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Volume 26
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Int. J. Mol. Sci., Volume 26, Issue 6 (March-2 2025) – 452 articles

Cover Story (view full-size image): Local disruption of iron homeostasis leading to oxidative stress is one of the main mechanisms of asbestos genotoxicity, although individual genetics also play a key role. Inhaled asbestos fibres dramatically impact on the iron homeostasis of alveoli and pleura. Once internalized by professional phagocytes, they sequester the host metal, causing the cell to perceive a functional iron deficiency. This event triggers a homeostatic response aimed at restoring the intracellular iron concentration. Only in a permissive context is this demand promptly satisfied, leading to a harmful iron overload. The ferroxidase hephaestin acts as a sensor for iron demand. Therefore, any functional variant altering iron sensing ability is likely to influence the individual responses to environmental carcinogens. View this paper
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17 pages, 1414 KiB  
Review
Extracellular Vesicles in the Mesenchymal Stem Cell/Macrophage Axis: Potential Targets for Inflammatory Treatment
by Zhen Che, Wenbin Yan and Qun Zhao
Int. J. Mol. Sci. 2025, 26(6), 2827; https://doi.org/10.3390/ijms26062827 - 20 Mar 2025
Viewed by 523
Abstract
Mesenchymal stem cells (MSCs) have been widely used for the treatment of autoimmune and inflammatory diseases due to their pluripotent differentiation potential and immunomodulatory function. Macrophage (Mφ) polarization also acts an essential and central role in regulating inflammation, basically the dynamic balance of [...] Read more.
Mesenchymal stem cells (MSCs) have been widely used for the treatment of autoimmune and inflammatory diseases due to their pluripotent differentiation potential and immunomodulatory function. Macrophage (Mφ) polarization also acts an essential and central role in regulating inflammation, basically the dynamic balance of pro-inflammatory M1-like (M1φ) and anti-inflammatory M2-like macrophages (M2φ), affecting the occurrence and progression of inflammatory diseases. Since a pivotal molecular crosstalk between MSCs and Mφ has been elucidated using in vitro and in vivo preclinical studies, we presume that the mesenchymal stem cell/macrophages axis (MSC/Mφ axis) acts an important role in pathophysiological mechanisms of inflammatory diseases and should be the potential therapeutic target. However, the crucial effects of EVs as intercellular communicators and therapeutic agents in the MSC/Mφ axis remains explorable. Therefore, this review elaborated on the mechanisms of EVs mediating the MSC/Mφ axis regulating inflammation in-depth, hoping to provide more references for related research in the future. Full article
(This article belongs to the Special Issue The Role of Extracellular Vesicles in Inflammatory Diseases)
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16 pages, 4723 KiB  
Review
An Emerging Perspective on the Role of Fascia in Complex Regional Pain Syndrome: A Narrative Review
by Carmelo Pirri, Nina Pirri, Lucia Petrelli, Caterina Fede, Raffaele De Caro and Carla Stecco
Int. J. Mol. Sci. 2025, 26(6), 2826; https://doi.org/10.3390/ijms26062826 - 20 Mar 2025
Viewed by 860
Abstract
Complex Regional Pain Syndrome (CRPS) is a debilitating pain disorder involving chronic inflammation, neural sensitization and autonomic dysfunction. Fascia, a highly innervated connective tissue, is increasingly recognized for its role in pain modulation, yet its contribution to CRPS remains underexplored. This narrative review [...] Read more.
Complex Regional Pain Syndrome (CRPS) is a debilitating pain disorder involving chronic inflammation, neural sensitization and autonomic dysfunction. Fascia, a highly innervated connective tissue, is increasingly recognized for its role in pain modulation, yet its contribution to CRPS remains underexplored. This narrative review synthesizes the current evidence on fascia’s involvement in CRPS pathophysiology and potential therapeutic strategies. A literature search was conducted in PubMed, Scopus and Web of Science, selecting studies on fascia, CRPS, inflammation, oxidative stress and autonomic dysfunction, with emphasis on recent experimental, anatomical and clinical research. Fascia contributes to CRPS through neuroinflammation, fibrosis and autonomic dysregulation. Its rich innervation facilitates peripheral and central sensitization, while inflammatory mediators drive fibrosis, reducing elasticity and exacerbating pain. Autonomic dysfunction worsens hypoxia and oxidative stress, fueling chronic dysfunction. Advances in sonoelastography provide new insights, while fascial manipulation and targeted therapies show promise in early studies. Fascia plays a key role in CRPS pathophysiology, yet its clinical relevance remains underexplored. Future research integrating imaging, molecular profiling and clinical trials is needed to develop evidence-based fascia-targeted interventions, potentially improving CRPS diagnosis and treatment. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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20 pages, 1096 KiB  
Case Report
Premutation Females with preFXTAS
by Valentina Liani, Carme Torrents, Elisa Rolleri, Nor Azyati Yusoff, Narueporn Likhitweerawong, Sydney Moore, Flora Tassone, Andrea Schneider, Ellery Santos, Hazel M. B. Biag, James A. Bourgeois, Kathryn E. Unruh, Matthew W. Mosconi and Randi J. Hagerman
Int. J. Mol. Sci. 2025, 26(6), 2825; https://doi.org/10.3390/ijms26062825 - 20 Mar 2025
Viewed by 573
Abstract
Fragile-X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurodegenerative disorder associated with the FMR1 gene premutation, characterized by the presence of 55 to 200 CGG triplet repeat expansions. Although the initial symptoms of FXTAS typically manifest in males around the age of 60 with [...] Read more.
Fragile-X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurodegenerative disorder associated with the FMR1 gene premutation, characterized by the presence of 55 to 200 CGG triplet repeat expansions. Although the initial symptoms of FXTAS typically manifest in males around the age of 60 with motor symptoms and cognitive deficits, the presentation and progression in females differ. Women, in fact, exhibit a higher prevalence of neuropsychiatric symptoms, with an earlier onset compared to the motor symptoms observed in men. The following article reports on ten cases of women with a diagnosis of FMR1 gene premutation, originating from two medical centers. All the women in the study exhibited neuropsychiatric symptoms and subtle neurological signs as common features. Symptoms typically observed in the male population, such as tremors and cerebellar ataxia, were either absent or significantly reduced in the female cohort. Conversely, there was a higher prevalence of neuropsychiatric symptoms among the women. Neurocognitive impairment was only minimally evident, with mild executive dysfunction and memory complaints noted in a subset of cases. For this reason, we propose the terminology preFXTAS or prodromic FXTAS to define a clinical presentation in women characterized by early manifestations of FXTAS that do not entirely fulfill the established diagnostic criteria but exhibit MRI evidence of white matter alterations suggesting the initiation of the disease process. The study underscores the importance of establishing new diagnostic criteria for FXTAS and, at the same time, developing new biomarkers and interview checklists/assessment scales dedicated to females. Full article
(This article belongs to the Special Issue Genetics and Molecular Mechanisms in Psychological and Neuropsychiatric Disorders)
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20 pages, 5919 KiB  
Article
Sustained Experimental Myopia Exacerbates the Effect of Eye Growth on Retinal Ganglion Cell Density and Function
by Carol Ren Lin, Reynolds Kwame Ablordeppey and Alexandra Benavente-Perez
Int. J. Mol. Sci. 2025, 26(6), 2824; https://doi.org/10.3390/ijms26062824 - 20 Mar 2025
Viewed by 478
Abstract
The aim of this study is to describe the effect that sustained myopic eye growth has on the cellular distribution and function of retinal ganglion cells as myopia progresses over time. Ganglion cell density and the photopic negative response (PhNR) were assessed using [...] Read more.
