High FAK signature scores correlated with worse survival outcomes. FAK inhibition by defactinib, both alone and in combination with mitotane, showed effective anti-tumour activity in vitro. No toxicity or drug—drug interactions were observed in vivo. Combination treatment significantly reduced tumour volume and the number of macrometastases compared to those in the mitotane and control groups, with defactinib-treated tumours showing increased necrosis in xenografts. Defactinib combined with conventionally used mitotane shows promise as a novel combination therapy for ACC and warrants further investigation. Full article
(This article belongs to the Special Issue Signalling Pathways in Metabolic Diseases and Cancers)
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21 pages, 795 KiB  
Review
The Role of Monocytes in the Natural History of Idiopathic Pulmonary Fibrosis: A Systematic Literature Review
by Diego Lema, Esteban Kosak Lopez, Justin Lam, Irakli Tskhakaia, Yurilu Gonzalez Moret and Shahrzad Abdollahi
Int. J. Mol. Sci. 2025, 26(13), 6538; https://doi.org/10.3390/ijms26136538 - 7 Jul 2025
Viewed by 402
Abstract
Emerging evidence suggests a significant association between monocytes and the pathophysiology and prognosis of idiopathic pulmonary fibrosis (IPF). This review aims to systematically evaluate current knowledge regarding blood monocyte counts and their relationship with the etiology, progression, and prognosis of IPF. We conducted [...] Read more.
Emerging evidence suggests a significant association between monocytes and the pathophysiology and prognosis of idiopathic pulmonary fibrosis (IPF). This review aims to systematically evaluate current knowledge regarding blood monocyte counts and their relationship with the etiology, progression, and prognosis of IPF. We conducted a systematic search in the PubMed database for articles published through 17 February 2025, using the MeSH terms “lung diseases, interstitial” and “monocytes,” which yielded 314 results. After filtering for full-text articles in English (n = 242), we included only studies focusing on blood monocyte counts with clinical implications in IPF. Articles relating to other cell types or non-IPF lung diseases were excluded. Our systematic search identified 12 relevant articles. Monocytes play an essential role in regulating inflammatory responses and resolution across multiple diseases, with established but incompletely understood contributions to lung fibrosis development in IPF. Correlations have been demonstrated between elevated blood monocyte counts and the following: (1) the presence and progression of interstitial lung abnormalities, (2) the progression from an indeterminate usual interstitial pneumonia (UIP) pattern on CT scans to definitive IPF, and (3) worse lung function parameters, an increased risk of acute exacerbations, and reduced overall survival in IPF patients. Monocytes serve as critical orchestrators throughout IPF’s natural history—from early interstitial changes to disease progression and acute exacerbations. Targeting monocyte recruitment pathways and reprogramming their differentiation represents a promising therapeutic approach, while circulating monocyte counts offer potential as accessible biomarkers for disease progression and treatment response. Future research should characterize stage-specific monocyte phenotypes to enable precision-targeted interventions. Full article
(This article belongs to the Special Issue New Advances in Autoimmune Diseases)
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17 pages, 847 KiB  
Review
Mechanistic Links Between Gut Dysbiosis, Insulin Resistance, and Autism Spectrum Disorder
by Patricia Guevara-Ramírez, Rafael Tamayo-Trujillo, Viviana A. Ruiz-Pozo, Santiago Cadena-Ullauri, Elius Paz-Cruz and Ana Karina Zambrano
Int. J. Mol. Sci. 2025, 26(13), 6537; https://doi.org/10.3390/ijms26136537 - 7 Jul 2025
Viewed by 495
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental condition frequently associated with gastrointestinal symptoms, gut dysbiosis, and metabolic dysfunctions such as insulin resistance (IR). Recent evidence suggests that the gut microbiota may influence both metabolic and neurological processes through the gut–brain–metabolic axis. This review [...] Read more.
Autism spectrum disorder (ASD) is a neurodevelopmental condition frequently associated with gastrointestinal symptoms, gut dysbiosis, and metabolic dysfunctions such as insulin resistance (IR). Recent evidence suggests that the gut microbiota may influence both metabolic and neurological processes through the gut–brain–metabolic axis. This review explores the molecular mechanisms linking dysbiosis, IR, and ASD, focusing on pathways such as TLR/NF-κB activation, PI3K/Akt/mTOR disruption, and the action of microbial metabolites, like short-chain fatty acids (SCFAs), lipopolysaccharide (LPS), and γ-aminobutyric acid (GABA). We discuss how dysbiosis may contribute to increased intestinal permeability, systemic inflammation, and neuroimmune activation, ultimately affecting brain development and behavior. Common microbial alterations in ASD and IR—including increased Clostridium, Desulfovibrio, and Alistipes, and reduced Bifidobacterium and butyrate-producing genera—suggest a shared pathophysiology. We also highlight potential therapeutic strategies, such as microbiota modulation, insulin-like growth factor 1 (IGF-1) treatment, and dietary interventions. Understanding these interconnected mechanisms may support the development of microbiota-targeted approaches for individuals with ASD metabolic comorbidities. Full article
(This article belongs to the Special Issue The Molecular and Cellular Aspects of Insulin Resistance)
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17 pages, 3220 KiB  
Article
An mRNA Vaccine Targeting the C-Terminal Region of P1 Protein Induces an Immune Response and Protects Against Mycoplasma pneumoniae
by Fenglian Zhang, Chengwei Li, Yanan Wu, Hongyun Chuan, Shaohui Song, Yun Xie, Qi Zhu, Qianqian Chen, Fei Tong, Runfang Zhang, Guangbo Yuan, Xiaoyan Wu, Jian Zhou and Guoyang Liao
Int. J. Mol. Sci. 2025, 26(13), 6536; https://doi.org/10.3390/ijms26136536 - 7 Jul 2025
Viewed by 244
Abstract
Mycoplasma pneumoniae, a cell wall-deficient pathogen, primarily affects children and adolescents, causing Mycoplasma pneumoniae pneumonia (MPP). Following the relaxation of non-pharmaceutical interventions (NPIs) post COVID-19, there has been a global increase in MPP cases and macrolide-resistant strains. Vaccination against M. pneumoniae is [...] Read more.
