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Int. J. Mol. Sci., Volume 26, Issue 9 (May-1 2025) – 543 articles

Cover Story (view full-size image): Mitochondria are essential for ATP production, apoptosis regulation, and calcium homeostasis, playing crucial roles in oocyte quality and embryo development. Proper mitochondrial function supports energy production, genomic stability, and fertilisation. Understanding these processes helps improve culture conditions and identify biomarkers for reproductive success and ARTs. Dysfunctional mitochondria, linked to ageing or metabolic issues, cause oxidative stress and reduce oocyte quality. Regeneration methods, such as mitochondrial replacement therapy (MRT) and antioxidants (resveratrol, melatonin, L-carnitine, and CoQ10), support mitochondrial function, reduce ROS, and boost ATP synthesis, offering potential in reproductive medicine. View this paper
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11 pages, 217 KB  
Article
Genetic Etiology of Permanent Congenital Hypothyroidism in Korean Patients: A Whole-Exome Sequencing Study
by Jungmin Ahn and Hwalrim Jeong
Int. J. Mol. Sci. 2025, 26(9), 4465; https://doi.org/10.3390/ijms26094465 - 7 May 2025
Cited by 1 | Viewed by 1236
Abstract
Congenital hypothyroidism (CH) is among the most common endocrine disorders in neonates. Genetic testing is essential for elucidating the underlying etiology, especially in cases of permanent CH. We enrolled 32 patients diagnosed with permanent CH from the Pediatric Endocrinology Clinics at Jeju National [...] Read more.
Congenital hypothyroidism (CH) is among the most common endocrine disorders in neonates. Genetic testing is essential for elucidating the underlying etiology, especially in cases of permanent CH. We enrolled 32 patients diagnosed with permanent CH from the Pediatric Endocrinology Clinics at Jeju National University Hospital and Soonchunhyang University Cheonan Hospital. Whole-exome sequencing (WES) was performed on genomic DNA extracted from buccal swabs. Variants were classified according to guidelines established by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP). WES identified 21 distinct genetic variants in 20 of the 32 patients (62.5%), spanning 6 CH-related genes: DUOX2, DUOXA2, TPO, PAX8, TG, and TSHR. Of these, 12 variants classified as pathogenic or likely pathogenic were detected in 15 patients (50%). When classified by inheritance patterns, nine patients had either homozygous (n = 1) or compound heterozygous (n = 8) variants, four patients exhibited oligogenic variants, and two patients carried a single heterozygous variant with pathogenicity. The most frequently affected gene was DUOX2, with pathogenic or likely pathogenic variants found in six patients. Notably, none of the six patients with thyroid agenesis or ectopic thyroid glands harbored detectable pathogenic variants. Our findings underscore the critical role of genetic analysis in determining the etiology of permanent CH. Whole-exome sequencing demonstrated a high prevalence of pathogenic variants, particularly in DUOX2, in Korean patients with CH. These data enhance our understanding of the genetic architecture of CH and have important implications for personalized treatment and genetic counseling. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
19 pages, 3235 KB  
Article
Metabolomics Combined with Photosynthetic Analysis Reveals Potential Mechanisms of Phenolic Compound Accumulation in Lonicera japonica Induced by Nitrate Nitrogen Supply
by Yiwen Cao, Yating Yang, Zhengwei Tan, Xihan Feng, Zhiyao Tian, Tianheng Liu, Yonghui Pan, Min Wang, Xiaoyu Su, Huizhen Liang and Shiwei Guo
Int. J. Mol. Sci. 2025, 26(9), 4464; https://doi.org/10.3390/ijms26094464 - 7 May 2025
Viewed by 832
Abstract
Mineral nutrition is of vital importance in plant growth and secondary metabolites accumulation, and thereby in the nutritional value of plants. In Lonicera japonica, a preference to nitrate (NO3−−N) in comparison to ammonium (NH4+−N) was found [...] Read more.
Mineral nutrition is of vital importance in plant growth and secondary metabolites accumulation, and thereby in the nutritional value of plants. In Lonicera japonica, a preference to nitrate (NO3−−N) in comparison to ammonium (NH4+−N) was found in our previous study, which can be revealed from the rapid growth rate of L. japonica under NO3−−N. This study assessed whether a preference for nitrogen sources could invoke metabolic reprogramming and interrelationships between factors. NO3−−fed plants exhibited substantial enhancement of carbon stimulation, which was strongly and positively correlated with mesophyll conductance. As a result, the elevated carbon flux by NO3− supplement was shuttled to phenolic metabolites synthesis, including flavones and caffeoylquinic acids compounds. Notably, the stimulation was triggered by changes in the NO3− and C/N ratio and was mediated by the induction of several enzymes in the phenylpropanoid pathway. On the contrary, NH4+ plants showed an increment in the content of nitrogen, carbohydrates, and amino acids (mainly a strong increase in citrulline and theanine). Within secondary metabolism, NH4+ may involve active lignin metabolism, showing a dramatic increment in hydroxy−ferulic acid and lignin content. This work provides significant insights regarding the mechanisms of L. japonica in response to diverse nitrogen regimes and effective strategies of nitrogen fertilizer input for L. japonica. Full article
(This article belongs to the Special Issue Exploring Abiotic Stress in Plants: Mechanisms, Adaptations, and Mitigation Strategies)
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22 pages, 2042 KB  
Review
High Concentrations of Circulating 2PY and 4PY—Potential Risk Factor of Cardiovascular Disease in Patients with Chronic Kidney Disease
by Agnieszka Dettlaff-Pokora and Julian Swierczynski
Int. J. Mol. Sci. 2025, 26(9), 4463; https://doi.org/10.3390/ijms26094463 - 7 May 2025
Viewed by 2560
Abstract
Recently published data indicate that elevated circulating concentrations of N1-methyl-2-pyridone-5-carboxamide (2PY, also described as Met2PY) and N1-methyl-4-pyridone-5-carboxamide (4PY, also described as Met4PY), terminal catabolites of nicotinamide adenine dinucleotide (NAD+), are associated with cardiovascular disease (CVD) risk in humans. Previously, we and [...] Read more.
Recently published data indicate that elevated circulating concentrations of N1-methyl-2-pyridone-5-carboxamide (2PY, also described as Met2PY) and N1-methyl-4-pyridone-5-carboxamide (4PY, also described as Met4PY), terminal catabolites of nicotinamide adenine dinucleotide (NAD+), are associated with cardiovascular disease (CVD) risk in humans. Previously, we and the others have shown that patients with advanced stages of chronic kidney disease (CKD) exhibit several-fold higher circulating 2PY and 4PY concentrations compared to healthy subjects or patients in the early stages of the disease. It is also well documented that patients with advanced CKD stages exhibit markedly elevated CVD risk, which is the main cause of premature death (in these patients). Therefore, we hypothesize that high concentrations of circulating 2PY and 4PY are important factors that may contribute to cardiovascular events and, ultimately, premature death in CKD patients. However, further, accurately controlled clinical research is needed to provide definitive answers concerning the role of 2PY and 4PY in CVD risk in CKD patients. Moreover, we are dealing with some issues related to the use of NAD+ precursors (NAD+ boosters) as drugs (also in CKD patients) and/or supplements. Due to the increase in circulating 2PY and 4PY levels during treatment with NAD+ boosters, these precursors should be used with caution, especially in patients with increased CVD risk. Full article
(This article belongs to the Special Issue Cardiovascular Diseases: Histopathological and Molecular Diagnostics)
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16 pages, 2865 KB  
Article
Single-Cell Transcriptomics Reveals Stem Cell-Derived Exosomes Attenuate Inflammatory Gene Expression in Pulmonary Oxygen Toxicity
by Jing Shi, Yabin Li, Houyu Zhao, Chenyang Yan, Ruxia Cui, Yukun Wen, Xuhua Yu, Wei Ding, Yunpeng Zhao and Yiqun Fang
Int. J. Mol. Sci. 2025, 26(9), 4462; https://doi.org/10.3390/ijms26094462 - 7 May 2025
Cited by 2 | Viewed by 1910
Abstract
In recent years, the role played by exosomes in lung diseases has been investigated. Exosomes have been shown to contribute to reductions in lung inflammation and pulmonary fibrosis. However, the role played by exosomes in pulmonary oxygen toxicity and the mechanism involved have [...] Read more.
