International Journal of Molecular Sciences

17 pages, 8612 KiB

Open AccessArticle

Single-Cell Transcriptomic Changes in Patient-Derived Glioma and U87 Glioblastoma Cell Cultures Infected with the Oncolytic Virus VV-GMCSF-Lact

by Dmitriy V. Semenov, Natalia S. Vasileva, Maxim E. Menyailo, Sergey V. Mishinov, Yulya I. Savinovskaya, Alisa B. Ageenko, Anna S. Chesnokova, Maya A. Dymova, Grigory A. Stepanov, Galina V. Kochneva, Vladimir A. Richter and Elena V. Kuligina

Int. J. Mol. Sci. 2025, 26(14), 6983; https://doi.org/10.3390/ijms26146983 (registering DOI) - 20 Jul 2025

Abstract

Oncolytic virotherapy is a rapidly evolving approach to cancer treatment. Our group previously designed VV-GMCSF-Lact, a recombinant oncolytic vaccinia virus targeting solid tumors including gliomas. In this study, we used single-cell RNA sequencing to compare transcriptional responses in human glioma cells, non-malignant brain [...] Read more.

Oncolytic virotherapy is a rapidly evolving approach to cancer treatment. Our group previously designed VV-GMCSF-Lact, a recombinant oncolytic vaccinia virus targeting solid tumors including gliomas. In this study, we used single-cell RNA sequencing to compare transcriptional responses in human glioma cells, non-malignant brain cells, and immortalized glioblastoma U87 MG cells following infection with this oncolytic virus. We found that proneural glioblastoma cells and microglia-like cells from patient-derived glioma cultures were the most susceptible to VV-GMCSF-Lact. Increased expressions of histones, translational regulators, and ribosomal proteins positively correlated with viral load at the transcript level. Furthermore, higher viral loads were accompanied by a large-scale downregulation of genes involved in mitochondrial translation, metabolism, and oxidative phosphorylation. Levels of early vaccinia virus transcripts are also positively correlated with infection intensity, suggesting that the fate of cells is determined at the early stage of infection. Full article

(This article belongs to the Section Molecular Oncology)

14 pages, 2367 KiB

Open AccessArticle

Beyond the Known: Expanding the Clinical and Genetic Spectrum of Rare RPL13-Related Spondyloepimetaphyseal Dysplasia

by Daria Gorodilova, Elena Dadali, Vladimir Kenis, Evgenii Melchenko, Daria Akimova, Maria Bulakh, Anna Orlova, Maria Orlova, Olga Shatokhina, Evgeniya Melnik, Marc Baud’huin, Mikhail Skoblov, Sergey Kutsev and Tatiana Markova

Int. J. Mol. Sci. 2025, 26(14), 6982; https://doi.org/10.3390/ijms26146982 (registering DOI) - 20 Jul 2025

Abstract

Spondyloepimetaphyseal dysplasia type Isidor-Toutain (RPL13-SEMD) is an autosomal dominant skeletal dysplasia caused by heterozygous pathogenic variants in the RPL13 gene, encoding the ribosomal protein eL13. To date, 13 pathogenic variants in RPL13 have been reported, all clustering within intron 5 and exon 6, [...] Read more.

Spondyloepimetaphyseal dysplasia type Isidor-Toutain (RPL13-SEMD) is an autosomal dominant skeletal dysplasia caused by heterozygous pathogenic variants in the RPL13 gene, encoding the ribosomal protein eL13. To date, 13 pathogenic variants in RPL13 have been reported, all clustering within intron 5 and exon 6, suggesting this hotspot region is critical for the function of ribosomes in skeletal tissues. Here, we present clinical and radiological characteristics of seven individuals, five children and two adults, from four unrelated families with RPL13-SEMD caused by two novel variants (c.477+5G>C and c.539_541del) and two previously reported variants (c.477+1G>C and c.548G>A) in RPL13. RNA analysis demonstrated that c.477+5G>C leads to a 54-nucleotide extension of exon 5, resulting in an 18-amino acid insertion. The phenotypic spectrum ranged from mild manifestations, such as Blount-like tibial deformity without significant short stature or Perthes-like femoral epiphyseal changes, to severe skeletal deformities with disproportionate short stature, accompanied by extraskeletal features (e.g., penoscrotal hypospadias, coccygeal abnormalities). For the first time, we describe Blount-like tibial deformity as a feature of this dysplasia, which resolves with age. Our study provides additional insights into the clinical, radiological, and genotypic features of RPL13-SEMD through detailed analysis of patients and their affected relatives. Full article

(This article belongs to the Special Issue Genetic and Genomic Diagnostics for Rare Diseases)

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19 pages, 2751 KiB

Open AccessArticle

Nano-Titanium Dioxide Induces Ovarian Function Damage in Mice by Mediating Granulosa Cell Apoptosis

by Jie Chen, Yaxuan Zhang, Shengbo Zhang, Changbao Wu, Jingyu Ren, Xiaoxiao You and Yanfeng Dai

Int. J. Mol. Sci. 2025, 26(14), 6981; https://doi.org/10.3390/ijms26146981 (registering DOI) - 20 Jul 2025

Abstract

The accumulation of nanoparticles (NPs) in the female body has raised global concerns regarding potential effects on the reproductive system. This study aimed to investigate the toxic effects of nano-titanium dioxide (nano-TiO₂) exposure on the ovaries and the underlying mechanisms. By [...] Read more.