Mycoplasma pneumoniae, a cell wall-deficient pathogen, primarily affects children and adolescents, causing Mycoplasma pneumoniae pneumonia (MPP). Following the relaxation of non-pharmaceutical interventions (NPIs) post COVID-19, there has been a global increase in MPP cases and macrolide-resistant strains. Vaccination against M. pneumoniae is being explored as a promising approach to reduce infections, limit antibiotic misuse, and prevent the emergence of drug-resistant variants. We developed an mRNA vaccine, mRNA-SP+P1, incorporating a eukaryotic signal peptide (tissue-type plasminogen activator signal peptide) fused to the C-terminal region of the P1 protein. Targeting amino acids 1288 to 1518 of the P1 protein, the vaccine was administered intramuscularly to BALB/c mice in a three-dose regimen. To evaluate immunogenicity, we quantified anti-P1 IgG antibody titers using enzyme-linked immunosorbent assays (ELISAs) and assessed cellular immune responses by analyzing effector memory T cell populations using flow cytometry. We also tested the functional activity of vaccine-induced sera for their ability to inhibit adhesion of the ATCC M129 strain to KMB17 cells. The vaccine’s protective efficacy was assessed against the ATCC M129 strain and its cross-protection against the ST3-resistant strain. Transcriptomic analysis was conducted to investigate gene expression changes in peripheral blood, aiming to uncover mechanisms of immune modulation. The mRNA-SP+P1 vaccine induces P1 protein-specific IgG antibodies and an effector memory T-cell response in BALB/c mice. Adhesion inhibition assays demonstrated that serum from vaccinated mice attenuatesthe adhesion ability of ATCC M129 to KMB17 cells. Furthermore, three doses of the vaccine confer significant and long-lasting, though partial, protection against the ATCC M129 strain and partial cross-protection against the ST3 drug-resistant strain. Transcriptome analysis revealed significant gene expression changes in peripheral blood, confirming the vaccine’s capacity to elicit an immune response from the molecular level. Our results indicate that the mRNA-SP+P1 vaccine appears to be an effective vaccine candidate against the prevalence of Mycoplasma pneumoniae. Full article
(This article belongs to the Section Molecular Immunology)
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19 pages, 2774 KiB  
Article
Genetic Variants in the Extracellular Matrix Gene TNXB Predicted to Alter Fibronectin III Domains in Arterial Aneurysmal and Dissection Diseases
by Charlene Norgan Radler, Tianci Wang, Jaden LeGate, Lily Crone, Parminder Deo, Jacob Wortley, Peyton Moore, Griffin Bryant, Katherine Smitherman and Mohanakrishnan Sathyamoorthy
Int. J. Mol. Sci. 2025, 26(13), 6535; https://doi.org/10.3390/ijms26136535 - 7 Jul 2025
Viewed by 359
Abstract
Arterial aneurysms are vascular conditions associated with life-threatening consequences in patients, such as dissection and rupture. Understanding their genetic basis is an evolving field, driven by the robust reporting of genetic variants associated with aneurysms in patients. In this study, we present clinical [...] Read more.
Arterial aneurysms are vascular conditions associated with life-threatening consequences in patients, such as dissection and rupture. Understanding their genetic basis is an evolving field, driven by the robust reporting of genetic variants associated with aneurysms in patients. In this study, we present clinical and genetic data from nine unrelated subjects with arterial aneurysms who were identified to harbor rare variants in the TNXB gene, mainly affecting fibronectin type III (FNIII) domains. The cohort included three female and six male subjects with a mean age of 53.5 years (SD = 14.4). The most frequently affected vascular territory was the thoracic ascending aorta (n = 7). A range of pathogenic impacts was predicted via multiple in silico tools that analyze evolutionary conservation and biochemical properties. Computational protein structure modeling with AlphaFold 3 predicted domain-specific alterations across multiple FNIII regions for four unique missense variants and one in-frame deletion, and premature protein truncation resulting from two frameshift variants. To our knowledge, this study is one of the first and largest to associate TNXB variants with arterial aneurysmal disease. Our findings demonstrate the potential of computational genomics and structural modeling to advance the understanding of extracellular matrix gene alterations in aneurysm pathogenesis. Full article
(This article belongs to the Special Issue Genes and Human Diseases 2.0)
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38 pages, 1314 KiB  
Review
Current Approaches to Aflatoxin B1 Control in Food and Feed Safety: Detection, Inhibition, and Mitigation
by Katarzyna Kępka-Borkowska, Katarzyna Chałaśkiewicz, Magdalena Ogłuszka, Mateusz Borkowski, Adam Lepczyński, Chandra Shekhar Pareek, Rafał Radosław Starzyński, Elżbieta Lichwiarska, Sharmin Sultana, Garima Kalra, Nihal Purohit, Barbara Gralak, Ewa Poławska and Mariusz Pierzchała
Int. J. Mol. Sci. 2025, 26(13), 6534; https://doi.org/10.3390/ijms26136534 - 7 Jul 2025
Viewed by 300
Abstract
Aflatoxins, toxic secondary metabolites produced primarily by Aspergillus flavus and Aspergillus parasiticus, pose a significant global health concern due to their frequent presence in crops, food, and feed—especially under climate change conditions. This review addresses the growing threat of aflatoxins by analyzing [...] Read more.
Aflatoxins, toxic secondary metabolites produced primarily by Aspergillus flavus and Aspergillus parasiticus, pose a significant global health concern due to their frequent presence in crops, food, and feed—especially under climate change conditions. This review addresses the growing threat of aflatoxins by analyzing recent advances in detection and mitigation. A comprehensive literature review was conducted, focusing on bioremediation, physical and chemical detoxification, and fungal growth inhibition strategies. The occurrence of aflatoxins in water systems was also examined, along with current detection techniques, removal processes, and regulatory frameworks. Emerging technologies such as molecular diagnostics, immunoassays, biosensors, and chromatographic methods are discussed for their potential to improve monitoring and control. Key findings highlight the increasing efficacy of integrative approaches combining biological and technological solutions and the potential of AI-based tools and portable devices for on-site detection. Intelligent packaging and transgenic crops are also explored for their role in minimizing contamination at the source. Overall, this review emphasizes the importance of continued interdisciplinary research and the development of sustainable, adaptive strategies to mitigate aflatoxin risks, thereby supporting food safety and public health in the face of environmental challenges. Full article
(This article belongs to the Section Molecular Microbiology)
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19 pages, 8019 KiB  
Article
Identification of a PAK6-Mediated MDM2/p21 Axis That Modulates Survival and Cell Cycle Control of Drug-Resistant Stem/Progenitor Cells in Chronic Myeloid Leukemia
by Andrew Wu, Min Chen, Athena Phoa, Zesong Yang, Donna L. Forrest and Xiaoyan Jiang
Int. J. Mol. Sci. 2025, 26(13), 6533; https://doi.org/10.3390/ijms26136533 - 7 Jul 2025
Viewed by 283
Abstract
Chronic myeloid leukemia (CML) is a leading example of a malignancy where a molecular targeted therapy revolutionized treatment but has rarely led to cures. Overcoming tyrosine kinase inhibitor (TKI) drug resistance remains a challenge in the treatment of CML. We have recently identified [...] Read more.