In recent years, the role played by exosomes in lung diseases has been investigated. Exosomes have been shown to contribute to reductions in lung inflammation and pulmonary fibrosis. However, the role played by exosomes in pulmonary oxygen toxicity and the mechanism involved have not yet been reported. In the present work, we aimed to investigate the mechanism by which stem cell exosomes protect lung tissue and the potential molecular regulatory network involved. In this study, we employed single-cell RNA sequencing techniques to elucidate the unique cellular and molecular mechanisms underlying the progression of exosome therapy for pulmonary oxygen toxicity. We found changes in cell populations after exosome treatment, characterized by the expression of different molecular markers. We also integrated single-cell RNA sequencing (scRNA-seq) and bulk analysis to identify the protective effects of mesenchymal stem cell exosomes (MSC-Exos) in a mouse pulmonary oxygen toxicity (POT) model. scRNA-seq revealed dynamic shifts in the lung cellular composition after exosome treatment, including a reduction in inflammatory lymphoid cells (NK, B cells, CD8+ T, CD4+ T) and restored alveolar epithelial populations (AT1/AT2). A comprehensive gene expression analysis showed that inflammatory pathways associated with oxidative stress were significantly upregulated. In addition, our analysis of the intercellular interaction network revealed that there was a significant reduction in intercellular signal transduction in the POT group compared to the exosome-treated group. These results not only shed light on the unique cellular heterogeneity and potential pathogenesis following exosome therapy, but they also deepen our understanding of molecular pathophysiology and provide new avenues for targeted therapeutic strategies. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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22 pages, 1412 KB  
Article
Hsa-miR-21-5p and Hsa-miR-145-5p Expression: From Normal Tissue to Malignant Changes—Context-Dependent Correlation with Estrogen- and Hypoxia–Vascularization-Related Pathways Genes: A Pilot Study
by Mateusz Górecki, Aleksandra Żbikowska, Małgorzata Tokłowicz, Stefan Sajdak, Monika Englert-Golon and Mirosław Andrusiewicz
Int. J. Mol. Sci. 2025, 26(9), 4461; https://doi.org/10.3390/ijms26094461 - 7 May 2025
Cited by 2 | Viewed by 1772
Abstract
Ovarian cancer (OC) is a severe gynecological malignancy with a high mortality rate among women worldwide. It is often diagnosed at advanced stages due to the lack of effective screening methods. This study investigated the expression patterns of microRNAs (miRNAs) hsa-miR-21-5p and hsa-miR-145-5p [...] Read more.
Ovarian cancer (OC) is a severe gynecological malignancy with a high mortality rate among women worldwide. It is often diagnosed at advanced stages due to the lack of effective screening methods. This study investigated the expression patterns of microRNAs (miRNAs) hsa-miR-21-5p and hsa-miR-145-5p as potential OC prognostic and diagnostic biomarkers and their correlation with estrogen-dependent (ESR1 & 2, PELP1 and c-SRC) and hypoxia–neovascularization-induced (HIF1A, EPAS1, and VEGFA) pathway genes. Tissue samples obtained from twenty patients with confirmed ovarian cancer and twenty controls were analyzed using quantitative polymerase chain reaction (qPCR) to examine miRNA and mRNA levels. The qPCR analysis revealed significantly higher hsa-miR-21-5p and lower hsa-miR-145-5p expression in OC tissues than controls. Moreover, a significant trend was observed in hsa-miR-21-5p and hsa-miR-145-5p expression levels across normal, non-cancerous changes and malignant ovarian tissues. The hsa-miR-21-5p showed better diagnostic potential than hsa-miR-145-5p. We also observed inconsistent correlations in hsa-miR-21-5p and hsa-mir-145-5p and estrogen-related and hypoxia–neovascularization-dependent genes in ovarian cancer across all groups. This suggests that the relationship between these miRNAs and the selected genes is context-specific. Our findings suggest that hsa-miR-21-5p and hsa-miR-145-5p expression levels may be prognostic or diagnostic markers for ovarian cancer patients. Full article
(This article belongs to the Special Issue Molecular Genetics in Ovarian Cancer)
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15 pages, 7862 KB  
Article
Transcriptional Study of Radiofrequency Device Using Experimental Mouse Model
by Xiaofeng Li, Zheng Wang, Xiaoman Li, Xiaofeng Fan, Xinyu Lu, Yanan Li, Yehua Pan, Ziyan Zhu, Mingxi Zhu, Wei Li, Leo Chan, Suyun Yu, Yanhong Pan and Yuanyuan Wu
Int. J. Mol. Sci. 2025, 26(9), 4460; https://doi.org/10.3390/ijms26094460 - 7 May 2025
Viewed by 1177
Abstract
Radiofrequencies have shown efficacy in addressing skin aging. Despite their effectiveness, few studies have explored how radiofrequencies affect the skin transcriptome. This study utilized mouse models divided into two age groups (four-month-old and one-year-old mice) to assess the impact of a radiofrequency device [...] Read more.
Radiofrequencies have shown efficacy in addressing skin aging. Despite their effectiveness, few studies have explored how radiofrequencies affect the skin transcriptome. This study utilized mouse models divided into two age groups (four-month-old and one-year-old mice) to assess the impact of a radiofrequency device on skin collagen and elastin. A combination of histological analysis, Western blot analysis, real-time PCR and transcriptome sequencing was employed. Histological analysis revealed significant increases in dermis thickness and collagen fiber volume following radiofrequency treatment in both age groups. Quantitative PCR and Western blot analysis indicated that the levels of collagen-related genes and proteins were higher in the four-month-old group. Transcriptome sequencing identified 465 and 1867 differentially expressed genes (DEGs) in the skin of the 4-month-old mice and 1-year-old mice, respectively. GO and KEGG analyses elucidated the molecular mechanisms, revealing that the interleukin-17 and tumor necrosis factor signaling pathways may play crucial roles in collagen regeneration induced by radiofrequencies. Additionally, decreased expression of matrix metalloproteinase-9 and increased expression of the transcription factor Fos were identified as potential biomarkers of collagen regeneration. Immunofluorescence and immunohistochemistry staining demonstrated that radiofrequencies activate fibroblasts and inhibit macrophage alternative activation in the skin. This study identifies key genes and biological pathways involved in radiofrequency treatment and provides a foundation for a deeper understanding of the molecular mechanisms underlying collagen regeneration facilitated by radiofrequencies. Full article
(This article belongs to the Section Molecular Biology)
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23 pages, 6786 KB  
Article
P-Type Pentatricopeptide Repeat Proteins YS1 and YS2 Function in Splicing of petB Intron to Maintain Chloroplast Homeostasis During Rice Seedling Development
by Hui Sun, Yanshen Nie, Li Yu, Xiaohong Yue, Xin Hou and Jie Zhao
Int. J. Mol. Sci. 2025, 26(9), 4459; https://doi.org/10.3390/ijms26094459 - 7 May 2025
Viewed by 688
Abstract
Regulating chloroplast gene expression is crucial for maintaining chloroplast function and plant development. Pentatricopeptide repeat (PPR) proteins form a vast protein family that regulates organelle genes and has multiple functions during plant development. Here, we found that two P-type PPR proteins, YS1 (yellow-green [...] Read more.