The accumulation of nanoparticles (NPs) in the female body has raised global concerns regarding potential effects on the reproductive system. This study aimed to investigate the toxic effects of nano-titanium dioxide (nano-TiO₂) exposure on the ovaries and the underlying mechanisms. By establishing a nano-TiO₂ accumulation model in mice, our research systematically evaluated the effects of different concentrations of nano-TiO₂ exposure on the development and reproductive endocrine functions of mice. The results showed that nano-TiO₂ exposure significantly reduced the littering rate, sex hormone levels, and ovarian index of mice, and the effects were dose-dependent. Studies on the mechanisms involved revealed that nano-TiO₂ induces an excessive production of reactive oxygen species (ROS), leading to the potential collapse of the mitochondrial membrane and an increase in the apoptosis rate of granulosa cells, thereby triggering oxidative stress and inhibiting the expression of ovarian-specific genes and granulosa-cell function genes. This study reveals the “dual blow” mechanism of nano-TiO₂-mediated ovarian morphology and function through oxidative stress in granulosa cells, namely directly disrupting cellular homeostasis and interfering with the reproductive-related gene network, ultimately leading to decreased ovarian function. This provides experimental evidence for assessing the reproductive risks of nanomaterials in women. Full article

(This article belongs to the Section Molecular Nanoscience)

51 pages, 2539 KiB

Open AccessReview

Alzheimer’s Disease Etiology Hypotheses and Therapeutic Strategies: A Perspective

by Naomi Scarano, Francesca Musumeci, Beatrice Casini, Chiara Brullo, Pasqualina D’Ursi, Paola Fossa, Silvia Schenone and Elena Cichero

Int. J. Mol. Sci. 2025, 26(14), 6980; https://doi.org/10.3390/ijms26146980 (registering DOI) - 20 Jul 2025

Abstract

Alzheimer’s disease (AD) is a progressive, complex, multifactorial, neurodegenerative disease and accounts for most cases of dementia. The currently approved therapy includes cholinesterase inhibitors, NMDA-receptor antagonists and monoclonal antibodies. However, these medications were gradually discovered to be ineffective in removing the root of [...] Read more.

Alzheimer’s disease (AD) is a progressive, complex, multifactorial, neurodegenerative disease and accounts for most cases of dementia. The currently approved therapy includes cholinesterase inhibitors, NMDA-receptor antagonists and monoclonal antibodies. However, these medications were gradually discovered to be ineffective in removing the root of AD pathogenesis, having only symptomatic effects. Thus, the priority remains prevention and clarifying AD etiology. A better understanding of the neuroprotective mechanisms undertaken by specific genes is crucial to guide the design of novel therapeutic agents via selective ligands and precision medicine. In this review, we present a perspective of the physiological phase of the AD spectrum, of risk factors in AD with a focus on therapeutic approaches in three categories: neurotransmitters/ion modulations, peptide deposit control and aspecific treatments, followed by a discussion of treatment limitations. An overview of innovative strategies and non-pharmaceutical ancillary support is given. Full article

(This article belongs to the Special Issue Molecular Insight into Alzheimer’s Disease)

14 pages, 2021 KiB

Open AccessReview

New Advances in Small Molecules Targeted at Viral Capsid–Genome Binding

by Jiamei Li, Chengfeng Zhang, Benteng Li and Yuqing Wu

Int. J. Mol. Sci. 2025, 26(14), 6979; https://doi.org/10.3390/ijms26146979 (registering DOI) - 20 Jul 2025

Abstract

The capsid protein plays a crucial role in the viral life cycle. By interacting with the viral genome, it facilitates the assembly of the nucleocapsid, ultimately leading to the formation of the viral particle. Therefore, interfering with or disrupting the interaction between the [...] Read more.

The capsid protein plays a crucial role in the viral life cycle. By interacting with the viral genome, it facilitates the assembly of the nucleocapsid, ultimately leading to the formation of the viral particle. Therefore, interfering with or disrupting the interaction between the capsid protein and viral genome can effectively inhibit viral replication and infection. This review focuses on elucidating the binding mechanisms between the capsid protein and the viral genome, as well as their potential applications as therapeutic targets. In particular, it summarizes the research progress on small-molecule drugs targeting the capsid–genome binding sites of dengue virus, HBV, and SARS-CoV-2. Notably, this review provides a detailed discussion on the mechanisms by which these small-molecule inhibitors interfere with the capsid–genome interaction, aiming to offer inspiration for the future development of novel antiviral drugs targeting the capsid–genome binding. Full article

(This article belongs to the Special Issue Latest Review Papers in Macromolecules 2025)

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20 pages, 4456 KiB

Open AccessArticle

Exploring the Regulatory Mechanism of Total Alkaloids from Portulaca oleracea L. in UC Treatment Based on Network Pharmacology

by Tianci Zhang, Linran Gao, Qianying Wang, Jiahui Zheng, Xinyu Wang, Meng Jiang, Kaixin Wu and Jinxia Ai

Int. J. Mol. Sci. 2025, 26(14), 6978; https://doi.org/10.3390/ijms26146978 (registering DOI) - 20 Jul 2025

Abstract

This study aimed to investigate the potential mechanisms of action of total alkaloids from Portulaca oleracea L. (POL) on ulcerative colitis (UC) using a network pharmacology approach. Network pharmacology analysis identified two bioactive alkaloids within POL as primary anti-UC constituents, targeting 16 core [...] Read more.