Chronic myeloid leukemia (CML) is a leading example of a malignancy where a molecular targeted therapy revolutionized treatment but has rarely led to cures. Overcoming tyrosine kinase inhibitor (TKI) drug resistance remains a challenge in the treatment of CML. We have recently identified miR-185 as a predictive biomarker where reduced expression in CD34+ treatment-naïve CML cells was associated with TKI resistance. We have also identified PAK6 as a target gene of miR-185 that was upregulated in CD34+ TKI-nonresponder cells. However, its role in regulating TKI resistance remains largely unknown. In this study, we specifically targeted PAK6 in imatinib (IM)-resistant cells and CD34+ stem/progenitor cells from IM-nonresponders using a lentiviral-mediated PAK6 knockdown strategy. Interestingly, the genetic and pharmacological suppression of PAK6 significantly reduced proliferation and increased apoptosis in TKI-resistant cells. Cell survivability was further diminished when IM was combined with PAK6 knockdown. Importantly, PAK6 inhibition in TKI-resistant cells induced cell cycle arrest in the G2-M phase and cellular senescence, accompanied by increased levels of DNA damage-associated senescence markers. Mechanically, we identified a PAK6-mediated MDM2-p21 axis that regulates cell cycle arrest and senescence. Thus, PAK6 plays a critical role in determining alternative cell fates in leukemic cells, and targeting PAK6 may offer a therapeutic strategy to selectively eradicate TKI-resistant cells. Full article
(This article belongs to the Special Issue New Developments in Chronic Myeloid Leukemia)
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13 pages, 3320 KiB  
Article
Regulation of Human Lung Adenocarcinoma Cell Proliferation by LncRNA AFAP-AS1 Through the miR-508/ZWINT Axis
by Sultan F. Kadasah and Abdulaziz M. S. Alqahtani
Int. J. Mol. Sci. 2025, 26(13), 6532; https://doi.org/10.3390/ijms26136532 - 7 Jul 2025
Viewed by 188
Abstract
Lung adenocarcinoma is a prevalent, aggressive cancer with a poor prognosis due to early metastasis and resistance to treatment. LncRNA AFAP1-AS1 has been shown to be associated with the development of multiple carcinomas. This study investigates the functional role of AFAP1-AS1 in lung [...] Read more.
Lung adenocarcinoma is a prevalent, aggressive cancer with a poor prognosis due to early metastasis and resistance to treatment. LncRNA AFAP1-AS1 has been shown to be associated with the development of multiple carcinomas. This study investigates the functional role of AFAP1-AS1 in lung adenocarcinoma cell proliferation via miR-508-3p and ZWINT. Human lung adenocarcinoma A549 cells were transfected with siRNA constructs against AFAP1-AS1 (si-AFAP1-AS1) to silence its expression. Cell proliferation was evaluated via CCK-8 and colony-forming assays. Apoptosis was assessed using AO/EB staining, and invasion was determined via Transwell assay. The interaction between AFAP1-AS1, miR-508-3p, and ZWINT was confirmed via dual luciferase reporter assay and qRT-PCR analysis. Data were analysed using appropriate statistical tests. AFAP1-AS1 was significantly upregulated in lung adenocarcinoma cells compared to normal BEAS-2B cells. Silencing of AFAP1-AS1 resulted in a marked reduction in A549 cell proliferation and colony development, as observed in CCK-8 and colony formation assays. The AO/EB assay showed a significant increase in apoptosis (30 ± 4.4%) in si-AFAP1-AS1 transfected cells compared to control si-NC (3 ± 1.2%). In addition, knockdown of AFAP1-AS1 led to an upsurge of pro-apoptotic Bax and decline of anti-apoptotic Bcl-2 expression. The dual luciferase assay established the interaction between AFAP1-AS1 and miR-508-3p. Furthermore, ZWINT, identified as a target of miR-508-3p, was significantly upregulated in lung adenocarcinoma tissues. Overexpression of ZWINT rescued the inhibitory effects of AFAP1-AS1 silencing on cell proliferation, colony formation, and apoptosis, while also reversing the reduction in cell invasion. AFAP1-AS1 accelerates the development of lung adenocarcinoma by cell proliferation, apoptosis, and invasion via the miR-508-3p/ZWINT axis. Thus, targeting AFAP1-AS1 or its downstream regulatory axis could offer novel therapeutic approaches in lung adenocarcinoma treatment. Full article
(This article belongs to the Special Issue Novel Molecular Pathways in Oncology, 3rd Edition)
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47 pages, 2075 KiB  
Review
Epigenetic Dysregulation in Cancer: Implications for Gene Expression and DNA Repair-Associated Pathways
by Nina Rembiałkowska, Katarzyna Rekiel, Piotr Urbanowicz, Mateusz Mamala, Karolina Marczuk, Maria Wojtaszek, Marta Żywica, Eivina Radzevičiūtė-Valčiukė, Vitalij Novickij and Julita Kulbacka
Int. J. Mol. Sci. 2025, 26(13), 6531; https://doi.org/10.3390/ijms26136531 - 7 Jul 2025
Viewed by 615
Abstract
Epigenetic modifications are heritable, reversible alterations that causally reshape chromatin architecture and thereby influence DNA repair without changing nucleotide sequence. DNA methylation, histone modifications and non-coding RNAs profoundly influence DNA repair mechanisms and genomic stability. Aberrant epigenetic patterns in cancer compromise DNA damage [...] Read more.