The aim of this study is to describe the effect that sustained myopic eye growth has on the cellular distribution and function of retinal ganglion cells as myopia progresses over time. Ganglion cell density and the photopic negative response (PhNR) were assessed using immunochemistry and electroretinography (ERG), respectively, on twelve common marmoset eyes (Callithrix jacchus). Myopia was induced in six eyes using negative defocus (three eyes from 2 to 6 months of age, 6-month-old myopes; three eyes from 2 to 12 months of age, 12-month-old myopes). These six treated eyes were compared to six age-matched control eyes. Marmosets induced with myopia for four months showed a reduced pan-retinal ganglion cell density, which continued to decrease in the peripapillary area of marmosets induced with sustained myopia for ten months. Ganglion cell density decreased as a function of axial length. Full-field ERGs revealed a dampening of the PhNR in the 12-month-old, but not 6-month-old myopes. The myopic changes observed in ganglion cell density and retinal function suggest a reorganization of the ganglion cell template during myopia development and progression that increases over time with sustained myopic eye growth and translates into functional alterations at later stages of myopia development in the absence of degenerative changes. It remains unknown whether these changes positively or negatively impact retinal function and health. Full article
(This article belongs to the Special Issue Advanced Research in Retina: 3rd Edition)
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19 pages, 3344 KiB  
Article
Proteomic Dynamics in the Interaction of Susceptible and Resistant Tomato Cultivars and Potato Cyst Nematodes
by Marek D. Koter, Marek Żurczak, Mateusz Matuszkiewicz, Magdalena Święcicka, Maciej Kotliński, Anna Barczak-Brzyżek and Marcin Filipecki
Int. J. Mol. Sci. 2025, 26(6), 2823; https://doi.org/10.3390/ijms26062823 - 20 Mar 2025
Viewed by 430
Abstract
This study investigates the proteomic dynamics in tomato cultivars with differing resistance to potato cyst nematodes (PCNs). Cyst-forming nematodes, significant agricultural pests, induce complex molecular responses in host plants, forming syncytia in roots for their nutrition. This research employs mass spectrometry to analyze [...] Read more.
This study investigates the proteomic dynamics in tomato cultivars with differing resistance to potato cyst nematodes (PCNs). Cyst-forming nematodes, significant agricultural pests, induce complex molecular responses in host plants, forming syncytia in roots for their nutrition. This research employs mass spectrometry to analyze the proteomes of infected and uninfected roots from susceptible (Moneymaker) and resistant (LA1792 and L10) tomato lines. Over 2800 high-confidence protein hits were identified, revealing significant differences in abundance between susceptible and resistant lines. Notably, resistant lines exhibited a higher number of newly expressed proteins compared to susceptible lines; however, the proportion of induced and suppressed proteins was strongly genotype-dependent. Gene ontology (GO) analysis highlighted that nematode infection in susceptible line significantly regulates many defense-related proteins, particularly those involved in oxidative stress, with a similar number being upregulated and downregulated. Some GO terms enriched among nematode-regulated proteins also indicate the involvement of programmed cell death (PCD)-related processes. The susceptible line exhibited a prevalence of downregulated proteins, among which defense associated GO terms were significantly overrepresented. Four proteins (APY2, NIA2, GABA-T, and AATP1) potentially crucial for nematode parasitism were identified and their Arabidopsis orthologs were studied. Mutant Arabidopsis lines showed altered nematode resistance, supporting the involvement of these proteins in plant defense. This study highlights the complexity of host-nematode interactions and emphasizes the importance of proteomic analyses in identifying key factors and understanding plant defense mechanisms. Full article
(This article belongs to the Special Issue Plant Response to Insects and Microbes 2.0)
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19 pages, 2996 KiB  
Review
GPCR Sense Communication Among Interaction Nematodes with Other Organisms
by Jie Wang, Changying Guo, Xiaoli Wei, Xiaojian Pu, Yuanyuan Zhao, Chengti Xu and Wei Wang
Int. J. Mol. Sci. 2025, 26(6), 2822; https://doi.org/10.3390/ijms26062822 - 20 Mar 2025
Viewed by 458
Abstract
Interactions between species give rise to chemical pathways of communication that regulate the interactions of transboundary species. The communication between nematodes and other species primarily occurs through the regulation of chemicals, with key species including plants, insects, bacteria, and nematode-trapping fungi that are [...] Read more.
Interactions between species give rise to chemical pathways of communication that regulate the interactions of transboundary species. The communication between nematodes and other species primarily occurs through the regulation of chemicals, with key species including plants, insects, bacteria, and nematode-trapping fungi that are closely associated with nematodes. G protein-coupled receptors (GPCRs) play a crucial role in interspecies communication. Certain flp genes, which function as GPCRs, exert varying degrees of influence on how nematodes interact with other species. These receptors facilitate the transmission of corresponding signals, thereby completing the interactions between species. This paper introduces the interactions between nematodes and other species and discusses the role of GPCRs in these organisms, contributing to a deeper understanding of the impact and significance of GPCRs in cross-border regulation between nematodes and other species. Furthermore, it is essential to leverage GPCRs in efforts to control pests. Full article
(This article belongs to the Special Issue Molecular Signalling in Multitrophic Systems Involving Arthropods)
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19 pages, 861 KiB  
Article
Prediction of 57Fe Mössbauer Nuclear Quadrupole Splittings with Hybrid and Double-Hybrid Density Functionals
by Yihao Zhang, Haonan Tang and Wenli Zou
Int. J. Mol. Sci. 2025, 26(6), 2821; https://doi.org/10.3390/ijms26062821 - 20 Mar 2025
Viewed by 329
Abstract
As a crucial parameter in Mössbauer spectroscopy, nuclear quadrupole splitting (NQS) exhibits a strong dependence on quantum chemistry methods, which makes accurate theoretical predictions challenging. Meanwhile, the continuous emergence of new density functionals presents opportunities to advance current NQS research. In this study, [...] Read more.
As a crucial parameter in Mössbauer spectroscopy, nuclear quadrupole splitting (NQS) exhibits a strong dependence on quantum chemistry methods, which makes accurate theoretical predictions challenging. Meanwhile, the continuous emergence of new density functionals presents opportunities to advance current NQS research. In this study, we evaluate the performance of eleven hybrid density functionals and twelve double-hybrid density functionals, selected from widely used functionals and newly developed functionals, in predicting the NQS values of the 57Fe nuclide for 32 iron-containing molecules within about 70 atoms. The calculations have incorporated scalar relativistic effects using the exact two-component (X2C) Hamiltonian. In general, the double-hybrid functional PBE-0DH demonstrates superior performance compared to the experimental values, achieving a mean absolute error (MAE) of 0.20 mm/s. Meanwhile, rSCAN38 is the best hybrid functional for our database with an MAE = 0.25 mm/s, and it offers a significant advantage in computational efficiency over PBE-0DH. The +/− sign of NQS has also been considered in our error statistics when it has a clear physical meaning; if neglected, the errors of many functionals decrease, but PBE-0DH and rSCAN38 remain unaffected. Notably, when calculating ferrocene [Fe(C5H5)2], which involves strong static correlations, all hybrid functionals that incorporate more than 10% exact exchange fail, while several double-hybrid functionals continue to deliver reliable results. In addition, we encountered two particularly challenging species characterized by strong static correlations: [Fe(H2O)5NO]2+ and FeO2−-porphyrin. Unfortunately, none of the density functionals tested in our study yielded satisfactory results for the two cases since the density functional theory (DFT) is a single-determinant approach, and it is imperative to explore large-scale multi-configurational methods for these species. This research offers valuable guidance for selecting density functionals in Mössbauer NQS calculations and serves as a reference point for the future development of new density functionals. Full article
(This article belongs to the Special Issue Advances in Density Functional Theory and Related Methods for Molecular Computational Chemistry)
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16 pages, 1844 KiB  
Article
Exploring the Potential of Optical Genome Mapping in the Diagnosis and Prognosis of Soft Tissue and Bone Tumors
by Alejandro Berenguer-Rubio, Esperanza Such, Neus Torres Hernández, Paula González-Rojo, Álvaro Díaz-González, Gayane Avetisyan, Carolina Gil-Aparicio, Judith González-López, Nicolay Pantoja-Borja, Luis Alberto Rubio-Martínez, Soraya Hernández-Girón, María Soledad Valera-Cuesta, Cristina Ramírez-Fuentes, María Simonet-Redondo, Roberto Díaz-Beveridge, Carolina de la Calva, José Vicente Amaya-Valero, Cristina Ballester-Ibáñez, Alessandro Liquori, Francisco Giner and Empar Mayordomo-Arandaadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2025, 26(6), 2820; https://doi.org/10.3390/ijms26062820 - 20 Mar 2025
Viewed by 570
Abstract
Sarcomas are rare malignant tumors of mesenchymal origin with a high misdiagnosis rate due to their heterogeneity and low incidence. Conventional diagnostic techniques, such as Fluorescence In Situ Hybridization (FISH) and Next-Generation Sequencing (NGS), have limitations in detecting structural variations (SVs), copy number [...] Read more.