Regulating chloroplast gene expression is crucial for maintaining chloroplast function and plant development. Pentatricopeptide repeat (PPR) proteins form a vast protein family that regulates organelle genes and has multiple functions during plant development. Here, we found that two P-type PPR proteins, YS1 (yellow-green seedling 1) and YS2, jointly regulated seedling development in rice. The loss of YS1 and YS2 exhibited the collapsed chloroplast thylakoids and decreased photosynthetic activity, leading to the yellowing and death of rice seedlings. YS1 and YS2 could directly bind to the transcript of the psbH-petB intergenic region to facilitate the splicing of petB intron, thereby affecting the splicing efficiency of petD, which is located downstream of petB in the five-cistronic transcription unit psbB-psbT-psbH-petB-petD. The mutations in YS1 and YS2 led to decreased mature transcripts of petB and petD after splicing, significantly reducing the protein levels of PetB and PetD. This further led to deficiencies in the cytochrome b6/f and photosystem I complexes of the electron transport chain (ETC), ultimately resulting in decreased ETC-produced NADPH and reduced contents of carbohydrates in ys mutants. Moreover, transcriptome sequencing analysis revealed that YS1 and YS2 were vital for chloroplast organization and carbohydrate metabolism, as well as chloroplast RNA processing. In previous studies, the mechanism of petB intron splicing in the five-cistronic transcription unit psbB-psbT-psbH-petB-petD of rice is unclear. Our study revealed that the two highly conserved proteins YS1 and YS2 were functionally redundant and played critical roles in photosynthesis and seedling development through their involvement in petB intron splicing to maintain chloroplast homeostasis in rice. This work broadened the perspective on PPR-mediated chloroplast development and laid a foundation for exploring the biofunctions of duplicated genes in higher plants. Full article
(This article belongs to the Special Issue Plant Biodiversity and Molecular Marker Technology: Discovery and Application of DNA Polymorphisms)
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19 pages, 3924 KB  
Article
Impact of Vehicle Composition on Solubility, Autoclave Sterilization Stability, and Antibacterial Activity of Ciprofloxacin Hydrochloride Ear Drops
by Weerasak Samee, Sarin Tadtong, Wanna Eiamart, Pattaraporn Singwiset, Sirivimon Yingyomsarn and Patcharawee Nunthanavanit
Int. J. Mol. Sci. 2025, 26(9), 4458; https://doi.org/10.3390/ijms26094458 - 7 May 2025
Cited by 1 | Viewed by 2184
Abstract
This research focused on the formulation of ciprofloxacin hydrochloride ear drops for the treatment of acute otitis externa, caused by pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa. The study aimed to enhance the solubility of ciprofloxacin at physiological pH and improve [...] Read more.
This research focused on the formulation of ciprofloxacin hydrochloride ear drops for the treatment of acute otitis externa, caused by pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa. The study aimed to enhance the solubility of ciprofloxacin at physiological pH and improve its stability during autoclave sterilization by employing polyalcohol vehicle systems composed of deionized water, glycerin, and propylene glycol. Formulations containing 0.33% w/v ciprofloxacin HCl were evaluated for solubility within a pH range of 4.0 to 7.0 and underwent autoclave sterilization to assess their chemical stability and antibacterial efficacy. Following sterilization, the formulations were stored at 25 °C in amber containers for a duration of 180 days. High-performance liquid chromatography (HPLC) was utilized to evaluate chemical stability, while antibacterial activity was determined using the disk diffusion method. The results demonstrated that glycerin and propylene glycol effectively inhibited ciprofloxacin precipitation at physiological pH. The ciprofloxacin content decreased by less than 3.58% while preserving antimicrobial efficacy against S. aureus and P. aeruginosa. Both formulations retained over 90% of their labeled drug content, indicating a minimum shelf life of 180 days under the specified storage conditions. Full article
(This article belongs to the Special Issue Molecular Advances on Solubility and Diffusivity in Water-Based Systems and in Biological Media)
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17 pages, 6609 KB  
Article
Rational Method for Structural Simplification as Key Step in Hit Discovery: The Case of FGFR2 and IGF1R Dual Inhibitors
by Endika Torres-Urtizberea, José I. Borrell, Raimon Puig de la Bellacasa and Roger Estrada-Tejedor
Int. J. Mol. Sci. 2025, 26(9), 4457; https://doi.org/10.3390/ijms26094457 - 7 May 2025
Viewed by 686
Abstract
In the classic medicinal chemistry hit discovery procedure, large virtual libraries undergo different filtering and prediction steps until a small group of molecules is selected for their subsequent synthesis and biological testing. The starting molecular libraries can easily be composed of millions of [...] Read more.
In the classic medicinal chemistry hit discovery procedure, large virtual libraries undergo different filtering and prediction steps until a small group of molecules is selected for their subsequent synthesis and biological testing. The starting molecular libraries can easily be composed of millions of molecules, hindering the selection of the most representative and promising compounds. Moreover, the resulting molecular systems tend to be overcomplex structures, hardly attainable, and often involve extrapolations of the prediction models used. We present a rational-based method to reduce the structural complexity of molecular candidates without compromising their biological activity, improving the attainability and efficiency of hit discovery. This approach has been successfully applied to identify potential tyrosine kinase dual inhibitors against Fibroblast Growth Factor Receptor 2 (FGFR2) and Insulin-Like Growth Factor 1 Receptor (IGF1R), a set of overexpressed proteins in different cancers, such as pancreatic ductal adenocarcinoma (PDAC). Full article
(This article belongs to the Special Issue Cheminformatics in Drug Discovery and Green Synthesis)
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33 pages, 2069 KB  
Review
Genetic Modifiers Associated with Vaso-Occlusive Crises and Acute Pain Phenomena in Sickle Cell Disease: A Scoping Review
by Froso Sophocleous, Natasha M. Archer and Carsten W. Lederer
Int. J. Mol. Sci. 2025, 26(9), 4456; https://doi.org/10.3390/ijms26094456 - 7 May 2025
Cited by 1 | Viewed by 1711
Abstract
Sickle cell disease (SCD) is a group of recessive diseases caused by the βS sickling mutation of HBB in homozygosity or in compound heterozygosity with other pathogenic HBB mutations. Patients with severe SCD typically experience painful vaso-occlusive crises and other pain-related phenomena, [...] Read more.
Sickle cell disease (SCD) is a group of recessive diseases caused by the βS sickling mutation of HBB in homozygosity or in compound heterozygosity with other pathogenic HBB mutations. Patients with severe SCD typically experience painful vaso-occlusive crises and other pain-related phenomena, including acute chest syndrome, priapism, dactylitis, avascular necrosis, and splenic sequestration and infarction. High variability of pain-related phenomena per SCD genotype indicates genetic disease modifiers (GDMs) as pathology determinants and, thus, as critical to prognosis, treatment choice, and therapy development. Articles likely holding genetic information for SCD pain phenomena were identified in PubMed and SCOPUS for article quality assessment and extraction of corresponding GDMs and observations indicative of development areas in our understanding of SCD GDMs. This process led to the initial selection of 183 articles matching the search terms, which, after two-step selection, resulted in the inclusion of 100 articles for content analysis and of significant findings for GDMs from 37 articles. Published data point to gender effects and to 51 GDM SNVs, deletions, and regions, including globin genes and significant overrepresentation of gene ontology pathways related, e.g., to oxidative stress, hypoxia, and regulation of blood pressure. Analyzed articles further pointed to additional candidate GDMs affecting SCD VOC and pain phenomena and to potential confounding factors for GWAS analyses. We found that despite the critical importance of VOC and pain phenomena for SCD pathology, corresponding clinically relevant genetic insights are held back by a shortage of large-scale, systematic multi-ethnic efforts, as undertaken by the INHERENT Network. Full article
(This article belongs to the Special Issue Genetic Modifiers of Hemoglobinopathies: Recent Advances and Future Directions)
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23 pages, 1073 KB  
Review
Fluid Biomarkers in Demyelinating Spectrum Disorders: Past, Present, and Prospects
by Anca-Maria Florea, Monica Neațu, Dimela-Gabriela Luca, Eugenia Irene Davidescu and Bogdan-Ovidiu Popescu
Int. J. Mol. Sci. 2025, 26(9), 4455; https://doi.org/10.3390/ijms26094455 - 7 May 2025
Cited by 2 | Viewed by 2033
Abstract
The diagnostic algorithm for the demyelinating disorders of the central nervous system remains a work in progress, with the search for the ideal biomarkers ongoing. The so-called “ideal” biomarker should ensure the accurate differentiation between the most common demyelinating pathologies of the CNS [...] Read more.