Epigenetic modifications are heritable, reversible alterations that causally reshape chromatin architecture and thereby influence DNA repair without changing nucleotide sequence. DNA methylation, histone modifications and non-coding RNAs profoundly influence DNA repair mechanisms and genomic stability. Aberrant epigenetic patterns in cancer compromise DNA damage recognition and repair, therefore impairing homologous recombination (HR), non-homologous end joining (NHEJ), and base excision repair (BER) by suppressing key repair genes and lowering access to repair sites. Then it is dissected how loss-of-function mutations in Switch/Sucrose non-fermentable, imitation switch and CHD (Chromodomain helicase DNA-binding) chromatin-remodeling complexes impair nucleosome repositioning, preventing effective damage sensing and assembly of repair machinery. Non-coding RNAs contribute to epigenetic silencing at DNA break sites, exacerbating repair deficiencies. This review evaluates recent advances concerning epigenetic dysfunction and DNA repair impairment. It is also highlighted that nanoparticle-mediated delivery strategies are designed to overcome pharmacologic resistance. It is presented how epigenetic dysregulation of DNA repair can guide more effective and drug-resistant cancer therapies. Full article
(This article belongs to the Special Issue Molecular Mechanisms and New Markers of Cancer)
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23 pages, 11218 KiB  
Article
Serotonin N-acetyltransferase SlSNAT2 Positively Regulates Tomato Resistance Against Ralstonia solanacearum
by Yixi Wang, Gengshou Xia, Xinyi Xie, Hao Wang, Lingyun Zheng, Zhijie He, Junxian Ye, Kangtong Xu, Qi Shi, Hui Yang and Yan Zhang
Int. J. Mol. Sci. 2025, 26(13), 6530; https://doi.org/10.3390/ijms26136530 - 7 Jul 2025
Viewed by 264
Abstract
Bacterial wilt (BW) is a globally serious soil-borne disease in a wide range of plants, caused by diverse strains of Ralstonia solanacearum. However, there are few research reports on melatonin regulating plant resistance against R. solanacearum. N-acetyltransferase SlSNAT2 is a [...] Read more.
Bacterial wilt (BW) is a globally serious soil-borne disease in a wide range of plants, caused by diverse strains of Ralstonia solanacearum. However, there are few research reports on melatonin regulating plant resistance against R. solanacearum. N-acetyltransferase SlSNAT2 is a rate-limiting enzyme in plant melatonin synthesis. This study elucidates the mechanisms of SlSNAT2 modulating tomato resistance to BW. SlSNAT2 was expressed in tomato roots, stems, and leaves and induced upon R. solanacearum inoculation. Knocking out SlSNAT2 significantly decreased the melatonin content in CRISPR/Cas9 mutant slsnat2. With R. solanacearum inoculation, the morbidity and disease index value of slsnat2 were significantly higher than those of the tomato wild-type plant Micro-Tom (MT) according to the wilt rate and severity. The chlorophyll levels, photosynthetic rates, and callus deposition quantity in slsnat2 were notably lower while the reactive oxygen species (ROS) level was considerably higher than those in the MT after inoculation. Additionally, the SlSNAT2 deficiency depressed the expression of the mitogen-activated protein kinase (MAPK) pathway genes (SlMPK1, SlMKK2), salicylic acid pathway genes (SlGluA, SlPR-1a), jasmonic acid pathway gene SlPin2, and pathogenesis-related (PR) protein genes (SlPR-STH2a, SlPR-STH2b, SlPR-STH2c, SlPR-STH2d). These results revealed SlSNAT2 enhanced the tomato resistance against R. solanacearum by orchestrating ROS homeostasis, callose deposition, MAPK signaling, hormone pathways, and PR gene transcripts. Full article
(This article belongs to the Section Molecular Plant Sciences)
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17 pages, 4128 KiB  
Article
Molecular Hybrids of Thiazolidinone: Bridging Redox Modulation and Cancer Therapy
by Nourah A. Al Zahrani, Manal A. Alshabibi, Abrar A. Bakr, Fahad A. Almughem, Abdullah A. Alshehri, Huda A. Al-Ghamdi, Essam A. Tawfik and Laila A. Damiati
Int. J. Mol. Sci. 2025, 26(13), 6529; https://doi.org/10.3390/ijms26136529 - 7 Jul 2025
Viewed by 323
Abstract
Heterocyclic compounds have shown that they hold significant therapeutic activities, highlighting the importance of discovering and developing novel candidates against cancers, infections, and oxidative stress-associated disorders. In this study, we demonstrated the biological activity of our previously synthesized thiazolidinone derivatives (TZDs-1, 6, and [...] Read more.
Heterocyclic compounds have shown that they hold significant therapeutic activities, highlighting the importance of discovering and developing novel candidates against cancers, infections, and oxidative stress-associated disorders. In this study, we demonstrated the biological activity of our previously synthesized thiazolidinone derivatives (TZDs-1, 6, and 7). Furthermore, we synthesized and structurally characterized a new derivative (TZD-5) using IR, 1H NMR, and 13C NMR spectroscopy, confirming the presence of its key functional groups, namely, carbonyl and imine. Their antioxidant activity was assessed through the DPPH assay, with TZD-5 showing the most potent effect (IC50 = 24.4 µg/mL), comparable to ascorbic acid, an effect attributed to the methoxy group introduced via N-alkylation. Cytotoxicity was evaluated using the MTS assay on normal (HFF-1) and cancerous (HepG2 and A549) cell lines at two time points: 24- and 48 h exposure. Our findings highlight clear differences in cytotoxicity and selectivity among the tested thiazolidinone derivatives. TZD-1 and TZD-6 demonstrated significant, dose-dependent cytotoxic effects on both cancerous (HepG2 and A549) and normal (HFF-1) cell lines, thus limiting their therapeutic potential due to insufficient selectivity. TZD-5 exhibited moderate selectivity with higher susceptibility for HepG2 cells compared to normal cells. Notably, TZD-7 showed the most favorable cytotoxic profile, demonstrating strong selective cytotoxicity toward cancer cell lines with minimal adverse effects on normal fibroblasts. Overall, the results highlight TZD-5 and TZD-7 as promising candidates for antioxidant and selective anticancer therapies. Full article
(This article belongs to the Section Biochemistry)
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13 pages, 786 KiB  
Article
Prevalence, Risk Factors and Potential Protective Strategies for Hypomagnesemia in Kidney Transplant Recipients
by Cristina Riaza Ortiz, Carlos Fernández Fernández, Marina Pujol Pujol, María Muñiz Rincón, Arianne Sofía Aiffil Meneses, Isabel María Pérez Flores, Natividad Calvo Romero, María Ángeles Moreno de la Higuera, Beatriz Rodríguez Cubillo, Raquel Ramos Corral and Ana Isabel Sánchez Fructuoso
Int. J. Mol. Sci. 2025, 26(13), 6528; https://doi.org/10.3390/ijms26136528 - 7 Jul 2025
Viewed by 233
Abstract
Hypomagnesemia is the most common electrolyte disorder in kidney transplant recipients (KTR), yet its causes remain unclear. Few studies have explored its underlying factors. This study aimed to assess its prevalence and identify risk factors in KTR. We conducted a retrospective cross-sectional study [...] Read more.