Sarcomas are rare malignant tumors of mesenchymal origin with a high misdiagnosis rate due to their heterogeneity and low incidence. Conventional diagnostic techniques, such as Fluorescence In Situ Hybridization (FISH) and Next-Generation Sequencing (NGS), have limitations in detecting structural variations (SVs), copy number variations (CNVs), and predicting clinical behavior. Optical genome mapping (OGM) provides high-resolution genome-wide analysis, improving sarcoma diagnosis and prognosis assessment. This study analyzed 53 sarcoma samples using OGM. Ultra-high molecular weight (UHMW) DNA was extracted from core and resection biopsies, and data acquisition was performed with the Bionano Saphyr platform. Bioinformatic pipelines identified structural variations, comparing them with known alterations for each sarcoma subtype. OGM successfully analyzed 62.3% of samples. Diagnostic-defining alterations were found in 95.2% of cases, refining diagnoses and revealing novel oncogenic and tumor suppressor gene alterations. The challenges included DNA extraction and quality issues from some tissue samples. Despite these limitations, OGM proved to be a powerful diagnostic and predictive tool for bone and soft tissue sarcomas, surpassing conventional methods in resolution and scope, enhancing the understanding of sarcoma genetics, and enabling better patient stratification and personalized therapies. Full article
(This article belongs to the Special Issue Cancer Diagnosis and Treatment: Exploring Molecular Research)
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10 pages, 2004 KiB  
Article
Antiviral Activity of Berbamine Against Influenza A Virus Infection
by Won-Kyung Cho, Hee-Jeong Choi and Jin Yeul Ma
Int. J. Mol. Sci. 2025, 26(6), 2819; https://doi.org/10.3390/ijms26062819 - 20 Mar 2025
Viewed by 226
Abstract
Berbamine (BBM) is a bibenzyl isoquinoline present in the traditional Chinese herbal medicine Berberis amurensisis Rupr. The present study demonstrates that BBM exerts strong antiviral efficacy against influenza A virus (IAV) infection. We examined the anti-IAV effect of BBM using green fluorescent protein [...] Read more.
Berbamine (BBM) is a bibenzyl isoquinoline present in the traditional Chinese herbal medicine Berberis amurensisis Rupr. The present study demonstrates that BBM exerts strong antiviral efficacy against influenza A virus (IAV) infection. We examined the anti-IAV effect of BBM using green fluorescent protein (GFP)-expressing influenza A and H1N1 IAV. The fluorescence microscopy, fluorescence-activated cell sorting analysis, and plaque assay showed that BBM significantly hinders IAV infection. The immunofluorescence analysis confirmed the anti-influenza activity of BBM. From the time-of-addition and hemagglutination inhibition results, it is elucidated that the antiviral effect of BBM is closely related to its inhibitory effect against viral binding and entry at an early infection stage. Our findings imply that BBM has the potential to be developed as a potent antiviral drug against influenza viral infection. Full article
(This article belongs to the Special Issue Viral and Host Targets to Fight RNA Viruses)
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22 pages, 6944 KiB  
Article
Folic Acid Alleviates Hydrogen Peroxide-Induced Oxidative Stress in Bovine Placental Trophoblast Cells by Regulating the NRF2/mTOR Signaling Pathway
by Liyuan Shi, Zhisheng Wang, Jianxin Xiao, Rui Hu, Huawei Zou, Junmei Wang, Ziqi Yue, Quanhui Peng, Yahui Jiang, Bai Xue and Lizhi Wang
Int. J. Mol. Sci. 2025, 26(6), 2818; https://doi.org/10.3390/ijms26062818 - 20 Mar 2025
Viewed by 364
Abstract
As one of the important components of placental structure, the integrity of placental trophoblast cells is crucial for placental function. When oxidative stress continues to act on placental trophoblast cells, it can cause changes in placental structure and function. Research has shown that [...] Read more.
As one of the important components of placental structure, the integrity of placental trophoblast cells is crucial for placental function. When oxidative stress continues to act on placental trophoblast cells, it can cause changes in placental structure and function. Research has shown that folic acid (FA) has a certain alleviating effect on the functional damage of trophoblast cells caused by oxidative stress, but the mechanism of action is still unclear. Therefore, this study focuses on bovine placental trophoblast cells (BPTCs) to explore the effects and mechanisms by which FA regulates oxidative stress in cells, with the aim of providing a theoretical foundation for improving the reproductive performance of cows. The results show that, compared with the H2O2 group, the FA+ H2O2 group showed an increase in the cell proliferation index (PI), superoxide dismutase 2 (SOD2), glutathione peroxidase (GSH-px), and catalase (CAT) mRNA expression and total antioxidant capacity (T-AOC) of cells, while the content of reactive oxygen species (ROS) decreased. In addition, the mRNA expression of tight junction factors, nutrient transporters, placental functional factors, mammalian rapamycin (mTOR) and its downstream factors, and nuclear factor erythroid 2-related factor 2 (NRF2) and its downstream factors in the FA+ H2O2 group increased, while the protein abundance of nuclear NRF2 decreased. After treatment with the inhibitor ML385, it was found that the protective effect of FA on H2O2-induced cellular oxidative damage was alleviated. These results indicate that FA can regulate the NRF2/mTOR signaling pathway, promote the expression of antioxidant factors, and alleviate the damage to the cell barrier and nutrient transport function in BPTCs caused by oxidative stress. Full article
(This article belongs to the Section Molecular Biology)
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17 pages, 2978 KiB  
Article
Unraveling the Complex Genomic Interplay of Sickle Cell Disease Among the Saudi Population: A Case-Control GWAS Analysis
by Ali Alghubayshi, Dayanjan Wijesinghe, Deemah Alwadaani, Farjah H. Algahtani, Salah Abohelaika, Mohsen Alzahrani, Hussain H. Al Saeed, Abdullah Al Zayed, Suad Alshammari, Yaseen Alhendi, Barrak Alsomaie, Abdulmonem Alsaleh and Mohammad A. Alshabeeb
Int. J. Mol. Sci. 2025, 26(6), 2817; https://doi.org/10.3390/ijms26062817 - 20 Mar 2025
Viewed by 626
Abstract
Sickle cell disease (SCD) is a severe inherited blood disorder characterized by abnormal hemoglobin (HbS) that leads to varying degrees of severity, including chronic hemolysis, episodic vaso-occlusion, and damage to multiple organs, causing significant morbidity and mortality. While SCD is a monogenic disease, [...] Read more.
Sickle cell disease (SCD) is a severe inherited blood disorder characterized by abnormal hemoglobin (HbS) that leads to varying degrees of severity, including chronic hemolysis, episodic vaso-occlusion, and damage to multiple organs, causing significant morbidity and mortality. While SCD is a monogenic disease, its complications are influenced by polygenic factors. SCD prevalence is notably high in regions including the Middle East, with Saudi Arabia reporting significant cases, particularly in the Eastern Province. Most genetic factors associated with SCD outcomes have been identified in populations predominantly from Africa or of African ancestry. This study aims to identify genetic variants that characterize Saudi SCD patients with the potential to influence disease outcomes in this population. A multicenter case-control genome-wide association study (GWAS) was conducted involving 350 adult Saudi SCD patients and 202 healthy controls. Participants were genotyped using the Affymetrix Axiom array, covering 683,030 markers. Rigorous quality control measures were applied to ensure data integrity. Fisher’s exact was used to identify genetic variants with a significant difference in allele frequency (p < 5 × 10−8). Functional annotations and regulatory functions of variants were determined using the Ensembl Variant Effect Predictor (VEP) and RegulomeDB databases. The GWAS identified numerous significant genetic variants characterizing SCD cases in the Saudi population. These variants, distributed across multiple chromosomes, were found in genes with known functional consequences. A substantial proportion of the markers were detected in the olfactory receptor cluster, TRIM family, and HBB locus genes. Many of the identified genes were reported in previous studies showing significant associations with various SCD outcomes, including hemoglobin regulation, inflammation, immune response, and vascular function. The findings highlight the genetic complexity underlying SCD and its clinical manifestations. The identified variants suggest potential molecular biomarkers and therapeutic targets, enhancing our understanding of the molecular basis of SCD in the Saudi population. This is the first genetic analysis characterizing SCD patients compared to healthy individuals, uncovering genetic markers that could serve as diagnostic biomarkers and therapeutic targets. Given the known molecular mechanisms of the detected genetic loci, these provide a foundation for precision medicine in SCD management, highlighting the need for further studies to validate these results and explore their clinical implications. Full article
(This article belongs to the Special Issue Perspectives of Molecular Genetics and Genomics in Human Mendelian Diseases)
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22 pages, 4045 KiB  
Article
Differential Response and Recovery Dynamics of HSPC Populations Following Plasmodium chabaudi Infection
by Federica Bruno, Christiana Georgiou, Deirdre Cunningham, Lucy Bett, Marine A. Secchi, Samantha Atkinson, Sara González Antón, Flora Birch, Jean Langhorne and Cristina Lo Celso
Int. J. Mol. Sci. 2025, 26(6), 2816; https://doi.org/10.3390/ijms26062816 - 20 Mar 2025
Viewed by 398
Abstract
Severe infections such as malaria are on the rise worldwide, driven by both climate change and increasing drug resistance. It is therefore paramount that we better understand how the host responds to severe infection. Hematopoiesis is particularly of interest in this context because [...] Read more.