This study aimed to investigate the potential mechanisms of action of total alkaloids from Portulaca oleracea L. (POL) on ulcerative colitis (UC) using a network pharmacology approach. Network pharmacology analysis identified two bioactive alkaloids within POL as primary anti-UC constituents, targeting 16 core therapeutic proteins and 113 UC-associated signaling pathways. To further explore the therapeutic effects, in vitro cell assays and in vivo animal experiments were conducted. In vitro, high concentrations of Portulaca oleracea total alkaloids (POAs) demonstrated dose-dependent cytotoxicity, significantly reducing Caco-2 cell viability and impairing migration. In a murine model of UC, disease induction led to substantial weight loss, elevated disease activity index (DAI) scores, colon shortening, and severe colonic tissue damage compared to controls. Furthermore, the UC group displayed significantly upregulated serum levels of pro-inflammatory cytokines, TNF-α and IL-1β, as well as increased protein and mRNA expression of TLR4 and NF-κB in colon tissues. Crucially, POAs treatment effectively ameliorated UC symptoms in mice, significantly reducing DAI scores, mitigating colon shortening, and markedly suppressing TLR4/NF-κB pathway activation. These findings strongly suggest that the therapeutic effects of POAs in UC are, at least in part, mediated by the inhibition of the TLR4/NF-κB signaling pathway, leading to a reduction in colonic inflammation. Full article

(This article belongs to the Section Molecular Pharmacology)

14 pages, 273 KiB

Open AccessArticle

Plasma Diacylglycerols Are Associated with Carotid Intima-Media Thickness Among Patients with Type 2 Diabetes: Findings from a Supercritical Fluid Chromatography/Mass Spectrometry-Based Semi-Targeted Lipidomic Analysis

by Naohiro Taya, Naoto Katakami, Kazuo Omori, Shigero Hosoe, Hirotaka Watanabe, Mitsuyoshi Takahara, Kazuyuki Miyashita, Yutaka Konya, Sachiko Obara, Ayako Hidaka, Motonao Nakao, Masatomo Takahashi, Yoshihiro Izumi, Takeshi Bamba and Iichiro Shimomura

Int. J. Mol. Sci. 2025, 26(14), 6977; https://doi.org/10.3390/ijms26146977 (registering DOI) - 20 Jul 2025

Abstract

Abnormalities in plasma lipoproteins observed in patients with diabetes promote atherosclerosis. However, the association between various lipid species and classes and atherosclerosis remains unclear. Here, we aimed to identify the plasma lipid characteristics associated with atherosclerosis progression in patients with diabetes. We performed [...] Read more.

Abnormalities in plasma lipoproteins observed in patients with diabetes promote atherosclerosis. However, the association between various lipid species and classes and atherosclerosis remains unclear. Here, we aimed to identify the plasma lipid characteristics associated with atherosclerosis progression in patients with diabetes. We performed semi-targeted lipidomic analysis of fasting plasma samples using supercritical fluid chromatography coupled with mass spectrometry in two independent patient groups with type 2 diabetes (n = 223 and 31) and evaluated cross-sectional associations between plasma lipids and carotid intima-media thickness (CIMT). Ten plasma lipid species, including eight diacylglycerols (DGs), and total DG levels were significantly associated with CIMT in both groups. Patients of the former group were partly observed for 5 years, and we investigated associations between DGs and CIMT progression in these patients (n = 101). As a result, 22 DGs among the 26 identified DGs and total DG (β = 0.398, p < 0.001) were significantly associated with the annual change in CIMT. Furthermore, plasma DG levels improved the predictive ability for CIMT progression, with an adjusted R-squared increase of 0.105 [95% confidence interval: 0.010, 0.232] in the models. Plasma DGs are associated with CIMT progression in patients with type 2 diabetes. Measurement of total plasma DG levels may be beneficial in assessing the risk of atherosclerosis progression. Full article

(This article belongs to the Special Issue Identification of Novel Biomarkers Towards Improved Diagnosis and Management of Peripheral Vascular Diseases)

18 pages, 2036 KiB

Open AccessArticle

Alterations in P-glycoprotein Expression in the Placenta of Obese Rats and Humans

by Péter Szatmári, Kata Kira Kemény, Andrea Surányi, Yakov Rachamim and Eszter Ducza

Int. J. Mol. Sci. 2025, 26(14), 6976; https://doi.org/10.3390/ijms26146976 (registering DOI) - 20 Jul 2025

Abstract

Obesity affects approximately 30% of pregnancies worldwide and is one of the leading metabolic disorders among pregnant women. Maternal obesity is often associated with placental dysfunction and structural alterations, which increase the risk of developing complications. Efflux transporters, including P-glycoprotein (P-gp), may impact [...] Read more.