Hypomagnesemia is the most common electrolyte disorder in kidney transplant recipients (KTR), yet its causes remain unclear. Few studies have explored its underlying factors. This study aimed to assess its prevalence and identify risk factors in KTR. We conducted a retrospective cross-sectional study in 489 outpatient KTR. Demographic, clinical, and laboratory data were collected. Univariate and multivariate logistic regression analyses were used to identify factors associated with hypomagnesemia (≤1.7 mg/dL). Hypomagnesemia was present in 50.7% of patients. Multivariate analysis identified tacrolimus [OR 2.91 (1.62–5.22)], thiazides [OR 2.23 (1.21–4.08)], cinacalcet [OR 2.31 (1.29–4.13)], serum phosphate < 3.7 mg/dL [1.99 (1.29–3.05)], serum calcium ≤ 10 mg/dL [1.99 (1.29–3.05)] and diabetes [1.94 (1.22–3.08)] as risk factors. Protective factors included SGLT2 inhibitors (SGLT2i) [OR 0.17 (0.10–0.27)] and mTOR inhibitors (mTORi) [OR 0.62 (0.38–0.98)]. Among hypomagnesemic patients, those receiving Mg2+ supplements had lower Mg2+ levels [1.54 (0.15) vs. 1.59 (0.13) mg/dL, p = 0.005] and higher fractional Mg2+ excretion [8.28 (4.48)% vs. 7.36 (4.19)%, p = 0.05]. Hypomagnesemia is highly prevalent in KTR. Tacrolimus, thiazides, and cinacalcet are key risk factors and, in some patients, risks and benefits of continuing these medications should be carefully weighed. In refractory cases, SGLT2i or mTORi may offer benefit. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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18 pages, 6726 KiB  
Article
Genome-Wide Identification and Analysis of the AHL Gene Family in Pepper (Capsicum annuum L.)
by Xiao-Yan Sui, Yan-Long Li, Xi Wang, Yi Zhong, Qing-Zhi Cui, Yin Luo, Bing-Qian Tang, Feng Liu and Xue-Xiao Zou
Int. J. Mol. Sci. 2025, 26(13), 6527; https://doi.org/10.3390/ijms26136527 - 7 Jul 2025
Viewed by 282
Abstract
AT-hook motif nuclear-localized (AHL) genes play critical roles in chromatin remodeling and gene transcription regulation, profoundly influencing plant growth, development, and stress responses. While AHL genes have been extensively characterized in multiple plant species, their biological functions in pepper (Capsicum [...] Read more.
AT-hook motif nuclear-localized (AHL) genes play critical roles in chromatin remodeling and gene transcription regulation, profoundly influencing plant growth, development, and stress responses. While AHL genes have been extensively characterized in multiple plant species, their biological functions in pepper (Capsicum annuum L.) remain largely uncharacterized. In this study, we identified 45 CaAHL genes in the pepper genome through bioinformatics approaches. Comprehensive analyses were conducted to examine their chromosomal distribution, phylogenetic relationships, and the structural and functional features of their encoded proteins. Phylogenetic clustering classified the CaAHL proteins into six distinct subgroups. Transcriptome profiling revealed widespread expression of CaAHL genes across diverse tissues—including roots, stems, leaves, flowers, seeds, pericarp, placenta, and fruits—at various developmental stages. Quantitative real-time PCR further demonstrated that CaAHL1, CaAHL33, and CaAHL23 exhibited consistently high expression throughout flower bud development, whereas CaAHL36 showed preferential upregulation at early bud development stages. Expression profiling under hormone treatments and abiotic stresses indicated that CaAHL36 and CaAHL23 are auxin-inducible but are repressed by ABA, cold, heat, salt, and drought stress. Subcellular localization assays in Nicotiana benthamiana leaf epidermal cells showed that both CaAHL36 and CaAHL23 were predominantly localized in the nucleus, with faint expression also detected in the cytoplasm. Collectively, this study provides foundational insights into the CaAHL gene family, laying the groundwork for future functional investigations of these genes in pepper. Full article
(This article belongs to the Special Issue Vegetable Genetics and Genomics, 3rd Edition)
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18 pages, 3042 KiB  
Article
Mapping Morphine’s Antinociceptive Impact on the Ventral Tegmental Area During Nociceptive Stimulation: A Novel Microimaging Approach in a Neuropathic Pain Model
by Austin Ganaway, Airi Kamata, Dunyan Yao, Kazuto Sakoori, Ryoma Okada, Ting Chen, Yasumi Ohta, Jun Ohta, Masahiro Ohsawa, Metin Akay and Yasemin M. Akay
Int. J. Mol. Sci. 2025, 26(13), 6526; https://doi.org/10.3390/ijms26136526 - 7 Jul 2025
Viewed by 235
Abstract
The neurobiology of chronic pain is complex and multifaceted, intertwining with the mesocorticolimbic system to regulate the behavioral and perceptional response to adverse stimuli. Specifically, the ventral tegmental area (VTA), the dopaminergic hub of the reward pathways located deep within the midbrain, is [...] Read more.
The neurobiology of chronic pain is complex and multifaceted, intertwining with the mesocorticolimbic system to regulate the behavioral and perceptional response to adverse stimuli. Specifically, the ventral tegmental area (VTA), the dopaminergic hub of the reward pathways located deep within the midbrain, is crucial for regulating the release of dopamine (DA) throughout the central nervous system (CNS). To better understand the nuances among chronic pain, VTA response, and therapeutics, implementing progressive approaches for mapping and visualizing the deep brain in real time during nociceptive stimulation is crucial. In this study, we utilize a fluorescence imaging platform with a genetically encoded calcium indicator (GCaMP6s) to directly visualize activity in the VTA during acute nociceptive stimulation in both healthy adult mice and adult mice with partial nerve ligation (PNL)-induced neuropathic pain. We also investigate the visualization of the analgesic properties of morphine. Deep brain imaging using our self-fabricated µ-complementary metal–oxide–semiconductor (CMOS) imaging device allows the tracking of the VTA’s response to adverse stimuli. Our findings show that nociceptive stimulation is associated with a reduction in VTA fluorescence activity, supporting the potential of this platform for visualizing pain-related responses in the central nervous system. Additionally, treatment with morphine significantly reduces the neuronal response caused by mechanical stimuli and is observable using the CMOS imaging platform, demonstrating a novel way to potentially assess and treat neuropathic pain. Full article
(This article belongs to the Special Issue Development of Dopaminergic Neurons, 4th Edition)
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23 pages, 7664 KiB  
Article
Impact of Aerobic Training on Transcriptomic Changes in Skeletal Muscle of Rats with Cardiac Cachexia
by Daniela Sayuri Inoue, Quinten W. Pigg, Dillon R. Harris, Dongmei Zhang, Devon J. Boland and Mariana Janini Gomes
Int. J. Mol. Sci. 2025, 26(13), 6525; https://doi.org/10.3390/ijms26136525 - 7 Jul 2025
Viewed by 278
Abstract
Cardiac cachexia (CC) is an advanced stage of heart failure (HF) characterized by structural and functional abnormalities in skeletal muscle, leading to muscle loss. Aerobic training provides benefits; however, the underlying molecular mechanisms remain poorly understood. This study aimed to investigate the therapeutic [...] Read more.