Severe infections such as malaria are on the rise worldwide, driven by both climate change and increasing drug resistance. It is therefore paramount that we better understand how the host responds to severe infection. Hematopoiesis is particularly of interest in this context because hematopoietic stem and progenitor cells (HSPCs) maintain the turnover of all blood cells, including all immune cells. Severe infections have been widely acknowledged to affect HSPCs; however, this disruption has been mainly studied during the acute phase, and the process and level of HSPC recovery remain understudied. Using a self-resolving model of natural rodent malaria, infection by Plasmodium chabaudi, here we systematically assess phenotypically defined HSPCs’ acute response and recovery upon pathogen clearance. We demonstrate that during the acute phase of infection the most quiescent and functional stem cells are depleted, multipotent progenitor compartments are drastically enlarged, and oligopotent progenitors virtually disappear, underpinned by dramatic, population-specific and sometimes unexpected changes in proliferation rates. HSPC populations return to homeostatic size and proliferation rate again through specific patterns of recovery. Overall, our data demonstrate that HSPC populations adopt different responses to cope with severe infection and suggest that the ability to adjust proliferative capacity becomes more restricted as differentiation progresses. Full article
(This article belongs to the Special Issue Hematopoietic System under Physiological Conditions and Following Hematopoietic Reconstitution or Stress: 2nd Edition)
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18 pages, 2075 KiB  
Article
Acute Effects of the Psychedelic Phenethylamine 25I-NBOMe in C57BL/6J Male Mice
by Sabrine Bilel, Cristina Miliano, Giorgia Corli, Marta Bassi, Massimo Trusel, Raffaella Tonini, Maria Antonietta De Luca and Matteo Marti
Int. J. Mol. Sci. 2025, 26(6), 2815; https://doi.org/10.3390/ijms26062815 - 20 Mar 2025
Viewed by 478
Abstract
25I-NBOMe (4-Iodo-2,5-dimethoxy-N-(2-methoxybenzyl) phenethylamine) is a synthetic psychedelic compound abused for its ambiguous legal state as a counterfeit lysergic acid diethylamide (LSD). 25I-NBOMe acts as a selective agonist of 5HT2A receptors leading to hallucinations, intoxications, and fatalities. Here, we assessed the rewarding properties [...] Read more.
25I-NBOMe (4-Iodo-2,5-dimethoxy-N-(2-methoxybenzyl) phenethylamine) is a synthetic psychedelic compound abused for its ambiguous legal state as a counterfeit lysergic acid diethylamide (LSD). 25I-NBOMe acts as a selective agonist of 5HT2A receptors leading to hallucinations, intoxications, and fatalities. Here, we assessed the rewarding properties of 25I-NBOMe and its behavioral and neurotoxic acute effects on the central nervous system of C57BL/6J mice. We evaluated the dopamine (DA) levels using in vivo microdialysis in the nucleus accumbens (NAc) shell after 25I-NBOMe (0.1–1 mg/kg i.p.) injection. We also investigated the effects of 25I-NBOMe (0.1–1 mg/kg i.p.) on locomotor activity, reaction time, and prepulse inhibition. Moreover, we assessed the acute 25I-NBOMe (1 µM) effects on synaptic transmission and plasticity in the medial prefrontal cortex (mPFC) by using ex vivo electrophysiology. Our findings suggest that 25I-NBOMe affects the DA transmission in NAc shell at the highest dose tested, increases the reaction time within 30 min after the administration, and disrupts the PPI. In slices, it prevents long-term synaptic potentiation (LTP) in the mPFC, an effect that could not be reverted by the co-administration of the selective 5HT2A antagonist (MDL100907). Overall, these findings provide valuable new insights into the effects of 25I-NBOMe and the associated risks of its use. Full article
(This article belongs to the Special Issue Toxicology of Psychoactive Drugs)
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15 pages, 1011 KiB  
Article
The Sequence [RRKLPVGRS] Is a Nuclear Localization Signal for Importin 8 Binding (NLS8): A Chemical Biology and Bioinformatics Study
by Athanasios A. Panagiotopoulos, Konstantina Kalyvianaki, Aikaterini Angelidaki, Dimitris Dellis, Christos A. Panagiotidis, Marilena Kampa and Elias Castanas
Int. J. Mol. Sci. 2025, 26(6), 2814; https://doi.org/10.3390/ijms26062814 - 20 Mar 2025
Viewed by 404
Abstract
Karyopherins, carrier proteins that recognize particular cargo protein patterns known as nuclear localization signals (NLSs), mediate the nuclear translocation of big proteins. In order to better understand the process of nuclear transport of proteins and create the groundwork for the development of innovative [...] Read more.
Karyopherins, carrier proteins that recognize particular cargo protein patterns known as nuclear localization signals (NLSs), mediate the nuclear translocation of big proteins. In order to better understand the process of nuclear transport of proteins and create the groundwork for the development of innovative treatments that specifically target importins, it is imperative to clarify the intricate interactions between nuclear transporters and their cargo proteins. Until recently, very few NLSs have been documented. In the current work, an in silico method was used to identify NLSs for importin 8. It was determined that the sequence RRKLPVGRS serves as a recognition motif for importin 8 binding a karyopherin that is involved in the nuclear transportation of several important proteins like AGOs, SMADs, RPL23A, and TFE3. The sequence was validated in vitro in the breast cancer cell line T47D. This work subscribes to the effort to clarify the intricate relationships between nuclear transporters and their cargo proteins, in order to better understand the mechanism of nuclear transport of proteins and lay the groundwork for the development of novel therapeutics that target particular importins and have an immediate translational impact. Full article
(This article belongs to the Special Issue Molecular Advances in Bioinformatics Analysis of Protein Properties)
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20 pages, 9092 KiB  
Article
NCKAP1 Inhibits the Progression of Renal Carcinoma via Modulating Immune Responses and the PI3K/AKT/mTOR Signaling Pathway
by Xin Zhang, Jianqing Ye, Lixiang Sun, Wanli Xu, Xiaomeng He, Juan Bao and Jin Wang
Int. J. Mol. Sci. 2025, 26(6), 2813; https://doi.org/10.3390/ijms26062813 - 20 Mar 2025
Viewed by 361
Abstract
Nck-associated protein 1 (NCKAP1) is critical for cytoskeletal functions and various cellular activities, and deregulation of NCKAP1 in many cancers significantly influences the outcomes of malignant diseases. However, the functions of NCKAP1 in the progression of renal cancer are yet unknown. To investigate [...] Read more.