The diagnostic algorithm for the demyelinating disorders of the central nervous system remains a work in progress, with the search for the ideal biomarkers ongoing. The so-called “ideal” biomarker should ensure the accurate differentiation between the most common demyelinating pathologies of the CNS and between the subtypes of the same pathology (for example, the conversion from relapsing–remitting multiple sclerosis to the secondary progressive phenotype). Advances in technology facilitated this research and in the following sections we will comprehensively review most of these, outlining the past, present, and prospects and the impact they had on both diagnosis and therapeutic approach. Full article
(This article belongs to the Special Issue New Insights in Biomarkers of Autoimmune and Autoinflammatory Diseases)
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16 pages, 3352 KB  
Article
Integrated Analysis of Disulfidptosis-Related Genes Identifies CD2AP as a Potential Therapeutic Target for Hepatocellular Carcinoma
by Ning Shang, Jianwei Wang, Zihan Liu, Yake Wang, Di Zhang, Huanfei Liu, Yaqing Zhang, Guifu Dai and Xiaowen Guan
Int. J. Mol. Sci. 2025, 26(9), 4454; https://doi.org/10.3390/ijms26094454 - 7 May 2025
Viewed by 978
Abstract
Hepatocellular carcinoma (HCC) is a deadly cancer with limited treatment options for patients at advanced stages. It is urgent to develop reliable prognostic risk models and identify more biomarkers to improve the clinical outcomes of patients with HCC. Disulfidptosis is a newly discovered [...] Read more.
Hepatocellular carcinoma (HCC) is a deadly cancer with limited treatment options for patients at advanced stages. It is urgent to develop reliable prognostic risk models and identify more biomarkers to improve the clinical outcomes of patients with HCC. Disulfidptosis is a newly discovered form of regulated cell death (RCD), and research on the comprehensive roles of disulfidptosis-related genes (DRGs) in HCC prognosis and development remains limited. In this paper, we systematically analyzed the expression levels and prognostic profiles of 26 DRGs in HCC samples from The Cancer Genome Atlas (TCGA) cohort and developed a prognostic risk model using seven hub DRGs. The independent prognostic value of the risk model was further validated in the external cohort. The overall survival of patients with HCC in the low-risk group was significantly longer than that of those in the high-risk group. Subsequently, the protein level of CD2-associated protein (CD2AP) was found to be highly expressed in HCC clinical tissues and associated with the severity of HCC. In vitro experiments demonstrated that the down-regulation of CD2AP attenuated the proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) abilities of HCC cells. Taken together, our study revealed that the DRG CD2AP may serve as a potential biomarker for HCC and offer support for prognosis prediction of patients with HCC. Full article
(This article belongs to the Section Molecular Oncology)
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44 pages, 18191 KB  
Article
A Multi-Modal Graph Neural Network Framework for Parkinson’s Disease Therapeutic Discovery
by Ömer Akgüller, Mehmet Ali Balcı and Gabriela Cioca
Int. J. Mol. Sci. 2025, 26(9), 4453; https://doi.org/10.3390/ijms26094453 - 7 May 2025
Cited by 3 | Viewed by 2119
Abstract
Parkinson’s disease (PD) is a complex neurodegenerative disorder lacking effective disease-modifying treatments. In this study, we integrated large-scale protein–protein interaction networks with a multi-modal graph neural network (GNN) to identify and prioritize multi-target drug repurposing candidates for PD. Network analysis and advanced clustering [...] Read more.
Parkinson’s disease (PD) is a complex neurodegenerative disorder lacking effective disease-modifying treatments. In this study, we integrated large-scale protein–protein interaction networks with a multi-modal graph neural network (GNN) to identify and prioritize multi-target drug repurposing candidates for PD. Network analysis and advanced clustering methods delineated functional modules, and a novel Functional Centrality Index was employed to pinpoint key nodes within the PD interactome. The GNN model, incorporating molecular descriptors, network topology, and uncertainty quantification, predicted candidate drugs that simultaneously target critical proteins implicated in lysosomal dysfunction, mitochondrial impairment, synaptic disruption, and neuroinflammation. Among the top hits were compounds such as dithiazanine, ceftolozane, DL-α-tocopherol, bromisoval, imidurea, medronic acid, and modufolin. These findings provide mechanistic insights into PD pathology and demonstrate that a polypharmacology approach can reveal repurposing opportunities for existing drugs. Our results highlight the potential of network-based deep learning frameworks to accelerate the discovery of multi-target therapies for PD and other multifactorial neurodegenerative diseases. Full article
(This article belongs to the Special Issue New Insights in Artificial Intelligence for Drug Design and Target Discovery)
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15 pages, 2844 KB  
Article
Effects of Apigenin and Luteolin on Myzus persicae (Hemiptera: Aphididae) Probing Behavior
by Anna Wróblewska-Kurdyk, Bożena Kordan, Jan Bocianowski, Katarzyna Stec and Beata Gabryś
Int. J. Mol. Sci. 2025, 26(9), 4452; https://doi.org/10.3390/ijms26094452 - 7 May 2025
Cited by 1 | Viewed by 775
Abstract
Apigenin and luteolin are products of the phenylpropanoid pathway, where apigenin serves as a substrate for the synthesis of luteolin. Apigenin and luteolin are highly bioactive flavones; therefore, in search of prospective biopesticides, the receptiveness of the polyphagous green peach aphid Myzus persicae [...] Read more.
Apigenin and luteolin are products of the phenylpropanoid pathway, where apigenin serves as a substrate for the synthesis of luteolin. Apigenin and luteolin are highly bioactive flavones; therefore, in search of prospective biopesticides, the receptiveness of the polyphagous green peach aphid Myzus persicae (Sulzer) (Hemiptera: Aphididae) to apigenin and luteolin was studied. The flavones were applied as 0.1% ethanolic solutions to the host plant leaf surface, and aphid probing and feeding activities were monitored using the Electrical Penetration Graph (EPG) technique. The structural difference between apigenin and luteolin, which was the number of hydroxyl groups in the molecule, had an impact on the activity of these flavones. On apigenin-treated plants, the duration of the first probe was three times as short as on the control and five times as short as on the luteolin-treated plants; the duration of the time to the first ingestion phase within the successful probe was shorter than on the control and luteolin-treated plants; the mean duration of xylem sap ingestion bouts and the proportion of xylem phase in all probing activities were the highest; and the duration of salivation before phloem sap ingestion was the longest. Aphids’ response to luteolin-treated plants was less distinct as compared to apigenin-treated plants. Full article
(This article belongs to the Special Issue Insect–Plant Interactions: From Genes to Biochemical Elements)
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38 pages, 2728 KB  
Review
Mitochondrial Dysfunction in Genetic and Non-Genetic Parkinson’s Disease
by Martina Lucchesi, Letizia Biso, Marco Bonaso, Biancamaria Longoni, Bianca Buchignani, Roberta Battini, Filippo Maria Santorelli, Stefano Doccini and Marco Scarselli
Int. J. Mol. Sci. 2025, 26(9), 4451; https://doi.org/10.3390/ijms26094451 - 7 May 2025
Cited by 5 | Viewed by 3831
Abstract
Mitochondrial dysfunction is a hallmark of Parkinson’s disease (PD) pathogenesis, contributing to increased oxidative stress and impaired endo-lysosomal-proteasome system efficiency underlying neuronal injury. Genetic studies have identified 19 monogenic mutations—accounting for ~10% of PD cases—that affect mitochondrial function and are associated with early- [...] Read more.
Mitochondrial dysfunction is a hallmark of Parkinson’s disease (PD) pathogenesis, contributing to increased oxidative stress and impaired endo-lysosomal-proteasome system efficiency underlying neuronal injury. Genetic studies have identified 19 monogenic mutations—accounting for ~10% of PD cases—that affect mitochondrial function and are associated with early- or late-onset PD. Early-onset forms typically involve genes encoding proteins essential for mitochondrial quality control, including mitophagy and structural maintenance, while late-onset mutations impair mitochondrial dynamics, bioenergetics, and trafficking. Atypical juvenile genetic syndromes also exhibit mitochondrial abnormalities. In idiopathic PD, environmental neurotoxins such as pesticides and MPTP act as mitochondrial inhibitors, disrupting complex I activity and increasing reactive oxygen species. These converging pathways underscore mitochondria as a central node in PD pathology. This review explores the overlapping and distinct mitochondrial mechanisms in genetic and non-genetic PD, emphasizing their role in neuronal vulnerability. Targeting mitochondrial dysfunction finally offers a promising therapeutic avenue to slow or modify disease progression by intervening at a key point of neurodegenerative convergence. Full article
(This article belongs to the Special Issue Mitochondrial Function in Human Health and Disease: 2nd Edition)
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23 pages, 21973 KB  
Article
Transcriptome Analysis Reveals Association of E-Class AmMADS-Box Genes with Petal Malformation in Antirrhinum majus L.
by Dongmei Yang, Yiwen Chen, Yutong He, Jiayi Song, Ye Jiang, Meiyun Yang, Xingyan Zheng, Li Wang and Huizhen Hu
Int. J. Mol. Sci. 2025, 26(9), 4450; https://doi.org/10.3390/ijms26094450 - 7 May 2025
Viewed by 882
Abstract
Snapdragon (Antirrhinum majus) serves as a model system for dissecting floral morphogenesis mechanisms. Petal malformation in A. majus impacts ornamental value, but its genetic basis remains poorly understood. We compared transcriptomes of the wild-type (Am11) and a petal-malformed mutant (AmDP2) to [...] Read more.