Cardiac cachexia (CC) is an advanced stage of heart failure (HF) characterized by structural and functional abnormalities in skeletal muscle, leading to muscle loss. Aerobic training provides benefits; however, the underlying molecular mechanisms remain poorly understood. This study aimed to investigate the therapeutic effects of aerobic training on transcriptomic alterations associated with disease progression in cachectic skeletal muscle. HF was induced in male Wistar rats by a single monocrotaline injection (60 mg/Kg). Aerobic training consisted of 30 min treadmill running at ~55% of maximal capacity, 5×/week for 4 weeks. Assessments included body mass, right ventricle mass, skeletal muscle fiber size and exercise tolerance. RNA-seq analysis was performed on the medial gastrocnemius muscle. Sedentary cachectic rats exhibited 114 differentially expressed genes (DEGs) while exercised cachectic rats had only 18 DEGs. Enrichment pathways analyses and weighted gene co-expression network analysis (WGCNA) identified potential key genes involved in disrupted lipid metabolism in sedentary cachectic rats, which were not observed in the exercised cachectic rats. Validation of DEGs related to lipid metabolism confirmed that Dgat2 gene expression was modulated by aerobic training in CC rats. These findings suggest that aerobic training mitigates transcriptional alterations related to lipid metabolism in rats with CC, highlighting its therapeutic potential. Full article
(This article belongs to the Special Issue Molecular Advances in Heart Disease: Genomics, Proteomics, and Bioinformatics of Heart Research)
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24 pages, 4568 KiB  
Article
Greener Synthesis of Eco-Friendly Biodegradable Mesoporous Bioactive Glasses with and Without Thermal Treatment and Its Effects on Drug Delivery and In Vitro Bioactivity
by Dana Almasri and Yaser Dahman
Int. J. Mol. Sci. 2025, 26(13), 6524; https://doi.org/10.3390/ijms26136524 - 7 Jul 2025
Viewed by 241
Abstract
This study investigates the use of a salt template to synthesize mesoporous bioactive glass (MBG). Different salts were used as hard templates to create pores in the glass structure to investigate the possibility of using acid-soluble salt templates and to understand the properties [...] Read more.
This study investigates the use of a salt template to synthesize mesoporous bioactive glass (MBG). Different salts were used as hard templates to create pores in the glass structure to investigate the possibility of using acid-soluble salt templates and to understand the properties of glass synthesized without thermal treatment. The MBGs were synthesized in a TRIS buffer solution at a pH of 9.5 to allow hydrolysis of the metal oxide precursors. The glass was then washed with mild acid to remove the template. After the samples were washed, some were subjected to thermal treatment, while others were not to investigate the impact of thermal treatment on the structure of the MBG. The successful synthesis of MBG was confirmed by X-ray diffraction, Fourier-transfer infrared spectroscopy, scanning emission scanning microscope, and nitrogen adsorption–desorption analysis. This synthesized MBG had a large surface area, pore volume, pore size, and high drug loading efficiency. MBG synthesized without thermal treatment had slower degradation over the test period, but higher loading efficiency and slower drug release, making it appropriate for applications requiring long-term drug delivery while maintaining its bioactivity. Full article
(This article belongs to the Special Issue Polymeric Materials for Biomedical Applications, Drug and Gene Delivery)
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24 pages, 855 KiB  
Review
Antibody–Drug Conjugates Powered by Deruxtecan: Innovations and Challenges in Oncology
by Jung Yoon Jang, Donghwan Kim, Na Kyeong Lee, Eunok Im and Nam Deuk Kim
Int. J. Mol. Sci. 2025, 26(13), 6523; https://doi.org/10.3390/ijms26136523 - 7 Jul 2025
Viewed by 455
Abstract
Antibody–drug conjugates (ADCs) have revolutionized precision oncology by enabling targeted drug delivery with improved therapeutic indices. Among these, deruxtecan (DXd)-based ADCs have demonstrated remarkable efficacy across a range of cancers, particularly in tumors expressing human epidermal growth factor receptor 2 (HER2), human epidermal [...] Read more.
Antibody–drug conjugates (ADCs) have revolutionized precision oncology by enabling targeted drug delivery with improved therapeutic indices. Among these, deruxtecan (DXd)-based ADCs have demonstrated remarkable efficacy across a range of cancers, particularly in tumors expressing human epidermal growth factor receptor 2 (HER2), human epidermal growth factor receptor 3 (HER3), and trophoblast cell surface antigen 2 (TROP2), including breast, lung, gastric, and other solid tumors. DXd, a potent topoisomerase I inhibitor, enhances the cytotoxic potential of ADCs through a cleavable and stable linker and a high drug-to-antibody ratio that ensures optimal drug release. The clinical success of trastuzumab DXd (Enhertu®) and datopotamab DXd (Datroway®), along with the ongoing development of patritumab DXd, has expanded the therapeutic potential of ADCs. However, challenges remain, including toxicity, resistance, and manufacturing scalability. This review discusses the mechanisms of action, clinical progress, and challenges of DXd-based ADCs, highlighting their transformative role in modern oncology and exploring future directions to optimize their efficacy and accessibility. Full article
(This article belongs to the Special Issue New Wave of Cancer Therapeutics: Challenges and Opportunities)
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16 pages, 839 KiB  
Review
Occupational Radiation Exposure and Thyroid Nodules in Healthcare Workers: A Review
by Aikaterini Andreadi, Stella Andreadi, Marco Cerilli, Federica Todaro, Massimiliano Lazzaroni, Pietro Lodeserto, Marco Meloni, Cristiana Ferrari, Alfonso Bellia, Luca Coppeta, Andrea Magrini and Davide Lauro
Int. J. Mol. Sci. 2025, 26(13), 6522; https://doi.org/10.3390/ijms26136522 - 7 Jul 2025
Viewed by 170
Abstract
Thyroid nodules are a common clinical finding, with their prevalence influenced by multiple environmental and occupational factors, including exposure to ionizing radiation. Healthcare workers, particularly those operating in radiology, nuclear medicine, interventional cardiology, and radiation oncology, are potentially at increased risk due to [...] Read more.