Obesity affects approximately 30% of pregnancies worldwide and is one of the leading metabolic disorders among pregnant women. Maternal obesity is often associated with placental dysfunction and structural alterations, which increase the risk of developing complications. Efflux transporters, including P-glycoprotein (P-gp), may impact placental function and fetal development. Consequently, our research examined the effects of obesity on P-glycoprotein expression in both a rat model and human placental tissue. P-gp expression was measured by RT-PCR and Western blot techniques in human and rat placental tissues. Moreover, we further characterized the high-fat and high-sugar diet (HFHSD)-induced gestational obesity rat model by measuring tissue weights. Significant decreases were observed in fetal, placental, and uterus weights in the obese animals near the end of pregnancy. In obese rats, mRNA and protein expression of placental P-gp showed a reduction on gestation days 15, 20, and 22. A similar P-gp reduction was observed in the term placenta in obese women in mRNA and protein levels. We hypothesize that the reduced expression of P-gp may heighten the susceptibility of both the fetus and placenta to P-gp substrates. This alteration could potentially result in an increased risk of pregnancy complications and obesity-related drug contraindications linked to P-gp transport during pregnancy. Full article

(This article belongs to the Special Issue Molecular and Cellular Research in Pregnancy-Related Complications, 2nd Edition)

37 pages, 2605 KiB

Open AccessReview

Mechanistic Insight into the Antioxidant and Antimicrobial Activities of Palm Oil-Derived Biomaterials: Implications for Dental and Therapeutic Applications

by Syafira Masri, Nurulhuda Mohd, Noor Hayaty Abu Kasim and Masfueh Razali

Int. J. Mol. Sci. 2025, 26(14), 6975; https://doi.org/10.3390/ijms26146975 (registering DOI) - 20 Jul 2025

Abstract

Palm oil is a highly versatile natural resource that has gathered significant attention due to its bioactive properties, particularly its antimicrobial and antioxidant effects. Rich in tocotrienols, tocopherols, and carotenoids, palm oil exhibits potent antioxidant activity, while its fatty acid content and other [...] Read more.

Palm oil is a highly versatile natural resource that has gathered significant attention due to its bioactive properties, particularly its antimicrobial and antioxidant effects. Rich in tocotrienols, tocopherols, and carotenoids, palm oil exhibits potent antioxidant activity, while its fatty acid content and other bioactive molecules contribute to its antimicrobial efficacy against various pathogens. The underlying mechanisms of action driving these bioactivities involve intricate molecular interactions, biochemical pathways, and redox processes, which influence microbial cell function and oxidative stress reduction. This review provides a critical analysis of the current mechanistic understanding of palm oil’s biofunctional properties, emphasizing its potential incorporation into engineered biomaterials. Particular focus is given to the chemical composition, reaction pathways, and synergistic potential of palm oil derivatives in material-based formulations. Furthermore, the potential applications of palm oil as a standalone or synergistic agent in novel therapeutic and industrial formulations are explored. By elucidating the mechanistic basis of its bioactivity within material contexts, this review highlights palm oil’s promising role in the development of advanced functional materials for pharmaceutical and dental technologies. Full article

(This article belongs to the Special Issue Bone and Cartilage Injury and Repair: Molecular Aspects)

13 pages, 1201 KiB

Open AccessArticle

Disruption Events in the HPV18 E1 and E2 Genes in Precancerous Cervical Lesions

by Eirini Agnanti, Dimitris Tsakogiannis, Theologos Papadopoulos, Konstantinos I. Arvanitidis, Zaharoula Kyriakopoulou, Ioannis Karakasiliotis and Christine Kottaridi

Int. J. Mol. Sci. 2025, 26(14), 6974; https://doi.org/10.3390/ijms26146974 (registering DOI) - 20 Jul 2025

Abstract

Human papillomavirus 18 (HPV18) is the second most oncogenic high-risk HPV genotype, after HPV16, and is responsible for about 15% of cervical cancer cases worldwide. The integration of high-risk HPV DNA into the host genome leads to the disruption of the E1 and/or [...] Read more.

Human papillomavirus 18 (HPV18) is the second most oncogenic high-risk HPV genotype, after HPV16, and is responsible for about 15% of cervical cancer cases worldwide. The integration of high-risk HPV DNA into the host genome leads to the disruption of the E1 and/or E2 genes, which is considered a risk factor for viral-induced carcinogenesis. This study examined the disruption events of HPV18 E1 and E2 genes in precancerous cervical lesions to investigate the rates and sites of gene disruption in the Greek population. The complete E1 and E2 genes were amplified using three and four overlapping primer sets, respectively. Extensive analysis revealed that the disruption/deletion events of the E1 and E2 genes were detected in all grades of cytology-determined lesions, with high frequency. E2 gene disruption was significantly related to LSIL+ cases (Fisher’s exact test, p = 0.022). No significant association was found in the analysis of the E1 gene. Additionally, no preferential sites of E1/E2 gene disruption were detected. This is the first study to provide evidence of disruption events of the HPV18 E1 gene. The data from the current analysis suggest that disruption of the E2 gene could be a significant marker for the progression of cytology-determined cervical dysplasia. However, future studies are required to evaluate whether different geographic populations have particular profiles regarding the rates and sites of gene disruption to further determine population-specific biomarkers. Full article

(This article belongs to the Special Issue DNA Virus Infection: HPV-Related Cancers, Pathology, Biomarkers and Immunotherapy)

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36 pages, 1175 KiB

Open AccessReview

Daidzein and Genistein: Natural Phytoestrogens with Potential Applications in Hormone Replacement Therapy

by Aekkhaluck Intharuksa, Warunya Arunotayanun, Mingkwan Na Takuathung, Siripat Chaichit, Anchalee Prasansuklab, Kamonwan Chaikhong, Buntitabhon Sirichanchuen, Suthunya Chupradit and Nut Koonrungsesomboon

Int. J. Mol. Sci. 2025, 26(14), 6973; https://doi.org/10.3390/ijms26146973 (registering DOI) - 20 Jul 2025

Abstract

Menopause is characterized by a decline in estrogen levels, leading to symptoms such as vasomotor instability, osteoporosis, and increased cardiovascular and cognitive risk. Hormone replacement therapy (HRT) remains the gold standard for managing menopausal symptoms; however, concerns regarding its long-term safety, including elevated [...] Read more.