Snapdragon (Antirrhinum majus) serves as a model system for dissecting floral morphogenesis mechanisms. Petal malformation in A. majus impacts ornamental value, but its genetic basis remains poorly understood. We compared transcriptomes of the wild-type (Am11) and a petal-malformed mutant (AmDP2) to identify 2303 differentially expressed genes (DEGs), including E-class MIKC-type MADS-box genes SEP3 (AmMADS25/61/20/26) and SEP2 (AmMADS85). Weighted gene co-expression network (WGCNA), protein-protein interaction (PPI), qRT-PCR and virus-induced gene silencing (VIGS) analyses revealed interactions between SEP2/SEP3 and C/A/B-class MADS-box genes (AG, AP1, AP3), co-regulated MADS transcription factors (MTFs) AGL15 (AmMADS16), and auxin signaling genes (SAUR1, IAA13). qRT-PCR validated upregulation of SEP3 and downregulation of SEP2 in AmDP2. Our results suggest that E-class MADS-box genes are associated with petal malformation through coordinated interactions with hormonal pathways. These findings provide candidate targets for further functional studies in snapdragon. Full article
(This article belongs to the Section Molecular Plant Sciences)
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13 pages, 1501 KB  
Article
Non-Thermal Plasma Attenuates TNF-α-Induced Endothelial Inflammation via ROS Modulation and NF-κB Inhibition
by Joo-Hak Kim, Seonhee Kim, Shuyu Piao, Minsoo Kim, Dae-Woong Kim, Byeong Hwa Jeon, Sang-Ha Oh and Cuk-Seong Kim
Int. J. Mol. Sci. 2025, 26(9), 4449; https://doi.org/10.3390/ijms26094449 - 7 May 2025
Cited by 2 | Viewed by 919
Abstract
Non-thermal plasma (NTP) has emerged as a promising therapeutic tool due to its anti-inflammatory properties; however, its molecular effects on vascular endothelial inflammation remain unclear. This study investigated the effects of NTP on tumor necrosis factor-alpha (TNF-α)-induced inflammation in human umbilical vein endothelial [...] Read more.
Non-thermal plasma (NTP) has emerged as a promising therapeutic tool due to its anti-inflammatory properties; however, its molecular effects on vascular endothelial inflammation remain unclear. This study investigated the effects of NTP on tumor necrosis factor-alpha (TNF-α)-induced inflammation in human umbilical vein endothelial cells (HUVECs). NTP treatment significantly reduced intracellular reactive oxygen species (ROS) levels and downregulated the expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), which are key markers of endothelial activation. In addition, NTP suppressed mRNA expression of pro-inflammatory cytokines, including TNF-α, interleukin-1 beta (IL-1β), and interleukin-6 (IL-6). Mechanistically, NTP inhibited the nuclear translocation of phosphorylated NF-κB p65, indicating attenuation of NF-κB signaling. These results demonstrate that NTP modulates inflammatory responses in endothelial cells by attenuating ROS generation and suppressing NF-κB-mediated signaling. Our findings suggest that NTP may serve as a potential therapeutic strategy for treating vascular inflammation and related pathologies. Full article
(This article belongs to the Section Biochemistry)
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15 pages, 1139 KB  
Review
Altering the Hydrogen Isotopic Composition of the Essential Nutrient Water as a Promising Tool for Therapy: Perspectives and Risks
by Nataliya V. Yaglova, Sergey S. Obernikhin, Ekaterina P. Timokhina, Elina S. Tsomartova, Valentin V. Yaglov, Svetlana V. Nazimova, Marina Y. Ivanova, Elizaveta V. Chereshneva, Tatiana A. Lomanovskaya and Dibakhan A. Tsomartova
Int. J. Mol. Sci. 2025, 26(9), 4448; https://doi.org/10.3390/ijms26094448 - 7 May 2025
Cited by 2 | Viewed by 891
Abstract
Water is a vital nutrient that is needed to maintain almost all biological processes in living organisms. The natural water contains two isotopes of hydrogen—protium and deuterium. Deuterium, the trace component of natural water, significantly changes its physical and chemical properties and biological [...] Read more.
Water is a vital nutrient that is needed to maintain almost all biological processes in living organisms. The natural water contains two isotopes of hydrogen—protium and deuterium. Deuterium, the trace component of natural water, significantly changes its physical and chemical properties and biological action. In this review, the authors summarize data on the isotopic effects of deuterium and discuss the possible magnetic effects of isotopes and the molecular basis of the biological effects of deuterium-depleted water. The review also presents new data on the already known and potential use of deuterium-depleted water in medicine (oncology, neurology) and previously unknown new directions of its use (immunological and endocrine disorders, anemia). Based on the analysis of collected data, the authors presented mechanisms of action of deuterium-depleted water in the organism. The authors also identified the least-studied effects of deuterium-depleted water, particularly its influence on morphogenetic processes. The review discloses the perspectives on deuterium-depleted water as a tool for therapy and substantiates the risks of its uncontrolled intake. Full article
(This article belongs to the Special Issue Macro- and Micronutrients in Health and Diseases)
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41 pages, 1536 KB  
Review
The Role of Salicylic Acid in Activating Plant Stress Responses—Results of the Past Decade and Future Perspectives
by Kincső Decsi, Mostafa Ahmed, Donia Abdul-Hamid and Zoltán Tóth
Int. J. Mol. Sci. 2025, 26(9), 4447; https://doi.org/10.3390/ijms26094447 - 7 May 2025
Cited by 3 | Viewed by 4691
Abstract
Salicylic acid (SA) is one of the most commonly used natural plant protection compounds, considered one of the most effective in mitigating the damage caused by abiotic and biotic stressors. The current review article summarizes the most significant achievements in stress management over [...] Read more.
Salicylic acid (SA) is one of the most commonly used natural plant protection compounds, considered one of the most effective in mitigating the damage caused by abiotic and biotic stressors. The current review article summarizes the most significant achievements in stress management over the past ten years. We also provide insights into new perspectives on the use of salicylic acid. The article summarizes the role of SA in signaling, its effects on biotic, abiotic and oxidative stress, evaluates the possibilities of its use in combination with other active compounds, and presents the promising application opportunities offered by new techniques that may become available in the coming decades. Full article
(This article belongs to the Special Issue Latest Advances in Plant Abiotic Stress)
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22 pages, 61157 KB  
Article
Genome-Wide Association Study to Identify Soybean Lodging Resistance Loci and Candidate Genes
by Zicong Liang, Nianhua Qi, Ruoning Li, Ruijia Gao, Junxia Huang, Wei Zhao, Huijun Zhang, Haiying Wang, Xue Ao, Xingdong Yao and Futi Xie
Int. J. Mol. Sci. 2025, 26(9), 4446; https://doi.org/10.3390/ijms26094446 - 7 May 2025
Cited by 1 | Viewed by 1025
Abstract
High-density planting is crucial for maximizing the genetic potential of soybean cultivars to achieve higher yields. However, increasing the planting density can lead to the risk of plant lodging. Therefore, the identification of gene loci associated with lodging resistance is considered critical for [...] Read more.