Thyroid nodules are a common clinical finding, with their prevalence influenced by multiple environmental and occupational factors, including exposure to ionizing radiation. Healthcare workers, particularly those operating in radiology, nuclear medicine, interventional cardiology, and radiation oncology, are potentially at increased risk due to chronic low-dose radiation exposure. This review aims to evaluate the current evidence regarding the association between occupational radiation exposure and the development of thyroid nodules among healthcare professionals. The findings suggest a higher prevalence of thyroid nodules in radiation-exposed workers compared to the general population, although data heterogeneity and methodological limitations exist. Factors such as the duration of exposure, radiation protection practices, and frequency of monitoring play critical roles in modulating the individual risk. While some studies report no significant difference in malignancy rates, the increased detection of nodules underlines the need for regular thyroid surveillance in at-risk populations. Further longitudinal and multicentric studies are warranted to clarify the causality and guide preventive strategies. This review highlights the importance of occupational health protocols, including radiation shielding and periodic thyroid evaluation, in safeguarding the long-term endocrine health of healthcare workers. Full article
(This article belongs to the Special Issue Thyroid-Related Diseases: Molecular Pathology, Diagnosis and Treatment: 2nd Edition)
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20 pages, 8347 KiB  
Article
bFGF-Mediated Inhibition of Astrocytes’ Optogenetic Activation Impairs Neuronal Repair in Female Rats After Stroke
by Xinfa Shao, Yangqianbo Yao, Victoria Shi, Qian Suo, Shengju Wu, Han Wang, Muyassar Mamtilahun, Wanlu Li, Yaohui Tang, Guo-Yuan Yang, Qun Xu and Zhijun Zhang
Int. J. Mol. Sci. 2025, 26(13), 6521; https://doi.org/10.3390/ijms26136521 - 7 Jul 2025
Viewed by 207
Abstract
Astrocyte activation and gender differences play critical roles in the prognosis following stroke. Recent studies have shown that optogenetic technology can promote brain repair after stroke by activating astrocytes in male rats. However, it remains unclear whether gender differences influence the efficacy of [...] Read more.
Astrocyte activation and gender differences play critical roles in the prognosis following stroke. Recent studies have shown that optogenetic technology can promote brain repair after stroke by activating astrocytes in male rats. However, it remains unclear whether gender differences influence the efficacy of optogenetic activation of astrocytes in regulating post-stroke brain repair and its underlying mechanisms. In this study, we activated astrocytes in the ipsilateral cortex of adult glial fibrillary acidic protein-channelrhodopsin 2-enhanced yellow fluorescent protein (GFAP-ChR2-EYFP) transgenic Sprague Dawley rats using optogenetic stimulation at 24, 36, 48, and 60 h after inducing photothrombosis stroke. Neurobehavioral tests, cresyl violet staining, RT-qPCR, Western blot, and immunofluorescence analysis were performed on both female and male rats. Our results showed that male rats exhibited significant improvements in behavioral scores and reduction in infarct size after optogenetic activation of astrocytes at three days post-stroke (p < 0.05), whereas no significant changes were observed in female rats. Additionally, in female rats, the expression of basic fibroblast growth factor (bFGF) increased after ischemic stroke and astrocytic optogenetic stimulation (p < 0.05), leading to enhanced endothelial cell proliferation compared to male rats (p < 0.05). In vitro experiments further demonstrated that the astrocyte activation was inhibited in the presence of bFGF (p < 0.05). These findings suggest that the increase in bFGF levels in females following stroke may inhibit the optogenetic activation of astrocytes, thereby attenuating the therapeutic effect of astrocyte activation on post-stroke brain repair. This study provides important insights into the gender-specific roles of astrocytes in the acute phase of ischemic stroke. Full article
(This article belongs to the Section Molecular Neurobiology)
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17 pages, 2518 KiB  
Article
Blockade of Dopamine D3 Receptors in the Ventral Tegmental Area Mitigates Fear Memory Generalization
by Xiangjun Fang, Xiaoyan Ding, Ning Wu, Jin Li and Rui Song
Int. J. Mol. Sci. 2025, 26(13), 6520; https://doi.org/10.3390/ijms26136520 - 7 Jul 2025
Viewed by 177
Abstract
The generalization of fear memories is an adaptive neurobiological process that promotes survival in complex and dynamic environments. While generalization has adaptive value, fear generalization is maladaptive and is a significant feature of stress-related disorders such as post-traumatic stress disorder (PTSD). The dopamine [...] Read more.
The generalization of fear memories is an adaptive neurobiological process that promotes survival in complex and dynamic environments. While generalization has adaptive value, fear generalization is maladaptive and is a significant feature of stress-related disorders such as post-traumatic stress disorder (PTSD). The dopamine system plays a crucial role in both reward- and fear-related processes; however, the contribution of dopamine D3 receptors (D3Rs) to fear generalization in intense foot-shock models remains unclear. In this study, we administered a highly selective D3R antagonist, YQA14 (1 μg/0.2 μL/side), in the ventral tegmental area (VTA), which significantly inhibited fear generalization in novel contexts within foot-shock models. This effect was mediated by reducing the neuronal activity in the basolateral amygdala (BLA). These findings enhance our understanding of the neurobiology of generalization, which is essential from a translational perspective and has broad implications for treating generalized fear disorders. Full article
(This article belongs to the Special Issue Development of Dopaminergic Neurons, 4th Edition)
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15 pages, 1254 KiB  
Article
Salivary Metabolomics Discloses Metabolite Signatures of Oral Leukoplakia with and Without Dysplasia
by Elena Ferrari, Rita Antonelli, Mariana Gallo, Marco Meleti, Giacomo Setti, Adele Mucci, Valeria Righi, Anna Gambini, Cristina Magnoni, Alberto Spisni and Thelma A. Pertinhez
Int. J. Mol. Sci. 2025, 26(13), 6519; https://doi.org/10.3390/ijms26136519 - 7 Jul 2025
Viewed by 186
Abstract
Leukoplakia is a condition marked by white patches on the inner surfaces of the oral cavity. Its potential to progress to oral squamous cell carcinoma underscores the need for effective screening and early diagnosis procedures. We employed NMR-based salivary and tissue metabolomics to [...] Read more.