Nck-associated protein 1 (NCKAP1) is critical for cytoskeletal functions and various cellular activities, and deregulation of NCKAP1 in many cancers significantly influences the outcomes of malignant diseases. However, the functions of NCKAP1 in the progression of renal cancer are yet unknown. To investigate the specific roles of NCKAP1 in the immune regulation and tumor progression of renal cancer, the expression of NCKAP1 and genetic variations were analyzed across cancer types at different pathological stages via UALCAN and cBioPortal. Immune cell infiltration in renal cancer was also assessed by ssGSEA and single-cell gene expression data from the GEO. RNA sequencing of NCKAP1-overexpressing 769P cells further examined the impact of NCKAP1 on kidney cancer. Our pancancer analyses revealed a complex NCKAP1 expression profile across various cancer types, with reduced levels in renal cancer patients linked to patient prognosis. CIBERSORT and single-cell RNA sequencing revealed the expression patterns of NCKAP1 in different cell lineages in renal cancer and a significant correlation between NCKAP1 and immune cell infiltration in the kidney tumor microenvironment. We further verified that NCKAP1 suppressed cancer cell growth and affected tumor development in renal cancer via the PI3K/AKT/mTOR signaling pathway. Our results indicate that NCKAP1 is a potential predictive marker and treatment target for renal cancer. Full article
(This article belongs to the Special Issue Kidney Diseases: Molecular Pathogenesis and Therapeutic Strategies—2nd Edition)
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9 pages, 801 KiB  
Case Report
Rare Case with Pathogenic Variant in DHX16 Gene Causing Neuromuscular Disease and Oculomotor Anomalies
by Stefania Kalampokini, Dimitrios G. Goulis, Georgia Pepe, Stavrenia Koukoula, Antonis Frontistis, Maria Moschou, Marianthi Arnaoutoglou, Vasileios Papaliagkas and Vasilios K. Kimiskidis
Int. J. Mol. Sci. 2025, 26(6), 2812; https://doi.org/10.3390/ijms26062812 - 20 Mar 2025
Viewed by 304
Abstract
The DEAD/DExD/H-box RNA helicases are a group of RNA-binding proteins involved in the metabolism of mRNAs. They coordinate gene expression programs and play a role in cellular signaling, fate, and survival. We describe a case of a 36-year-old female with neuromuscular disease, sensorineural [...] Read more.
The DEAD/DExD/H-box RNA helicases are a group of RNA-binding proteins involved in the metabolism of mRNAs. They coordinate gene expression programs and play a role in cellular signaling, fate, and survival. We describe a case of a 36-year-old female with neuromuscular disease, sensorineural hearing loss, retinitis pigmentosa, and primary ovarian insufficiency harboring a heterozygous de novo missense pathogenic variant in the DEAH-box helicase 16 (DHX16) gene. This is the first case exhibiting a high intellectual level and the highest survival outcome so far. Eight previous cases of DHX16 disease-causing variant carriers have been described with common features, including muscle weakness with hypotonia, myopathy or peripheral neuropathy, sensorineural hearing loss, abnormal retinal findings, and infantile spasms or epilepsy. Increasing evidence associates RNA-binding proteins, including the DEAD/DExD/H-box helicase family genes, with neuropsychiatric or neurodevelopmental disorders. DHX16 genetic analysis should be considered early when diagnosing a child or young adult with muscular disease, severe hearing loss, and ocular anomalies. Full article
(This article belongs to the Special Issue Neurophysiology and Genetics of Neurological Diseases)
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21 pages, 3211 KiB  
Article
Generation of New Knock-Out Mouse Strains of Lysophosphatidic Acid Receptor 1
by Georgia Antonopoulou, Christiana Magkrioti, Ismini Chatzidaki, Dimitris Nastos, Sofia Grammenoudi, Konstantinos Bozonelos and Vassilis Aidinis
Int. J. Mol. Sci. 2025, 26(6), 2811; https://doi.org/10.3390/ijms26062811 - 20 Mar 2025
Viewed by 343
Abstract
The lysophosphatidic acid receptor 1 (LPAR1) is one of the six cognate G protein-coupled receptors of the bioactive, growth factor-like phospholipid lysophosphatidic acid (LPA). LPAR1 is widely expressed in different cell types and mediates many LPA effects. LPAR1 has been implicated in several [...] Read more.
The lysophosphatidic acid receptor 1 (LPAR1) is one of the six cognate G protein-coupled receptors of the bioactive, growth factor-like phospholipid lysophosphatidic acid (LPA). LPAR1 is widely expressed in different cell types and mediates many LPA effects. LPAR1 has been implicated in several chronic inflammatory diseases, and especially pulmonary fibrosis, where it has been established as a promising therapeutic target. Herein, we present the generation of several Lpar1 mouse strains through genetic recombination. These strains include an initial versatile Lpar1 strain (tm1a) from which three other strains derive: an Lpar1 reporter knockout strain (tm1b) where LacZ has replaced exon 3 of Lpar1; a “floxed” Lpar1 strain (tm1c), where exon 3 is flanked by two loxP sites allowing conditional, cell-specific Lpar1 inactivation; and a complete KO strain of Lpar1 (tm1d), where exon 3 has been deleted. The generated strains are novel genetic tools, that can have various applications in studying LPA-LPAR1 signaling and its role in normal physiology and disease. Full article
(This article belongs to the Collection Feature Papers in Molecular Genetics and Genomics)
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20 pages, 644 KiB  
Article
Effects of Different Intensities of Endurance Training on Neurotrophin Levels and Functional and Cognitive Outcomes in Post-Ischaemic Stroke Adults: A Randomised Clinical Trial
by Sara Górna, Tomasz Podgórski, Paweł Kleka and Katarzyna Domaszewska
Int. J. Mol. Sci. 2025, 26(6), 2810; https://doi.org/10.3390/ijms26062810 - 20 Mar 2025
Viewed by 434
Abstract
This study aimed to examine the effects of different intensities of endurance training combined with standard neurorehabilitation on selected blood biomarkers and physical outcomes of post-stroke individuals. We randomised patients with first-episode ischaemic stroke to an experimental group that received 4 × 45 [...] Read more.
This study aimed to examine the effects of different intensities of endurance training combined with standard neurorehabilitation on selected blood biomarkers and physical outcomes of post-stroke individuals. We randomised patients with first-episode ischaemic stroke to an experimental group that received 4 × 45 min sessions of moderate-intensity continuous training (MICT) each week and 2 × 45 min of standard rehabilitation each day or to a control group that received 4 × 45 min sessions of low-intensity continuous training (LICT) each week and 2 × 45 min of standard rehabilitation each day. We measured the following outcomes at baseline and 3 weeks after the intervention: aerobic capacity; cognitive and motor function; and blood levels of brain-derived neurotrophic factor (BDNF), glial cell line–derived neurotrophic factor (GDNF), vascular endothelial growth factor A (VEGF-A), insulin-like growth factor-1 (IGF-1), and irisin. We included 52 patients with a mean age of 66.1 ± 8.0 years. After 3 weeks of rehabilitation, there was a clinically significant improvement in the Rivermead Motor Assessment—arm score in the MICT group. The study showed that after 3 weeks, an intervention combining MICT with standard neurorehabilitation was significantly more beneficial in improving aerobic capacity and arm motor function than an intervention combining LICT and standard neurorehabilitation. Full article
(This article belongs to the Special Issue Neurotrophins: Roles and Function in Human Diseases 2.0)
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22 pages, 3496 KiB  
Review
Carbon Monoxide and Prokaryotic Energy Metabolism
by Vitaliy B. Borisov and Elena Forte
Int. J. Mol. Sci. 2025, 26(6), 2809; https://doi.org/10.3390/ijms26062809 - 20 Mar 2025
Viewed by 444
Abstract
Carbon monoxide (CO) plays a multifaceted role in both physiology and pathophysiology. At high levels, it is lethal to humans due to its tight binding to globins and cytochrome c oxidase. At low doses, CO can exhibit beneficial effects; it serves as an [...] Read more.