High-density planting is crucial for maximizing the genetic potential of soybean cultivars to achieve higher yields. However, increasing the planting density can lead to the risk of plant lodging. Therefore, the identification of gene loci associated with lodging resistance is considered critical for the development of high-yielding, lodging-resistant soybean cultivars. In this study, 338 natural soybean accessions from the similar latitude were used to identify candidate genes associated with lodging resistance. Based on 9,400,987 SNPs, the soybean population was classified into three subpopulations. Genome-wide association analysis revealed that under planting densities of 300,000 and 150,000 plants/ha, a total of 20 significant SNPs were repeatedly detected under both planting densities, distributed across 14 chromosomes of soybeans. A hotspot region was identified on chromosome 19, from which seven candidate genes were detected. Based on haplotype and gene expression analyses, Glyma.19g212800 (SUS3) and Glyma.19g212700 (GH9B13) were found to be associated with significant phenotypic variations and were identified as candidate genes. RNA-seq analysis showed that DEGs were primarily enriched in the starch and sucrose metabolism pathways. The differential expression of Glyma.19g212800 among soybean haplotypes was further validated by qRT-PCR. By participating in sucrose decomposition and polysaccharide metabolism processes, it regulated cellulose content, thereby affecting the soybean plant lodging. This study facilitated the dissection of genetic networks underlying lodging traits in soybean, which benefits the genetic improvement of high-yield soybean with dense planting. Full article
(This article belongs to the Section Molecular Plant Sciences)
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25 pages, 2641 KB  
Review
Precise Electromagnetic Modulation of the Cell Cycle and Its Applications in Cancer Therapy
by Keni Shi, Xiqing Peng, Ting Xu, Ziqi Lin, Mingyu Sun, Yiran Li, Qingyi Xian, Tingting Xiao, Siyuan Chen, Ying Xie, Ruihan Zhang, Jincheng Zeng and Bingzhe Xu
Int. J. Mol. Sci. 2025, 26(9), 4445; https://doi.org/10.3390/ijms26094445 - 7 May 2025
Cited by 2 | Viewed by 2938
Abstract
Precise modulation of the cell cycle via electromagnetic (EM) control presents a groundbreaking approach for cancer therapy, especially in the development of personalized treatment strategies. EM fields can precisely regulate key cellular homeostatic mechanisms such as proliferation, apoptosis, and repair by finely tuning [...] Read more.
Precise modulation of the cell cycle via electromagnetic (EM) control presents a groundbreaking approach for cancer therapy, especially in the development of personalized treatment strategies. EM fields can precisely regulate key cellular homeostatic mechanisms such as proliferation, apoptosis, and repair by finely tuning parameters like frequency, intensity, and duration. This review summarizes the mechanisms through which EM fields influence cancer cell dynamics, highlighting recent developments in high-throughput electromagnetic modulation platforms that facilitate precise cell cycle regulation. Additionally, the integration of electromagnetic modulation with emerging technologies such as artificial intelligence, immunotherapy, and nanotechnology is explored, collectively enhancing targeting precision, immune activation, and therapeutic efficacy. A systematic analysis of existing clinical studies indicates that EM modulation technology significantly overcomes key challenges such as tumor heterogeneity, microenvironment complexity, and treatment-related adverse effects. This review summarizes the prospects of electromagnetic modulation in clinical translation and future research directions, emphasizing its critical potential as a core element in individualized and multimodal cancer treatment strategies. Full article
(This article belongs to the Section Molecular Oncology)
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17 pages, 4839 KB  
Article
Functional Analysis of Antipsychotics in Human iPSC-Based Neural Progenitor 2D and 3D Schizophrenia Models
by Kiara Gitta Farkas, Katalin Vincze, Csongor Tordai, Ece İlay Özgen, Derin Gürler, Vera Deli, Julianna Lilienberg, Zsuzsa Erdei, Balázs Sarkadi, János Miklós Réthelyi and Ágota Apáti
Int. J. Mol. Sci. 2025, 26(9), 4444; https://doi.org/10.3390/ijms26094444 - 7 May 2025
Cited by 1 | Viewed by 1399
Abstract
Schizophrenia is a complex psychiatric disorder of complex etiology. Despite decades of antipsychotic drug development and treatment, the mechanisms underlying cellular drug effects remain incompletely understood. Induced pluripotent stem cell (iPSC)-based disease and pharmacological modelling offer new avenues for drug development. In this [...] Read more.
Schizophrenia is a complex psychiatric disorder of complex etiology. Despite decades of antipsychotic drug development and treatment, the mechanisms underlying cellular drug effects remain incompletely understood. Induced pluripotent stem cell (iPSC)-based disease and pharmacological modelling offer new avenues for drug development. In this study, we explored the development of two- and three-dimensional neural progenitor cultures and the impact of different antipsychotics in a schizophrenia model. Four human iPSC lines, including two carrying a de novo ZMYND11 gene mutation associated with schizophrenia, were differentiated into hippocampal neural progenitor cells (NPCs), cultured either in monolayers or as 3D spheroids. While in monolayers the proliferation of the NPCs was similar, spheroids showed significant differences in scattered cell number and outgrowth size between schizophrenia mutant and wild-type NPCs. Since there is only limited information about the effects of antipsychotic agents on neural progenitor cell proliferation and differentiation, we investigated the effects of three molecules, representing three subgroups of antipsychotics, in the 2D and 3D NPC models. Our findings suggest that cell adhesion may play a crucial role in the molecular disease pathways of schizophrenia, highlighting the value of spheroid models for mechanistic and drug development studies. These studies may significantly help our understanding of the effects of schizophrenia on neural development and the response of progenitors to antipsychotic medications. Full article
(This article belongs to the Special Issue Molecular Underpinnings of Schizophrenia Spectrum Disorders)
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12 pages, 589 KB  
Article
The Association of Resistin with Metabolic Health and Obesity in a Mexican-American Population
by Reem Al-Dallal, Keziah Thomas, MinJae Lee, Aysha Chaudhri, Eleanor Davis, Priyanka Vaidya, Miryoung Lee, Joseph B. McCormick, Susan P. Fisher-Hoch and Absalon D. Gutierrez
Int. J. Mol. Sci. 2025, 26(9), 4443; https://doi.org/10.3390/ijms26094443 - 7 May 2025
Cited by 1 | Viewed by 954
Abstract
Research on the relationship between resistin levels, metabolic health, and obesity has produced inconsistent findings across different ethnic groups, making it unclear whether lower resistin levels are associated with these conditions in Mexican-Americans. This cross-sectional study investigated the relationship between resistin, metabolic health, [...] Read more.
Research on the relationship between resistin levels, metabolic health, and obesity has produced inconsistent findings across different ethnic groups, making it unclear whether lower resistin levels are associated with these conditions in Mexican-Americans. This cross-sectional study investigated the relationship between resistin, metabolic health, and obesity in an adult Mexican-American cohort (n = 1511) using multivariable linear regression analysis. Related adipokines (leptin and adiponectin) were measured simultaneously. Participants were categorized into four groups by metabolic health (healthy/unhealthy) and obesity (obese/non-obese) status. “Metabolically unhealthy” was defined as ≥2 cardiometabolic abnormalities. Obesity was defined as a BMI ≥ 30 kg/m2. We also investigated the associations of related proinflammatory cytokines, demographic/anthropometric variables, and medications with each outcome variable of interest. The results showed no statistically significant differences in resistin levels between the groups. Leptin was higher and adiponectin was lower in groups with obesity and/or metabolically unhealthy status. The resistin findings contrast studies in other populations, while other leptin and adiponectin findings confirm those seen in many ethnic groups. Thiazolidinedione use was associated with lower resistin, confirming earlier research. These findings suggest that resistin’s role in metabolic health may be different in Mexican-Americans compared to other populations. Full article
(This article belongs to the Special Issue Cytokines in Inflammatory Signaling: 2nd Edition)
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18 pages, 5594 KB  
Article
Intradermal Injection of a Protein Alone Without Additional Adjuvants Using a Needle-Free Pyro-Drive Jet Injector Induces Potent CD8+ T Cell-Mediated Antitumor Immunity
by Jukito Sonoda, Izuru Mizoguchi, Natsuki Yamaguchi, Eri Horio, Satomi Miyakawa, Mingli Xu, Toshihiko Yoneto, Yasuhiro Katahira, Hideaki Hasegawa, Takashi Hasegawa, Kunihiko Yamashita and Takayuki Yoshimoto
Int. J. Mol. Sci. 2025, 26(9), 4442; https://doi.org/10.3390/ijms26094442 - 7 May 2025
Cited by 1 | Viewed by 1446
Abstract
Vaccines usually contain an adjuvant that activates innate immunity to promote the acquisition of adaptive immunity. Aluminum and lipid nanoparticles have been used for this purpose, but their accumulation or widespread circulation in the body can lead to adverse effects. In contrast, physical [...] Read more.