Menopause is characterized by a decline in estrogen levels, leading to symptoms such as vasomotor instability, osteoporosis, and increased cardiovascular and cognitive risk. Hormone replacement therapy (HRT) remains the gold standard for managing menopausal symptoms; however, concerns regarding its long-term safety, including elevated risks of cancer and cardiovascular events, have prompted interest in alternative therapies. Phytoestrogens, particularly the isoflavones daidzein and genistein, are plant-derived compounds structurally similar to 17β-estradiol (E2) and capable of binding estrogen receptors. Found abundantly in soybeans and red clover, these compounds exhibit selective estrogen receptor modulator (SERM)-like activity, favoring ERβ over ERα, which underlies their tissue-specific effects. In vitro, in silico, and in vivo studies demonstrate their ability to modulate estrogenic pathways, inhibit oxidative stress, and influence reproductive and neurological function. Clinical trials show that daidzein and genistein, especially in equol-producing individuals, can reduce vasomotor symptoms such as hot flashes and night sweats. While results across studies vary, consistent findings support their safety and modest efficacy, particularly for women unable or unwilling to use HRT. Pharmacokinetic studies reveal moderate bioavailability and interindividual variability due to gut microbiota metabolism. At dietary levels, these compounds are generally safe, although high-dose supplementation is discouraged in individuals with hormone-sensitive cancers. Emerging evidence suggests lifelong consumption of soy-based foods may reduce cancer risk. In conclusion, daidzein and genistein represent promising, well-tolerated natural alternatives to conventional HRT, offering symptom relief and additional health benefits. Further research is warranted to optimize dosing, improve clinical outcomes, and clarify long-term safety in diverse populations, particularly with genetic variations in isoflavone metabolism. Full article

(This article belongs to the Special Issue Phytochemicals of Natural Products: Source, Analysis, and Bioactivities)

23 pages, 5132 KiB

Open AccessArticle

Comparative Analysis of Tyrosine Hydroxylase Amacrine Cells in the Mammalian Retina: Distribution and Quantification in Mouse, Rat, Ground Squirrel and Macaque Retinas

by Kiyoharu J. Miyagishima, Xiaomin Lai, Amurta Nath, William N. Grimes, Xiyuan Ping, Jeffrey S. Diamond, Morven A. Cameron, Wei Li and Francisco M. Nadal-Nicolás

Int. J. Mol. Sci. 2025, 26(14), 6972; https://doi.org/10.3390/ijms26146972 (registering DOI) - 20 Jul 2025

Abstract

Dopaminergic amacrine cells (DACs) are a subclass of amacrine cells that modulate retinal processing and light adaptation by releasing dopamine. Although the role of dopamine is largely conserved, their retinal distribution across mammals remains incompletely characterized. In mice, rats, thirteen-lined ground squirrels (TLGSs), [...] Read more.

Dopaminergic amacrine cells (DACs) are a subclass of amacrine cells that modulate retinal processing and light adaptation by releasing dopamine. Although the role of dopamine is largely conserved, their retinal distribution across mammals remains incompletely characterized. In mice, rats, thirteen-lined ground squirrels (TLGSs), and macaques, we systematically compared the localization, number, and topography of DACs by their expression of tyrosine hydroxylase (TH), a crucial enzyme in the biosynthesis of dopamine. In all species examined, TH+ cells were primarily located in the inner nuclear layer; however, there was a species-dependent influence on their number and distribution. Mice exhibited the highest density of TH+cells but completely lacked displaced TH+cells (dTH+cells) in the ganglion cell layer. Despite interspecies variation in the total number of TH+cells in the retina, the overall density in rats, TLGSs, and macaques was similar. Most species displayed a higher density of DACs toward central retinal regions. However, rats exhibited a distinctive dorsal concentration, particularly among dTH+cells. Although most species examined exhibited a similar ratio of TH+cells to Brn3a+ retinal ganglion cells, TLGSs showed a marked reduction, indicating a potentially diminished dopaminergic modulatory role. Species-specific DAC topographies aligned with specialized visual regions, such as the visual streak in TLGS and the macula in macaques. These results reveal both conserved and divergent features of retinal dopamine circuitry, reflecting evolutionary adaptations to visual processing demands. Full article

(This article belongs to the Section Molecular Nanoscience)

26 pages, 5701 KiB

Open AccessArticle

Design of a Multi-Epitope Vaccine Based on Fasciola gigantica Cathepsin B and Evaluation of Immunological Responses in Mice

by Supanan Chansap, Werachon Cheukamud, Thitikul Suthisintong, Pornanan Kueakhai and Narin Changklungmoa

Int. J. Mol. Sci. 2025, 26(14), 6971; https://doi.org/10.3390/ijms26146971 (registering DOI) - 20 Jul 2025

Abstract

Fasciola gigantica (F. gigantica) is a vital parasite that causes fasciolosis. Liver fluke infections affect livestock animals, and the Fasciola species (Fasciola spp.) vaccine has been tested for many types of these diseases. Currently, computer-based vaccine design represents an attractive [...] Read more.