Carbon monoxide (CO) plays a multifaceted role in both physiology and pathophysiology. At high levels, it is lethal to humans due to its tight binding to globins and cytochrome c oxidase. At low doses, CO can exhibit beneficial effects; it serves as an endogenous signaling molecule and possesses antibacterial properties, which opens up possibilities for its use as an antimicrobial agent. For this purpose, research is in progress to develop metal-based CO-releasing molecules, metal-free organic CO prodrugs, and CO-generating hydrogel microspheres. The energy metabolism of prokaryotes is a key point that may be targeted by CO to kill invading pathogens. The cornerstone of prokaryotic energy metabolism is a series of membrane-bound enzyme complexes, which constitute a respiratory chain. Terminal oxidases, at the end of this chain, contain hemes and are therefore potential targets for CO. However, this research area is at its very early stage. The impact of CO on bacterial energy metabolism may also provide a basis for biotechnological applications in which this gas is present. This review discusses the molecular basis of the effects of CO on microbial growth and aerobic respiration supported by different terminal oxidases in light of recent findings. Full article
(This article belongs to the Special Issue Latest Review Papers in Biochemistry 2024)
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18 pages, 4146 KiB  
Article
Identification and Assessment of lncRNAs and mRNAs in PM2.5-Induced Hepatic Steatosis
by Peixuan Tian, Hui Xia, Xinbao Li, Ying Wang, Bihuan Hu, Yu Yang, Guiju Sun and Jing Sui
Int. J. Mol. Sci. 2025, 26(6), 2808; https://doi.org/10.3390/ijms26062808 - 20 Mar 2025
Viewed by 392
Abstract
Research indicates that fine particulate matter (PM2.5) exposure is associated with the onset of non-alcoholic fatty liver disease (NAFLD), the most prevalent chronic liver disorder. However, the underlying pathogenesis mechanisms remain to be fully understood. Our study investigated the hub long non-coding RNAs [...] Read more.
Research indicates that fine particulate matter (PM2.5) exposure is associated with the onset of non-alcoholic fatty liver disease (NAFLD), the most prevalent chronic liver disorder. However, the underlying pathogenesis mechanisms remain to be fully understood. Our study investigated the hub long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) associated with hepatic steatosis caused by PM2.5 exposure and their pathological mechanisms. The analysis of gene profiles in the GSE186900 dataset from the Gene Expression Omnibus (GEO) enabled the identification of 38 differentially expressed lncRNAs and 1945 mRNAs. To explore further, a co-expression network was established utilizing weighted gene co-expression network analysis (WGCNA). Moreover, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases were utilized for functional enrichment analysis. Our analysis identified specific modules, particularly the blue and turquoise modules, which showed a strong correlation with NAFLD. Through functional enrichment analysis, we identified several lncRNAs (including Gm15446, Tmem181b-ps, Adh6-ps1, Gm5848, Zfp141, Rmrp, and Rb1) which may be involved in modulating NAFLD, multiple metabolic pathways, inflammation, cell senescence, apoptosis, oxidative stress, and various signaling pathways. The hub lncRNAs identified in our study provide novel biomarkers and potential targets for the diagnosis and treatment of NAFLD. Full article
(This article belongs to the Special Issue Chronic Liver Disease: From Pathophysiology to Treatment)
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11 pages, 1391 KiB  
Article
DNA Demethylase ROS1 Interferes with DNA Methylation and Activates Stress Response Genes in Plants Infected with Beet Severe Curly Top Virus
by Taicheng Jin, Yushuo Li, Xu Sun, Yidi Li, Zhuyi Xiao, Weiyan Wang, Jiaxue Yu and Liping Yang
Int. J. Mol. Sci. 2025, 26(6), 2807; https://doi.org/10.3390/ijms26062807 - 20 Mar 2025
Viewed by 225
Abstract
DNA methylation is one mechanism of epigenetic regulation in plants. Small interfering RNAs (siRNAs) targeted endogenous genes and caused the promoters to be hypermethylated, namely RNA-directed DNA methylation (RdDM). Repressor of silencing 1 (ROS1) is an active DNA demethylase involved in the regulation [...] Read more.
DNA methylation is one mechanism of epigenetic regulation in plants. Small interfering RNAs (siRNAs) targeted endogenous genes and caused the promoters to be hypermethylated, namely RNA-directed DNA methylation (RdDM). Repressor of silencing 1 (ROS1) is an active DNA demethylase involved in the regulation of DNA methylation. This study indicates that ROS1-mediated DNA demethylation plays important roles in regulating the expression of these stress response genes and in response to biotic stresses. Further experiments confirmed that the expression level of the ROS1 gene was significantly upregulated in A. thaliana plants infected with beet severe curly top virus (BSCTV). Moreover, the DNA sequencing results demonstrated that ROS1 interferes with DNA methylation of repeat regions in the promoters of ACD6, GSTF14, and ACO3 in A. thaliana plants infected with BSCTV. These findings reveal the epigenetic mechanisms by which ROS1 regulates the expression of the stress response genes, thereby improving the adaptability of plants to biotic stresses. Full article
(This article belongs to the Special Issue Physiology and Molecular Biology of Plant Stress Tolerance: 2nd Edition)
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12 pages, 2075 KiB  
Article
SurvDB: Systematic Identification of Potential Prognostic Biomarkers in 33 Cancer Types
by Zejun Wu, Congcong Min, Wen Cao, Feiyang Xue, Xiaohong Wu, Yanbo Yang, Jianye Yang, Xiaohui Niu and Jing Gong
Int. J. Mol. Sci. 2025, 26(6), 2806; https://doi.org/10.3390/ijms26062806 - 20 Mar 2025
Viewed by 352
Abstract
The identification of cancer prognostic biomarkers is crucial for predicting disease progression, optimizing personalized therapies, and improving patient survival. Molecular biomarkers are increasingly being identified for cancer prognosis estimation. However, existing studies and databases often focus on single-type molecular biomarkers, deficient in comprehensive [...] Read more.
The identification of cancer prognostic biomarkers is crucial for predicting disease progression, optimizing personalized therapies, and improving patient survival. Molecular biomarkers are increasingly being identified for cancer prognosis estimation. However, existing studies and databases often focus on single-type molecular biomarkers, deficient in comprehensive multi-omics data integration, which constrains the comprehensive exploration of biomarkers and underlying mechanisms. To fill this gap, we conducted a systematic prognostic analysis using over 10,000 samples across 33 cancer types from The Cancer Genome Atlas (TCGA). Our study integrated nine types of molecular biomarker-related data: single-nucleotide polymorphism (SNP), copy number variation (CNV), alternative splicing (AS), alternative polyadenylation (APA), coding gene expression, DNA methylation, lncRNA expression, miRNA expression, and protein expression. Using log-rank tests, univariate Cox regression (uni-Cox), and multivariate Cox regression (multi-Cox), we evaluated potential biomarkers associated with four clinical outcome endpoints: overall survival (OS), disease-specific survival (DSS), disease-free interval (DFI), and progression-free interval (PFI). As a result, we identified 4,498,523 molecular biomarkers significantly associated with cancer prognosis. Finally, we developed SurvDB, an interactive online database for data retrieval, visualization, and download, providing a comprehensive resource for biomarker discovery and precision oncology research. Full article
(This article belongs to the Special Issue Genetic and Epigenetic Analyses in Cancer)
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16 pages, 2241 KiB  
Article
A Two-Phage Cocktail Modulates Gut Microbiota Composition and Metabolic Profiles in an Ex Vivo Colon Model
by Sthefhany Nohemí Rodríguez-Arellano, Jean Pierre González-Gómez, Bruno Gomez-Gil, Marisela González-Ávila, Juan Ramón Palomera-Hernández, Elisa Barrón-Cabrera, Marcela de Jesús Vergara-Jiménez and Cristobal Chaidez
Int. J. Mol. Sci. 2025, 26(6), 2805; https://doi.org/10.3390/ijms26062805 - 20 Mar 2025
Viewed by 339
Abstract
Bacteriophage therapy is a promising approach for targeting antibiotic-resistant bacteria and modulating gut microbiota in metabolic diseases such as obesity. This study evaluated the impact of a two-phage cocktail on an ex vivo colonic simulation model of gut microbiota derived from obese individuals, [...] Read more.