Leukoplakia is a condition marked by white patches on the inner surfaces of the oral cavity. Its potential to progress to oral squamous cell carcinoma underscores the need for effective screening and early diagnosis procedures. We employed NMR-based salivary and tissue metabolomics to identify potential biomarkers for leukoplakia and dysplastic leukoplakia. Univariate and multivariate methods were used to evaluate the NMR-derived metabolite concentrations. The salivary metabolite profile of leukoplakia exhibited specific alterations compared to healthy controls. These metabolic changes were more pronounced in cases of dysplastic lesions. Multivariate ROC curve analysis, based on a selection of salivary metabolites, ascribed high diagnostic accuracy to the models that discriminate between dysplastic and healthy cases. However, NMR analysis of tissue biopsies was ineffective in extracting metabolic signatures to differentiate between lesional, peri-lesional, and healthy tissues. Our pilot study employing a metabolomics-based approach led to the development of salivary models that represent a complementary strategy for clinically detecting leukoplakia. However, larger-scale validation is required to fully evaluate their diagnostic potential and to effectively stratify leukoplakia patients according to dysplasia status. Full article
(This article belongs to the Special Issue Insights in Metabolomics: Chromatography and Mass Spectrometry Applications in Cancer Research)
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27 pages, 1975 KiB  
Review
Pharmacological Treatment of MASLD: Contemporary Treatment and Future Perspectives
by Krzysztof Drygalski
Int. J. Mol. Sci. 2025, 26(13), 6518; https://doi.org/10.3390/ijms26136518 - 7 Jul 2025
Viewed by 293
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly NAFLD, is the most prevalent chronic liver disease worldwide. Strongly linked to obesity, type 2 diabetes, and metabolic syndrome, MASLD poses a growing health burden. Despite its high prevalence and risk of progression, no pharmacological treatment [...] Read more.
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly NAFLD, is the most prevalent chronic liver disease worldwide. Strongly linked to obesity, type 2 diabetes, and metabolic syndrome, MASLD poses a growing health burden. Despite its high prevalence and risk of progression, no pharmacological treatment is currently approved. This narrative review provides an overview of emerging pharmacological treatments under clinical investigation, with a particular focus on agents recently evaluated in randomized clinical trials. A systematic search of the ClinicalTrials.gov database through to April 2025 was conducted to identify relevant studies. Investigational drugs were categorized by their molecular mechanisms, and data on efficacy, safety, and clinical development phases were summarized. The most extensively studied drug classes include GLP-1 receptor agonists, PPAR agonists, and FXR agonists, as well as inhibitors of ACC and DGAT. These therapies have shown promising effects on hepatic steatosis, liver enzyme levels, and metabolic markers and may be introduced into clinical practice in the near future. Full article
(This article belongs to the Special Issue Steatotic Liver Disease: From Bench to Bedside and Back)
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14 pages, 1245 KiB  
Review
Annexin–Membrane Interactions Across Eukaryotic Domains of Life—A Comparative Approach
by Dawid Warmus, Erina Alexandra Balmer and Carmen Faso
Int. J. Mol. Sci. 2025, 26(13), 6517; https://doi.org/10.3390/ijms26136517 - 7 Jul 2025
Viewed by 256
Abstract
This review explores the interaction of annexins with membranes across a variety of eukaryotic domains of life, highlighting this protein family’s role in cellular processes due to its lipid and calcium-binding properties. By comparing annexins’ functions in diverse organisms, we aim to uncover [...] Read more.
This review explores the interaction of annexins with membranes across a variety of eukaryotic domains of life, highlighting this protein family’s role in cellular processes due to its lipid and calcium-binding properties. By comparing annexins’ functions in diverse organisms, we aim to uncover novel insights into their mechanisms of action, particularly in membrane repair, protein trafficking, and potential channel formation. Despite extensive research on mammalian and plant annexins, there is limited information on annexins in invertebrates, fungi, and protists. This review seeks to bridge this knowledge gap, providing a comprehensive understanding of annexin–membrane interactions and their potential implications for cellular function and disease mechanisms across eukaryotic lineages. Full article
(This article belongs to the Section Molecular Biology)
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12 pages, 469 KiB  
Article
Urinary Inflammatory and Oxidative Stress Biomarkers as Indicators for the Clinical Management of Benign Prostatic Hyperplasia
by Yuan-Hong Jiang, Jimmy Lee, Hann-Chorng Kuo and Ya-Hui Wu
Int. J. Mol. Sci. 2025, 26(13), 6516; https://doi.org/10.3390/ijms26136516 - 6 Jul 2025
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Abstract
Oxidative stress and hypoxia-induced inflammation contribute to benign prostatic hyperplasia (BPH) progression. This study investigated the roles of urinary inflammatory and oxidative stress biomarkers in BPH patients. This prospective study enrolled 62 clinical BPH patients (33 treated medically, 29 surgically) and 20 controls. [...] Read more.
Oxidative stress and hypoxia-induced inflammation contribute to benign prostatic hyperplasia (BPH) progression. This study investigated the roles of urinary inflammatory and oxidative stress biomarkers in BPH patients. This prospective study enrolled 62 clinical BPH patients (33 treated medically, 29 surgically) and 20 controls. Symptom scores, uroflowmetry, and urinary biomarker levels were assessed at baseline and three months post-treatment. Before treatment, BPH patients exhibited elevated urinary levels of total antioxidant capacity (TAC), PGE2, IL-1β, and IL-6. Post-treatment, successful outcomes were reported in 63.6% of the medical treatment group and 86.2% of the surgical treatment group, with improvements in symptom scores and urinary flow rate, along with reductions in urinary 8-isoprostane, TAC, and IL-1β. Prior to treatment, voiding efficiency (VE) was negatively correlated with urinary IL-1β, IL-6, and IL-8 levels, while bladder wall thickness was positively correlated with TAC. After treatment, changes in VE were negatively correlated with changes in IL-1β, and changes in post-void residual urine were positively correlated with changes in IL-1β, IL-6, IL-8, and TNF-α. Urinary inflammatory and oxidative stress biomarkers may serve as non-invasive indicators of disease severity and treatment response in clinical BPH. Their significant correlations with clinical improvements underscore their potential utility in monitoring treatment efficacy. Full article
(This article belongs to the Special Issue Oxidative Stress and Inflammation in Health and Disease)
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