Fasciola gigantica (F. gigantica) is a vital parasite that causes fasciolosis. Liver fluke infections affect livestock animals, and the Fasciola species (Fasciola spp.) vaccine has been tested for many types of these diseases. Currently, computer-based vaccine design represents an attractive alternative for constructing vaccines. Thus, this study aimed to design the epitopes of linear B-cells (BCL) and helper T lymphocytes (HTL) using an immunoinformatic approach and to investigate in silico and the mice’s immune response. A non-conserved host region, overlapping F. gigantica cathepsin B proteins (FgCatB), and the highest conserved residue percentages were the criteria used to construct epitopes. The GPGPG linker was used to link epitopes in the multi-epitope Fasciola gigantica cathepsin B (MeFgCatB) peptide. The MeFgCatB peptide has high antigenicity, non-allergenicity, non-toxicity, good solubility, and a high-quality structure. The molecular docking between the MeFgCatB peptide and Toll-like receptor 2 (TLR-2) was evaluated. The IgM, IgG1, and IgG2 levels were elevated in silico. In mice, the MeFgCatB peptide was synthesized and administered as an injection. The MeFgCatB-specific IgG1 and IgG2a levels were elevated after week 2, showing a predominance of IgG1. The rFgCatB1, rFgCatB2, and rFgCatB3 were detected using the MeFgCatB peptide-immunized sera. The MeFgCatB peptide-immunized sera were detected at approximately 28–34 kDa in the whole body. In addition, the MeFgCatB immunized sera can positively signal at the caecal epithelium in the NEJ, 4WKJ, and adult stages. In summary, the MeFgCatB peptide is able to induce mixed Th1/Th2 immune responses with Th2 dominating and to detect the native protein of F. gigantica. The MeFgCatB peptide should help against F. gigantica in future experiments. Full article

(This article belongs to the Section Molecular Immunology)

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26 pages, 3769 KiB

Open AccessArticle

Rest Induces a Distinct Transcriptional Program in the Nervous System of the Exercised L. stagnalis

by Julian M. Rozenberg, Dmitri Boguslavsky, Ilya Chistopolsky, Igor Zakharov and Varvara Dyakonova

Int. J. Mol. Sci. 2025, 26(14), 6970; https://doi.org/10.3390/ijms26146970 (registering DOI) - 20 Jul 2025

Abstract

In the freshwater snail L. stagnalis, two hours of shallow water crawling exercise are accompanied by the formation of memory, metabolic, neuronal, and behavioral changes, such as faster orientation in a novel environment. Interestingly, rest following exercise enhances serotonin and dopamine metabolism [...] Read more.

In the freshwater snail L. stagnalis, two hours of shallow water crawling exercise are accompanied by the formation of memory, metabolic, neuronal, and behavioral changes, such as faster orientation in a novel environment. Interestingly, rest following exercise enhances serotonin and dopamine metabolism linked to the formation of memory and adaptation to novel conditions. However, the underlying transcriptional responses are not characterized. In this paper, we show that, while two hours of forced crawling exercise in L. stagnalis produce significant changes in nervous system gene expression, the subsequent rest induces a completely distinct transcriptional program. Chromatin-modifying, vesicle transport, and cell cycle genes were induced, whereas neurodevelopmental, behavioral, synaptic, and hormone response genes were preferentially repressed immediately after two hours of exercise. These changes were normalized after two hours of the subsequent rest. In turn, rest induced the expression of genes functioning in neuron differentiation and synapse structure/activity, while mitotic, translational, and protein degradation genes were repressed. Our findings are likely relevant to the physiology of exercise, rest, and learning in other species. For example, chronic voluntary exercise training in mice affects the expression of many homologous genes in the hippocampus. Moreover, in humans, homologous genes are pivotal for normal development and complex neurological functions, and their mutations are associated with behavioral, learning, and neurodevelopmental abnormalities. Full article

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

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23 pages, 11818 KiB

Open AccessArticle

Cryopreservation and Validation of Microfragmented Adipose Tissue for Autologous Use in Knee Osteoarthritis Treatment

by Marija Zekušić, Petar Brlek, Lucija Zenić, Vilim Molnar, Maja Ledinski, Marina Bujić Mihica, Adela Štimac, Beata Halassy, Snježana Ramić, Dominik Puljić, Tiha Vučemilo, Carlo Tremolada, Srećko Sabalić, David C. Karli, Dimitrios Tsoukas and Dragan Primorac

Int. J. Mol. Sci. 2025, 26(14), 6969; https://doi.org/10.3390/ijms26146969 (registering DOI) - 20 Jul 2025

Abstract

Micro-fragmented adipose tissue (MFAT) is a promising autologous therapy for knee osteoarthritis. To avoid repeated liposuction procedures for its clinical application, MFAT obtained from patients with knee osteoarthritis was stored at −80 °C in a tissue bank. This study describes the preparation, cryopreservation, [...] Read more.