Bacteriophage therapy is a promising approach for targeting antibiotic-resistant bacteria and modulating gut microbiota in metabolic diseases such as obesity. This study evaluated the impact of a two-phage cocktail on an ex vivo colonic simulation model of gut microbiota derived from obese individuals, both in its normalized state and after enrichment with Enterobacter cloacae, an obesity-related bacteria. Microbiological analyses confirmed that the phage cocktail remained active throughout the colonic regions over three digestion cycles and effectively reduced enterobacterial populations in the enriched microbiota. Metabarcoding of the 16S rRNA gene revealed that phage therapy did not significantly alter the abundance of dominant genera, but selectively reduced E. cloacae across all colonic regions. Alpha diversity was significantly affected only in the enriched microbiota, while beta diversity analysis indicated significant compositional shifts during therapy, with reduced dispersion in the final treatment stage. Short-chain fatty acid profiling demonstrated region- and group-specific metabolic responses, with increased lactic and butyric acid concentrations in the ascending colon of the enriched microbiota following phage treatment. This study provides the first ex vivo evidence that a two-phage cocktail can selectively eliminate E. cloacae while preserving overall microbiota structure and functionality. These findings establish a foundation for future in vivo studies exploring the role of phage therapy in reshaping gut microbial communities and metabolic profiles, highlighting its potential as a precision tool for managing gut dysbiosis in metabolic disorders. Full article
(This article belongs to the Special Issue Molecular Research on Bacteria)
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22 pages, 4175 KiB  
Article
TBG096 Ameliorates Memory Deficiency in AD Mouse Model via Promoting Neurogenesis and Regulation of Hsc70/HK2/PKM2/LAMP2A Signaling Pathway
by Danni Chen, Opeyemi B. Fasina, Jiahui Lin, Jiayuan Zeng, Majid Manzoor, Hiroshi Ohno, Lan Xiang and Jianhua Qi
Int. J. Mol. Sci. 2025, 26(6), 2804; https://doi.org/10.3390/ijms26062804 - 20 Mar 2025
Viewed by 394
Abstract
In previous studies, we isolated a series of novel gentisides with nerve growth factor (NGF)-mimic activities from Gentiana rigescens Franch and conducted continuous structure–activity relationship (SAR) studies. Recently, a lead compound named TBG096 was discovered with significant NGF-mimic activity, low toxicity, and ability [...] Read more.
In previous studies, we isolated a series of novel gentisides with nerve growth factor (NGF)-mimic activities from Gentiana rigescens Franch and conducted continuous structure–activity relationship (SAR) studies. Recently, a lead compound named TBG096 was discovered with significant NGF-mimic activity, low toxicity, and ability to pass through the blood–brain barrier (BBB). At the cell level, TBG096 exerts NGF-mimic activity by regulation of heat-shock cognate protein 70 (Hsc70) and downstream proteins. Subsequently, high-fat diet (HFD)-induced Alzheimer disease (AD) mouse models were used to evaluate the anti-AD efficacy of the compound. TBG096 significantly improved the memory dysfunction of AD mice at doses of 0.1, 5, and 20 mg/kg, respectively. In order to elucidate the mechanism of action of the compound against AD, the RNA-sequence analysis of transcriptomics, quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence staining, and Western blot analysis were performed using animal samples. TBG096 significantly increased the expression of the Wnt gene family (Wnt10b, Wnt5a, and Wnt1) and the number of mature neurons and newborn neurons in the hippocampus and cerebral cortex of AD mice, respectively. At the same time, it reduced the activity of microglia, astrocyte cells, and expression of inducible nitric oxide synthase (INOS) in the brain. Moreover, this compound significantly increased phosphorylated-adenosine 5′-monophosphate-activated protein kinase (AMPK), Hsc70, and lysosomal-associated membrane protein 2a (LAMP2A) and decreased the expression of hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), amyloid precursor protein (APP), microtubule-associated protein tau (Tau), phosphoryl-Tau, and β-amyloid (Aβ) at the protein level. These results suggest that TBG096 produced the NGF-mimic activity and the anti-AD effect via promoting neurogenesis and modification of the Hsc70/HK2/PKM2/LAMP2A signaling pathway, proposing a potential novel approach to counteracting cognitive decline by developing small molecules that promote neurogenesis and the Hsc70 signaling pathway. Full article
(This article belongs to the Topic Natural Products and Drug Discovery)
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21 pages, 2148 KiB  
Article
The Role of Rapid Curing on the Interrelationship Between Temperature Rise, Light Transmission, and Polymerisation Kinetics of Bulk-Fill Composites
by Danijela Marovic, Matej Par, Paulina Daničić, Ana Marošević, Gloria Bojo, Marta Alerić, Svenia Antić, Krunoslav Puljić, Ana Badovinac, Adrian C. Shortall and Zrinka Tarle
Int. J. Mol. Sci. 2025, 26(6), 2803; https://doi.org/10.3390/ijms26062803 - 20 Mar 2025
Viewed by 292
Abstract
The first seconds of light curing are crucial for the development of most properties of dental composites, especially for the 3s high-irradiance curing. This study investigated the influence of rapid high-irradiance curing on temporal development of temperature, transmittance and conversion of bulk-fill composites. [...] Read more.
The first seconds of light curing are crucial for the development of most properties of dental composites, especially for the 3s high-irradiance curing. This study investigated the influence of rapid high-irradiance curing on temporal development of temperature, transmittance and conversion of bulk-fill composites. Four materials were tested: Filtek One (FO), Tetric PowerFill (PFill), Tetric PowerFlow (PFlow) and SDR flow+ (SDR+) and cured with three curing units (LCU): Valo Cordles, Bluephase PowerCure and Translux Wave in 3s (3 W/cm2), 10s (1 W/cm2) and 20s (1 W/cm2) curing protocols. Light transmittance was measured at 2 and 4 mm, while temperature rise and polymerisation kinetics were evaluated at 4 mm depth during 5 min. Both light transmittance and temperature rise were greatest for SDR+ > PFlow > PFill > FO. The 20s curing protocol resulted in the highest degree of conversion (DC) for all materials and LCUs, but also contributed to the greatest temperature rise. Rapid curing with the 3s protocol caused the lowest temperature rise and the shortest time to reach maximum temperature. The polymerisation and temperature kinetics were strongly dependent on the material. The DC of PFill was statistically similar for 3s, 10s or 20s curing with BPC. Rapid curing is only recommended for materials developed for this purpose. Full article
(This article belongs to the Special Issue Molecular Engineering in Dental Restorative and Regenerative Materials)
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22 pages, 2085 KiB  
Review
Mechanotransduction and Skeletal Muscle Atrophy: The Interplay Between Focal Adhesions and Oxidative Stress
by Khaled Y. Kamal and Marina Trombetta-Lima
Int. J. Mol. Sci. 2025, 26(6), 2802; https://doi.org/10.3390/ijms26062802 - 20 Mar 2025
Viewed by 607
Abstract
Mechanical unloading leads to profound musculoskeletal degeneration, muscle wasting, and weakness. Understanding the specific signaling pathways involved is essential for uncovering effective interventions. This review provides new perspectives on mechanotransduction pathways, focusing on the critical roles of focal adhesions (FAs) and oxidative stress [...] Read more.
Mechanical unloading leads to profound musculoskeletal degeneration, muscle wasting, and weakness. Understanding the specific signaling pathways involved is essential for uncovering effective interventions. This review provides new perspectives on mechanotransduction pathways, focusing on the critical roles of focal adhesions (FAs) and oxidative stress in skeletal muscle atrophy under mechanical unloading. As pivotal mechanosensors, FAs integrate mechanical and biochemical signals to sustain muscle structural integrity. When disrupted, these complexes impair force transmission, activating proteolytic pathways (e.g., ubiquitin–proteasome system) that accelerate atrophy. Oxidative stress, driven by mitochondrial dysfunction and NADPH oxidase-2 (NOX2) hyperactivation, exacerbates muscle degeneration through excessive reactive oxygen species (ROS) production, impaired repair mechanisms, and dysregulated redox signaling. The interplay between FA dysfunction and oxidative stress underscores the complexity of muscle atrophy pathogenesis: FA destabilization heightens oxidative damage, while ROS overproduction further disrupts FA integrity, creating a self-amplifying vicious cycle. Therapeutic strategies, such as NOX2 inhibitors, mitochondrial-targeted antioxidants, and FAK-activating compounds, promise to mitigate muscle atrophy by preserving mechanotransduction signaling and restoring redox balance. By elucidating these pathways, this review advances the understanding of muscle degeneration during unloading and identifies promising synergistic therapeutic targets, emphasizing the need for combinatorial approaches to disrupt the FA-ROS feedback loop. Full article
(This article belongs to the Section Molecular Biology)
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13 pages, 7755 KiB  
Article
Identification of Cysteine synthase (Cys) Gene Family in Tomato (Solanum lycopersicum) and Functional of SlCys5 in Cold Stress Tolerance
by Rui Lv, Yan Gao, Xueying Yang, Xin Li, Chengyu Zhu, Fulei Mo and Kuihua Li
Int. J. Mol. Sci. 2025, 26(6), 2801; https://doi.org/10.3390/ijms26062801 - 20 Mar 2025
Viewed by 235
Abstract
Sulfur is an intermediate element in plants. It plays an important role in the growth and development of plants. Plant roots absorb sulfate from their external environment and produce cysteine under the catalysis of cysteine synthase. Cysteine is a synthetic precursor of sulfur-containing [...] Read more.