Vaccines usually contain an adjuvant that activates innate immunity to promote the acquisition of adaptive immunity. Aluminum and lipid nanoparticles have been used for this purpose, but their accumulation or widespread circulation in the body can lead to adverse effects. In contrast, physical adjuvants, which use physical energy to transiently stress tissues, do not persist in exposed tissues or cause lasting adverse effects. Herein, we investigate the effects of intradermal injection of endotoxin-free ovalbumin (OVA) protein alone without additional adjuvants using a needle-free pyro-drive jet injector (PJI) on tumor vaccination efficacy. Intradermal injection of OVA protein alone using PJI significantly increased OVA-specific CD8+ T cell expansion in the lymph node, although lymph node swelling was much less than when aluminum hydroxide was used. The injection also induced OVA-specific killing activity and antibody production and showed strong CD8+ T cell-dependent prophylactic antitumor effects against transplanted E.G7-OVA tumors. In particular, intradermal injection of the fluorescent OVA protein significantly enhanced its uptake by XCR1+ dendritic cells, which have a strong ability to cross-present extracellular proteins in the skin and draining lymph nodes. In addition, the injection increased the expression of HMGB1, one of the potent danger signals whose expression has been reported to increase in response to shear stress. Thus, intradermal injection of OVA protein alone without any additional adjuvants using PJI induces potent CD8+ T cell-mediated antitumor immunity by enhancing its uptake into XCR1+ dendritic cells, which have a high cross-presentation capacity accompanied by an increased expression of shear stress-induced HMGB1. Full article
(This article belongs to the Special Issue The Discovery and Characterization of New Oncological Molecules)
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13 pages, 3212 KB  
Case Report
Radiation-Induced Synchronous Parathyroid Carcinoma and Papillary Thyroid Carcinoma: Clinical, Morphological, and Genetic Insights
by Gábor Iványi, Alexandros Christofi, Gábor Sipka, Tamás Zombori, Levente Kuthi, Andrea Simon, Deján Dobi, György Lázár, Zsuzsanna Valkusz and Béla Iványi
Int. J. Mol. Sci. 2025, 26(9), 4441; https://doi.org/10.3390/ijms26094441 - 7 May 2025
Viewed by 1308
Abstract
The clinicopathological and molecular features of synchronous parathyroid carcinoma (PC) and thyroid carcinoma in a male patient are presented. At 11, he received mantle field radiotherapy for Hodgkin lymphoma. He had a 26-year adulthood history of recurrent nephrolithiasis treated five times with lithotripsy. [...] Read more.
The clinicopathological and molecular features of synchronous parathyroid carcinoma (PC) and thyroid carcinoma in a male patient are presented. At 11, he received mantle field radiotherapy for Hodgkin lymphoma. He had a 26-year adulthood history of recurrent nephrolithiasis treated five times with lithotripsy. At 52, he was referred to our clinic for hypercalcemia. Primary hyperparathyroidism was diagnosed (calcium: 3.46 mmol/L, parathormone: 150 pmol/L, preserved renal function, nephrolithiasis, and osteoporosis). Neck ultrasound revealed a 41 × 31 × 37 mm nodule in the left thyroid and smaller nodules in the right thyroid. Enlarged cervical lymph nodes were not observed. The large nodule was interpreted as parathyroid adenoma on 99Tc-pertechnetate scintigraphy/99Tc-MIBI scintigraphy with SPECT/CT. Total left-sided and subtotal right-sided thyroidectomy were performed. Histopathology confirmed locally invasive, low-grade PC (pT2; positive for parafibromin and E-cadherin, negative for galectin-3 and PGP9.5; wild-type expression for p53 and retinoblastoma protein; Ki-67 index 10%) and incidental papillary thyroid carcinoma (pT1b). Genetic profiling revealed no loss in CDC73, MEN1, CCND1, PIK3CA, CDH1, RB1, and TP53 genes. Deletions in CDKN2A, LATS1, ARID1A, ARID1B, RAD54L, and MUTYH genes and monosomies in nine chromosomes were identified. The tumor mutational burden and genomic instability score were low, and the tumor was microsatellite-stable. The thyroid carcinoma exhibited a TRIM24::BRAF fusion. Following surgery, the parathormone and calcium levels had normalized, and the patient underwent radioiodine treatment for thyroid cancer. The follow-up of 14 months was eventless. In summary, the clinical, laboratory, and imaging features of hyperparathyroidism taken together could have suggested malignancy, then confirmed histologically. The synchronous carcinomas were most likely caused by irradiation treatment diagnosed 41 years after exposure. It seems that the radiation injury initially induced parathyroid adenoma in young adulthood, which underwent a malignant transformation around age fifty. Full article
(This article belongs to the Section Molecular Oncology)
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16 pages, 1438 KB  
Article
The Effect of Reduced Dietary Protein on Adipose Tissue in Local Krškopolje Pigs
by Klavdija Poklukar, Marjeta Čandek-Potokar, Milka Vrecl, Jana Brankovič, Matjaž Uršič and Martin Škrlep
Int. J. Mol. Sci. 2025, 26(9), 4440; https://doi.org/10.3390/ijms26094440 - 7 May 2025
Viewed by 1021
Abstract
The Slovenian autochthonous breed, Krškopolje pig, is known for high fatness and better adaptability to different environmental conditions and feed resources. However, the metabolic processes underlying these adaptations, especially in response to different diets, have not yet been studied. A deeper understanding of [...] Read more.
The Slovenian autochthonous breed, Krškopolje pig, is known for high fatness and better adaptability to different environmental conditions and feed resources. However, the metabolic processes underlying these adaptations, especially in response to different diets, have not yet been studied. A deeper understanding of these mechanisms could provide valuable insights into the breed’s adaptability to different environmental conditions. Therefore, the main objective of this study was to evaluate the effect of a low-protein (LP) diet on adipose tissue in Krškopolje pigs reared in either organic outdoor (n = 2 × 12) or conventional indoor (n = 2 × 14) systems. In the outdoor system, the LP diet had no effect on adipocyte size compared to the control (high-protein) diet, while it increased lipogenic enzyme activities and monounsaturated fatty acid content, and decreased polyunsaturated fatty acid content (p < 0.05). RNA sequencing revealed the upregulation of 28 genes and the downregulation of 37 genes. The upregulated genes were mainly involved in lipid metabolism (ACLY, FASN, ACACA, MOGAT2), oxidative stress, and mitochondrial function. In the indoor system, pigs on the LP diet had smaller adipocytes (p < 0.05), whereas no differences were detected in the lipogenic enzyme activities or fatty acid composition (p > 0.10). RNA sequencing revealed 30 upregulated and 28 downregulated genes. In the indoor system, heat shock proteins (HSP70.2, HSPA6) were upregulated in pigs on the LP diet, while genes involved in the innate immune system (MSR1, TREM2, CSF3R) were downregulated. To conclude, the present study showed that LP diet affected adipose tissue metabolism and gene expression in Krškopolje pigs, with different transcriptomic responses observed in outdoor and indoor rearing conditions. Full article
(This article belongs to the Special Issue Adipose Tissue and Gene Expression)
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15 pages, 4436 KB  
Article
Transcriptomic Plasticity of Human Alveolar Macrophages Revealed by Single-Cell RNA Sequencing Following Drug Exposure: Implications for Therapeutic Development
by Penny L. Groves, Levi Hockey, Brendan J. O’Sullivan, Lai-Ying Zhang, Zherui Xiong, Quan H. Nguyen, Maxine E. Tan, Viviana P. Lutzky, Rohan A. Davis, Daniel C. Chambers and Simon H. Apte
Int. J. Mol. Sci. 2025, 26(9), 4439; https://doi.org/10.3390/ijms26094439 - 7 May 2025
Viewed by 2240
Abstract
Alveolar macrophages (AM) must perform three seemingly opposing roles including homeostasis, driving inflammation, and facilitating tissue repair. Whilst there is now consensus (supported by a large body of human single cell RNA sequencing (scRNA-seq) data) that the cell subsets that perform these tasks [...] Read more.