Micro-fragmented adipose tissue (MFAT) is a promising autologous therapy for knee osteoarthritis. To avoid repeated liposuction procedures for its clinical application, MFAT obtained from patients with knee osteoarthritis was stored at −80 °C in a tissue bank. This study describes the preparation, cryopreservation, thawing, and washing, as well as comprehensive analysis of cell populations in fresh and MFAT thawed after two years. Immunophenotyping of both fresh and thawed MFAT showed a significant presence of endothelial progenitors and pericytes in the stromal vascular fraction. Viability before (59.75%) and after freezing (55.73%) showed no significant difference. However, the average cell count per gram of MFAT was significantly reduced in thawed samples (3.00 × 10⁵) compared to fresh ones (5.64 × 10⁵), likely due to processing steps. Thawed MFAT samples showed increased CD73 expression on the CD31^highCD34^high subset of EP and SA-ASC, as well as increased expression of CD105 on EP, the CD31^lowCD34^low subset of EP, pericytes, and SA-ASC. Microbiological testing confirmed 100% sterility, and double washing efficiently removed DMSO, confirming sample safety. Histological analysis revealed healthy, uniformly shaped adipocytes with intact membranes. This approach allows accurate estimation of cell yield for intra-articular injection, ensuring delivery of the target cell number into the knee. Quality control analysis confirms that cryopreserved MFAT retains high cellular and structural integrity, supporting its safety and suitability for clinical application. Full article

(This article belongs to the Section Molecular Biology)

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32 pages, 1319 KiB

Open AccessReview

Effects of Targeted Radionuclide Therapy on Cancer Cells Beyond the Ablative Radiation Dose

by Guillermina Ferro-Flores, Erika Azorín-Vega, Blanca Ocampo-García, Myrna Luna-Gutiérrez, Pedro Cruz-Nova and Laura Meléndez-Alafort

Int. J. Mol. Sci. 2025, 26(14), 6968; https://doi.org/10.3390/ijms26146968 (registering DOI) - 20 Jul 2025

Abstract

Targeted radionuclide therapy (TRT) utilizes radiopharmaceuticals to deliver radiation directly to cancer cells while sparing healthy tissues. Beyond the absorbed dose of ablative radiation, TRT induces non-targeted effects (NTEs) that significantly enhance its therapeutic efficacy. These effects include radiation-induced bystander effects (RIBEs), abscopal [...] Read more.

Targeted radionuclide therapy (TRT) utilizes radiopharmaceuticals to deliver radiation directly to cancer cells while sparing healthy tissues. Beyond the absorbed dose of ablative radiation, TRT induces non-targeted effects (NTEs) that significantly enhance its therapeutic efficacy. These effects include radiation-induced bystander effects (RIBEs), abscopal effects (AEs), radiation-induced genomic instability (RIGI), and adaptive responses, which collectively influence the behavior of cancer cells and the tumor microenvironment (TME). TRT also modulates immune responses, promoting immune-mediated cell death and enhancing the efficacy of combination therapies, such as the use of immune checkpoint inhibitors. The molecular mechanisms underlying TRT involve DNA damage, oxidative stress, and apoptosis, with repair pathways like homologous recombination (HR) and non-homologous end joining (NHEJ) playing critical roles. However, challenges such as tumor heterogeneity, hypoxia, and radioresistance limit the effectiveness of this approach. Advances in theranostics, which integrate diagnostic imaging with TRT, have enabled personalized treatment approaches, while artificial intelligence and improved dosimetry offer potential for treatment optimization. Despite the significant survival benefits of TRT in prostate cancer and neuroendocrine tumors, 30–40% of patients remain unresponsive, which highlights the need for further research into molecular pathways, long-term effects, and combined therapies. This review outlines the dual mechanisms of TRT, direct toxicity and NTEs, and discusses strategies to enhance its efficacy and expand its use in oncology. Full article

(This article belongs to the Special Issue Targeted Therapy of Cancer: Innovative Drugs and Molecular Tools)

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20 pages, 2494 KiB

Open AccessArticle

Effect of Environmental Exposure to Zearalenone on the Metabolic Profile of Patients with Sigmoid Colorectal Cancer or Colorectal Cancer on the Day of Hospital Admission

by Sylwia Lisieska-Żołnierczyk, Magdalena Gajęcka, Łukasz Zielonka, Katarzyna E. Przybyłowicz and Maciej T. Gajęcki

Int. J. Mol. Sci. 2025, 26(14), 6967; https://doi.org/10.3390/ijms26146967 (registering DOI) - 20 Jul 2025

Abstract

Colorectal cancer is one of the most commonly diagnosed types of cancer and constitutes the second most frequent cancer in women (W) and the third most frequent cancer in men (M). The aim of the study was to determine if environmental exposure to [...] Read more.

Colorectal cancer is one of the most commonly diagnosed types of cancer and constitutes the second most frequent cancer in women (W) and the third most frequent cancer in men (M). The aim of the study was to determine if environmental exposure to zearalenone (ZEN) (a mycoestrogen) affects the metabolic profile of patients diagnosed with sigmoid colorectal cancer (SCC) and colorectal cancer (CRC) (division based on their location) at hospital admission. Male and female patients who were diagnosed with SCC or CRC and whose blood samples tested positive or negative for ZEN participated in a year-long study. Seventeen patients with symptoms of SCC and CRC, in whom ZEN and its metabolites were not detected in peripheral blood, constituted the patients without ZEN (PWZ) group. The experimental groups comprised a total of 16 patients who were diagnosed with SCC or CRC and tested positive for ZEN but negative for ZEN metabolites. Patients exposed to ZEN were characterized by increased levels of liver enzymes (alanine aminotransferase (ALT) from 5.8 to 18.1 IU/L; aspartate aminotransferase (AST) from 2.8 to 10.7 IU/L) and decrease in the value of the De Ritis ratio (below 1.0), different gamma glutamyl transpeptidase and AST activity, lower albumin (from 0.24 g/dL in M to 0.67 g/dL in W) and total protein levels (from 0.75 to 1.76 g/dL), a decrease in total cholesterol (from 21.6 to 40.3 mg/dL) and triglyceride levels (from 7.8 to 37.2 mg/dL), and lower activity of lipase C (from 28.72 to 64.75 IU/L). The metabolic profile of M and W patients diagnosed with SCC and CRC and exposed to ZEN revealed intensified biotransformation processes in the liver, liver damage, and a predominance of catabolic processes. Full article