Sulfur is an intermediate element in plants. It plays an important role in the growth and development of plants. Plant roots absorb sulfate from their external environment and produce cysteine under the catalysis of cysteine synthase. Cysteine is a synthetic precursor of sulfur-containing metabolites and critical molecules including glutathione (GSH), methionine, vitamins, coenzymes, and antioxidants. It also plays a central role in plant stress resistance. In this study, we identified the Cys family genes in tomato and analyzed the expression of SlCys genes under cold stress. A bioinformatics analysis showed that the SlCys gene promoters were rich in cis-acting elements related to stress response. Transcriptome data analysis and qRT-PCR (real-time fluorescent quantitative polymerase chain reaction) experiments showed that SlCys5 may be the key gene in the Cys gene family for cold tolerance in tomato. After cold stress treatment, the SlCys5-silenced tomato plants were more sensitive to cold stress, and wilting was more severe than in control plants. Thus, SlCys5 is a positive regulator of cold tolerance in tomato. In this study, we elucidated the evolutionary pattern and functional differentiation of the Cys gene family in tomato, deepening our understanding of the regulatory mechanism of cold stress tolerance in plants. Full article
(This article belongs to the Special Issue Plant Adaptation Mechanisms to Stress: 2nd Edition)
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15 pages, 6304 KiB  
Article
Polydatin Alleviates Cyclophosphamide-Induced Mouse Immunosuppression by Promoting Splenic Lymphocyte Proliferation and Thymic T Cell Development and Differentiation
by Na Sun, Huimin Yan, Xiuping Liu, Xingdi Xu, Wei Zhao, Jing Zhang, Meng Wang, Yuxuan Liu and Lin Miao
Int. J. Mol. Sci. 2025, 26(6), 2800; https://doi.org/10.3390/ijms26062800 - 20 Mar 2025
Viewed by 240
Abstract
Immunosuppression increases disease risk, and the natural compound polydatin (PD) has been reported to modulate immune-related disorders. In cyclophosphamide-induced immunosuppressed mice, PD was evaluated for its immunomodulatory effects. Immune organ indices were measured, while H&E staining and ELISA assessed spleen pathology and serum [...] Read more.
Immunosuppression increases disease risk, and the natural compound polydatin (PD) has been reported to modulate immune-related disorders. In cyclophosphamide-induced immunosuppressed mice, PD was evaluated for its immunomodulatory effects. Immune organ indices were measured, while H&E staining and ELISA assessed spleen pathology and serum cytokine levels. The proliferation of splenic lymphocytes, both total and subpopulation, was determined using concanavalin A or lipopolysaccharide stimulation, with flow cytometry analyzing peripheral blood and splenic lymphocytes, thymic T cell subtypes, cell cycling, and bromodeoxyuridine incorporation. Western blotting was used to assess Ki67, PCNA expression, and MAPK activation. PD significantly alleviated cyclophosphamide-induced reductions in spleen and thymus indices, improved the organization of red and white pulp in the spleen, and restored TNF-α and IFN-γ levels. It reversed cyclophosphamide-induced cell cycle arrest, characterized by increased PCNA and decreased Ki67, and corrected the diminished numbers of B and T cells and the reduced CD4+/CD8+ ratio in the thymus. In vitro, PD directly promoted splenic lymphocyte proliferation and cell cycling via MAPK activation. Overall, our findings demonstrated that PD alleviated mouse immunosuppression by activating splenic lymphocyte proliferation and re-organizing thymic T cell development and differentiation. Full article
(This article belongs to the Section Molecular Pharmacology)
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16 pages, 2849 KiB  
Article
An In-Depth Exploration of the Autoantibody Immune Profile in ME/CFS Using Novel Antigen Profiling Techniques
by Arnaud Germain, Jillian R. Jaycox, Christopher J. Emig, Aaron M. Ring and Maureen R. Hanson
Int. J. Mol. Sci. 2025, 26(6), 2799; https://doi.org/10.3390/ijms26062799 - 20 Mar 2025
Viewed by 3870
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder characterized by serious physical and cognitive impairments. Recent research underscores the role of immune dysfunction, including the role of autoantibodies, in ME/CFS pathophysiology. Expanding on previous studies, we analyzed 7542 antibody–antigen interactions in ME/CFS [...] Read more.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder characterized by serious physical and cognitive impairments. Recent research underscores the role of immune dysfunction, including the role of autoantibodies, in ME/CFS pathophysiology. Expanding on previous studies, we analyzed 7542 antibody–antigen interactions in ME/CFS patients using two advanced platforms: a 1134 autoantibody Luminex panel from Oncimmune and Augmenta Bioworks, along with Rapid Extracellular Antigen Profiling (REAP), a validated high-throughput method that measures autoantibody reactivity against 6183 extracellular human proteins and 225 human viral pathogen proteins. Unlike earlier reports, our analysis of 172 participants revealed no significant differences in autoantibody reactivities between ME/CFS patients and controls, including against GPCRs such as β-adrenergic receptors. However, subtle trends in autoantibody ratios between male and female ME/CFS subgroups, along with patterns of herpesvirus reactivation, suggest the need for broader and more detailed exploration. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Autoimmune Disorders)
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17 pages, 2362 KiB  
Article
Gemcitabine–Doxorubicin Combination Polymer-Drug Conjugate Prepared by SPAAC Click Chemistry: In Vitro Characterization
by Omotola D. Gbadegesin and Simeon K. Adesina
Int. J. Mol. Sci. 2025, 26(6), 2798; https://doi.org/10.3390/ijms26062798 - 20 Mar 2025
Viewed by 275
Abstract
Combination chemotherapy is preferred for the treatment of ovarian cancer (OC). Systemic toxicity, however, frequently limits the effectiveness of treatment. Polymer–drug conjugates (PDCs) containing synergistic combinations of chemotherapeutic drugs can be used to enhance therapeutic efficacy. We earlier reported the use of a [...] Read more.
Combination chemotherapy is preferred for the treatment of ovarian cancer (OC). Systemic toxicity, however, frequently limits the effectiveness of treatment. Polymer–drug conjugates (PDCs) containing synergistic combinations of chemotherapeutic drugs can be used to enhance therapeutic efficacy. We earlier reported the use of a strain-promoted [3 + 2] azide–alkyne cycloaddition (SPAAC)-mediated polymerization method for the preparation of single-drug PDCs. In this report, the polymerization method was used to prepare gemcitabine–doxorubicin combination PDC. The PDC had a high molecular weight (Mw 1360 kDa) and high drug loading (36.6% weight gemcitabine; 7.0% weight doxorubicin). It demonstrated cathepsin B-catalyzed drug release at pH 5.0 and good hydrolytic stability at pH 7.4. The combination index analysis of free gemcitabine and free doxorubicin showed a concentration-dependent synergism (combination index < 1) in OVCAR-3 OC cells. Compared to individual gemcitabine PDC (the concentration that inhibited 50% growth (IC50) > 50 µg/mL) and doxorubicin PDC (IC50 = 1.79 µg/mL), the combination PDC (IC50 = 0.99 µg/mL) showed greater cytotoxicity against OVCAR-3 cells and was less cytotoxic than the equivalent free drug combination (IC50 = 0.11 µg/mL). The gemcitabine–doxorubicin combination PDC is promising for targeted combination chemotherapy of OC. Full article
(This article belongs to the Special Issue Gynecologic Oncology: Molecular Mechanisms and Therapies)
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