Alveolar macrophages (AM) must perform three seemingly opposing roles including homeostasis, driving inflammation, and facilitating tissue repair. Whilst there is now consensus (supported by a large body of human single cell RNA sequencing (scRNA-seq) data) that the cell subsets that perform these tasks can readily be found based on their transcriptome, their ontogeny has remained unclear. Moreover, there is agreement that in all types of pulmonary fibrosis (PF) there is an expanded population of profibrotic AM that may aberrantly drive PF. From a therapeutic viewpoint, there is great appeal in the notion that the transcriptional program in different AM subsets is not fixed but remains plastic and amenable to pharmacological reprogramming. Accordingly, this study addresses this question by performing scRNA-seq on human AM following treatment with drugs or perturbagens including pioglitazone, trametinib, nintedanib, lipopolysaccharide and the natural compound endiandrin A. Each treatment induced a unique global transcriptional change, driving the cells towards distinct subsets, further supported by trajectory analysis, confirming a high level of plasticity. Confirmatory experiments using qPCR demonstrated that single exposure to a compound induced a relatively stable transcriptome, whereas serial exposure to a different compound allowed the cells to be reprogrammed yet again to a different phenotype. These findings add new insight into the biology of AM and support the development of novel therapies to treat PF. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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22 pages, 48624 KB  
Article
Evaluation of the Efficacy of Three Antagonistic Bacteria Strains in the Management of Fire Blight
by Jianhui Zhang, Zhidong Zhang, Yue Wen, Jing Zhu, Abudusufuer Wufuerjiang and Jia Tian
Int. J. Mol. Sci. 2025, 26(9), 4438; https://doi.org/10.3390/ijms26094438 - 7 May 2025
Viewed by 1026
Abstract
Fire blight, caused by Erwinia amylovora, poses a significant threat to the sustainable development of the Korla Xiangli (Pyrus×sinkiangensis. Yu) industry. In this study, we used multiple experimental approaches to comprehensively evaluate the efficacy of three antagonistic bacterial strains—namely, Mg-7 [...] Read more.
Fire blight, caused by Erwinia amylovora, poses a significant threat to the sustainable development of the Korla Xiangli (Pyrus×sinkiangensis. Yu) industry. In this study, we used multiple experimental approaches to comprehensively evaluate the efficacy of three antagonistic bacterial strains—namely, Mg-7 (Leuconostoc mesenteroides), Rt-10 (Alcaligenes faecalis), and Rt-11 (Bacillus siamensis)—in controlling fire blight. In vitro plate inhibition assays revealed that Mg-7 exhibited the largest inhibition zone diameter, exceeding Rt-10 and Rt-11 in this respect, suggesting its strong antifungal potential. In therapeutic tests conducted on detached leaves, Mg-7 achieved the highest control efficiency, 60.39%, while Rt-10 demonstrated the greatest efficiency (76.96%) in protective tests. Conversely, in therapeutic trials focusing on detached branches, Mg-7 showed a control efficiency of 45.90%, whereas Rt-11 exhibited the highest efficiency, 86.27%, in protective trials. Furthermore, in vitro evaluations indicated that the Mg-7 treatment significantly reduced the lesion spread area. Enzymatic analyses revealed that, in the leaf protection assay, catalase activity (CAT) demonstrated significant increases of 65.56%, 85.46%, and 45.55% under the Mg-7, RT-10, and RT-11 treatments, respectively, when compared with the EA control group on day four. Correspondingly, in the branch protection assay, polyphenol oxidase (PPO) activity displayed marked elevations of 62.84%, 52.06%, and 82.69% under identical experimental conditions at the same time point. These treatments not only upregulated antioxidant enzyme activities but also significantly reduced malondialdehyde (MDA) content, effectively mitigating oxidative damage while enhancing foliar and branch resistance to fire blight infection. Field trials conducted in outdoor orchards confirmed that the Mg-7 bacterial suspension provided more effective and stable control against fire blight than Rt-10 and Rt-11. Overall, Mg-7 shows significant potential for use as a biocontrol agent for managing fire blight because of its high efficacy, stability, and ability to enhance plant defense responses. Full article
(This article belongs to the Section Molecular Microbiology)
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22 pages, 1544 KB  
Review
Interaction Between Neutrophils and Elements of the Blood–Brain Barrier in the Context of Multiple Sclerosis and Ischemic Stroke
by Anna Nowaczewska-Kuchta, Dominika Ksiazek-Winiarek and Andrzej Glabinski
Int. J. Mol. Sci. 2025, 26(9), 4437; https://doi.org/10.3390/ijms26094437 - 7 May 2025
Cited by 4 | Viewed by 2386
Abstract
The blood–brain barrier (BBB) is a semi-permeable membrane in physiological conditions, but in pathologies like multiple sclerosis (MS) and ischemic stroke (IS), its permeability increases. In this review, we focus on neutrophils and their interaction with cellular components of the BBB: endothelial cells [...] Read more.
The blood–brain barrier (BBB) is a semi-permeable membrane in physiological conditions, but in pathologies like multiple sclerosis (MS) and ischemic stroke (IS), its permeability increases. In this review, we focus on neutrophils and their interaction with cellular components of the BBB: endothelial cells (EC), pericytes (PC), and astrocytes (AC). Nowadays, neutrophils receive more attention, mostly due to advanced research techniques that show the complexity of their population. Additionally, neutrophils have the ability to secrete extracellular vesicles (EVs), reactive oxygen species (ROS) and cytokines, which both destroy and restore the BBB. Astrocytes, PCs, and ECs also have dual roles in the pathogenesis of MS and IS. The interaction between neutrophils and cellular components of the BBB provides us with a wider insight into the pathogenesis of common diseases in the central nervous system. Further, we comprehensively review knowledge about the influence of neutrophils on the BBB in the context of MS and IS. Moreover, we describe new therapeutic strategies for patients with MS and IS like cell-based therapies and therapies that use the neutrophil function. Full article
(This article belongs to the Special Issue New Insights into Immune Dysregulation Disorders)
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16 pages, 2473 KB  
Article
A 3D Co-Culture Scaffold Approach to Assess Spatially Fractionated Radiotherapy Bystander and Abscopal Immune Effects on Clonogenic Survival
by Nicholas Casteloes, Carrie D. House and Mauro Tambasco
Int. J. Mol. Sci. 2025, 26(9), 4436; https://doi.org/10.3390/ijms26094436 - 7 May 2025
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Abstract
Spatially fractionated radiotherapy (SFRT) offers a promising approach for debulking large tumors by delivering high-dose radiation to a fraction of the tumor volume. However, the complex tumor microenvironment necessitates models beyond traditional 2D cultures and resource-intensive animal studies for SFRT investigations. Three-dimensional (3D) [...] Read more.
Spatially fractionated radiotherapy (SFRT) offers a promising approach for debulking large tumors by delivering high-dose radiation to a fraction of the tumor volume. However, the complex tumor microenvironment necessitates models beyond traditional 2D cultures and resource-intensive animal studies for SFRT investigations. Three-dimensional (3D) scaffold-based models with an adequate cross-sectional area have emerged as uniquely suited platforms to bridge this gap, by providing a more realistic platform for GRID-based SFRT research. In this study, we employed a 3D co-culture scaffold model to dissect the contributions of the radiation-induced bystander effect, abscopal effect, and immune system response on clonogenic survival following GRID irradiation. MDA-MB-231 breast cancer cells were seeded on commercial 3D scaffolds and irradiated at a 20 Gy peak dose using lead grids with three- and six-hole patterns, exposing ~12.8% and 25.7% of the scaffold area, respectively. An assessment of reproductive cell survival revealed a significant bystander effect, as the survival was notably lower than predicted based solely on the directly irradiated fraction. Evidence of an abscopal effect was observed by culturing non-irradiated cells in media exposed to GRID irradiation. Furthermore, a co-culture with allogeneic peripheral blood mononuclear cells (PBMCs) modulated clonogenic survival, with an additive effect observed when combined with SFRT. These findings underscore the presence of a bystander effect in GRID radiotherapy and indicate an abscopal immune component, particularly with the three-hole GRID configuration. This study established the utility of in vitro 3D co-culture scaffolds as an effective model system for elucidating complex SFRT-mediated biological responses. Full article
(This article belongs to the Section Molecular Oncology)
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