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

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37 pages, 804 KiB

Open AccessReview

Precision Recovery After Spinal Cord Injury: Integrating CRISPR Technologies, AI-Driven Therapeutics, Single-Cell Omics, and System Neuroregeneration

by Răzvan-Adrian Covache-Busuioc, Corneliu Toader, Mugurel Petrinel Rădoi and Matei Șerban

Int. J. Mol. Sci. 2025, 26(14), 6966; https://doi.org/10.3390/ijms26146966 (registering DOI) - 20 Jul 2025

Abstract

Spinal cord injury (SCI) remains one of the toughest obstacles in neuroscience and regenerative medicine due to both severe functional loss and limited healing ability. This article aims to provide a key integrative, mechanism-focused review of the molecular landscape of SCI and the [...] Read more.

Spinal cord injury (SCI) remains one of the toughest obstacles in neuroscience and regenerative medicine due to both severe functional loss and limited healing ability. This article aims to provide a key integrative, mechanism-focused review of the molecular landscape of SCI and the new disruptive therapy technologies that are now evolving in the SCI arena. Our goal is to unify a fundamental pathophysiology of neuroinflammation, ferroptosis, glial scarring, and oxidative stress with the translation of precision treatment approaches driven by artificial intelligence (AI), CRISPR-mediated gene editing, and regenerative bioengineering. Drawing upon advances in single-cell omics, systems biology, and smart biomaterials, we will discuss the potential for reprogramming the spinal cord at multiple levels, from transcriptional programming to biomechanical scaffolds, to change the course from an irreversible degeneration toward a directed regenerative pathway. We will place special emphasis on using AI to improve diagnostic/prognostic and inferred responses, gene and cell therapies enabled by genomic editing, and bioelectronics capable of rehabilitating functional connectivity. Although many of the technologies described below are still in development, they are becoming increasingly disruptive capabilities of what it may mean to recover from an SCI. Instead of prescribing a particular therapeutic fix, we provide a future-looking synthesis of interrelated biological, computational, and bioengineering approaches that conjointly chart a course toward adaptive, personalized neuroregeneration. Our intent is to inspire a paradigm shift to resolve paralysis through precision recovery and to be grounded in a spirit of humility, rigor, and an interdisciplinary approach. Full article

(This article belongs to the Special Issue Molecular Research in Spinal Cord Injury)

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22 pages, 1616 KiB

Open AccessArticle

Genetic Correlates of Presenile Dementia and Cognitive Decline in the Armenian Population Following COVID-19: A Case-Control Study

by Yekaterina Hovhannisyan, Hermine Yeritsyan, Gohar Hakobjanyan, Gayane Petrosyan, Hayk Harutyunyan, Armen Muradyan, Allen Azizian and Konstantin Yenkoyan

Int. J. Mol. Sci. 2025, 26(14), 6965; https://doi.org/10.3390/ijms26146965 (registering DOI) - 20 Jul 2025

Abstract

The presence of cognitive lapses in the post-COVID-19 period, particularly among younger individuals, suggests a potential genetic predisposition. This case–control study aimed to assess the association between neurodegeneration-associated genes and cognitive declines in the post-COVID-19 Armenian population under the age of 65. In [...] Read more.

The presence of cognitive lapses in the post-COVID-19 period, particularly among younger individuals, suggests a potential genetic predisposition. This case–control study aimed to assess the association between neurodegeneration-associated genes and cognitive declines in the post-COVID-19 Armenian population under the age of 65. In addition, we examined other contributing factors, including depressive symptoms, hypovitaminosis D, vitamin B12 and B9 deficiencies, and some viral infections, as potential confounders or effect modifiers. A total of 162 participants (ages 19–65, Med = 43), who were exposed to SARS-CoV-2 in Armenia between 2020 and 2022, participated in this study. Standardized assessments, including the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Montreal Cognitive Assessment (MoCA), were used to evaluate cognitive functions and mental status, while the Patient Health Questionnaire-9 (PHQ-9) was utilized to assess depressive symptoms. Clinical interview data, comprising yes/no self-reports regarding the presence of cognitive problems and depressive symptoms, were also included. Genetic analysis identified copy number variations (CNVs) in the APP, PSEN1, PSEN2, MAPT, and GRN genes, while viral infections (HSV-1, HSV-2, CMV, EBV, HIV, SARS-CoV-2, Hepatitis A, B, and C) and vitamin D, B12, and B9 deficiencies were measured. Lower cognitive performance was associated with CNVs in PSEN1 (exons 1, 9, 12), GRN (exons 1, 6, 12), and MAPT (exons 2, 8), along with viral infections (HSV-1, HSV-2, HAV-2). The findings indicate that post-COVID-19 cognitive problems are multifactorial and are linked to genetic mutations, viral infections, age, gender, and folic acid deficiency. Full article

(This article belongs to the Section Molecular Neurobiology)

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